![10 CLINICAL DECISION-MAKING
Problem representation/list and differential
diagnosis
Once all the available data from history, physical examination and (some-
times) initial test results are available, these need to be synthesised into
a problem representation or problem list. The process of generating a
problem list ensures nothing is missed. The process of generating a
differential diagnosis works against anchoring on a particular diagnosis
too early, thereby avoiding search satiscing and premature closure (see
Fig. 1.6).
Mnemonics and checklists
These are used frequently in medicine in order to reduce reliance on
fallible human memory. ABCDE (airway, breathing, circulation, disability,
exposure/examination) is probably the most successful checklist in med-
icine, used during the assessment and treatment of critically ill patients
(ABCDE is sometimes prexed with ‘C’ for ‘control of any obvious prob-
lem’; see p. 191). Checklists ensure that important issues have been
considered and completed, especially under conditions of complexity,
stress or fatigue.
Red ags and ROWS (‘rule out worst-case scenario’)
These are strategies that force doctors to consider serious diseases that
can present with common symptoms. Red ags in back pain are listed
in Box 26.19. Considering and investigating for possible pulmonary
embolism in patients who present with pleuritic chest pain and breath-
lessness is a common example of ruling out a worst-case scenario, as
pulmonary embolism can be fatal if missed. Red ags and ROWS help
to avoid cognitive biases such as the ‘framing effect’ and ‘premature
closure’.
Newer strategies to avoid cognitive biases and errors in decision-mak-
ing are emerging. These involve explicit training in clinical reasoning and
human factors. In theory, if doctors are aware of the science of human
thinking and decision-making, then they are more able to think about
their thinking, understand situations in which their decision-making may
be affected, and take steps to mitigate this.
Clinical decision-making: putting it all
together
The following is a practical example that brings together many of the
concepts outlined in this chapter:
A 25-year-old woman presents with right-sided pleuritic chest pain
and breathlessness. She reports that she had an upper respiratory tract
infection a week ago and was almost back to normal when the symp-
toms started. The patient has no past medical history and no family his-
tory, and her only medication is the combined oral contraceptive pill.
On examination, her vital signs are normal (respiratory rate 19 breaths/
min, oxygen saturations 98% on air, blood pressure 115/60mmHg, heart
rate 90 beats/min, temperature 37.5°C) and the physical examination is
also normal. You have been asked to assess her for the possibility of a
pulmonary embolism.
(More information on pulmonary embolism can be found in Chapter 17.)
Evidence-based history and examination
Information from the history and physical examination is vital in deciding
whether this could be a pulmonary embolism. Pleurisy and breathless-
ness are common presenting features of this disease but are also com-
mon presenting features in other diseases. There is nothing in the history
to suggest an alternative diagnosis (e.g. high fever, productive cough,
recent chest trauma). The patient’s vital signs are normal, as is the phys-
ical examination. However, very few individual ndings help to distinguish
patients with pulmonary embolism from those without it. The presence of
wheeze and a high fever modestly decrease the probability of pulmonary
embolism. The presence of hypoxaemia is unhelpful (likelihood ratio not
signicant).
Deciding pre-test probability
The prevalence of pulmonary embolism (PE) in 25-year-old women is
low. We anchor on this prevalence and then adjust for individual patient
factors. This patient has no major risk factors for pulmonary embolism.
To assist our estimate of pre-test probability, we could use a clinical
1.7 The SBAR system of communicating
SBAR Example (a telephone call to the
Intensive Care team)
Situation I am [name] calling from [place] about
a patient with a NEWS* of 10.
Background [Patient’s name], 30-year-old woman,
no past medical history, was admitted
last night with community-acquired
pneumonia. Since then her oxygen
requirements have been steadily
increasing.
Assessment Her vital signs are: blood pressure
115/60mmHg, heart rate 120 beats/
min, temperature 38°C, respiratory
rate 32 breaths/min, oxygen
saturations 89% on 15L via reservoir
bag mask.
An arterial blood gas shows H+
50nmol/L (pH 7.3), PaCO2
4.0kPa
(30mmHg), PaO2
7kPa (52.5mmHg),
standard bicarbonate 14mmol/L.
Chest X-ray shows extensive right
lower zone consolidation.
Recommendation Please can you come and see her as
soon as possible? I think she needs
admission to Intensive Care.
*NEWS = National Early Warning Score; a patient with normal vital signs scores 0. See Royal
College of Physicians. National Early Warning Score (NEWS) 2: Standardising the assessment of
acute-illness severity in the NHS. Updated report of a working party. London: RCP; December 2017.
Feel better
No difference
Stroke
Dead
Fig. 1.9 Visual portrayal of benets and risks. The image refers to an operation
that is expected to relieve symptoms in 90% of patients, but cause stroke in 2% and
death in 1%. From Edwards A, Elwyn G, Mulley A. Explaining risks: turning numerical
data into meaningful pictures. BMJ 2002; 324:827–830, reproduced with permission
from the BMJ Publishing Group.](https://image.slidesharecdn.com/davidsonmedicine24th-250911130730-aa733799/85/DavidsonMedicine24th-pdf-for-medicine-4th-year-31-320.jpg)
![Genomics, health and disease 43
3
Fig. 3.6 Splice-site variants.
result, splicing no longer occurs, leading to read-through of the mRNA into the intron, which contains a premature termination codon downstream of the variant.
Normal
Splice-site variant
Splice donor site
Exon Exon
Intron
Exon Exon
Intron
Intron removed by
splicing
Splice acceptor site
mRNA ‘reads through’ intron
Abnormal protein with
premature stop codon
A
B
3.2 Diseases associated with triplet and other repeat expansions*
Repeat No. of repeats Gene Gene location Inheritance
Normal Mutant
Coding repeat expansion
Huntington’s disease [CAG] 6–34 >35 Huntingtin 4p16 AD
Spinocerebellar ataxia (type 1) [CAG] 6–39 >40 Ataxin 6p22–23 AD
Spinocerebellar ataxia
(types 2, 3, 6, 7)
[CAG] Various Various Various Various AD
Dentatorubral-pallidoluysian atrophy [CAG] 7–25 >49 Atrophin 12p12–13 AD
Machado–Joseph disease [CAG] 12–40 >67 MJD 14q32 AD
Spinobulbar muscular atrophy [CAG] 11–34 >40 Androgen receptor Xq11–12 XL recessive
Non-coding repeat expansion
Myotonic dystrophy [CTG] 5–37 >50 DMPK-3 UTR 19q13 AD
Friedreich’s ataxia [GAA] 7–22 >200 Frataxin-intronic 9q13 AR
Progressive myoclonic epilepsy [CCCCGCCCCGCG]4–8
2–3 >25 Cystatin B-5 UTR 21q AR
Fragile X mental retardation [CGG] 5–52 >200 FMR1–5 UTR Xq27 XL dominant
Fragile site mental retardation 2 (FRAXE) [GCC] 6–35 >200 FMR2 Xq28 XL, probably recessive
*The triplet repeat diseases fall into two major groups: those with disease stemming from expansion of [CAG]n repeats in coding DNA, resulting in multiple adjacent glutamine residues (polyglutamine
tracts), and those with non-coding repeats. The latter tend to be longer. Unaffected parents usually display ‘pre-mutation’ allele lengths that are just above the normal range.
(AD/AR = autosomal dominant/recessive; UTR = untranslated region; XL = X-linked)
Loss-of-function variants result in loss or reduction in the normal
protein function. Whole-gene deletions are the archetypal loss-of-
function variants but stop-gain or indel variants (early in the ORF),
missense variants affecting a critical domain and splice-site variants
can also result in loss of protein function.
Gain-of-function variants result in a gain of protein function. They are
typically non-synonymous variants that alter the protein structure,
leading to activation/alteration of its normal function through causing
either an interaction with a novel substrate or a change in its normal
function.
Dominant negative variants are the result of non-synonymous sub-
stitutions or in-frame deletions/duplications but may also, less fre-
quently, be caused by triplet repeat expansions. Dominant negative
variants are heterozygous changes that result in the production of
an abnormal protein that interferes with the normal functioning of the
wild-type protein.](https://image.slidesharecdn.com/davidsonmedicine24th-250911130730-aa733799/85/DavidsonMedicine24th-pdf-for-medicine-4th-year-66-320.jpg)
![88 POPULATION HEALTH AND EPIDEMIOLOGY
The UK Faculty of Public Heath denes public health as ‘The science
and art of promoting and protecting health and well-being, preventing
ill-health and prolonging life through the organised efforts of society’.
This recognises that there is a collective responsibility for the health of
the population which requires partnerships between government, health
services and other partners to promote and protect health and prevent
disease. Population health has been dened as ‘the health outcomes of
a group of individuals, including the distribution of such outcomes within
the group’. Medical doctors can play a role in all these efforts to improve
health both as part of their clinical work but also through supporting
broader actions to improve public health.
Global burden of disease and underlying risk
factors
The Global Burden of Disease (GBD) exercise was initiated by the World
Bank in 1992, with rst estimates appearing in the World Development
Report in 1993. Regular updated estimates have been published since
that time together with projections of future disease burden. The aim of
the exercise was to produce reliable and internally consistent estimates
of disease burden for all diseases and injuries and to assess their physi-
ological, behavioural and social risk factors so that this information could
be made available to health workers, researchers and policy-makers.
The GBD exercise adopted the metric ‘disability life year’ or DALY to
describe population health. This combines information about prema-
ture mortality in a population (measured as Years of Life Lost from an
‘expected’ life expectancy) and years of life lived with disability (Years
of Life lived with Disability (YLD), which is weighted by a severity factor).
The International Classication of Disease (ICD) rules, which assign one
cause to each death, are followed. All estimates are presented by age
and sex groups and by regions of the world. Many countries now also
report their own national burden of disease data.
Life expectancy
Global life expectancy at birth increased from 61.7 years in 1980 to 73.0
years in 2017, an increase of about 0.3 years per calendar year. This
change is due to a substantial fall in child mortality (mainly due to com-
mon infections) partly offset by rises in mortality from adult conditions
such as diabetes and chronic kidney disease. Some areas have not
shown these increases in life expectancy in men, often due to war and
interpersonal violence.
Global causes of death and disability
Box 5.1 shows a ranked list of the major causes of global deaths in 2019.
Communicable, maternal, neonatal and nutritional causes accounted for
about one-quarter of deaths worldwide – down from about one-third in
1990. In contrast, deaths from non-communicable diseases are increas-
ing in importance and now account for about two-thirds of all deaths
globally,: including about 18.5 million from cardiovascular disease (ischae-
mic heart disease and stroke), 10 million from cancer and about 4 million
from chronic respiratory diseases. The age standardised death rates for
most diseases globally are falling. However, despite this, the numbers of
deaths from many diseases are rising due to global population growth
and the change in age structure of the population to older ages and
this is placing an increasing burden on health systems. For a few con-
ditions (e.g. HIV/AIDS, diabetes mellitus and chronic kidney disease)
age-standardised death rates continue to rise. Within this overall pattern,
signicant regional variations exist – for example, communicable, mater-
nal, neonatal and nutritional causes still account for about two-thirds of
premature mortality in sub-Saharan Africa.
GBD also provides estimates of disability from disease (Box 5.2). This
has raised awareness of the importance of conditions like depression
and other common mental health conditions, low back and neck pain
and other musculo-skeletal conditions, and asthma, which account for a
relatively large disease burden but relatively few deaths. This in turn has
resulted in greater health policy priority given to these conditions. Since
the policy focus in national health systems is increasingly on keeping
people healthy rather than only on reducing premature deaths it is impor-
tant to have measures of these health outcomes.
It is important to recognise that although these estimates represent
the best overall picture of burden of disease globally, they are based on
limited and imperfect data. Nevertheless, the quality of data underlying
the estimates and the modelling processes are improving steadily over
time and provide an increasingly robust basis for evidence-based health
planning and priority setting.
Risk factors underlying disease
Box 5.3 shows a ranked list of the main risk factors underlying GBD
in 2019 and how this ranking has changed over the past 29 years. A
number of key insights have been identied in this, the most recent, GBD
exercise:
Socio-demographic development has been progressing steadily
since 1990 but it has increased faster in countries with the highest
socio-demographic development index and thus gaps have been
widening.
5.1 Global causes of death – top 15 ranked causes 2019
[rank in 1990]
1. Cardiovascular disease [1]
2. Neoplasms [2]
3. Chronic respiratory [6]
4. Respiratory infections and TB [3]
5. Diabetes and CKD [10]
6. Digestive diseases [8]
7. Neurological disorders [15]
8. Maternal and neonatal [15]
9. Unintentional injuries [9]
10. Enteric infections [5]
11. Transport injuries [13]
12. Self harm and violence [12]
13. Other non-communicable diseases [11]
14. HIV/AIDS and STIs [17]
15. NTDs and malaria [14]
(CKD = chronic kidney disease; TB = tuberculosis; STIs = sexually transmitted infections;
NTDs = neglected tropical diseases)
From GBD 2019. https://vizhub.healthdata.org/gbd-compare/.
5.2 Global disability – top 15 ranked causes 2019 [rank in 1990]*
1. Musculoskeletal disorders [1]
2. Mental disorders [2]
3. Other non-communicable diseases [3]
4. Sense organ diseases [5]
5. Neurological disorders [4]
6. Diabetes and CKD [12]
7. Skin diseases [7]
8. Unintentional injuries [8]
9. Nutritional deciencies [6]
10. Cardiovascular diseases [11]
11. Chronic respiratory diseases [9]
12. Substance use [13]
13. Maternal and neonatal conditions [17]
14. Transport injuries [16]
15. Digestive diseases [15]
*By years of life lived with disability (YLD).
(CKD = chronic kidney disease)
From GBD 2019. https://vizhub.healthdata.org/gbd-compare/.](https://image.slidesharecdn.com/davidsonmedicine24th-250911130730-aa733799/85/DavidsonMedicine24th-pdf-for-medicine-4th-year-114-320.jpg)
![Social determinants of health 89
5
5.4 ‘Hierarchy of systems’ applied to ischaemic heart disease
Level in the hierarchy Example of effect
Molecular ApoB mutation causing hypercholesterolaemia
Cellular Foam cells accumulate in vessel wall
Tissue Atheroma and thrombosis of coronary artery
Organ Ischaemia and infarction of myocardium
System Cardiac failure
Person Limited exercise capacity, impact on employment
Family Passive smoking, diet
Community Shops and leisure opportunities
Population Prevalence of obesity
Society Policies on smoking, screening for risk factors
Ecology Agriculture inuencing fat content in diet
Health systems need to transform to be better able to respond to
the changing pattern of NCDs and disabilities.
The Millennium Development Goal (MDG) programme from 2000 to
2015 has led to faster progress in reducing deaths from maternal,
child and neonatal conditions/TB/HIV/malaria but this level of atten-
tion now needs to be directed at NCDs.
Public health is not giving sufcient priority to important global risk
factors which are increasing over time, such as high blood pressure,
high fasting glucose, high BMI, ambient particulate matter pollution
and drug and alcohol use.
There are many challenges resulting from the change in global
population pyramid structures, which have become inverted over
recent decades and now pose many health, nancial and political
challenges.
Social determinants of health
Health emerges from a highly complex interaction between a person’s
genetic background and environmental factors (aspects of the physical,
biological (microbes), built and social environments and also distant inu-
ences such as the global ecosystem) (Fig. 5.1).
The hierarchy of systems – from molecules to
ecologies
Inuences on health exist at many levels and extend beyond the individual
to include the family, community, population and ecology. Box 5.4 shows
an example of this for determinants of coronary heart disease and demon-
strates the importance of considering not only the disease process in a
patient but also its context. Health care is not the only determinant – and is
usually not the major determinant – of health status in the population. The
concept of ‘global health’ recognises the global dimension of health prob-
lems, whether these be, for example, emerging or pandemic infections or
global economic inuences on health internationally.
The life course
The determinants of health operate over the whole lifespan. Values and
behaviours acquired during childhood and adolescence have a pro-
found inuence on educational outcomes, job prospects and risk of
disease. These can have a strong inuence, for example, on whether
a young person takes up a damaging behaviour like smoking, risky
sexual activity and drug misuse. Inuences on health can even operate
before birth. Low birth weight can lead to higher risk hypertension and
type 2 diabetes in young adults and of cardiovascular disease in mid-
dle age. It has been suggested that under-nutrition during middle to
late gestation permanently ‘programmes’ cardiovascular and metabolic
responses.
This ‘life course’ perspective highlights the cumulative effect (through
each stage of life) on health of exposures to illness, adverse environmen-
tal conditions and behaviours that damage health.
Preventive medicine
The complexity of the interactions between physical, social and eco-
nomic determinants of health means that successful prevention is often
difcult. Moreover, the life course perspective illustrates that it may be
necessary to intervene early in life or even before birth, to prevent impor-
tant disease in later life. Successful prevention is likely to require many
interventions across the life course and at several levels in the hierarchy
of systems. The examples below illustrate this principle.
5.3 Global risk factors – top 10 ranked causes 2019 [rank in
1990]*
1. High blood pressure [7]
2. Smoking/second hand smoke exposure [5]
3. High fasting blood glucose [11]
4. Low birth weight [2]
5. High BMI [16]
6. Short gestation [3]
7. Ambient particulate matter pollution [13]
8. High LDL cholesterol [14]
9. Alcohol use [15]
10. Household air pollution [4]
From GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and
injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global
Burden of Disease Study 2019. Lancet 2020; 396:1204–1222.
M
acro-econom
y,
politics, culture,
global forces
Other
neighbourhoods,
other regions
People
Age, sex and
hereditary
factors
L festyle
W
o
r
k
p
l
a
y
D
i
e
t
p
h
y
s
i
c
a
l
a
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tivity
S
o
c
a
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c
a
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t
a
l
Community
N
e
t
w
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k
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W
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e
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M
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B
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Environment
A
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Globa ecosystem
B
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i
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Fig. 5.1 Hierarchy of systems that inuence population health. Adapted from
an original model by Whitehead M, Dahlgren G. What can be done about inequalities
in health? Lancet 1991; 338:1059–1063
*Risk factors ranked by % of burden of disease they cause.
(BMI = body mass index; LDL = low density lipoprotein)](https://image.slidesharecdn.com/davidsonmedicine24th-250911130730-aa733799/85/DavidsonMedicine24th-pdf-for-medicine-4th-year-115-320.jpg)
![Further information 95
5
Management of epidemics
An epidemic, as dened by the World Health Organization, occurs when
‘in a community or region [the] cases of an illness, specic health-related
behaviour, or other health-related events [are] clearly in excess of normal
expectancy’. Epidemics that are small-scale or conned to a small geo-
graphic area are informally referred to as ‘outbreaks’.
Epidemics are regularly caused where preventative measures break
down; examples include breaches of food safety procedures in restau-
rants resulting in outbreaks of enteropathogenic E. coli infection, failure
to adequately maintain cooling towers causing Legionella infections and
falls in vaccination coverage resulting in measles epidemics.
Epidemics can also arise from novel infectious agents such as the
SARS-CoV-1, MERS, SARS-CoV-2 and H1N1 viruses, for which new
preventative measures require to be developed. Where epidemics from
novel agents are not controlled locally, but instead spread beyond inter-
national borders, these are termed pandemics, of which SARS-CoV-2
and H1N1 are examples.
To detect epidemics early, public health agencies undertake surveil-
lance. Surveillance involves the collection and review of cases that have
been identied via statutory notications, or health information systems
(such as microbiology reporting systems). For some infections such as
E. coli and Legionella, one challenge for public health agencies is to
distinguish epidemics from ‘sporadic’ cases at an early stage. This is
done using human judgement, for example, if a large number of cases of
E. coli occur in individuals who ate a specic food, although this task is
sometimes supported using computer algorithms.
Epidemics require an incident management team, some of whose
members have legal powers to impose measures to control infection.
The team establish a formal case denition for conrmed, probable and
possible cases (based on epidemiological features as well as clinical and/
or microbiological ndings), interview individuals with whom cases have
had signicant contact (termed contact tracing), test potential sources
of infections (e.g. foodstuffs or industrial cooling towers), and implement
control measures. The latter might include requiring infected individuals
to isolate for a time period (e.g. until they are asymptomatic or until they
test negative depending on the infectious agent), and/or ordering tem-
porary closure of businesses thought to be sources of infection (e.g. a
restaurant with poor food hygiene practices).
Epidemic curves are crucial to the monitoring and management of
epidemics. Figure 5.6 shows a notional epidemic curve for an epidemic
caused by a single source, which is eliminated after 31 days. However,
they are also used in more complex epidemics where there is per-
son-to-person spread. In the latter, epidemic curves are used to esti-
mate key statistics such as the basic reproduction number (R0) in the
population, as well as to make projections about future infections. Where
the source of an epidemic is not apparent, comparative epidemiological
methods can be used to identify the likely source, for example, a case–
control design may identify a higher than expected consumption of a
given food – for example uncooked legumes – among cases compared
to controls prompting testing of foods, an education campaign and/or
product recalls.
The principles for managing pandemics are similar to those for man-
aging epidemics but operate on a national or international scale. The
universality of pandemics, however, means that they pose special prob-
lems. First, they pose risks to the society-wide infrastructure needed
to deal with diseases, including, but not limited to health-care facilities.
Secondly, pandemics, unlike local and regional epidemics are rare, so
agencies have little direct experience with their management. For this
reason, most settings develop pandemic plans and undertake regu-
lar table-top simulations to test and improve their preparedness. The
COVID-19 pandemic, caused by SARS-CoV-2, is a key example and is
discussed in detail in Chapter 13
Further information
Kindig D, Stoddart G. What is population health? Am J Publ Health 2003;93:
380–383.
UK Faculty of Public Health. What is public health? http://www.fph.org.uk/what_
is_public_health
Burden of disease
GBD Diseases and Injuries Collaborators. Global burden of 369 diseases and
injuries in 204 countries and territories, 1990–2019: a systematic analysis for
the Global Burden of Disease Study 2019. Lancet 2019; 2020(396):
1204–1222.
GBD Risk Factors Collaborators. Global burden of 87 risk factors in 204
countries and territories, 1990–2019: a systematic analysis for the Global
Burden of Disease Study 2019. Lancet 2019; 2020(396):1223–1249.
GBD Viewpoint Collaborators. Five insights from the Global Burden of Disease
Study 2019. Lancet 2019; 2020(396):1135–1159.
Screening
Gov.UK. Population screening programmes. https://www.gov.uk/topic/population-
screening-programmes Detailed information on 11 NHS population screening
programmes.
Immunisation
Gov.UK. Immunisation against infectious disease. https://www.gov.uk/
government/collections/immunisation-against-infectious-disease-the-green-
book The Green Book has the latest information on vaccines and vaccination
procedures, for vaccine-preventable infectious diseases in the UK.
Epidemiology
Burgess S, Davey Smith G, Davies NM, et al. Guidelines for performing Mendelian
randomization investigations. Wellcome Open Res 2020;4:186.
STROBE-MR Steering Group: STROBE-MR: Guidelines for strengthening the
reporting of Mendelian randomization studies. PeerJ https://peerj.com/
preprints/27857/
Days
New
cases
1
0
5
10
15
6 11 16 21 26 31 26 41
Fig. 5.6 Epidemic curve for a notional outbreak within a single ongoing
source. Red line indicates time point where source of infection was removed (e.g.
closure of a restaurant).](https://image.slidesharecdn.com/davidsonmedicine24th-250911130730-aa733799/85/DavidsonMedicine24th-pdf-for-medicine-4th-year-121-320.jpg)
![Treatment of infectious diseases 117
6
infectious mononucleosis may develop a rash if given aminopenicillins;
this does not imply lasting allergy. The relationship between allergy to
penicillin and allergy to cephalosporins depends on the specic cephalo-
sporin used. Avoidance of cephalosporins, however, is recommended in
patients who have IgE-mediated penicillin allergy (p. 80). Cross-reactivity
between penicillin and carbapenems is rare (approximately 1% by skin
testing) and carbapenems may be administered if there are no suitable
alternatives and appropriate resuscitation facilities are available.
Gastrointestinal upset and diarrhoea are common, and a mild reversible
hepatitis is recognised with many β-lactams. More severe forms of hep-
atitis can be observed with ucloxacillin and co-amoxiclav. Leucopenia,
thrombocytopenia, coagulation deciencies, interstitial nephritis and
potentiation of aminoglycoside-mediated kidney damage are also rec-
ognised. Seizures and encephalopathy have been reported, particularly
with high doses in the presence of renal insufciency. Thrombophlebitis
occurs in up to 5% of patients receiving parenteral β-lactams.
Drug interactions
Synergism occurs in combination with aminoglycosides in vitro. Ampicillin
decreases the biological effect of oral contraceptives and the whole class
is signicantly affected by concurrent administration of probenecid, pro-
ducing a 2–4-fold increase in the peak serum concentration.
Penicillins
Natural penicillins are primarily effective against Gram-positive organ-
isms (except staphylococci, most of which produce a penicillinase) and
anaerobic organisms. Streptococcus pyogenes has remained sensitive
to natural penicillins worldwide. According to the European Antimicrobial
Resistance Surveillance Network (EARS-Net), the prevalence of non-sus-
ceptibility to penicillin in Streptococcus pneumoniae in Europe in 2018
varied widely from 0.1% (Belgium) to 40% (Romania).
Penicillinase-resistant penicillins are the mainstay of treatment for
infections with Staph. aureus, other than MRSA. However, EARS-Net
data from 2018 indicate that MRSA rates in Europe vary widely from 0%
(Iceland) to 43% (Romania).
Aminopenicillins have the same spectrum of activity as the natural pen-
icillins, with additional Gram-negative cover against Enterobacterales.
Amoxicillin has better oral absorption than ampicillin. Unfortunately,
resistance to these agents is widespread (Escherichia coli Europe-wide
in 2018, range 35.3%–67.6%), so they are no longer appropriate for
empiric use in Gram-negative infections. In many organisms, resistance
is due to β-lactamase production, which can be overcome by the addi-
tion of β-lactamase inhibitors (clavulanic acid or sulbactam).
Carboxypenicillins (e.g. ticarcillin) and ureidopenicillins (e.g. piperacil-
lin) are particularly active against Gram-negative organisms, especially
Pseudomonas spp., which are resistant to the aminopenicillins. ß-lactamase
inhibitors may be added to extend their spectrum of activity (e.g. piperacillin–
tazobactam). Temocillin is derived from ticarcillin; it has good activity against
Enterobacterales, including those that produce ESBL enzymes, but poor
activity against P. aeruginosa and Gram-positive bacteria.
6.21 Problems with antimicrobial therapy in old age
Clostridioides difcile infection: all antibiotics predispose to some extent, but
second- and third-generation cephalosporins, co-amoxiclav and clindamycin
especially so.
Hypersensitivity reactions: rise in incidence due to increased previous exposure.
Renal impairment: may be signicant in old age, despite creatinine levels
being within the reference range.
Nephrotoxicity: more likely, e.g. aminoglycosides.
Accumulation of β-lactam antibiotics: may result in myoclonus, seizures or coma.
Reduced gastric acid production: gastric pH is higher, which causes
increased penicillin absorption.
Reduced hepatic metabolism: results in a higher risk of isoniazid-related
hepatotoxicity.
Quinolones: associated with delirium and may increase the risk of seizures.
ß-lactam antibiotics
These antibiotics have a β-lactam ring structure and exert a bactericidal action
by inhibiting PBPs and cell wall synthesis. They are classied in Box 6.22
Pharmacokinetics
Good drug levels are achieved in lung, kidney, bone, muscle and
liver, and in pleural, synovial, pericardial and peritoneal uids.
CSF levels are low, except when meninges are inamed.
‘Inoculum effect’: the activity of ß-lactams is reduced in the pres-
ence of a high organism burden, although the clinical relevance of
this effect is a subject of debate.
Generally safe in pregnancy (except imipenem/cilastatin).
Adverse effects
Immediate (IgE-mediated) allergic reactions are rare but life-threaten-
ing. Approximately 90% of patients who report a penicillin allergy do not
have a true IgE-mediated allergy, highlighting the importance of careful
allergy histories and documentation of reactions. Other reactions, such
as rashes, fever and haematological effects (e.g. low white cell count),
usually follow more prolonged therapy (more than 2 weeks). Patients with
6.22 ß-lactam antibiotics
Penicillins
Natural penicillins: benzylpenicillin, phenoxymethylpenicillin
Penicillinase-resistant penicillins: methicillin*, ucloxacillin, nafcillin, oxacillin
Aminopenicillins: ampicillin, amoxicillin
Carboxy- and ureido-penicillins: ticarcillin, piperacillin, temocillin
Cephalosporins
See Box 6.23
Monobactams
Aztreonam
Carbapenems
Imipenem, meropenem, ertapenem, doripenem
*Not used for treatment.
6.20 Antimicrobial agents in pregnancy1
Contraindicated
Chloramphenicol:neonatal‘grey baby’ syndrome – collapse,hypotension and cyanosis
Fluconazole: teratogenic in high doses
Quinolones: arthropathy in animal studies
Sulphonamides: neonatal haemolysis and methaemoglobinaemia
Tetracyclines, glycylcyclines: skeletal abnormalities in animals in rst trimester;
fetal dental discoloration and maternal hepatotoxicity with large parenteral
doses in second or third trimesters
Trimethoprim: teratogenic in rst trimester
Macrolides2
: major malformations in rst trimester and genital malformations
any trimester
Relatively contraindicated
Aminoglycosides: potential damage to fetal auditory and vestibular nerves in
second and third trimesters
Metronidazole: avoidance of high dosages is recommended3
Not known to be harmful; use only when necessary
Aciclovir
Penicillins and cephalosporins
Clindamycin
Glycopeptides
Linezolid
Meropenem
1
Data extracted from Joint Formulary Committee. British National Formulary (online). London:
BMJ Group and Pharmaceutical Press; (medicinescomplete.com) [accessed 16 March 2013].
2
Fan H, Gilbert R, O’Callaghan F, Li L. Associations between macrolide antibiotics prescribing
during pregnancy and adverse child outcomes in the UK: population based cohort study. BMJ
2020; 368:m331. 3
Theoretical risk of teratogenicity, not supported by available clinical evidence.](https://image.slidesharecdn.com/davidsonmedicine24th-250911130730-aa733799/85/DavidsonMedicine24th-pdf-for-medicine-4th-year-144-320.jpg)
![Pain 159
8
Magnetic resonance imaging
Magnetic resonance imaging (MRI) can be helpful in the assessment of
an underlying cause in patients with focal pain that follows a nerve root
or peripheral nerve distribution. Imaging is seldom helpful in individuals
with CWP.
Blood tests
Blood tests are not generally helpful in the diagnosis of chronic pain,
except in patients with peripheral neuropathy; in this case, a number of
blood tests may be required to investigate the underlying causes of the
neuropathy. Full details are provided in Box 28.85. Genetic testing may
Stimulus
ATP
Temperature or low pH
Osmosis
Cold or limitants
Cool
Low pH
Mechanical
Bradykinin
Prostanoids
ATP
NGF
Transducer
P2X
TRPV1/2
TRPV4
TRPA1
TRPM8
ASIC
Unknown
BK1/2
EP
P2Y
NTRK1
Kv
HCN2
Nav1.7
Sensitisation
Stimulus
Agonists
[H+]
Receptors
Response
Nav1.8 Nav1.9
B
A
C
Fig. 8.3
channels that act as mediators of pain. They include sodium channels implicated in congenital pain syndromes; the purinergic 2X (P2X) and purinergic 2Y (P2Y) receptor for
adenosine triphosphate (ATP); members of the transient receptor potential (TRP) superfamily of ion channel receptors, which detect changes in osmolality and temperature;
acid-sensing ion channel (ASIC) receptors, which detect hydrogen ions; G-protein-coupled receptors, which detect bradykinin (BK), prostaglandins and ATP; sodium-potassium
hyperpolarization-activated cyclic nucleotide-gated channels (HCN2), and voltage gated potassium channels (Kv) and the neurotrophic tyrosine kinase 1 (NTRK1) receptor, which
+
] and high temperature (>42°C) amplies action potentials, which increase pain
signals and cause peripheral sensitisation. (EP = E-prostanoid receptor) Adapted from Bennett DL, Woods CG. Painful and painless channelopathies. The Lancet Neurol 2014;
13:587–599; reproduced with permission from Elsevier.
Glutamate
Amino acids
(and other
neurotransmitters)
Pain
signal
Amplified
signal
Kinase
Dorsal root
ganglia
Neurotransmitter
changes
Glycine
NR1 NR2
Mg2+
Regulation of
pain response
NMDA receptor
Fig. 8.4 Mechanisms of central sensitisation. Post-synaptic activation of the N-methyl-D-aspartate (NMDA) receptor requires the amino acids glycine and glutamate, which
bind to the NR1 and NR2 subunits, respectively; these amplify pain signals at the level of the spinal cord. In contrast, magnesium ions block receptor activation.](https://image.slidesharecdn.com/davidsonmedicine24th-250911130730-aa733799/85/DavidsonMedicine24th-pdf-for-medicine-4th-year-189-320.jpg)
![10 CLINICAL DECISION-MAKING
Problem representation/list and differential
diagnosis
Once all the available data from history, physical examination and (some-
times) initial test results are available, these need to be synthesised into
a problem representation or problem list. The process of generating a
problem list ensures nothing is missed. The process of generating a
differential diagnosis works against anchoring on a particular diagnosis
too early, thereby avoiding search satiscing and premature closure (see
Fig. 1.6).
Mnemonics and checklists
These are used frequently in medicine in order to reduce reliance on
fallible human memory. ABCDE (airway, breathing, circulation, disability,
exposure/examination) is probably the most successful checklist in med-
icine, used during the assessment and treatment of critically ill patients
(ABCDE is sometimes prexed with ‘C’ for ‘control of any obvious prob-
lem’; see p. 191). Checklists ensure that important issues have been
considered and completed, especially under conditions of complexity,
stress or fatigue.
Red ags and ROWS (‘rule out worst-case scenario’)
These are strategies that force doctors to consider serious diseases that
can present with common symptoms. Red ags in back pain are listed
in Box 26.19. Considering and investigating for possible pulmonary
embolism in patients who present with pleuritic chest pain and breath-
lessness is a common example of ruling out a worst-case scenario, as
pulmonary embolism can be fatal if missed. Red ags and ROWS help
to avoid cognitive biases such as the ‘framing effect’ and ‘premature
closure’.
Newer strategies to avoid cognitive biases and errors in decision-mak-
ing are emerging. These involve explicit training in clinical reasoning and
human factors. In theory, if doctors are aware of the science of human
thinking and decision-making, then they are more able to think about
their thinking, understand situations in which their decision-making may
be affected, and take steps to mitigate this.
Clinical decision-making: putting it all
together
The following is a practical example that brings together many of the
concepts outlined in this chapter:
A 25-year-old woman presents with right-sided pleuritic chest pain
and breathlessness. She reports that she had an upper respiratory tract
infection a week ago and was almost back to normal when the symp-
toms started. The patient has no past medical history and no family his-
tory, and her only medication is the combined oral contraceptive pill.
On examination, her vital signs are normal (respiratory rate 19 breaths/
min, oxygen saturations 98% on air, blood pressure 115/60mmHg, heart
rate 90 beats/min, temperature 37.5°C) and the physical examination is
also normal. You have been asked to assess her for the possibility of a
pulmonary embolism.
(More information on pulmonary embolism can be found in Chapter 17.)
Evidence-based history and examination
Information from the history and physical examination is vital in deciding
whether this could be a pulmonary embolism. Pleurisy and breathless-
ness are common presenting features of this disease but are also com-
mon presenting features in other diseases. There is nothing in the history
to suggest an alternative diagnosis (e.g. high fever, productive cough,
recent chest trauma). The patient’s vital signs are normal, as is the phys-
ical examination. However, very few individual ndings help to distinguish
patients with pulmonary embolism from those without it. The presence of
wheeze and a high fever modestly decrease the probability of pulmonary
embolism. The presence of hypoxaemia is unhelpful (likelihood ratio not
signicant).
Deciding pre-test probability
The prevalence of pulmonary embolism (PE) in 25-year-old women is
low. We anchor on this prevalence and then adjust for individual patient
factors. This patient has no major risk factors for pulmonary embolism.
To assist our estimate of pre-test probability, we could use a clinical
1.7 The SBAR system of communicating
SBAR Example (a telephone call to the
Intensive Care team)
Situation I am [name] calling from [place] about
a patient with a NEWS* of 10.
Background [Patient’s name], 30-year-old woman,
no past medical history, was admitted
last night with community-acquired
pneumonia. Since then her oxygen
requirements have been steadily
increasing.
Assessment Her vital signs are: blood pressure
115/60mmHg, heart rate 120 beats/
min, temperature 38°C, respiratory
rate 32 breaths/min, oxygen
saturations 89% on 15L via reservoir
bag mask.
An arterial blood gas shows H+
50nmol/L (pH 7.3), PaCO2
4.0kPa
(30mmHg), PaO2
7kPa (52.5mmHg),
standard bicarbonate 14mmol/L.
Chest X-ray shows extensive right
lower zone consolidation.
Recommendation Please can you come and see her as
soon as possible? I think she needs
admission to Intensive Care.
*NEWS = National Early Warning Score; a patient with normal vital signs scores 0. See Royal
College of Physicians. National Early Warning Score (NEWS) 2: Standardising the assessment of
acute-illness severity in the NHS. Updated report of a working party. London: RCP; December 2017.
Feel better
No difference
Stroke
Dead
Fig. 1.9 Visual portrayal of benets and risks. The image refers to an operation
that is expected to relieve symptoms in 90% of patients, but cause stroke in 2% and
death in 1%. From Edwards A, Elwyn G, Mulley A. Explaining risks: turning numerical
data into meaningful pictures. BMJ 2002; 324:827–830, reproduced with permission
from the BMJ Publishing Group.](https://image.slidesharecdn.com/davidsonmedicine24th-250911130730-aa733799/75/DavidsonMedicine24th-pdf-for-medicine-4th-year-31-2048.jpg)
![Genomics, health and disease 43
3
Fig. 3.6 Splice-site variants.
result, splicing no longer occurs, leading to read-through of the mRNA into the intron, which contains a premature termination codon downstream of the variant.
Normal
Splice-site variant
Splice donor site
Exon Exon
Intron
Exon Exon
Intron
Intron removed by
splicing
Splice acceptor site
mRNA ‘reads through’ intron
Abnormal protein with
premature stop codon
A
B
3.2 Diseases associated with triplet and other repeat expansions*
Repeat No. of repeats Gene Gene location Inheritance
Normal Mutant
Coding repeat expansion
Huntington’s disease [CAG] 6–34 >35 Huntingtin 4p16 AD
Spinocerebellar ataxia (type 1) [CAG] 6–39 >40 Ataxin 6p22–23 AD
Spinocerebellar ataxia
(types 2, 3, 6, 7)
[CAG] Various Various Various Various AD
Dentatorubral-pallidoluysian atrophy [CAG] 7–25 >49 Atrophin 12p12–13 AD
Machado–Joseph disease [CAG] 12–40 >67 MJD 14q32 AD
Spinobulbar muscular atrophy [CAG] 11–34 >40 Androgen receptor Xq11–12 XL recessive
Non-coding repeat expansion
Myotonic dystrophy [CTG] 5–37 >50 DMPK-3 UTR 19q13 AD
Friedreich’s ataxia [GAA] 7–22 >200 Frataxin-intronic 9q13 AR
Progressive myoclonic epilepsy [CCCCGCCCCGCG]4–8
2–3 >25 Cystatin B-5 UTR 21q AR
Fragile X mental retardation [CGG] 5–52 >200 FMR1–5 UTR Xq27 XL dominant
Fragile site mental retardation 2 (FRAXE) [GCC] 6–35 >200 FMR2 Xq28 XL, probably recessive
*The triplet repeat diseases fall into two major groups: those with disease stemming from expansion of [CAG]n repeats in coding DNA, resulting in multiple adjacent glutamine residues (polyglutamine
tracts), and those with non-coding repeats. The latter tend to be longer. Unaffected parents usually display ‘pre-mutation’ allele lengths that are just above the normal range.
(AD/AR = autosomal dominant/recessive; UTR = untranslated region; XL = X-linked)
Loss-of-function variants result in loss or reduction in the normal
protein function. Whole-gene deletions are the archetypal loss-of-
function variants but stop-gain or indel variants (early in the ORF),
missense variants affecting a critical domain and splice-site variants
can also result in loss of protein function.
Gain-of-function variants result in a gain of protein function. They are
typically non-synonymous variants that alter the protein structure,
leading to activation/alteration of its normal function through causing
either an interaction with a novel substrate or a change in its normal
function.
Dominant negative variants are the result of non-synonymous sub-
stitutions or in-frame deletions/duplications but may also, less fre-
quently, be caused by triplet repeat expansions. Dominant negative
variants are heterozygous changes that result in the production of
an abnormal protein that interferes with the normal functioning of the
wild-type protein.](https://image.slidesharecdn.com/davidsonmedicine24th-250911130730-aa733799/75/DavidsonMedicine24th-pdf-for-medicine-4th-year-66-2048.jpg)
![88 POPULATION HEALTH AND EPIDEMIOLOGY
The UK Faculty of Public Heath denes public health as ‘The science
and art of promoting and protecting health and well-being, preventing
ill-health and prolonging life through the organised efforts of society’.
This recognises that there is a collective responsibility for the health of
the population which requires partnerships between government, health
services and other partners to promote and protect health and prevent
disease. Population health has been dened as ‘the health outcomes of
a group of individuals, including the distribution of such outcomes within
the group’. Medical doctors can play a role in all these efforts to improve
health both as part of their clinical work but also through supporting
broader actions to improve public health.
Global burden of disease and underlying risk
factors
The Global Burden of Disease (GBD) exercise was initiated by the World
Bank in 1992, with rst estimates appearing in the World Development
Report in 1993. Regular updated estimates have been published since
that time together with projections of future disease burden. The aim of
the exercise was to produce reliable and internally consistent estimates
of disease burden for all diseases and injuries and to assess their physi-
ological, behavioural and social risk factors so that this information could
be made available to health workers, researchers and policy-makers.
The GBD exercise adopted the metric ‘disability life year’ or DALY to
describe population health. This combines information about prema-
ture mortality in a population (measured as Years of Life Lost from an
‘expected’ life expectancy) and years of life lived with disability (Years
of Life lived with Disability (YLD), which is weighted by a severity factor).
The International Classication of Disease (ICD) rules, which assign one
cause to each death, are followed. All estimates are presented by age
and sex groups and by regions of the world. Many countries now also
report their own national burden of disease data.
Life expectancy
Global life expectancy at birth increased from 61.7 years in 1980 to 73.0
years in 2017, an increase of about 0.3 years per calendar year. This
change is due to a substantial fall in child mortality (mainly due to com-
mon infections) partly offset by rises in mortality from adult conditions
such as diabetes and chronic kidney disease. Some areas have not
shown these increases in life expectancy in men, often due to war and
interpersonal violence.
Global causes of death and disability
Box 5.1 shows a ranked list of the major causes of global deaths in 2019.
Communicable, maternal, neonatal and nutritional causes accounted for
about one-quarter of deaths worldwide – down from about one-third in
1990. In contrast, deaths from non-communicable diseases are increas-
ing in importance and now account for about two-thirds of all deaths
globally,: including about 18.5 million from cardiovascular disease (ischae-
mic heart disease and stroke), 10 million from cancer and about 4 million
from chronic respiratory diseases. The age standardised death rates for
most diseases globally are falling. However, despite this, the numbers of
deaths from many diseases are rising due to global population growth
and the change in age structure of the population to older ages and
this is placing an increasing burden on health systems. For a few con-
ditions (e.g. HIV/AIDS, diabetes mellitus and chronic kidney disease)
age-standardised death rates continue to rise. Within this overall pattern,
signicant regional variations exist – for example, communicable, mater-
nal, neonatal and nutritional causes still account for about two-thirds of
premature mortality in sub-Saharan Africa.
GBD also provides estimates of disability from disease (Box 5.2). This
has raised awareness of the importance of conditions like depression
and other common mental health conditions, low back and neck pain
and other musculo-skeletal conditions, and asthma, which account for a
relatively large disease burden but relatively few deaths. This in turn has
resulted in greater health policy priority given to these conditions. Since
the policy focus in national health systems is increasingly on keeping
people healthy rather than only on reducing premature deaths it is impor-
tant to have measures of these health outcomes.
It is important to recognise that although these estimates represent
the best overall picture of burden of disease globally, they are based on
limited and imperfect data. Nevertheless, the quality of data underlying
the estimates and the modelling processes are improving steadily over
time and provide an increasingly robust basis for evidence-based health
planning and priority setting.
Risk factors underlying disease
Box 5.3 shows a ranked list of the main risk factors underlying GBD
in 2019 and how this ranking has changed over the past 29 years. A
number of key insights have been identied in this, the most recent, GBD
exercise:
Socio-demographic development has been progressing steadily
since 1990 but it has increased faster in countries with the highest
socio-demographic development index and thus gaps have been
widening.
5.1 Global causes of death – top 15 ranked causes 2019
[rank in 1990]
1. Cardiovascular disease [1]
2. Neoplasms [2]
3. Chronic respiratory [6]
4. Respiratory infections and TB [3]
5. Diabetes and CKD [10]
6. Digestive diseases [8]
7. Neurological disorders [15]
8. Maternal and neonatal [15]
9. Unintentional injuries [9]
10. Enteric infections [5]
11. Transport injuries [13]
12. Self harm and violence [12]
13. Other non-communicable diseases [11]
14. HIV/AIDS and STIs [17]
15. NTDs and malaria [14]
(CKD = chronic kidney disease; TB = tuberculosis; STIs = sexually transmitted infections;
NTDs = neglected tropical diseases)
From GBD 2019. https://vizhub.healthdata.org/gbd-compare/.
5.2 Global disability – top 15 ranked causes 2019 [rank in 1990]*
1. Musculoskeletal disorders [1]
2. Mental disorders [2]
3. Other non-communicable diseases [3]
4. Sense organ diseases [5]
5. Neurological disorders [4]
6. Diabetes and CKD [12]
7. Skin diseases [7]
8. Unintentional injuries [8]
9. Nutritional deciencies [6]
10. Cardiovascular diseases [11]
11. Chronic respiratory diseases [9]
12. Substance use [13]
13. Maternal and neonatal conditions [17]
14. Transport injuries [16]
15. Digestive diseases [15]
*By years of life lived with disability (YLD).
(CKD = chronic kidney disease)
From GBD 2019. https://vizhub.healthdata.org/gbd-compare/.](https://image.slidesharecdn.com/davidsonmedicine24th-250911130730-aa733799/75/DavidsonMedicine24th-pdf-for-medicine-4th-year-114-2048.jpg)
![Social determinants of health 89
5
5.4 ‘Hierarchy of systems’ applied to ischaemic heart disease
Level in the hierarchy Example of effect
Molecular ApoB mutation causing hypercholesterolaemia
Cellular Foam cells accumulate in vessel wall
Tissue Atheroma and thrombosis of coronary artery
Organ Ischaemia and infarction of myocardium
System Cardiac failure
Person Limited exercise capacity, impact on employment
Family Passive smoking, diet
Community Shops and leisure opportunities
Population Prevalence of obesity
Society Policies on smoking, screening for risk factors
Ecology Agriculture inuencing fat content in diet
Health systems need to transform to be better able to respond to
the changing pattern of NCDs and disabilities.
The Millennium Development Goal (MDG) programme from 2000 to
2015 has led to faster progress in reducing deaths from maternal,
child and neonatal conditions/TB/HIV/malaria but this level of atten-
tion now needs to be directed at NCDs.
Public health is not giving sufcient priority to important global risk
factors which are increasing over time, such as high blood pressure,
high fasting glucose, high BMI, ambient particulate matter pollution
and drug and alcohol use.
There are many challenges resulting from the change in global
population pyramid structures, which have become inverted over
recent decades and now pose many health, nancial and political
challenges.
Social determinants of health
Health emerges from a highly complex interaction between a person’s
genetic background and environmental factors (aspects of the physical,
biological (microbes), built and social environments and also distant inu-
ences such as the global ecosystem) (Fig. 5.1).
The hierarchy of systems – from molecules to
ecologies
Inuences on health exist at many levels and extend beyond the individual
to include the family, community, population and ecology. Box 5.4 shows
an example of this for determinants of coronary heart disease and demon-
strates the importance of considering not only the disease process in a
patient but also its context. Health care is not the only determinant – and is
usually not the major determinant – of health status in the population. The
concept of ‘global health’ recognises the global dimension of health prob-
lems, whether these be, for example, emerging or pandemic infections or
global economic inuences on health internationally.
The life course
The determinants of health operate over the whole lifespan. Values and
behaviours acquired during childhood and adolescence have a pro-
found inuence on educational outcomes, job prospects and risk of
disease. These can have a strong inuence, for example, on whether
a young person takes up a damaging behaviour like smoking, risky
sexual activity and drug misuse. Inuences on health can even operate
before birth. Low birth weight can lead to higher risk hypertension and
type 2 diabetes in young adults and of cardiovascular disease in mid-
dle age. It has been suggested that under-nutrition during middle to
late gestation permanently ‘programmes’ cardiovascular and metabolic
responses.
This ‘life course’ perspective highlights the cumulative effect (through
each stage of life) on health of exposures to illness, adverse environmen-
tal conditions and behaviours that damage health.
Preventive medicine
The complexity of the interactions between physical, social and eco-
nomic determinants of health means that successful prevention is often
difcult. Moreover, the life course perspective illustrates that it may be
necessary to intervene early in life or even before birth, to prevent impor-
tant disease in later life. Successful prevention is likely to require many
interventions across the life course and at several levels in the hierarchy
of systems. The examples below illustrate this principle.
5.3 Global risk factors – top 10 ranked causes 2019 [rank in
1990]*
1. High blood pressure [7]
2. Smoking/second hand smoke exposure [5]
3. High fasting blood glucose [11]
4. Low birth weight [2]
5. High BMI [16]
6. Short gestation [3]
7. Ambient particulate matter pollution [13]
8. High LDL cholesterol [14]
9. Alcohol use [15]
10. Household air pollution [4]
From GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and
injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global
Burden of Disease Study 2019. Lancet 2020; 396:1204–1222.
M
acro-econom
y,
politics, culture,
global forces
Other
neighbourhoods,
other regions
People
Age, sex and
hereditary
factors
L festyle
W
o
r
k
p
l
a
y
D
i
e
t
p
h
y
s
i
c
a
l
a
c
tivity
S
o
c
a
l
c
a
p
i
t
a
l
Community
N
e
t
w
o
r
k
s
W
e
a
t
h
c
r
e
a
t
i
o
n
Loca economy
M
a
r
k
e
t
s
B
u
d
n
g
s
p
l
a
c
e
s
Environment
A
i
r
w
a
t
er
l
a
n
d
C
m
a
t
e
c
h
a
n
g
e
Globa ecosystem
B
o
d
v
e
r
s
i
t
y
Fig. 5.1 Hierarchy of systems that inuence population health. Adapted from
an original model by Whitehead M, Dahlgren G. What can be done about inequalities
in health? Lancet 1991; 338:1059–1063
*Risk factors ranked by % of burden of disease they cause.
(BMI = body mass index; LDL = low density lipoprotein)](https://image.slidesharecdn.com/davidsonmedicine24th-250911130730-aa733799/75/DavidsonMedicine24th-pdf-for-medicine-4th-year-115-2048.jpg)
![Further information 95
5
Management of epidemics
An epidemic, as dened by the World Health Organization, occurs when
‘in a community or region [the] cases of an illness, specic health-related
behaviour, or other health-related events [are] clearly in excess of normal
expectancy’. Epidemics that are small-scale or conned to a small geo-
graphic area are informally referred to as ‘outbreaks’.
Epidemics are regularly caused where preventative measures break
down; examples include breaches of food safety procedures in restau-
rants resulting in outbreaks of enteropathogenic E. coli infection, failure
to adequately maintain cooling towers causing Legionella infections and
falls in vaccination coverage resulting in measles epidemics.
Epidemics can also arise from novel infectious agents such as the
SARS-CoV-1, MERS, SARS-CoV-2 and H1N1 viruses, for which new
preventative measures require to be developed. Where epidemics from
novel agents are not controlled locally, but instead spread beyond inter-
national borders, these are termed pandemics, of which SARS-CoV-2
and H1N1 are examples.
To detect epidemics early, public health agencies undertake surveil-
lance. Surveillance involves the collection and review of cases that have
been identied via statutory notications, or health information systems
(such as microbiology reporting systems). For some infections such as
E. coli and Legionella, one challenge for public health agencies is to
distinguish epidemics from ‘sporadic’ cases at an early stage. This is
done using human judgement, for example, if a large number of cases of
E. coli occur in individuals who ate a specic food, although this task is
sometimes supported using computer algorithms.
Epidemics require an incident management team, some of whose
members have legal powers to impose measures to control infection.
The team establish a formal case denition for conrmed, probable and
possible cases (based on epidemiological features as well as clinical and/
or microbiological ndings), interview individuals with whom cases have
had signicant contact (termed contact tracing), test potential sources
of infections (e.g. foodstuffs or industrial cooling towers), and implement
control measures. The latter might include requiring infected individuals
to isolate for a time period (e.g. until they are asymptomatic or until they
test negative depending on the infectious agent), and/or ordering tem-
porary closure of businesses thought to be sources of infection (e.g. a
restaurant with poor food hygiene practices).
Epidemic curves are crucial to the monitoring and management of
epidemics. Figure 5.6 shows a notional epidemic curve for an epidemic
caused by a single source, which is eliminated after 31 days. However,
they are also used in more complex epidemics where there is per-
son-to-person spread. In the latter, epidemic curves are used to esti-
mate key statistics such as the basic reproduction number (R0) in the
population, as well as to make projections about future infections. Where
the source of an epidemic is not apparent, comparative epidemiological
methods can be used to identify the likely source, for example, a case–
control design may identify a higher than expected consumption of a
given food – for example uncooked legumes – among cases compared
to controls prompting testing of foods, an education campaign and/or
product recalls.
The principles for managing pandemics are similar to those for man-
aging epidemics but operate on a national or international scale. The
universality of pandemics, however, means that they pose special prob-
lems. First, they pose risks to the society-wide infrastructure needed
to deal with diseases, including, but not limited to health-care facilities.
Secondly, pandemics, unlike local and regional epidemics are rare, so
agencies have little direct experience with their management. For this
reason, most settings develop pandemic plans and undertake regu-
lar table-top simulations to test and improve their preparedness. The
COVID-19 pandemic, caused by SARS-CoV-2, is a key example and is
discussed in detail in Chapter 13
Further information
Kindig D, Stoddart G. What is population health? Am J Publ Health 2003;93:
380–383.
UK Faculty of Public Health. What is public health? http://www.fph.org.uk/what_
is_public_health
Burden of disease
GBD Diseases and Injuries Collaborators. Global burden of 369 diseases and
injuries in 204 countries and territories, 1990–2019: a systematic analysis for
the Global Burden of Disease Study 2019. Lancet 2019; 2020(396):
1204–1222.
GBD Risk Factors Collaborators. Global burden of 87 risk factors in 204
countries and territories, 1990–2019: a systematic analysis for the Global
Burden of Disease Study 2019. Lancet 2019; 2020(396):1223–1249.
GBD Viewpoint Collaborators. Five insights from the Global Burden of Disease
Study 2019. Lancet 2019; 2020(396):1135–1159.
Screening
Gov.UK. Population screening programmes. https://www.gov.uk/topic/population-
screening-programmes Detailed information on 11 NHS population screening
programmes.
Immunisation
Gov.UK. Immunisation against infectious disease. https://www.gov.uk/
government/collections/immunisation-against-infectious-disease-the-green-
book The Green Book has the latest information on vaccines and vaccination
procedures, for vaccine-preventable infectious diseases in the UK.
Epidemiology
Burgess S, Davey Smith G, Davies NM, et al. Guidelines for performing Mendelian
randomization investigations. Wellcome Open Res 2020;4:186.
STROBE-MR Steering Group: STROBE-MR: Guidelines for strengthening the
reporting of Mendelian randomization studies. PeerJ https://peerj.com/
preprints/27857/
Days
New
cases
1
0
5
10
15
6 11 16 21 26 31 26 41
Fig. 5.6 Epidemic curve for a notional outbreak within a single ongoing
source. Red line indicates time point where source of infection was removed (e.g.
closure of a restaurant).](https://image.slidesharecdn.com/davidsonmedicine24th-250911130730-aa733799/75/DavidsonMedicine24th-pdf-for-medicine-4th-year-121-2048.jpg)
![Treatment of infectious diseases 117
6
infectious mononucleosis may develop a rash if given aminopenicillins;
this does not imply lasting allergy. The relationship between allergy to
penicillin and allergy to cephalosporins depends on the specic cephalo-
sporin used. Avoidance of cephalosporins, however, is recommended in
patients who have IgE-mediated penicillin allergy (p. 80). Cross-reactivity
between penicillin and carbapenems is rare (approximately 1% by skin
testing) and carbapenems may be administered if there are no suitable
alternatives and appropriate resuscitation facilities are available.
Gastrointestinal upset and diarrhoea are common, and a mild reversible
hepatitis is recognised with many β-lactams. More severe forms of hep-
atitis can be observed with ucloxacillin and co-amoxiclav. Leucopenia,
thrombocytopenia, coagulation deciencies, interstitial nephritis and
potentiation of aminoglycoside-mediated kidney damage are also rec-
ognised. Seizures and encephalopathy have been reported, particularly
with high doses in the presence of renal insufciency. Thrombophlebitis
occurs in up to 5% of patients receiving parenteral β-lactams.
Drug interactions
Synergism occurs in combination with aminoglycosides in vitro. Ampicillin
decreases the biological effect of oral contraceptives and the whole class
is signicantly affected by concurrent administration of probenecid, pro-
ducing a 2–4-fold increase in the peak serum concentration.
Penicillins
Natural penicillins are primarily effective against Gram-positive organ-
isms (except staphylococci, most of which produce a penicillinase) and
anaerobic organisms. Streptococcus pyogenes has remained sensitive
to natural penicillins worldwide. According to the European Antimicrobial
Resistance Surveillance Network (EARS-Net), the prevalence of non-sus-
ceptibility to penicillin in Streptococcus pneumoniae in Europe in 2018
varied widely from 0.1% (Belgium) to 40% (Romania).
Penicillinase-resistant penicillins are the mainstay of treatment for
infections with Staph. aureus, other than MRSA. However, EARS-Net
data from 2018 indicate that MRSA rates in Europe vary widely from 0%
(Iceland) to 43% (Romania).
Aminopenicillins have the same spectrum of activity as the natural pen-
icillins, with additional Gram-negative cover against Enterobacterales.
Amoxicillin has better oral absorption than ampicillin. Unfortunately,
resistance to these agents is widespread (Escherichia coli Europe-wide
in 2018, range 35.3%–67.6%), so they are no longer appropriate for
empiric use in Gram-negative infections. In many organisms, resistance
is due to β-lactamase production, which can be overcome by the addi-
tion of β-lactamase inhibitors (clavulanic acid or sulbactam).
Carboxypenicillins (e.g. ticarcillin) and ureidopenicillins (e.g. piperacil-
lin) are particularly active against Gram-negative organisms, especially
Pseudomonas spp., which are resistant to the aminopenicillins. ß-lactamase
inhibitors may be added to extend their spectrum of activity (e.g. piperacillin–
tazobactam). Temocillin is derived from ticarcillin; it has good activity against
Enterobacterales, including those that produce ESBL enzymes, but poor
activity against P. aeruginosa and Gram-positive bacteria.
6.21 Problems with antimicrobial therapy in old age
Clostridioides difcile infection: all antibiotics predispose to some extent, but
second- and third-generation cephalosporins, co-amoxiclav and clindamycin
especially so.
Hypersensitivity reactions: rise in incidence due to increased previous exposure.
Renal impairment: may be signicant in old age, despite creatinine levels
being within the reference range.
Nephrotoxicity: more likely, e.g. aminoglycosides.
Accumulation of β-lactam antibiotics: may result in myoclonus, seizures or coma.
Reduced gastric acid production: gastric pH is higher, which causes
increased penicillin absorption.
Reduced hepatic metabolism: results in a higher risk of isoniazid-related
hepatotoxicity.
Quinolones: associated with delirium and may increase the risk of seizures.
ß-lactam antibiotics
These antibiotics have a β-lactam ring structure and exert a bactericidal action
by inhibiting PBPs and cell wall synthesis. They are classied in Box 6.22
Pharmacokinetics
Good drug levels are achieved in lung, kidney, bone, muscle and
liver, and in pleural, synovial, pericardial and peritoneal uids.
CSF levels are low, except when meninges are inamed.
‘Inoculum effect’: the activity of ß-lactams is reduced in the pres-
ence of a high organism burden, although the clinical relevance of
this effect is a subject of debate.
Generally safe in pregnancy (except imipenem/cilastatin).
Adverse effects
Immediate (IgE-mediated) allergic reactions are rare but life-threaten-
ing. Approximately 90% of patients who report a penicillin allergy do not
have a true IgE-mediated allergy, highlighting the importance of careful
allergy histories and documentation of reactions. Other reactions, such
as rashes, fever and haematological effects (e.g. low white cell count),
usually follow more prolonged therapy (more than 2 weeks). Patients with
6.22 ß-lactam antibiotics
Penicillins
Natural penicillins: benzylpenicillin, phenoxymethylpenicillin
Penicillinase-resistant penicillins: methicillin*, ucloxacillin, nafcillin, oxacillin
Aminopenicillins: ampicillin, amoxicillin
Carboxy- and ureido-penicillins: ticarcillin, piperacillin, temocillin
Cephalosporins
See Box 6.23
Monobactams
Aztreonam
Carbapenems
Imipenem, meropenem, ertapenem, doripenem
*Not used for treatment.
6.20 Antimicrobial agents in pregnancy1
Contraindicated
Chloramphenicol:neonatal‘grey baby’ syndrome – collapse,hypotension and cyanosis
Fluconazole: teratogenic in high doses
Quinolones: arthropathy in animal studies
Sulphonamides: neonatal haemolysis and methaemoglobinaemia
Tetracyclines, glycylcyclines: skeletal abnormalities in animals in rst trimester;
fetal dental discoloration and maternal hepatotoxicity with large parenteral
doses in second or third trimesters
Trimethoprim: teratogenic in rst trimester
Macrolides2
: major malformations in rst trimester and genital malformations
any trimester
Relatively contraindicated
Aminoglycosides: potential damage to fetal auditory and vestibular nerves in
second and third trimesters
Metronidazole: avoidance of high dosages is recommended3
Not known to be harmful; use only when necessary
Aciclovir
Penicillins and cephalosporins
Clindamycin
Glycopeptides
Linezolid
Meropenem
1
Data extracted from Joint Formulary Committee. British National Formulary (online). London:
BMJ Group and Pharmaceutical Press; (medicinescomplete.com) [accessed 16 March 2013].
2
Fan H, Gilbert R, O’Callaghan F, Li L. Associations between macrolide antibiotics prescribing
during pregnancy and adverse child outcomes in the UK: population based cohort study. BMJ
2020; 368:m331. 3
Theoretical risk of teratogenicity, not supported by available clinical evidence.](https://image.slidesharecdn.com/davidsonmedicine24th-250911130730-aa733799/75/DavidsonMedicine24th-pdf-for-medicine-4th-year-144-2048.jpg)
![Pain 159
8
Magnetic resonance imaging
Magnetic resonance imaging (MRI) can be helpful in the assessment of
an underlying cause in patients with focal pain that follows a nerve root
or peripheral nerve distribution. Imaging is seldom helpful in individuals
with CWP.
Blood tests
Blood tests are not generally helpful in the diagnosis of chronic pain,
except in patients with peripheral neuropathy; in this case, a number of
blood tests may be required to investigate the underlying causes of the
neuropathy. Full details are provided in Box 28.85. Genetic testing may
Stimulus
ATP
Temperature or low pH
Osmosis
Cold or limitants
Cool
Low pH
Mechanical
Bradykinin
Prostanoids
ATP
NGF
Transducer
P2X
TRPV1/2
TRPV4
TRPA1
TRPM8
ASIC
Unknown
BK1/2
EP
P2Y
NTRK1
Kv
HCN2
Nav1.7
Sensitisation
Stimulus
Agonists
[H+]
Receptors
Response
Nav1.8 Nav1.9
B
A
C
Fig. 8.3
channels that act as mediators of pain. They include sodium channels implicated in congenital pain syndromes; the purinergic 2X (P2X) and purinergic 2Y (P2Y) receptor for
adenosine triphosphate (ATP); members of the transient receptor potential (TRP) superfamily of ion channel receptors, which detect changes in osmolality and temperature;
acid-sensing ion channel (ASIC) receptors, which detect hydrogen ions; G-protein-coupled receptors, which detect bradykinin (BK), prostaglandins and ATP; sodium-potassium
hyperpolarization-activated cyclic nucleotide-gated channels (HCN2), and voltage gated potassium channels (Kv) and the neurotrophic tyrosine kinase 1 (NTRK1) receptor, which
+
] and high temperature (>42°C) amplies action potentials, which increase pain
signals and cause peripheral sensitisation. (EP = E-prostanoid receptor) Adapted from Bennett DL, Woods CG. Painful and painless channelopathies. The Lancet Neurol 2014;
13:587–599; reproduced with permission from Elsevier.
Glutamate
Amino acids
(and other
neurotransmitters)
Pain
signal
Amplified
signal
Kinase
Dorsal root
ganglia
Neurotransmitter
changes
Glycine
NR1 NR2
Mg2+
Regulation of
pain response
NMDA receptor
Fig. 8.4 Mechanisms of central sensitisation. Post-synaptic activation of the N-methyl-D-aspartate (NMDA) receptor requires the amino acids glycine and glutamate, which
bind to the NR1 and NR2 subunits, respectively; these amplify pain signals at the level of the spinal cord. In contrast, magnesium ions block receptor activation.](https://image.slidesharecdn.com/davidsonmedicine24th-250911130730-aa733799/75/DavidsonMedicine24th-pdf-for-medicine-4th-year-189-2048.jpg)
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- 1. 24th Edition ,�. . ELSLVlER - Editedby Ian D. Penman Stuart H. Ralston Mark W. J. Strachan Richard P. Hobson II
- 2. Medicine Davidson’s Principles and Practiceof PDF Collected By: Dr.NazmulAlamFaruki
- 3. Sir Stanley Davidson(1894–1981) This famous textbook was the brainchild of one of the great Professors of Medicine of the 20th century. Stanley Davidson was born in Sri Lanka and began his medical undergraduate training at Trinity College, Cambridge; this was interrupted by World War I and later resumed in Edinburgh. He was seriously wounded in battle, and the carnage and shocking waste of young life that he encountered at that time had a profound effect on his subsequent attitudes and values. In 1930 Stanley Davidson was appointed Professor of Medicine at the University of Aberdeen, one of the rst full-time Chairs of Medicine anywhere and the rst in Scotland. In 1938 he took up the Chair of Medicine at Edinburgh and was to remain in this post until retirement in 1959. He was a renowned educator and a particularly gifted teacher at the bedside, where he taught that everything had to be questioned and explained. He personally gave most of the systematic lectures in Medicine, which were made available as typewritten notes that empha- sised the essentials and far surpassed any textbook available at the time. Principles and Practice of Medicine was conceived in the late 1940s with its origins in those lecture notes. The rst edition, published in 1952, was a masterpiece of clarity and uniformity of style. It was of modest size and price, but sufciently comprehensive and up to date to provide students with the main elements of sound medical practice. Although the format and presentation have seen many changes in 23 subsequent editions, Sir Stanley’s original vision and objectives remain. More than half a century after its rst publication, his book continues to inform and educate students, doctors and health professionals all over the world.
- 4. 24th Edition Edited by IanD Penman BSc(Hons), MBChB, MD, FRCPE Consultant Gastroenterologist, Royal Inrmary of Edinburgh; Honorary Senior Lecturer, University of Edinburgh, UK Stuart H Ralston MBChB, MD, FRCP, FMedSci, FRSE, FFPM(Hon) Professor of Rheumatology, Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer University of Edinburgh; Honorary Consultant Rheumatologist, Western General Hospital, Edinburgh, UK Mark WJ Strachan BSc(Hons), MBChB(Hons), MD, FRCPE Consultant Endocrinologist, Metabolic Unit, Western General Hospital, Edinburgh; Honorary Professor, University of Edinburgh, UK Richard P Hobson MBBS, LLM, PhD, MRCP(UK), FRCPath Consultant Microbiologist, Harrogate and District NHS Foundation Trust; Honorary Senior Lecturer, University of Leeds, UK Illustrations by Robert Britton London New York Oxford Philadelphia St Louis Sydney 2023 Medicine Davidson’s Principles and Practice of
- 5. © 2023, ElsevierLimited. All rights reserved. Illustrations and boxes in Chapter 11 © Julian White. First edition 1952 Second edition 1954 Third edition 1956 Fourth edition 1958 Fifth edition 1960 Sixth edition 1962 Seventh edition 1964 Eighth edition 1966 Ninth edition 1968 Tenth edition 1971 Eleventh edition 1974 Twelfth edition 1977 Thirteenth edition 1981 Fourteenth edition 1984 Fifteenth edition 1987 Sixteenth edition 1991 Seventeenth edition 1995 Eighteenth edition 1999 Nineteenth edition 2002 Twentieth edition 2006 Twenty-rst edition 2010 Twenty-second edition 2014 Twenty-third edition 2018 Twenty-fourth edition 2022 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein.Because of rapid advances in the medical sciences, in particular, independent verication of diagnoses and drug dosages should be made.To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-7020-8347-1 International ISBN: 978-0-7020-8348-8 Printed in the UK Last digit is the print number: 9 8 7 6 5 4 3 2 1 Content Strategist: Jeremy Bowes Content Development Specialist: Siân Jarman Project Manager: Anne Collett Design: Miles Hitchen Illustration Manager: Narayanan Ramakrishnan Marketing Manager: Kathleen Patton
- 6. Contents Preface ix Contributors xi InternationalAdvisory Board xv Acknowledgements xvii Introduction xix PART 1 FUNDAMENTALS OF MEDICINE 1 1. Clinical decision-making 1 N Cooper, AL Cracknell 2. Clinical therapeutics and good prescribing 13 SRJ Maxwell 3. Clinical genetics 37 K Tatton-Brown 4. Clinical immunology 59 SL Johnston 5. Population health and epidemiology 87 H Campbell, DA McAllister 6. Principles of infectious disease 97 JAT Sandoe, DH Dockrell 7. Oncology 127 S Clive, M Stares 8. Pain and palliative care 153 LA Colvin, M Fallon PART 2 EMERGENCY AND CRITICAL CARE MEDICINE 175 9. Acute medicine and critical illness 175 VR Tallentire, MJ MacMahon 10. Poisoning 219 SHL Thomas
- 7. vi CONTENTS 11.Envenomation 239 J White 12. Medicine in austere environments 251 AC Baker PART 3 CLINICAL MEDICINE 261 13. Infectious disease 261 DH Dockrell, S Sundar, BJ Angus 14. HIV infection and AIDS 349 G Maartens 15. Sexually transmitted infections 369 DJ Clutterbuck 16. Cardiology 385 DE Newby, NR Grubb 17. Respiratory medicine 479 IJ Clifton, DAB Ellames 18. Nephrology and urology 557 B Conway, PJ Phelan, GD Stewart 19. Clinical biochemistry and metabolic medicine 613 A Mather, DR Sullivan, E Miller-Hodges 20. Endocrinology 647 JDC Newell-Price, FW Gibb 21. Diabetes mellitus 703 JR Petrie, JG Boyle 22. Nutritional factors in disease 755 AG Shand, MEJ Lean 23. Gastroenterology 781 A Rej, TS Chew, DS Sanders 24. Hepatology 859 MJ Williams, TT Gordon-Walker 25. Haematology and transfusion medicine 921 HG Watson, DJ Culligan, LM Manson 26. Rheumatology and bone disease 989 GPR Clunie, SH Ralston 27. Dermatology 1063 SH Ibbotson 28. Neurology 1119 DPJ Hunt, MD Connor
- 8. CONTENTS vii 29.Stroke medicine 1201 W Whiteley, R Woodeld 30. Medical ophthalmology 1217 JA Olson 31. Medical psychiatry 1235 RM Steel, SM Lawrie 32. Maternal medicine 1263 L Mackillop, FEM Neuberger 33. Adolescent and transition medicine 1281 RJ Mann 34. Ageing and disease 1295 TJ Quinn 35. Laboratory reference ranges 1309 SJ Jenks Index 1317 Get the most out of your Davidson’s! Redeem your unique e-content PIN code today (see inside front cover) to access: The complete, downloadable eBook – for quick reference, anytime access BONUS NEW self-assessment material – 166 interactive questions and answers supplement each chapter, to help test your understanding of key points and aid exam preparation
- 9. This page intentionallyleft blank
- 10. Preface Well over 2.5million copies of Davidson’s Principles and Practice of Medicine have been sold since it was rst published in 1952. Now in its 24th Edition, Davidson’s is regarded as a ‘must-have’ textbook for thousands of medical students, doctors and health professionals across the world, describing the pathophysiology and clinical features of the most important conditions encountered in the major specialties of adult medicine and explaining how to investigate, diagnose and manage them. The book is the winner of numerous prizes and awards and has been translated into many languages. Taking its origins from Sir Stanley Davidson’s much-admired lecture notes, the book has endured because it continues to keep pace with how modern medicine is taught and to provide a wealth of information in an easy-to-read, concise and beauti- fully illustrated format. Davidson’s strives to ensure that readers can not only recognise the clinical features of a disease, but also understand the underlying causes. To achieve this, each chapter begins with a summary of the relevant pre-clinical science, linking pathophysiology with clinical presentation and treatment so that students can use the book from the start of their medical studies right through to their nal examinations and beyond. The regular introduction of new authors and editors is important for maintaining freshness. On this occasion, 21 new authors have joined our existing contributors to make up an outstanding team of authorities in their respective elds. As well as recruiting authors from around the globe, particularly for topics such as infectious diseases, HIV and enven- omation, we welcome members from 10 countries on to our International Advisory Board. These leading experts provide detailed comments that are crucial to our revision of each new edition. A particularly important aspect in planning the revision is for the editors to meet students and faculty in medical schools in those countries where the book is most widely read, so that we can respond to the feedback of our global read- ership and their tutors. We use this feedback, along with the information we gather via detailed student reviews and surveys, to craft each edition. The authors, editors and publishing team aim to ensure that readers all over the world are best served by a book that integrates medical science with clinical medicine to convey key knowledge and practical advice in an accessible and readable format. The amount of detail is tailored to the needs of medical students working towards their nal examinations, as well as candidates preparing for Membership of the Royal Colleges of Physicians (MRCP) or its equivalent. With this new edition we have introduced several changes in both structure and content. The opening eight chapters provide an account of the principles of genetics, immunology, infectious diseases, population health, oncology and pain management, along with a discussion of the core principles behind clinical decision-making and good prescribing. Subsequent chapters discuss medical emergencies in poisoning, enven- omation and medicine in austere environments, while common presenta- tions in acute medicine, including recognition and management of the critically ill patient, are also addressed. The disease-specic chapters that follow cover the major medical specialties, each one thoroughly revised and updated to ensure that readers have access to the ‘cutting edge’ of medical knowledge and practice. As we publish the 24th edi- tion, the world is in the grip of the COVID-19 pandemic and while our knowledge of virology, epidemiology, clinical impact and management of SARS-CoV-2 is still evolving, we have dedicated a new section on core aspects of this hugely important topic in Chapter 13, but also in Chapter6 and, as appropriate, elsewhere throughout the book. The innovations introduced in recent editions have been maintained and, in many cases, developed. The highly popular ‘Clinical Examination’ overviews have been extended and updated. The ‘Presenting Problems’ sections continue to provide an invaluable overview of the most common presentations in each disease area. The ‘Emergency’ and ‘Practice Point’ boxes have been retained along with the ‘In Old Age’, ‘In Pregnancy’ and ‘In Adolescence’ boxes, which emphasise key practical points in the presentation and management of the older adult, women with medi- cal disorders who are pregnant or planning pregnancy, and adolescents transitioning between paediatric and adult services. Education is achieved by assimilating information from many sources and readers of this book can enhance their learning experience by using several complementary resources. We developed a self-testing compan- ion book entitled Davidson’s Assessment in Medicine, containing over 1250 multiple choice questions specically tailored to the contents of Davidson’s for the 23rd edition and have added more new online MCQs to accompany this edition. The long-standing association of Davidson’s with its sister books, Macleod’s Clinical Examination and Principles and Practice of Surgery, still holds good. Our ‘family’ has also expanded with the publication of Davidson’s Essentials of Medicine, a pocket-sized version of the main text, now in its 3rd edition; and Macleod’s Clinical Diagnosis, which describes a systematic approach to the differential diagnosis of symptoms and signs. We congratulate the editors and authors of these books for continuing the tradition of easily digested and expertly illustrated texts. We all take immense pride in continuing the great tradition rst estab- lished by Sir Stanley Davidson and in producing an outstanding book for the next generation of doctors. IDP, SHR, MWJS, RPH Edinburgh 2022
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- 12. Contributors Brian J AngusMD, FRCP, DTM&H Associate Professor, Nufeld Department of Medicine, Oxford University, Oxford, UK Adam C Baker BM, BMedSci(Hons), MSc ExMed Pre-Hospital Emergency Medicine Fellow, Honorary Senior Clinical Research Fellow, Department of Emergency Medicine, University Hospitals Plymouth NHS Trust, Devon Air Ambulance, University of Exeter, Devon, UK James G Boyle MBChB, MD, MSc, FRCP Consultant Diabetologist, Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Inrmary; Honorary Associate Clinical Professor, School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK Harry Campbell MBChB, MD, FRCPE, FFPH, FRSE, FMedSci Professor of Genetic Epidemiology and Public Health, Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK Thean Soon Chew MBChB, MRCP, PhD Consultant Gastroenterologist and Honorary Senior Lecturer in Gastroenterology, Academic Unit of Gastroenterology, University of Shefeld, Shefeld, UK Ian J Clifton MD, FRCP Consultant Respiratory Physician and Honorary Senior Lecturer, Department of Respiratory Medicine, St James’s University Hospital, Leeds, UK Sally Clive BMedSci(Hons), MBChB, MD, FRCPE Consultant Medical Oncologist, Edinburgh Cancer Centre, Western General Hospital, Edinburgh, UK Gavin PR Clunie MD, FRCP Consultant Rheumatologist and Metabolic Bone Physician, Department of Rheumatology, Cambridge University Hospital NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK Daniel J Clutterbuck BSc(Hons), FRCP Consultant in Genitourinary and HIV Medicine, NHS Lothian; Chalmers Sexual Health Centre, Edinburgh, UK Lesley A Colvin MBChB, PhD, FRCA, FFPMRCA, FRCPE Professor of Pain Medicine, Division of Population Health and Genomics, University of Dundee School of Medicine, Dundee, UK Myles D Connor MBBCh, FCP(SA), FCNeurol(SA), PhD, FRCPE Consultant Neurologist, Department of Neurology, NHS Borders, Melrose, UK; Honorary Senior Lecturer, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK; Honorary Senior Researcher, School of Public Health, University of the Witwatersrand, Johannesburg, South Africa Bryan Conway MB, MRCP, PhD Senior Lecturer and Honorary Consultant Nephrologist, Department of Renal Medicine, University of Edinburgh and Edinburgh Royal Inrmary, Edinburgh, UK Nicola Cooper MBChB, MMedSci, FRCPE, FRACP, FAcadMEd, SFHEA Consultant Physician and Clinical Associate Professor in Medical Education, Department for Acute Internal Medicine, University Hospitals of Derby & Burton NHS Foundation Trust, Derby, UK Alison L Cracknell MBChB, FRCP Consultant in Medicine for Older People, Department of Medicine for Older People, Leeds Teaching Hospitals NHS Trust; Honorary Clinical Associate Professor, University of Leeds, Leeds, UK Dominic J Culligan BSc, MD, FRCP, FRCPath Consultant Haematologist and Honorary Senior Lecturer, Department of Haematology, Aberdeen Royal Inrmary, Aberdeen, UK David H Dockrell MD, FRCPI, FRCPG, FACP Chair of Infection Medicine, Centre for Inammation Research, University of Edinburgh; Professor of Infection Medicine, UoE Centre for Inammation Research, University of Edinburgh, Edinburgh, UK Deborah AB Ellames BSc(Hons), MBChB Consultant Physician in Respiratory Medicine, Department of Respiratory Medicine, Leeds Teaching Hospitals NHS Trust, Leeds, UK Marie Fallon MBChB, MD, FRCPG, FRCPE, DCH, DRCOG, MRCGP St Columba’s Hospice Chair of Palliative Medicine, Edinburgh Cancer Research Centre, Institute for Genetics and Cancer, University of Edinburgh, Edinburgh, UK Fraser W Gibb MBChB, BSc(Hons), FRCP, PhD Consultant Physician/Honorary Clinical Reader, Edinburgh Centre for Endocrinology and Diabetes, Royal Inrmary of Edinburgh/ University of Edinburgh, Edinburgh, UK
- 13. xii CONTRIBUTORS TimothyT Gordon-Walker MBChB, PhD, MRCP Consultant Hepatologist, Department of Gastroenterology and Scottish Liver Transplant Unit, The Royal Inrmary of Edinburgh, Edinburgh, UK Neil R Grubb MD, FRCP Consultant in Cardiology and Cardiac Electrophysiology, Department of Cardiology, Royal Inrmary of Edinburgh, Edinburgh, UK David PJ Hunt MB BChir, PhD, FRCP Wellcome Senior Clinical Fellow, Department of Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK Sally H Ibbotson BSc(Hons), MD, FRCPE Professor of Photodermatology, University of Dundee; Honorary Consultant Dermatologist and Head of Photobiology Unit, Ninewells Hospital and Medical School, Dundee, UK Sara J Jenks MBChB, MRCP, FRCPath Consultant in Metabolic Medicine, Department of Clinical Biochemistry, Royal Inrmary of Edinburgh, Edinburgh, UK Sarah L Johnston FRCP, FRCPath Consultant Immunologist, Department of Immunology and Immunogenetics, North Bristol NHS Trust, Bristol, UK Stephen M Lawrie MD(Hons), FRCPsych, Hon FRCPE, FRSE Professor of Psychiatry and Neuroimaging, Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK Michael EJ Lean MA, MB, BChir, MD, FRCP, FRSE Professor of Human Nutrition, Human Nutrition, University of Glasgow, Glasgow, UK Gary Maartens MBChB, MMed, FCP(SA) Chair of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa Lucy H Mackillop BM BCh, MA(Oxon), FRCP Consultant Obstetric Physician, Oxford University Hospitals, NHS Foundation Trust; Honorary Senior Clinical Lecturer, Nufeld Department of Women’s and Reproductive Health, University of Oxford, Oxford, UK Michael J MacMahon FRCA, EDIC Consultant Intensivist, Department of Anaesthesia and Intensive Care, Victoria Hospital, Kirkcaldy, UK Rebecca J Mann BMedSci, BMBS, MRCP, FRCPCh Consultant Paediatrician, Department of Paediatrics, Taunton and Somerset NHS Foundation Trust, Taunton, UK Lynn M Manson MBChB, MD Consultant Haematologist, Department of Transfusion Medicine, Royal Inrmary of Edinburgh, Edinburgh, UK Amanda Mather MBBS, FRACP, PhD Renal Staff Specialist, Department of Renal Medicine, Royal North Shore Hospital; Conjoint Senior Lecturer, Faculty of Medicine, University of Sydney, Sydney, NSW, Australia Simon RJ Maxwell MD, PhD, FRCP, FRCPE, FBPhS Professor of Student Learning (Clinical Pharmacology and Prescribing), Clinical Pharmacology Unit, University of Edinburgh, Edinburgh, UK David A McAllister MBChB, MPH, MD, MRCP, MFPH Wellcome Trust Intermediate Clinical Fellow and Beit Fellow and Honorary Consultant in Public Health Medicine, Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK Eve Miller-Hodges MBChB, PhD Senior Clinical Lecturer and Honorary Consultant in Inherited Metabolic Disorders and Renal Medicine, Centre for Cardiovascular Science & Scottish IMD Service, University of Edinburgh, Edinburgh, UK Francesca EM Neuberger MBChB, FRCP Consultant Physician in Acute and Obstetric Medicine, Medical Division, North Bristol NHS Trust, Bristol, UK David E Newby BA BSc(Hons), PhD, BM DM DSc, FRSE, FESC, FACC, FMedSci British Heart Foundation Duke of Edinburgh Chair of Cardiology, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK John DC Newell-Price MA, PhD, FRCP Professor of Endocrinology, Department of Oncology and Metabolism, University of Shefeld, Shefeld, UK John A Olson MD, FRCPE, FRCOphth Consultant Ophthalmic Physician, Aberdeen Royal Inrmary; Honorary Reader, University of Aberdeen, Aberdeen, UK John R Petrie BSc, MBChB, PhD, FRCPE, FRCPG Professor of Diabetic Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK Paul J Phelan MD, FRCPE Consultant Nephrologist and Renal Transplant Physician, Department of Nephrology, Royal Inrmary of Edinburgh, Edinburgh, UK Terence J Quinn FRCP, MD, MBChB, BSc Senior Clinical Lecturer and Honorary Consultant in Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK Stuart H Ralston MBChB, MD, FRCP, FFPM(Hon), FMedSci, FRSE Professor of Rheumatology, Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK Anupam Rej MBChB, BMedSci(Hons), MRCP(UK) Clinical Research Fellow, Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Shefeld, UK David S Sanders MBChB, MD, FACG Professor of Gastroenterology, Academic Unit of Gastroenterology, Royal Hallamshire Hospital and University of Shefeld, Shefeld, UK Jonathan AT Sandoe FRCPath, PhD Associate Clinical Professor, Consultant Microbiologist, Department of Microbiology, University of Leeds and Leeds Teaching Hospitals NHS Trust, Leeds, UK Alan G Shand MD, FRCPE Consultant Gastroenterologist, Gastrointestinal Unit, Western General Hospital, Edinburgh, UK Mark Stares MBBS, MD(Res), MRes, BSc, MRCP Medical Oncologist, Edinburgh Cancer Centre, Western General Hospital, NHS Lothian, Edinburgh, UK
- 14. CONTRIBUTORS xiii RobbyM Steel MA, MD, FRCPsych Consultant Liaison Psychiatrist and Honorary (Clinical) Senior Lecturer in Psychiatry, Department of Psychological Medicine, Royal Inrmary of Edinburgh, Edinburgh, UK Grant D Stewart BSc, MBChB, PhD Edin, MA Cantab, FRCSE (Urol) Professor of Surgical Oncology, Department of Surgery, University of Cambridge, Cambridge, and Honorary Consultant Urological Surgeon, Addenbrooke’s Hospital, Cambridge, UK David R Sullivan MBBS, FRACP, FRCPA, FCSANZ Head of Department, Department of Chemical Pathology, NSW Health Pathology, Sydney, NSW, Australia Shyam Sundar MD, FRCP, FAMS, FASc, FNA Distinguished Professor, Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India Victoria R Tallentire MBChB, MD, FRCP Consultant Acute Physician and Associate Postgraduate Dean, Medical Directorate, NHS Education for Scotland, Edinburgh, UK Katrina Tatton-Brown BM BCh, BA, MD Professor of Clinical Genetics and Genomic Education and Consultant in Clinical Genetics, South West Thames Regional Genetics Service, St George’s University Hospitals NHS Foundation Trust, London, UK Simon HL Thomas BSc, MD, FRCP, FRCPE, FEAPCCT, FACCT Professor of Clinical Pharmacology and Therapeutics, Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK Henry G Watson MD, FRCP, FRCPath Consultant Haematologist and Honorary Professor of Medicine, Department of Haematology, Aberdeen Royal Inrmary, Aberdeen, UK Julian White MD, FACTM Clinical Toxinologist and Head of Toxinology, Toxinology Department and University of Adelaide Department of Paediatrics, Women’s & Children’s Hospital, North Adelaide, SA, Australia William Whiteley BA, BM BCh, MSc, PhD, FRCP Reader in Neurology, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK; Senior Research Fellow, Nufeld Department of Population Health, University of Oxford, Oxford, UK Michael J Williams BM BCh, PhD Consultant Hepatologist, Scottish Liver Transplant Unit, Royal Inrmary of Edinburgh, Edinburgh, UK Rebecca Woodeld MA, MB BChir, MRCP, PhD Consultant Geriatrician and Stroke Physician, Department of Medicine for the Elderly, Western General Hospital, Edinburgh, UK
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- 16. International Advisory Board ABMAbdullah MRCP(UK), FRCPE UGC Professor, Department of Medicine, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh Amitesh Aggarwal MD, FRCPE, FACP(USA), FRCPG, FICP, FIACM, FIMSA, FISE, FIAMS, FUPDA, FGSI, FISH, FRSSDI Professor, Department of Medicine, University College of Medical Sciences (University of Delhi) and GTB Hospital, Delhi, India Matthew A Brown MBBS, MD, FRACP, FAHMS, FAA Director, Guy’s and St Thomas’ NHS Foundation Trust and King’s College London NIHR Biomedical Research Centre, King’s College London, London, UK Arnold N Cohen MD, FACP, FACG, AGAF Professor of Medicine, Department of Medical Education and Science, Elson S. Floyd College of Medicine of Washington State University; Associate Clinical Professor of Medicine Emeritus, University of Washington School of Medicine, Spokane, Washington, USA Mradul Kumar Daga MD, FRCP, FCCP Professor of Medicine and In-Charge Medical ICU, Department of Internal Medicine, Maulana Azad Medical College, New Delhi, India D Dalus MD, PhD, FRCP, FRCPE, FRCPG Professor of Medicine and Senior Consultant, Department of Internal Medicine, Cosmopolitan Hospitals, Trivandrum, Kerala, India Sydney C Dsouza MD Professor and Head, Department of Internal Medicine, Yenepoya Medical College, Mangaluru, Karnataka, India Tarun K Dutta MBBS, MD Emeritus Professor, Department of General Medicine, Mahatma Gandhi Medical College and Research Institute, Puducherry, India M Abul Faiz MBBS, FCPS, PhD Professor of Medicine (Retired), Department of Medicine, Sir Salimullah Medical College and Dev Care Foundation, Dhaka, Bangladesh Albert G Frauman MD, FRACP, FACP, FACCP, FBPhS Professor of Clinical Pharmacology and Therapeutics, The University of Melbourne; Director, Department of Clinical Pharmacology and Therapeutics, Austin Health, Victoria, Australia Sujoy Ghosh MD, DM, FRCP, FRCPE, FRCPG, FACE Professor, Department of Endocrinology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India Hadi Goubran MBBCh, MSc, MD, FACP, FRCPE Professor, Division of Hematology and Oncology, Saskatoon Cancer Centre and College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada Rajiva Gupta MD, MRCP, FRCP Vice Chairman and Head, Department of Rheumatology and Clinical Immunology, Medanta The Medicity, Gurgaon, India Quazi T Islam FCPS, FRCP, FRCPE, MACP Professor of Medicine, Department of Medicine, Popular Medical College, Dhaka, Bangladesh Saroj Jayasinghe MBBS, MD, MRCP(UK), PhD, FRCP, FCCP, FNASSL Consultant Physician and former Chair Professor of Medicine, Department of Clinical Medicine, University of Colombo, Colombo, Sri Lanka AL Kakrani MD, FICP Professor of Clinical Eminence and Director of Academic Collaborations, Department of Medicine, Dr. D.Y. Patil Medical College, Hospital and Research Centre, Pune, Maharashtra, India Vasantha Kamath MD, FICP Senior Professor in Internal Medicine, Department of Internal Medicine, MVJ Medical College and Research Hospital, Hoskote, Bangalore, Karnataka, India Ammar F Mubaidin MD, FRCPE, FRCPG Professor of Clinical Neurology, Department of Neurology, Al Khalidi Medical Centre, Amman, Jordan Milind Y Nadkar MD, FICP, FACP Additional Dean (Academic) and Professor and Head, Department of Medicine and Rheumatology Services, Seth G S Medical College and KEM Hospital, Mumbai, Maharashtra, India Viswanathan Neelakantan MBBS, DNB, FRCPG, FRCP, FACP, AB Senior Professor of Medicine and Consultant in Tropical Medicine, Department of Internal Medicine, Sri Manakula Vinayagar Medical College Hospital, Puducherry, India Matthew Ng FRCP, FRCPE Honorary Clinical Professor, Department of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong
- 17. xvi INTERNATIONALADVISORY BOARD Ami Prakashvir Parikh MD Professor and Head, Department of Medicine, Smt. NHL Municipal Medical College and SVP Hospital, Ahmedabad, Gujarat, India Medha Y Rao MBBS, MD, PGDHHM Senior Professor of Internal Medicine and Principal and Dean, Department of General Medicine, M.S. Ramaiah Medical College, Bangalore, Karnataka, India NR Rau MD, FICP Consultant Physician, Anugraha Medical Center, Udupi, Karnataka, India; Consultant Physician and Head, Department of Internal Medicine, Adarsh Hospital, Udupi, Karnataka, India; Former Professor and Head, Department of Medicine, Kasturba Medical College, Manipal, India Jacek Rozanski MD, PhD Professor of Medicine, Department of Nephrology, Transplantology, and Internal Medicine, Pomeranian Medical University, Szczecin, Poland Sarkar Nirmalendu MD Honorary Professor, Department of General Medicine, Ramakrishna Mission Sevapratishthan and Vivekananda Institute of Medical Sciences, Kolkata, West Bengal, India Surendra K Sharma MD (Internal Medicine), PhD Adjunct Professor, Department of Molecular Medicine, Jamia Hamdard Institute of Molecular Medicine, Hamdard University, Hamdard Nagar, Delhi, India Arvind K Vaish MD, FICP Professor and Head, Department of Medicine, Hind Institute of Medical Sciences; Former Professor and Head of Medicine, King George’s Medical University, Lucknow, India Josanne Vassallo MD, PhD, FRCP, FACP, FACE Professor and Consultant Endocrinologist, Department of Medicine, Division of Endocrinology, University of Malta Medical School, Msida, Malta Special Content Advisor for the Indian National Medical Commission undergraduate curriculum Professor Dilip R Karnad MD, FRCPG, FACP Senior Consultant in Critical Care, Jupiter Hospital, Thane, India
- 18. Acknowledgements The editors wouldlike to acknowledge and offer grateful thanks for the input of all previous editions’ contributors, without whom this new edition would not have been possible. In particular we are indebted to those former authors who step down with the arrival of this new edition. They include Quentin M Anstee, Leslie Burnett, Mark Byers, Graham G Dark, Richard J Davenport, Emad El-Omar, David R FitzPatrick, J Alastair Innes, David EJ Jones, Peter Langhorne, John Paul Leach, Sara E Marshall, Rory J McCrimmon, Mairi H McLean, Ewan R Pearson, Peter T Reid, Gordon R Scott, Peter Stewart, John PH Wilding and Miles D Witham. We are grateful to members of the International Advisory Board, all of whom provided detailed suggestions that have improved the book. Several members have now retired from the Board and we are grate- ful for their support during the preparation of previous editions. They include Ragavendra Bhat, Khalid I Bzeizi, Piotr Kuna, Pravin Manga, Moffat Nyirenda, Tommy Olsson, KR Sethuraman, Ibrahim Sherif, Ian J Simpson, SG Siva Chidambaram and Josanne Vassallo. We are equally grateful to new members of our International Advisory Board, who have given us valuable advice as we prepared this new edition, including ABM Abdullah, Quazi T Islam, Viswanathan Neelakantan and Jacek Rozanski. We would like to extend special thanks to Professor Dilip Karnad, Jupiter Hospital, Thane, India, who thoroughly reviewed all chapters of this 24th edition in draft form, to help ensure the coverage of this edition is more relevant than ever to our large readership in India, Pakistan and Bangladesh. He provided invaluable advice to the editorial team dur- ing preparation of the 24th edition and exhaustive feedback on how the content aligns with competencies in the current Indian National Medical Commission undergraduate curriculum. Readers of the International Edition of this book can now access a comprehensive Competency Mapping Guide with full page references for the rst time as a result of this thorough review. Detailed chapter reviews were commissioned to help plan this new edition and we are grateful to all those who assisted, including Professor Rustam Al-Shahi, Dr Daniel Beckett, Dr Helen Cohen, Dr Ian Edmond, Dr David Enoch, Professor Tonks Fawcett, Dr Colin Forfar, Professor Richard Gilson, Dr Helena Gleeson, Dr Peter Hall, Dr Greg Heath, Dr Richard Herriot, Dr Robert Lindsay, Dr Catherine Nelson-Piercy and Dr Alex Rowe. The Editors and Publisher would like to thank all those who have pro- vided valuable feedback on this textbook and whose comments have helped shape this new edition. We would particularly like to extend our thanks to the many readers who contact us with suggestions for improvements. This input has been invaluable and is much appreciated; we regret the names are too numerous to mention individually. The authors of Chapter 20 would like to thank Dr Drew Henderson, who reviewed the ‘Diabetic nephropathy’ section, and we are indebted to Dr Ruth Darbyshire for assistance with the Ophthalmology multiple choice questions to accompany Chapter 30. Two short sections in Chapter 3 on array comparative genomic hybridisation and single-molecule sequencing are adapted from Dr K Tatton-Brown’s Massive Open Online Course for FutureLearn. We would like to thank the Open University and St George’s, University of London, for permission to use this material. We are especially grateful to Laurence Hunter and Wendy Lee from Elsevier for their endless support and expertise in the shaping, collation and publication of Davidson’s over many years and who have now retired. We have thoroughly enjoyed working with a new team including Jeremy Bowes, Siân Jarman and Anne Collett who have seamlessly taken over the reins. We are delighted that Robert Britton continues to work on the book and illustrate it beautifully. We are proud of this new edition and are condent it will remain an essential and invaluable resource for readers the world over.
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- 20. Introduction The opening chaptersof the book, making up Part 1 on ‘Fundamentals of Medicine’, provide an account of the principles of genetics, immunol- ogy, infectious diseases and population health, oncology and pain man- agement, along with a discussion of the core principles behind clinical decision-making and good prescribing. Subsequent chapters in Part 2, ‘Emergency and Critical Care Medicine’, discuss medical emergencies in poisoning, envenomation and medicine in austere environments, while Chapter 9 explores common presentations in acute medicine, as well as the recognition and management of the critically ill. The third part, ‘Clinical Medicine’, is devoted to the major medical specialties. Each chapter has been written by experts in the eld to provide the level of detail expected of trainees in their discipline. To maintain the book’s virtue of being concise, care has been taken to avoid unnecessary duplication between chapters. The system-based chapters in Part 3 follow a standard format, begin- ning with an overview of the relevant aspects of clinical examination, followed by an account of functional anatomy, physiology and investi- gations, then the common presentations of disease, and details of the individual diseases and treatments relevant to that system. In chapters that describe the immunological, cellular and molecular basis of disease, this problem-based approach brings the close links between modern medical science and clinical practice into sharp focus. The methods used to present information are described below. Clinical examination overviews The value of good clinical skills is highlighted by a two-page overview of the important elements of the clinical examination at the beginning of most chapters. The left-hand page includes a mannikin to illustrate key steps in examination of the relevant system, beginning with simple observations and progressing in a logical sequence around the body. The right-hand page expands on selected themes and includes tips on examination technique and interpretation of physical signs. These over- views are intended to act as an aide-mémoire and not as a replacement for a detailed text on clinical examination, as provided in our sister title, Macleod’s Clinical Examination Presenting problems Medical students and junior doctors must not only assimilate a great many facts about various disorders, but also develop an analytical approach to formulating a differential diagnosis and a plan of investigation for patients who present with particular symptoms or signs. In Davidson’s this is addressed by incorporating a ‘Presenting Problems’ section into all rel- evant chapters. Nearly 250 presentations are included, which represent the most common reasons for referral to each medical specialty. Boxes Boxes are a popular way of presenting information and are particularly useful for revision. They are classied by the type of information they contain, using specic symbols. General Information These include causes, clinical features, investigations, treatments and other useful information. Practice Point There are many practical skills that students and doctors must master. These vary from inserting a nasogastric tube to reading an ECG or X-ray, or interpreting investigations such as arterial blood gases or thyroid func- tion tests. ‘Practice Point’ boxes provide straightforward guidance on how these and many other skills can be acquired and applied. Emergency These boxes describe the management of many of the most common emergencies in medicine. In Old Age Life expectancy is increasing in many countries and older people are the chief users of health care. While they contract the same diseases as those who are younger, there are often important differences in the way they present and how they are best managed. Chapter 34, ‘Ageing and disease’, concentrates on the principles of managing the frailest group, who suffer from multiple comorbidity and disability, and who tend to present with non-specic problems such as falls or delirium. Many older people, though, also suffer from specic single-organ pathology. ‘In Old Age’ boxes are thus included in each chapter and describe common presentations, implications of physiological changes of ageing, effects of age on investigations, problems of treatment in old age, and the benets and risks of intervention in older people. In Pregnancy Many conditions are different in the context of pregnancy, while some arise only during or shortly after pregnancy. Particular care must be taken with investigations (for example, to avoid radiation exposure to the fetus) and treatment (to avoid the use of drugs that harm the fetus). These issues are highlighted by ‘In Pregnancy’ boxes distributed throughout the book, which complement Chapter 32, ‘Maternal medicine’.
- 21. xx INTRODUCTION InAdolescence Although paediatric medicine is not covered in Davidson’s, many chronic disorders begin in childhood, and physicians who look after adults often contribute to multidisciplinary teams that manage young patients ‘in transition’ between paediatric and adult health-care services. This group of patients often presents a particular challenge, due to the physiological and psychological changes that occur in adolescence, and which can have a major impact on the disease and its management. Adolescents can be encouraged to take over responsibility from their parents/carers in managing their disease, but are naturally rebellious and often struggle to adhere to the impositions of chronic treatment. Chapter 33, ‘Adolescent and transition medicine’, highlights these issues, alongside the ‘In Adolescence’ boxes that appear in relevant chapters. Terminology The recommended International Non-proprietary Names (INNs) are used for all drugs, with the exception of adrenaline and noradrenaline. British spellings have been retained for drug classes and groups (e.g. amphet- amines not amfetamines). Units of measurement The International System of Units (SI units) is the recommended means of presentation for laboratory data and has been used throughout Davidson’s. We recognise, however, that many laboratories around the world continue to provide data in non-SI units, so these have been included in the text for the commonly measured analytes. Both SI and non-SI units are also given in Chapter 35, which describes the reference ranges used in laboratories in Edinburgh. It is important to appreciate that these reference ranges may vary from those used in other laboratories. Finding what you are looking for A contents list is given on the opening page of each chapter. In addi- tion, the book contains cross-references to help readers nd their way around, along with an extensive index. A list of up-to-date reviews and useful websites with links to management guidelines appears at the end of each chapter. Giving us your feedback The Editors and Publisher hope that you will nd this edition of Davidson’s informative and easy to use. We would be delighted to hear from you if you have any comments or suggestions to make for future editions of the book. Please contact us by e-mail at: [email protected]. All comments received will be much appreciated and will be considered by the editorial team.
- 22. Clinical decision-making 1 N Cooper ALCracknell Introduction 2 The problem of diagnostic error 2 Clinical reasoning: denitions 2 History and physical examination 2 Use and interpretation of diagnostic tests 3 Normal values 3 Factors other than disease that inuence test results 4 Operating characteristics 4 Sensitivity and specicity 4 Prevalence of disease 5 Dealing with uncertainty 5 Problem representation 5 Cognitive biases 6 Type 1 and type 2 thinking 6 Common cognitive biases in medicine 7 Thinking about thinking 7 Human factors 7 Shared decision-making 9 Patient-centred evidence-based medicine 9 Effective team communication 9 Using clinical prediction rules and other decision aids 9 Reducing errors in clinical decision-making 9 Deliberate practice 9 Cognitive debiasing strategies 9 Clinical decision-making: putting it all together 10 Answers to problems 11
- 23. 2 CLINICALDECISION-MAKING Introduction A great deal of knowledge and skill is required to practise as a doctor. Physicians in the 21st century need to have a comprehensive knowl- edge of basic and clinical sciences, have good communication skills, be able to perform procedures, work effectively in a team and demonstrate professional and ethical behaviour. But how doctors think, reason and make decisions is arguably their most critical skill. Knowledge is neces- sary, but not sufcient on its own for good performance and safe care. This chapter describes the principles of clinical decision-making, also known as ‘clinical reasoning’. The problem of diagnostic error It is estimated that diagnosis is wrong 10%–15% of the time in spe- cialties such as emergency medicine, internal medicine and general practice. Diagnostic error is associated with greater morbidity than other types of medical error, and the majority is considered to be preventable. For every diagnostic error there are usually several root causes. Studies identify three main categories, shown in Box 1.1. However, ‘human cog- nitive error’ appears to play a signicant role in the majority of diagnostic errors. Human cognitive error occurs when the clinician has all the information necessary to make the diagnosis, but then makes the wrong diagnosis. Why does this happen? Three main reasons have been identied: knowledge gaps misinterpretation of diagnostic tests cognitive biases. Examples of errors in these three categories are shown in Box 1.2. Clearly, clinical knowledge is required for sound clinical reasoning, and an incomplete knowledge base or inadequate experience can lead to diagnostic error. However, this chapter will focus on some other aspects of knowledge that are important for effective clinical reasoning, including use and interpretation of diagnostic tests, cognitive biases and human factors. Clinical reasoning: denitions ‘Clinical reasoning’ describes the thinking and decision-making processes associated with clinical practice. Our understanding of clinical reason- ing derives from the elds of education, cognitive psychology, studies of expertise and the diagnostic error and health systems literature. Clinical reasoning can be conceptualised as a process with different components, each requiring specic knowledge, skills and behaviours. The UK Clinical Reasoning in Medical Education group (see ‘Further information’) broadly lists these components as: history and physical examination use and interpretation of diagnostic tests problem identication and management shared decision-making. Not all of these components are necessary for effective clinical rea- soning and they do not necessarily happen in this order. They also occur in contexts that impact on decision-making, which will be explored later. Underpinning all of this is formal and experiential knowledge of basic sciences and clinical medicine. The knowledge required for effective clin- ical reasoning includes factual knowledge, but also conceptual knowl- edge (how things t together) as well as procedural knowledge (how to do something, what techniques to use) plus an awareness of and an ability to think about one’s own thinking (also known as metacogni- tive knowledge). This is where an understanding of cognitive biases and human factors is important. Fig. 1.1 shows the key components involved in clinical reasoning that will be explored further in this chapter. History and physical examination Even with major advances in medical technology, the history remains the most important part of the clinical decision-making process. Studies show that physicians make a diagnosis in 70%–90% of cases from the history alone. It is important to remember that the history is explored not only with the patient, but also (and with consent if required) from all available sources if necessary: for example, paramedic and emergency department notes, eye-witnesses, relatives and/or carers. However, clinicians need to be aware of the diagnostic usefulness of clinical features in the history and physical examination. For example, students are often taught that meningitis classically presents with the following features: headache fever meningism (photophobia, neck stiffness and other signs of menin- geal irritation, such as Kernig’s and Brudzinski’s signs). However, knowing the frequency with which patients present with certain features and the diagnostic weight of each feature are impor- tant in clinical decision-making. Many patients with meningitis do not 1.1 Root causes of diagnostic error in studies Error category Examples No fault Unusual presentation of a disease Missing information System error Inadequate diagnostic support Results not available Error-prone processes Poor supervision of inexperienced staff Poor team communication Human cognitive error Inadequate data-gathering Errors in reasoning Adapted from Graber M, Gordon R, Franklin N. Reducing diagnostic errors in medicine: what is the goal? Acad Med 2002; 77:981–992. 1.2 Reasons for errors in clinical reasoning Source of error Examples Knowledge gaps Telling a patient she cannot have biliary colic because she has had her gallbladder removed – gallstones can form in the bile ducts in patients who have had a cholecystectomy Misinterpretation of diagnostic tests Deciding a patient has not had a stroke because his brain scan is normal – computed tomography and even magnetic resonance imaging, especially when performed early, may not identify an infarct Cognitive biases Accepting a diagnosis handed over to you without question (the ‘framing effect’) instead of asking yourself ‘What is the evidence that supports this diagnosis?’
- 24. Use and interpretationof diagnostic tests 3 1 have classical signs of meningism and the clinical presentation varies among different patient populations and in different parts of the world. In one prospective study conducted in the United States, nearly all adult patients with meningitis had headache and a fever, but less than half had neck stiffness on examination and only 5% of patients had Kernig’s and Brudzinski’s signs. All three signs had a likelihood ratio of around 1, meaning their presence or absence was of little use in deciding whether a patient had meningitis or not (Fig. 1.2). Likelihood ratios (LR) are clinical diagnostic weights. An LR of greater than 1 increases the probability of disease (the higher the value, the greater the probability). Similarly, an LR of less than 1 decreases the probability of disease. LRs are developed against a diagnostic standard (in the case of meningitis, lumbar puncture results), so do not exist for all clinical ndings. LRs illustrate how an individual clinical nding changes the probability of a disease. For example, in a person presenting with headache and fever, the clinical nding of neck stiffness may carry little weight in deciding whether to perform a lumbar puncture because LRs do not determine the prior probability of disease; they reect only how a single clinical nding changes it. Clinicians have to take all the available information from the history and physical examination into account. If the overall clinical probability is high to begin with, a clinical nding with an LR of around 1 does not change this. ‘Evidence-based history and examination’ is a term used to describe how clinicians incorporate knowledge about the prevalence and diag- nostic weight of clinical ndings into their decision-making. In studies, students who are taught the probabilities of features being present in specic diseases rather than lists of features have better diagnostic accuracy. This is improved further by understanding the basic science explanation for symptoms and signs: bedside signs of meningism iden- tify patients with severe meningeal inammation but do not pick up those with early or mild inammation. Evidence-based history and examination is important because esti- mating the clinical (pre-test) probability is vital not only for diagnostic accuracy, but also in the use and interpretation of diagnostic tests. Use and interpretation of diagnostic tests There is no such thing as a perfect diagnostic test. Test results give us test probabilities, not real probabilities. Test results have to be interpreted because they are affected by the following: how ‘normal’ is dened factors other than disease operating characteristics sensitivity and specicity prevalence of disease in the population. Normal values Most tests provide quantitative results (i.e. a value on a continuous numerical scale). In order to classify quantitative results as normal or abnormal, it is necessary to dene a cut-off point. Many quantitative measurements in populations have a Gaussian or ‘normal’ distribution. By convention, the normal range is dened as those values that encom- pass 95% of the population, or 2 standard deviations above and below the mean. This means that 2.5% of the normal population will have values above, and 2.5% will have values below the normal range. For this reason, it is more appropriate to talk about the ‘reference range’ rather than the ‘normal range’ (Fig. 1.3). Test results in abnormal populations also have a Gaussian distribution, with a different mean and standard deviation. In some diseases there is no overlap between results from the abnormal and normal population. However, in many diseases there is overlap; in these circumstances, the greater the difference between the test result and the limits of the refer- ence range, the higher the chance that the person has the disease. However, there are also situations in medicine when ‘normal’ is abnor- mal and ‘abnormal’ is normal. For example, in the context of a severe asthma attack a ‘normal’ PaCO2 is abnormal and means the patient has life-threatening asthma. Conversely, a low ferritin in a young menstruating woman is not considered to be abnormal at all. Laboratory results (e.g. cholesterol, thyroid-stimulating hormone) also vary from day to day in the same person in the absence of a real change because of biological variation and laboratory variation. The extent to which a blood test is allowed to vary before it has truly changed is called Clinical reasoning (knowledge, skills and behaviours) History and physical examination Cognitive biases and human factors Thinking about thinking Shared decision-making Use and interpretation of diagnostic tests Problem representation Fig. 1.1 Elements of clinical reasoning. Change in probability of disease 10 Infinity Zero 5 2 1 0.5 0.2 0.1 + 45% + 30% + 15% Kernig’s sign Brudzinski’s sign Nuchal rigidity Increase probability LR Decrease probability – 15% – 30% – 45% Fig. 1.2 Likelihood ratio (LR) of Kernig’s sign, Brudzinski’s sign and nuchal rigidity in the clinical diagnosis of meningitis. LRs are also used for diagnostic tests; here a physical examination nding can be considered a diagnostic test. Data from Thomas KE, Hasbun R, Jekel J, et al. The diagnostic accuracy of Kernig’s sign, Brudzinski’s sign, and nuchal rigidity in adults with suspected meningitis. Clin Infect Dis 2002; 35:46–52. LR = probability of finding in patients with disease probab bility of finding in patients without disease
- 25. 4 CLINICALDECISION-MAKING the ‘critical difference’. The critical difference is different for each test, and can be high – 17% in the case of cholesterol and higher for some other tests. Factors other than disease that inuence test results A number of factors other than disease inuence test results: age ethnicity pregnancy sex spurious (in vitro) results. Box 1.3 gives some examples. Operating characteristics Tests are also subject to operating characteristics. This refers to the way the test is performed. Patients need to be able to comply fully with some tests, such as spirometry (p. 501), and if they cannot, the test result will be affected. Some tests are very dependent on the skill of the operator and are also affected by the patient's body habitus and clinical state; ultrasound of the heart and abdomen are examples. A common mistake is when doctors refer to a test result as ‘no abnor- mality detected’ when, in fact, the report describes a technically dif- cult and incomplete scan that should more accurately be described as ‘non-diagnostic’. Some conditions are paroxysmal. For example, around half of patients with epilepsy have a normal standard electroencephalogram (EEG). A normal EEG therefore does not exclude epilepsy. On the other hand, around 10% of patients who do not have epilepsy have epileptiform discharges on their EEG. This is referred to as an ‘incidental nding’. Incidental ndings are common in medicine, and are increasing in inci- dence with the greater availability of more sensitive tests. Test results should always be interpreted in the light of the patient’s history and phys- ical examination. Sensitivity and specicity Diagnostic tests have characteristics termed ‘sensitivity’ and ‘specicity’. Sensitivity is the ability to detect true positives; specicity is the ability to detect true negatives. Even a very good test, with 95% sensitivity, will miss 1 in 20 people with the disease. Every test therefore generates ‘false positives’ and ‘false negatives’ (Box 1.4). A very sensitive test will detect most disease but may generate abnor- mal ndings in healthy people. A negative result will therefore reliably exclude disease but a positive result does not mean the disease is pres- ent – it means further evaluation is required. On the other hand, a very specic test may miss signicant pathology but is likely to establish the diagnosis beyond doubt when the result is positive. All tests differ in their sensitivity and specicity, and clinicians require a working knowledge of the tests they use in order to accurately interpret them. In choosing how a test is used to guide decision-making there is a trade-off between sensitivity versus specicity. For example, dening an exercise electrocardiogram (p. 393) as abnormal if there is at least 0.5mm of ST depression would ensure that very few cases of coronary artery disease are missed but would generate many false-positive results (high sensitivity, low specicity). On the other hand, a cut-off point of 2.0mm of ST depression would detect most cases of important coronary artery disease with far fewer false positives. This trade-off is calculated using the receiver operating characteristic curve of the test (Fig. 1.4). An extremely important concept in clinical decision-making is this: the probability that a person has a disease depends on the pre-test proba- bility, and the sensitivity and specicity of the test. For example, imagine an older woman has fallen and hurt her left hip. On examination, the hip is extremely painful to move and she cannot stand. However, her hip X-rays are normal. Does she have a fracture? The sensitivity of plain X-rays of the hip performed in the emergency department for suspected hip fracture is around 95%. A small percent- age of fractures are therefore missed. If our patient has (or is at risk of) osteoporosis, has severe pain on hip movement and cannot bear weight on the affected side, then the clinical probability of hip fracture is high. If, on the other hand, she is unlikely to have osteoporosis, has no pain on Normal population Number of people having each value Abnormal populations Mean – 2SD Mean + 2SD Mean ‘Reference range’ Value Fig. 1.3 Normal distribution and reference range. For many tests, the frequency distribution of results in the normal healthy population (red line) is a symmetrical bell-shaped curve. The mean ±2 standard deviations (SD) encompasses 95% of the normal population and usually denes the ‘reference range’; 2.5% of the normal population have values above, and 2.5% below, this range (shaded areas). For some diseases (blue line), test results overlap with the normal population or even with the reference range. For other diseases (green line), tests may be more reliable because there is no overlap between the normal and abnormal population. 1.3 Examples of factors other than disease that inuence test results Factor Examples Age Creatinine is lower in old age (due to relatively lower muscle mass) – an older person can have a signicantly reduced eGFR with a ‘normal’ creatinine Ethnicity Healthy people of African ancestry have lower white cell counts Pregnancy Several tests are affected by late pregnancy, due to the effects of a growing fetus, including: Reduced urea and creatinine (haemodilution) Iron deciency anaemia (increased demand) Increased alkaline phosphatase (produced by the placenta) Raised D-dimer (physiological changes in the coagulation system) Mild respiratory alkalosis (physiological maternal hyperventilation) ECG changes (tachycardia, left axis deviation) Sex Males and females have different reference ranges for many tests, e.g. haemoglobin Spurious (in vitro) results A spurious high potassium is seen in haemolysis and in thrombocytosis (‘pseudohyperkalaemia’) (ECG = electrocardiogram; eGFR = estimated glomerular ltration rate, a better estimate of renal function than creatinine)
- 26. Problem representation 5 1 hip movement and is able to bear weight, then the clinical probability of hip fracture is low. Doctors are continually making judgements about whether something is true, given that something else is true. This is known as ‘conditional prob- ability’. Bayes’ Theorem (named after English clergyman Thomas Bayes, 1702–1761) is a mathematical way to describe the post-test probability of a disease by combining pre-test probability, sensitivity and specicity. In clinical practice, doctors are not able to make complex mathematical calculations for every decision they make. In practical terms, the answer to the question of whether there is a fracture is that in a high-probability patient a normal test result does not exclude it, but in a low-probability patient it (virtually) does. This principle is illustrated in Fig. 1.5 Sox and colleagues (see ‘Further information’) state a fundamental assertion, which they describe as a profound and subtle principle of clin- ical medicine: the interpretation of new information depends on what you believed beforehand. In other words, the interpretation of a test result depends on the probability of disease before the test. Prevalence of disease Consider this problem that was posed to a group of Harvard doctors. The problem originates from a 1978 article in the New England Journal of Medicine (Casscells et al, see ‘Further information’): if a test to detect a disease whose prevalence is 1:1000 has a false-positive rate of 5%, what is the chance that a person found to have a positive result actually has the disease, assuming you know nothing about the person’s symp- toms and signs? Assume the test generates no false negatives and take a moment to work this out. In this problem, we have removed clinical probability and are only considering prevalence. The answer is at the end of the chapter (p. 11). Predictive values combine sensitivity, specicity and prevalence. Sensitivity and specicity are characteristics of the test; the population does not change this. However, as doctors, we are interested in the question, ‘What is the probability that a person with a positive test actu- ally has the disease?’ This is illustrated in Box 1.5 Post-test probability and predictive values are different. Post-test probability is the probability of a disease after taking into account new information from a test result. Bayes’ Theorem can be used to calculate post-test probability for a patient in any population. The pre-test prob- ability of disease is decided by the doctor; it is a judgement based on information gathered prior to ordering the test. Predictive value is the proportion of patients with a test result who have the disease (or no disease) and is calculated from a table of results in a specic population (see Box 1.5). It is not possible to transfer this value to a different popula- tion. This is important to realise because published information about the performance of diagnostic tests may not apply to different populations. In deciding the pre-test probability of disease, clinicians often neglect to take prevalence into account and this distorts their estimate of proba- bility. To estimate the probability of disease in a patient more accurately, clinicians should anchor on the prevalence of disease in the subgroup to which the patient belongs and then adjust to take the individual factors into account. Dealing with uncertainty Clinical ndings are imperfect and diagnostic tests are imperfect. It is important to recognise that clinicians frequently deal with uncertainty. By expressing uncertainty as probability, new information from diagnostic tests can be incorporated more accurately. However, subjective estimates of probability can sometimes be unreliable. As the section on cognitive biases will demonstrate (see below), intuition can be a source of error. Knowing the patient’s true state is often unnecessary in clinical deci- sion-making. Sox and colleagues (see ‘Further information’) argue that there is a difference between knowing that a disease is present and act- ing as if it were present. The requirement for diagnostic certainty depends on the penalty for being wrong. Different situations require different levels of certainty before starting treatment. How we communicate uncertainty to patients will be discussed later in this chapter (see Fig. 1.9). The ‘treatment threshold’ combines factors such as the risks of the test, and the risks versus benets of treatment. The point at which the factors are all evenly weighed is the threshold. If a test or treatment for a disease is effective and low risk (e.g. giving antibiotics for a suspected urinary tract infection), then there is a lower threshold for going ahead. On the other hand, if a test or treatment is less effective or high risk (e.g. starting chemotherapy for a malignant brain tumour), then greater condence is required in the clinical diagnosis and potential benets of treatment rst. In principle, if a diagnostic test will not change the man- agement of the patient, then careful consideration should be given to whether it is necessary to do the test at all. In summary, test results shift our thinking, but rarely give a ‘yes’ or a ‘no’ answer in terms of a diagnosis. Sometimes tests shift the probability of disease by less than we realise. Pre-test probability is key, and this is derived from the history and physical examination, combined with a sound knowledge of medicine and an understanding of the prevalence of disease in the particular care setting or the population to which the patient belongs. Problem representation Many students are taught to formulate a differential diagnosis after the history, physical examination and initial test results, but the ability to accurately articulate a ‘problem representation’ (or problem list) rst and then construct a prioritised differential diagnosis based on this, including relevant ‘must-not-miss’ diagnoses, is a key step in the clinical reasoning process. A problem representation refers to how information about a problem is mentally organised. Studies show that expert clinicians spend far more time on dening a problem before trying to solve it compared with novices, and novices are more likely to be unsuccessful in solving 1.4 Sensitivity and specicity Disease No disease Positive test A (True positive) B (False positive) Negative test C (False negative) D (True negative) Sensitivity = A/(A+C) × 100 Specicity = D/(D+B) × 100 1.0 0.8 0.6 0.4 0.2 0.0 1.0 0.8 0.6 Specificity 0.4 0.2 0 Sensitivity Fig. 1.4 Receiver operating characteristic graph illustrating the trade-off between sensitivity and specicity for a given test. The curve is generated by ‘adjusting’ the cut-off values dening normal and abnormal results, calculating the effect on sensitivity and specicity and then plotting these against each other. The closer the curve lies to the top left-hand corner, the more useful the test. The red line illustrates a test with useful discriminant value and the green line illustrates a less useful, poorly discriminant test.
- 27. 6 CLINICALDECISION-MAKING a problem because they have not accurately represented the problem in the rst place. The ability to synthesise all the available information and encapsulate it into a problem representation using precise medical language is an important skill that helps to organise and retrieve knowl- edge from long-term memory relevant to the case and is associated with signicantly higher diagnostic accuracy, particularly in complex cases (Bordage, 1994; see ‘Further information’). Formulating a problem representation (e.g. a 30-year-old pregnant woman with acute left-sided pleuritic chest pain and breathlessness) or a problem list (e.g. persistent vomiting, hypokalaemia, acute kidney injury), not only helps to organise and retrieve knowledge relevant to the case which helps in diagnosis, it also helps to formulate an action plan while further information is being gathered when a diagnosis is not yet possible. Cognitive biases Advances in cognitive psychology in recent decades have demonstrated that human thinking and decision-making are prone to error. Cognitive biases are subconscious errors that lead to inaccurate judgement and illogical interpretation of information. They are prevalent in everyday life; as the famous saying goes, ‘to err is human’. Take a few moments to look at this simple puzzle. Do not try to solve it mathematically but listen to your intuition: A bat and ball cost £1.10. The bat costs £1 more than the ball. How much does the ball cost? The answer is at the end of the chapter. Most people get the answer to this puzzle wrong – even though they have all the knowledge and experience they need to solve this problem. Why? British psychologist and patient safety pioneer James Reason said that, ‘Our propensity for certain types of error is the price we pay for the brain’s remarkable ability to think and act intuitively – to sift quickly through the sensory information that constantly bombards us without wasting time trying to work through every situation anew.’ This property of human thinking is highly relevant to clinical decision-making. Type 1 and type 2 thinking Decades of studies in cognitive psychology and, more recently, func- tional magnetic resonance imaging demonstrate two distinct types of processes when it comes to decision-making: humans have a fast, intu- itive, pattern-recognising way of thinking which uses little cognitive effort (known as type 1 thinking) and a more deliberate, analytical one which engages our working memory (known as type 2 thinking). This is known as ‘dual process theory’ and Box 1.6 explains this in more detail. Psychologists estimate that we spend 95% of our daily lives engaged in type 1 thinking – the intuitive, fast, subconscious mode of decision-mak- ing. Imagine driving a car, for example: it would be impossible to function efciently if every decision and movement were as deliberate, conscious, slow and effortful as in our rst driving lesson. With experience, complex procedures become automatic, fast and effortless. The same applies to medical practice. There is evidence that expert decision-making is well served by intuitive thinking. The problem is that although intuitive process- ing is highly efcient in many circumstances, in others it is prone to error. Clinicians use both type 1 and type 2 thinking, and both types are important in clinical decision-making. When encountering a problem that is familiar, clinicians employ pattern recognition and reach a work- ing diagnosis or differential diagnosis quickly (type 1 thinking). When encountering a problem that is more complicated, they use a slower, systematic approach (type 2 thinking). Both types of thinking interplay – they are not mutually exclusive in the diagnostic process. Fig. 1.6 illus- trates the interplay between type 1 and type 2 thinking in clinical practice. Errors can occur in both type 1 and type 2 thinking. For example, people can apply the wrong rules or make errors in their application while using type 2 thinking. However, it has been argued that the common cognitive biases encountered in medicine tend to occur when clinicians are engaged in type 1 thinking. For example, imagine being asked to see a young woman who is drowsy. She is handed over to you as a ‘probable overdose’ because she has a history of depression and a packet of painkillers was found beside her at home. Her observations show she has a Glasgow Coma Scale score of 10/15, heart rate 100 beats/min, blood pressure 100/60mmHg, respiratory rate 14 breaths/min, oxygen saturations 98% on air and tem- perature 37.5°C. Already your mind has reached a working diagnosis. It ts a pattern (type 1 thinking). You think she has taken an overdose. At Patient A 90% chance of having the disease before the test is done 34.6% chance of having the disease if the test is negative 0 10 20 30 40 50 Percentage probability of having the disease 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100 98.3% chance of having the disease if the test is positive Patient B 50% chance of having the disease before the test is done 86.4% chance of having the disease if the test is positive 5.6% chance of having the disease if the test is negative Fig. 1.5 The interpretation of a test result depends on the probability of the disease before the test is carried out. In the example shown, the test being carried out has a sensitivity of 95% and a specicity of 85%. Patient A has very characteristic clinical ndings, which make the pre-test probability of the condition for which the test is being used very high – estimated as 90%. Patient B has more equivocal ndings, such that the pre-test probability is estimated as only 50%. If the result in Patient A is negative, there is still a signicant chance that he has the condition for which he is being tested; in Patient B, however, a negative result makes the diagnosis very unlikely. 1.5 Predictive values:‘What is the probability that a person with a positive test actually has the disease?’ Disease No disease Positive test A (True positive) B (False positive) Negative test C (False negative) D (True negative) Positive predictive value = A/(A+B) × 100 Negative predictive value = D/(D+C) × 100
- 28. Cognitive biases 7 1 this point you can stop to think about your thinking (rational override in Fig. 1.6): ‘What is the evidence for this diagnosis? What else could it be?’ On the other hand, imagine being asked to assess a patient who has been admitted with syncope. There are several different causes of syn- cope and a systematic approach is required to reach a diagnosis (type 2 thinking). However, you recently heard about a case of syncope due to a painless leaking abdominal aortic aneurysm. At the end of your assess- ment, following evidence-based guidelines, it is clear the patient can be discharged. Despite this, you decide to observe the patient overnight just in case (irrational override in Fig. 1.6). In this example, your intuition is actually ‘availability bias’ (when things are at the forefront of your mind) which has signicantly distorted your estimate of probability. Common cognitive biases in medicine Figure 1.7 illustrates the common cognitive biases prevalent in medical practice. Biases often work together; for example, in overcondence bias (the tendency to believe we know more than we actually do), too much faith is placed in opinion instead of gathered evidence. This bias can be augmented by the availability bias and nally by commission bias (the tendency towards action rather than inaction) – sometimes with disas- trous results. The mark of a well-calibrated thinker is the ability to recognise what mode of thinking is being employed and to anticipate and recognise situ- ations in which cognitive biases and errors are more likely to occur. Thinking about thinking Research has highlighted the importance of being aware of and being able to think about one’s own thinking (also known as metacognition). Several studies have demonstrated that engaging in reection during diagnostic decision-making improves performance (Prakash et al, see ‘Further information’). This can be as simple as asking, ‘What is the evidence for this diagnosis? What else could it be?’ Reection is most effective when the case is more complex (relative to the clinician). Some people have a natural tendency to look for evidence, weigh things up, be aware of context, not take things at face value, and think about their own thinking. Others can learn to do so. Psychologists con- sider this ‘reective mind’ a subset of analytical type 2 thinking. The ten- dency to engage in reection during decision-making is independent of knowledge and cognitive ability, and accounts for the greatest variation in individual performance on many reasoning tasks. With increasing knowledge and experience, intuitive type 1 think- ing is used more; it is fast and highly accurate and commonly used by experts. Novices cannot do this because they have not yet built a database of patterns in their long-term memory, known as illness scripts. Reection interrupts type 1 processing, even briey, to sim- ulate alternatives. So as you can see, good decision-making relies on knowledge and experience, but also the ability to ‘stop and think’ when needed. However, this requires cognitive effort (type 2 thinking), which may be impaired by things like fatigue, interruptions and cog- nitive overload. Human factors ‘Human factors’ is the science of the limitations of human performance, and how technology, the work environment and team communication can adapt for this to reduce diagnostic and other types of error. Analysis of serious adverse events in clinical practice shows that human factors and poor team communication play a signicant role when things go wrong. Research shows that many errors are beyond an individual’s con- scious control and are precipitated by many factors. The discipline of human factors seeks to understand interactions between: people and tasks or technology people and their work environment people in a team. 1.6 Type 1 and type 2 thinking Type 1 Type 2 Intuitive, heuristic (pattern recognition) Analytical, systematic Automatic, subconscious Deliberate, conscious Fast, effortless Slow, effortful Low/variable reliability High/consistent reliability Vulnerable to error Less prone to error Highly affected by context Less affected by context High emotional involvement Low emotional involvement Low scientic rigour High scientic rigour Experience Context Ambient conditions Education Training Logical competence Clinical presentation Recognised Not recognised Type 2 processes Type 1 processes Cognitive biases more likely Irrational override Rational override Working diagnosis Fig. 1.6 The interplay between type 1 and type 2 thinking in the diagnostic process. Adapted from Croskerry P. A universal model of diagnostic reasoning. Acad Med 2009; 84:1022–1028.
- 29. 8 CLINICALDECISION-MAKING An understanding of these interactions makes it easier for health-care professionals, who are committed to ‘rst, do no harm’, to work in the safest way possible. For example, performance is adversely affected by factors such as poorly designed processes and equipment, fatigue and poor com- munication. So simple, clear processes, good design of equipment and shift patterns, and clear team communication all help to minimise errors. The areas of the brain required for type 2 processing are most affected by things like fatigue and cognitive overload, and the brain reverts to type 1 processing to conserve cognitive energy. Figure 1.8 illustrates some of the internal and external factors that affect human judgement and decision-making. An awareness of the factors that impact on decision-making can allow clinicians to take steps to mitigate these. Anchoring The common human tendency to rely too heavily on the first piece of information offered (the ‘anchor’) when making decisions Diagnostic momentum Once a diagnostic label has been attached to a patient (by the patient or other health-care professionals), it can gather momentum with each review, leading others to exclude other possibilities in their thinking Premature closure The tendency to close the decision- making process prematurely and accept a diagnosis before it, and other possibilities, have been fully explored Ascertainment bias We sometimes see what we expect to see (‘self-fulfilling prophecy’). For example, a frequent self-harmer attends the emergency department with drowsiness; everyone assumes he has taken another overdose and misses a brain injury Psych-out error Psychiatric patients who present with medical problems are under- assessed, under-examined and under-investigated because problems are presumed to be due to, or exacerbated by, their psychiatric condition Framing effect How a case is presented – for example, in handover – can generate bias in the listener. This can be mitigated by always having ‘healthy scepticism’ about other people’s diagnoses Availability bias Things may be at the forefront of your mind because you have seen several cases recently or have been studying that condition in particular. For example, when one of the authors worked in an epilepsy clinic, all blackouts were possible seizures Hindsight bias Knowing the outcome may profoundly influence the perception of past events and decision-making, preventing a realistic appraisal of what actually occurred – a major problem in learning from diagnostic error Search satisficing We may stop searching because we have found something that fits or is convenient, instead of systematically looking for the best alternative, which involves more effort Base rate neglect The tendency to ignore the prevalence of a disease, which then distorts Bayesian reasoning. In some cases, clinicians do this deliberately in order to rule out an unlikely but worst-case scenario Omission bias The tendency towards inaction, rooted in the principle of ‘first, do no harm.’ Events that occur through natural progression of disease are more acceptable than those that may be attributed directly to the action of the health-care team Triage-cueing Triage ensures patients are sent to the right department. However, this leads to ‘geography is destiny’. For example, a diabetic ketoacidosis patient with abdominal pain and vomiting is sent to surgery. The wrong location (surgical ward) stops people thinking about medical causes of abdominal pain and vomiting Commission bias The tendency towards action rather than inaction, on the assumption that good can come only from doing something (rather than ‘watching and waiting’) Overconfidence bias The tendency to believe we know more than we actually do, placing too much faith in opinion instead of gathered evidence Unpacking principle Failure to ‘unpack’ all the available information may mean things are missed. For example, if a thorough history is not obtained from either the patient or carers (a common problem in geriatric medicine), diagnostic possibilities may be discounted Confirmation bias The tendency to look for confirming evidence to support a theory rather than looking for disconfirming evidence to refute it, even if the latter is clearly present. Confirmation bias is common when a patient has been seen first by another doctor Posterior probability Our estimate of the likelihood of disease may be unduly influenced by what has gone on before for a particular patient. For example, a patient who has been extensively investigated for headaches presents with a severe headache, and serious causes are discounted Visceral bias The influence of either negative or positive feelings towards patients, which can affect our decision- making Fig. 1.7 Common cognitive biases in medicine. Adapted from Croskerry P. Achieving quality in clinical decision-making: cognitive strategies and detection of bias. Acad Emerg Med 2002; 9:1184–1204.
- 30. 1 Reducing errors inclinical decision-making 9 Several studies demonstrate that we focus our attention to lter out distractions. This is advantageous in many situations (for example, when performing a procedure), but in focusing on what we are trying to see we may not notice the unexpected. In a team context, what is obvious to one person may be completely missed by someone else. Safe and effec- tive team communication therefore requires us never to assume, and to verbalise things, even though they may seem ‘obvious’. Shared decision-making Shared decision-making refers to the fact that clinical reasoning does not necessarily take place solely within a clinician’s head. Good deci- sion-making is often shared with patients, relatives and carers, within teams, and by using guidelines, clinical prediction rules and other decision aids. Integral to all of this is the ability to engage in optimal decision-making behaviours: involving the patient and/or carers in the diagnostic and management process, listening to others, following evi- dence-based guidelines, asking for help when needed, and using clear communication, especially when handing over care. Patient-centred evidence-based medicine ‘Patient-centred evidence-based medicine’ refers to the application of best available research evidence while taking individual patient factors into account; these include both clinical and non-clinical factors (e.g. the patient’s social circumstances, values and wishes). For example, a 95-year-old man with dementia and a recent gastrointestinal bleed is admitted with an inferior myocardial infarction. He is clinically well. Should he be treated with dual antiplatelet therapy and low-molecular-weight heparin as recommended in clinical guidelines? As this chapter has described, clinicians frequently deal with uncer- tainty/probability. Clinicians need to be able to explain risks and benets of treatment in an accurate and understandable way. Providing the rel- evant statistics is seldom sufcient to guide decision-making because a patient’s perception of risk may be inuenced by irrational factors as well as individual values. Research evidence provides statistics but these can be confusing. Terms such as ‘common’ and ‘rare’ are nebulous. Whenever possible, clinicians should quote numerical information using consistent denomi- nators (e.g. ‘90 out of 100 patients who have this operation feel much better, 1 will die during the operation and 2 will suffer a stroke’). Visual aids can be used to present complex statistical information (Fig. 1.9). How uncertainty is conveyed to patients is important. Many studies demonstrate a correlation between effective clinician–patient communi- cation and improved health outcomes. If patients feel they have been listened to and understand the problem and proposed treatment plan, they are more likely to follow the plan and less likely to re-attend. Effective team communication In increasingly complex health-care systems, patients are looked after by a wide variety of professionals, each of whom has access to important information required to make clinical decisions. Strict hierarchies are haz- ardous to patient safety if certain members of the team do not feel able to speak up. The SBAR system of communication has been recommended by the UK’s Patient Safety First campaign. It is a structured way to communicate about a patient with another health-care professional (e.g. during handover or when making a referral) and increases the amount of relevant informa- tion being communicated in a shorter time. It is illustrated in Box 1.7 Using clinical prediction rules and other decision aids A clinical prediction rule is a statistical model of the diagnostic process. When clinical prediction rules are matched against the opinion of experts, the model usually outperforms the experts, because it is applied con- sistently in each case. However, it is important that clinical prediction rules are used correctly – that is, applied to the patient population that was used to create the rule. Clinical prediction rules force a scientic assessment of the patient’s symptoms, signs and other data to develop a numerical probability of a disease or an outcome. They help clinicians to estimate probability more accurately. A good example of a clinical prediction rule to estimate pre-test prob- ability is the Wells score in suspected deep vein thrombosis (see Box 9.18). Other commonly used clinical prediction rules predict outcomes and therefore guide the management plan. These include the GRACE score in acute coronary syndromes (see Fig. 16.61) and the CURB-65 score in community-acquired pneumonia (see Fig. 17.32). Reducing errors in clinical decision-making Deliberate practice Studies of expertise reveal that extensive experience is necessary to achieve high levels of performance, but extensive experience does not by itself lead to expert levels of achievement. Something else is required, encapsulated in the term ‘deliberate practice’. This involves effortful practice, coaching and feedback, and the ability of an individual to plan, assess, reect and adjust so their performance improves. Cognitive debiasing strategies Knowledge and experience alone, however, do not eliminate errors. There are some simple and established techniques that can be used to avoid cognitive biases and errors in clinical decision-making. History and physical examination Taking a history and performing a physical examination may seem obvious, but these are sometimes carried out inadequately. This is the ‘unpacking principle’: failure to unpack all the available information means things can be missed and lead to error. Error Type 1 thinking/ conservation of cognitive effort Cognitive and affective biases Internal factors Knowledge Training Beliefs and values Emotions Sleep/fatigue Stress Physical illness Personality type External factors Interruptions Cognitive overload Time pressure Ambient conditions Insufficient data Team factors Patient factors Poor feedback Fig. 1.8 Factors that affect our judgement and decision-making. (Type 1 thinking = fast, intuitive, subconscious, low effort)
- 31. 10 CLINICALDECISION-MAKING Problem representation/list and differential diagnosis Once all the available data from history, physical examination and (some- times) initial test results are available, these need to be synthesised into a problem representation or problem list. The process of generating a problem list ensures nothing is missed. The process of generating a differential diagnosis works against anchoring on a particular diagnosis too early, thereby avoiding search satiscing and premature closure (see Fig. 1.6). Mnemonics and checklists These are used frequently in medicine in order to reduce reliance on fallible human memory. ABCDE (airway, breathing, circulation, disability, exposure/examination) is probably the most successful checklist in med- icine, used during the assessment and treatment of critically ill patients (ABCDE is sometimes prexed with ‘C’ for ‘control of any obvious prob- lem’; see p. 191). Checklists ensure that important issues have been considered and completed, especially under conditions of complexity, stress or fatigue. Red ags and ROWS (‘rule out worst-case scenario’) These are strategies that force doctors to consider serious diseases that can present with common symptoms. Red ags in back pain are listed in Box 26.19. Considering and investigating for possible pulmonary embolism in patients who present with pleuritic chest pain and breath- lessness is a common example of ruling out a worst-case scenario, as pulmonary embolism can be fatal if missed. Red ags and ROWS help to avoid cognitive biases such as the ‘framing effect’ and ‘premature closure’. Newer strategies to avoid cognitive biases and errors in decision-mak- ing are emerging. These involve explicit training in clinical reasoning and human factors. In theory, if doctors are aware of the science of human thinking and decision-making, then they are more able to think about their thinking, understand situations in which their decision-making may be affected, and take steps to mitigate this. Clinical decision-making: putting it all together The following is a practical example that brings together many of the concepts outlined in this chapter: A 25-year-old woman presents with right-sided pleuritic chest pain and breathlessness. She reports that she had an upper respiratory tract infection a week ago and was almost back to normal when the symp- toms started. The patient has no past medical history and no family his- tory, and her only medication is the combined oral contraceptive pill. On examination, her vital signs are normal (respiratory rate 19 breaths/ min, oxygen saturations 98% on air, blood pressure 115/60mmHg, heart rate 90 beats/min, temperature 37.5°C) and the physical examination is also normal. You have been asked to assess her for the possibility of a pulmonary embolism. (More information on pulmonary embolism can be found in Chapter 17.) Evidence-based history and examination Information from the history and physical examination is vital in deciding whether this could be a pulmonary embolism. Pleurisy and breathless- ness are common presenting features of this disease but are also com- mon presenting features in other diseases. There is nothing in the history to suggest an alternative diagnosis (e.g. high fever, productive cough, recent chest trauma). The patient’s vital signs are normal, as is the phys- ical examination. However, very few individual ndings help to distinguish patients with pulmonary embolism from those without it. The presence of wheeze and a high fever modestly decrease the probability of pulmonary embolism. The presence of hypoxaemia is unhelpful (likelihood ratio not signicant). Deciding pre-test probability The prevalence of pulmonary embolism (PE) in 25-year-old women is low. We anchor on this prevalence and then adjust for individual patient factors. This patient has no major risk factors for pulmonary embolism. To assist our estimate of pre-test probability, we could use a clinical 1.7 The SBAR system of communicating SBAR Example (a telephone call to the Intensive Care team) Situation I am [name] calling from [place] about a patient with a NEWS* of 10. Background [Patient’s name], 30-year-old woman, no past medical history, was admitted last night with community-acquired pneumonia. Since then her oxygen requirements have been steadily increasing. Assessment Her vital signs are: blood pressure 115/60mmHg, heart rate 120 beats/ min, temperature 38°C, respiratory rate 32 breaths/min, oxygen saturations 89% on 15L via reservoir bag mask. An arterial blood gas shows H+ 50nmol/L (pH 7.3), PaCO2 4.0kPa (30mmHg), PaO2 7kPa (52.5mmHg), standard bicarbonate 14mmol/L. Chest X-ray shows extensive right lower zone consolidation. Recommendation Please can you come and see her as soon as possible? I think she needs admission to Intensive Care. *NEWS = National Early Warning Score; a patient with normal vital signs scores 0. See Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the assessment of acute-illness severity in the NHS. Updated report of a working party. London: RCP; December 2017. Feel better No difference Stroke Dead Fig. 1.9 Visual portrayal of benets and risks. The image refers to an operation that is expected to relieve symptoms in 90% of patients, but cause stroke in 2% and death in 1%. From Edwards A, Elwyn G, Mulley A. Explaining risks: turning numerical data into meaningful pictures. BMJ 2002; 324:827–830, reproduced with permission from the BMJ Publishing Group.
- 32. Further information 11 1 prediction rule: in this case, the modied Wells score for pulmonary embolism, which would give a score of 3 (low probability – answering yes only to the criterion ‘PE is the number one diagnosis, an alternative is less likely’). Interpreting test results Imagine the patient went on to have a normal chest X-ray and blood results, apart from a raised D-dimer of 900 (normal <500ng/mL). A nor- mal chest X-ray is a common nding in pulmonary embolism. Several studies have shown that the D-dimer assay has at least 95% sensitivity in acute pulmonary embolism but it has a low specicity. A very sensitive test will detect most disease but generate abnormal ndings in healthy people. On the other hand, a negative result virtually, but not completely, excludes the disease. It is important at this point to realise that a raised D-dimer result does not mean this patient has a pulmonary embolism; it just means that we have not been able to exclude it. Since pulmonary embolism is a potentially fatal condition we need to rule out the worst- case scenario (ROWS), and the next step is therefore to arrange further imaging. What kind of imaging depends on individual patient character- istics and what is available. Treatment threshold The treatment threshold combines factors such as the risks of the test, and the risks versus benets of treatment. A CT pulmonary angiogram (CTPA) could be requested for this patient, although in some circum- stances ventilation–perfusion single-photon emission computed tomog- raphy (V/QSPECT, p. 547) may be a more suitable alternative. However, what if the scan cannot be performed until the next day? Because pul- monary embolism is potentially fatal and the risks of treatment in this case are low, the patient should be started on treatment while awaiting the scan. Post-test probability The patient’s scan result is subsequently reported as ‘no pulmonary embolism’. Combined with the low pre-test probability, this scan result reliably excludes pulmonary embolism. Cognitive biases Imagine during this case that the patient had been handed over to you as ‘nothing wrong – probably a pulled muscle’. Cognitive biases (sub- conscious tendencies to respond in a certain way) would come into play, such as the ‘framing effect’, ‘conrmation bias’ and ‘search satiscing’. The normal clinical examination might conrm the diagnosis of mus- culoskeletal pain in your mind, despite the examination being entirely consistent with pulmonary embolism and despite the lack of history and examination ndings (e.g. chest wall tenderness) to support the diagno- sis of musculoskeletal chest pain. Human factors Imagine that, after you have seen the patient, a colleague hands you some blood forms and asks you what tests you would like to request on ‘this lady’. You request blood tests including a D-dimer on the wrong patient. Luckily, this error is intercepted. Shared decision-making The diagnosis of pulmonary embolism can be difcult. Clinical prediction rules (e.g. modied Wells score), guidelines (e.g. from the UK’s National Institute for Health and Care Excellence, or NICE) and decision aids (e.g. simplied pulmonary embolism severity index, or PESI) are frequently used in combination with the doctor’s opinion, derived from information gathered in the history and physical examination. The patient is treated according to evidence-based guidelines that apply to her particular situation. Tests alone do not make a diagnosis and at the end of this process the patient is told that the combination of history, examination and test results mean she is extremely unlikely to have a pulmonary embolism. Viral pleurisy is offered as an alternative diagnosis and she is reassured that her symptoms are expected to settle over the coming days with analgesia. She is advised to re-present to hospital if her symptoms get worse. Answers to problems Harvard problem (p. 5) Almost half of doctors surveyed said 95%, but they neglected to take prevalence into account. If 1000 people are tested, there will be 51 pos- itive results: 50 false positives and 1 true positive (assuming 100% sen- sitivity). The chance that a person found to have a positive result actually has the disease is therefore only 1/51 or ~2%. Bat and ball problem (p. 6) This puzzle is from the book Thinking, Fast and Slow, by Nobel laureate Daniel Kahneman (see ‘Further information’). He writes, ‘A number came to your mind. The number, of course, is 10p. The distinctive mark of this easy puzzle is that it evokes an answer that is intuitive, appealing – and wrong. Do the math, and you will see.’ The correct answer is 5p. Further information Books and journal articles Bordage G. Elaborated knowledge: a key to successful diagnostic thinking. Acad Med 1994;69:883–885. Casscells W, Schoenberger A, Graboys TB. Interpretation by physicians of clinical laboratory results. N Engl J Med 1978;299:999–1001. Cooper N, Frain J, eds. ABC of clinical reasoning. Oxford: Wiley–Blackwell; 2016. Croskerry P. A universal model of diagnostic reasoning. Acad Med 2009;84:1022–1028. Kahneman D. Thinking, fast and slow. London: Penguin; 2012. McGee S. Evidence-based physical diagnosis, 4th edn. Philadelphia: Elsevier; 2018. Prakash S, Sladek RM, Schuwirth L. Interventions to improve diagnostic decision making: a systematic review and meta-analysis on reective strategies. Med Teacher 2019;41:517–524. Sox H, Higgins MC, Owens DK. Medical decision making, 2nd edn. Chichester: Wiley–Blackwell; 2013. Websites creme.org.uk UK Clinical Reasoning in Medical Education Group. improvediagnosis.org Society to Improve Diagnosis in Medicine (USA). chfg.org UK Clinical Human Factors Group. clinical-reasoning.org Clinical reasoning resources. vassarstats.net/index.html Suite of calculators for statistical computation (Calculator 2 is a calculator for predictive values and likelihood ratios) .
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- 34. Multiple Choice Questions 1.1.Which of the following best describes what is meant by the term ‘shared decision-making’? A. Allowing the patient to make decisions about his or her care B. Asking for help when needed C. Making decisions with the wider clinical team D. Patient-centred evidence-based medicine E. Sharing decision-making with the patient, relatives, clinical team, guidelines and decision aids Answer: E. Shared decision-making refers to the fact that clinical reasoning does not necessarily take place solely within a clinician’s head. Good deci- sion-making is often shared with patients, relatives and carers, within teams, and by using guidelines, clinical prediction rules and other decision aids. Integral to all of this is the ability to engage in optimal decision-making behaviours: involving the patient and/or carers in the diagnostic and management process, listening to others, following evi- dence-based guidelines, asking for help when needed, and using clear communication, especially when handing over care. 1.2. Which of the following best describes what is meant by the term ‘metacognitive knowledge’? A. An awareness of and an ability to think about one’s own thinking B. An understanding of how things t together C. An understanding of how to do something, what techniques to use D. The tendency to engage in deliberate practice E. The tendency to look for evidence, weigh things up and be aware of context Answer: A. Metacognition literally means ‘thinking about thinking’, ‘knowing about knowing’, and being ‘aware of one’s awareness’. Metacognitive knowledge is about being aware of one’s own cognitive processes and is a key ingredient for successful learning and the development of expertise. 1.3. When using a clinical prediction rule for a specic condition, which of the following is true? A. The tool can be applied to any patient with the condition B. The tool can determine the clinical probability that a patient has a disease C. The tool is not necessarily based on evidence D. The tool uses the receiver operating characteristic curve to statistically model the diagnostic process E. Use of the tool removes the need for clinical decision-making on the part of the clinician Answer: B. A clinical prediction rule is a statistical model of the diagnostic pro- cess. When clinical prediction rules are matched against the opinion of experts, the model usually outperforms the experts, because it is applied consistently in each case. However, it is important that clinical prediction rules are used correctly – that is, applied to the patient population that was used to create the rule. Clinical prediction rules force a scientic assessment of the patient’s symptoms, signs and other data to develop a numerical probability of a disease or an outcome. They help clinicians to estimate probability more accurately. A good example of a clinical prediction rule to estimate pre-test probability is the Wells score in sus- pected deep vein thrombosis. 1.4. Regarding normal values, which of the following statements is true? A. A normal result means that disease is not present B. A normal result specic to a particular disease is not found in a person with the disease C. Normal values do not vary signicantly within the same person D. Normal values follow a Poisson distribution E. One in 20 healthy people will have values that lie outside the reference range Answer: E. Most tests provide quantitative results on a continuous numerical scale. In order to classify quantitative results as normal or abnormal, it is necessary to dene a cut-off point. Many quantitative measurements in populations have a Gaussian or ‘normal’ distribution. By convention, the normal (reference) range is dened as those values that encompass 95% of the population, or 2 standard deviations above and below the mean. This means that 2.5% of the normal population will have values above, and 2.5% will have values below the normal range. In some diseases there is no overlap between results from the abnormal and normal pop- ulation. However, in many diseases there is overlap. So a healthy person can have an ‘abnormal’ result, and a person with disease can have a ‘normal’ result. Normal values also vary from day to day in the same per- son in the absence of a real change because of biological variation and laboratory variation. The extent to which a blood test is allowed to vary before it has truly changed is called the ‘critical difference’. 1.5. An 80-year-old man presented with a fall on a background of a 2-week history of his legs ‘giving way’ and a history of increasing low back pain. In this scenario, which of the following strategies to reduce errors in clinical reasoning would be most appropriate? A. An assessment of his mobility B. An X-ray of the lumbar spine C. Generating a problem representation D. Use of a clinical prediction rule E. Using red ags and ‘ROWS’ (rule out worst-case scenario) Answer: E. Various strategies can be used to reduce errors in clinical reasoning including: taking a proper history and performing a thorough physical examination, generating a problem representation, and using mnemon- ics and checklists. Using red ags and ROWS (rule out worst-case scenario) forces clinicians to think about serious diseases that can present with common symptoms. In this example, it forces clinicians to consider the possibility of cord compression. Red ags and ROWS helps to avoid cognitive biases such as the ‘framing effect’ and ‘pre- mature closure’.
- 35. Clinical therapeutics and goodprescribing Principles of clinical pharmacology 13 Pharmacodynamics 13 Pharmacokinetics 16 Inter-individual variation in drug responses 19 Adverse outcomes of drug therapy 19 Adverse drug reactions 19 Drug interactions 23 Medication errors 24 Drug regulation and management 25 Drug development and marketing 25 Managing the use of medicines 27 Prescribing in practice 28 Decision-making in prescribing 28 Prescribing in special circumstances 31 Writing prescriptions 32 Monitoring drug therapy 35 2 SRJ Maxwell
- 36. 14 CLINICALTHERAPEUTICS AND GOOD PRESCRIBING Prescribing medicines is the major tool used by doctors to restore or preserve the health of patients. Medicines contain drugs (the specic chemical substances with pharmacological effects), either alone or in combination with additional drugs, in a formulation mixed with other ingredients. The benecial effects of medicines must be weighed against their cost and potential adverse drug reactions and interactions. The lat- ter two factors are sometimes caused by injudicious prescribing deci- sions and by prescribing errors. The modern prescriber must meet the challenges posed by the increasing number of drugs and formulations available, of indications for prescribing them and the greater complexity of treatment regimens followed by individual patients (‘polypharmacy’, a particular challenge in the ageing population). The purpose of this chap- ter is to elaborate on the principles and practice that underpin good pre- scribing (Box 2.1). at a particular subtype of receptor to exhibit some effect at other subtypes. For example, β-adrenoceptors can be subtyped on the basis of their responsiveness to the endogenous agonist noradren- aline (norepinephrine): the concentration of noradrenaline required to cause bronchodilatation (via β2 -adrenoceptors) is 10 times higher than that required to cause tachycardia (via β1 -adrenoceptors). ‘Cardioselective’ β-adrenoceptor antagonists (β-blockers) have anti-anginal effects on the heart (β1 ), but may still cause broncho- spasm in the lung (β2 ) and are contraindicated for asthmatic patients. Agonists bind to a receptor to produce a conformational change that is coupled to a biological response. As agonist concentration increases, so does the proportion of receptors occupied, and hence the biological effect. Partial agonists activate the receptor, but can- not produce a maximal signalling effect equivalent to that of a full agonist even when all available receptors are occupied. Antagonists bind to a receptor, but do not produce the confor- mational change that initiates an intracellular signal. A competitive antagonist competes with endogenous agonist ligands to occupy receptor-binding sites, with the resulting antagonism depending on the relative afnities and concentrations of the antagonist drug and endogenous agonist. Non-competitive antagonists inhibit the effect of an agonist by mechanisms other than direct competition for receptor binding with the agonist (e.g. by affecting post-receptor signalling). Dose–response relationships Plotting the logarithm of drug dose against drug response typically pro- duces a sigmoidal dose–response curve (Fig. 2.2). Progressive increases in drug dose (which, for most drugs, is proportional to the plasma drug concentration) produce increasing response, but only within a relatively narrow range of dose; further increases in dose beyond this range pro- duce little extra effect. The following characteristics of the drug response are useful in comparing different drugs: Efcacy describes the extent to which a drug can produce a tar- get-specic response when all available receptors or binding sites are occupied (i.e. Emax on the dose–response curve). A full agonist can produce the maximum response of which the receptor is capa- ble, while a partial agonist at the same receptor will have lower efcacy. Therapeutic efcacy describes the effect of the drug on a desired biological endpoint and can be used to compare drugs that act via different pharmacological mechanisms (e.g. loop diuretics 2.1 Steps in good prescribing Make a diagnosis Consider factors that might inuence the patient’s response to therapy (age, concomitant drug therapy, renal and liver function etc.) Establish the therapeutic goal* Choose the therapeutic approach* Choose the drug and its formulation (the ‘medicine’) Choose the dose, route and frequency Choose the duration of therapy Write an unambiguous prescription (or ‘medication order’) Inform the patient about the treatment and its likely effects Monitor treatment effects, both benecial and harmful Review/alter the prescription *These steps in particular take the patient’s views into consideration to establish a therapeutic partnership that aims to achieve ‘concordance’ based on shared decision-making Dosage regimen Plasma concentration Concentration at the site of action Pharmacological effects Pharmacokinetics ‘what the body does to a drug’ Monitoring Measure plasma drug concentration ‘what a drug does to the body’ Monitoring Measure clinical effects Time Concentration Pharmacodynamics Concentration Effect Fig. 2.1 Pharmacokinetics and pharmacodynamics. Principles of clinical pharmacology Prescribers need to understand what the drug does to the body (phar- macodynamics) and what the body does to the drug (pharmacokinetics) (Fig. 2.1). Although this chapter is focused on the most common drugs, which are synthetic small molecules, the same principles apply to the increasingly numerous ‘biologic’ therapies (sometimes abbreviated to ‘biologics’) now in use, which include peptides, proteins, enzymes and monoclonal antibodies. Pharmacodynamics Drug targets and mechanisms of action Modern drugs are usually discovered by screening compounds for activ- ity either to stimulate or to block the function of a specic molecular tar- get, which is predicted to have a benecial effect in a particular disease (Box 2.2). Other drugs have useful but less selective chemical properties, such as chelators (e.g. for treatment of iron or copper overload), osmotic agents (used as diuretics in cerebral oedema) or general anaesthetics (that alter the biophysical properties of lipid membranes). The following characteristics of the interaction of drugs with receptors illustrate some of the important determinants of the effects of drugs: Afnity describes the propensity for a drug to bind to a receptor and is related to the ‘molecular t’ and the strength of the chemi- cal bond. Some drug–receptor interactions are irreversible, either because the afnity is so strong or because the drug modies the structure of its molecular target. Selectivity describes the propensity for a drug to bind to one target rather than another. Selectivity is a relative term, not to be con- fused with absolute specicity. It is common for drugs targeted
- 37. Principles of clinicalpharmacology 15 2 2.2 Examples of target molecules for drugs Drug target Description Examples Receptors Channel-linked receptors Ligand binding controls a linked ion channel, known as ‘ligand- gated’ (in contrast to ‘voltage-gated’ channels that respond to changes in membrane potential) Nicotinic acetylcholine receptor GABA receptor Sulphonylurea receptor G-protein-coupled receptors (GPCRs) Ligand binding affects one of a family of ‘G-proteins’ that mediate signal transduction either by activating intracellular enzymes (such as adenylate or guanylate cyclase, producing cyclic AMP or GMP, respectively) or by controlling ion channels Muscarinic acetylcholine receptor β-adrenoceptors Dopamine receptors 5-Hydroxytryptamine (5-HT, serotonin) receptors Opioid receptors Kinase-linked receptors Ligand binding activates an intracellular protein kinase that triggers a cascade of phosphorylation reactions Insulin receptor Cytokine receptors Transcription factor receptors Intracellular and also known as ‘nuclear receptors’; ligand binding promotes or inhibits gene transcription and hence synthesis of new proteins Steroid receptors Thyroid hormone receptors Vitamin D receptors Retinoid receptors PPARγ and α receptors Other targets Voltage-gated ion channels Mediate electrical signalling in excitable tissues (muscle and nervous system) Na+ channels Ca2+ channels Enzymes Catalyse biochemical reactions. Drugs interfere with binding of substrate to the active site or of co-factors Cyclo-oxygenase ACE Xanthine oxidase Transporter proteins Carry ions or molecules across cell membranes 5-HT re-uptake transporter Na+ /K+ ATPase Cytokines and other signalling molecules Small proteins that are important in cell signalling (autocrine, paracrine and endocrine), especially affecting the immune response Tumour necrosis factors Interleukins Cell surface antigens Block the recognition of cell surface molecules that modulate cellular responses Cluster of differentiation molecules (e.g. CD20, CD80) (ACE = angiotensin-converting enzyme; AMP = adenosine monophosphate; ATPase = adenosine triphosphatase; GABA = γ-aminobutyric acid; GMP = guanosine monophosphate; PPAR = peroxisome proliferator-activated receptor) Hypersusceptibility Side-effects 100 80 60 40 20 0 0.0001 0.001 0.01 0.1 1 10 100 1000 Therapeutic index 100/0.1 = 1000 Drug dose (mg) Response (% of maximum) Toxic effects Adverse effect ED50 =100 mg Beneficial effect ED50 =0.1 mg Emax ED50 ED50 Fig. 2.2 Dose–response curve. The green curve represents the benecial effect of the drug. The maximum response on the curve is the Emax and the dose (or concentration) producing half this value (Emax /2) is the ED50 (or EC50 ). The red curve illustrates the dose–response relationship for the most important adverse effect of this drug. This occurs at much higher doses; the ratio between the ED50 for the adverse effect and that for the benecial effect is the ‘therapeutic index’, which indicates how much margin there is for prescribers when choosing a dose that will provide benecial effects without also causing this adverse effect. Adverse effects that occur at doses above the therapeutic range are normally called ‘toxic effects’, while those occurring within the therapeutic range are ‘side-effects’ and those below it are ‘hyper-susceptibility effects’.
- 38. 16 CLINICALTHERAPEUTICS AND GOOD PRESCRIBING induce a greater diuresis than thiazide diuretics and so have greater therapeutic efcacy). Potency describes the amount of drug required for a given response. More potent drugs produce biological effects at lower doses, so they have a lower ED50 . A less potent drug can still have an equivalent or greater efcacy if it is given in higher doses. The dose–response relationship for a specic drug varies between patients because of variations in the many determinants of pharma- cokinetics and pharmacodynamics. In clinical practice, the prescriber is unable to construct a dose–response curve for each individual patient. Therefore, most drugs are licensed for use within a recommended range of doses that is expected to reach close to the top of the dose–response curve for most patients. However, it is sometimes possible to achieve the desired therapeutic efcacy at doses towards the lower end of, or even below, the recommended range. Therapeutic index The adverse effects of drugs are often dose-related in a similar way to the benecial effects, although the dose–response curve for these adverse effects is normally shifted to the right (see Fig. 2.2). The ratio of the ED50 for therapeutic efcacy and for a major adverse effect is known as the ‘therapeutic index’. In reality, drugs have multiple potential adverse effects, but the concept of therapeutic index is usually based on adverse effects that might require dose reduction or discontinuation. For most drugs, the therapeutic index is greater than 100, but there are some notable exceptions with therapeutic indices of less than 10 (e.g. digoxin, warfarin, insulin, phenytoin, opioids). The doses of such drugs have to be titrated carefully for individual patients to maximise benets, but avoid adverse effects. Desensitisation and withdrawal effects Desensitisation refers to the common situation in which the biological response to a drug diminishes when it is given continuously or repeat- edly. It may be possible to restore the response by increasing the dose of the drug but, in some cases, the tissues may become completely refractory to its effect. Tachyphylaxis describes desensitisation that occurs very rap- idly, sometimes with the initial dose. This rapid loss of response implies depletion of chemicals that may be necessary for the pharmacological actions of the drug (e.g. a stored neurotransmitter released from a nerve terminal) or receptor phosphorylation. Tolerance describes a more gradual loss of response to a drug that occurs over days or weeks. This slower change implies changes in receptor numbers or the development of counter-regulatory physio- logical changes that offset the actions of the drug (e.g. accumulation of salt and water in response to vasodilator therapy). Drug resistance is a term normally reserved for describing the loss of effectiveness of an antimicrobial (p. 113) or cancer chemotherapy drug. In addition to these pharmacodynamic causes of desensitisation, reduced response may be the consequence of lower plasma and tissue drug concentrations as a result of altered pharmacokinetics (see below). When drugs induce chemical, hormonal and physiological changes that offset their actions, discontinuation may allow these changes to cause ‘rebound’ withdrawal effects (Box 2.3). Pharmacokinetics Understanding ‘what the body does to the drug’ (Fig. 2.3) is extremely important for prescribers because this forms the basis on which the opti- mal route of administration and dose regimen are chosen and explains the majority of inter-individual variation in the response to drug therapy. Drug absorption and routes of administration Absorption is the process by which drug molecules gain access to the blood stream. The rate and extent of drug absorption depend on the route of administration (see Fig. 2.3). Enteral administration These routes involve administration via the gastrointestinal tract: Oral. This is the most common route of administration because it is simple, convenient and readily used by patients to self-admin- ister their medicines. Absorption after an oral dose is a complex process that depends on the drug being swallowed, surviving exposure to gastric acid, avoiding unacceptable food binding, being absorbed across the small bowel mucosa into the portal venous system, and surviving metabolism by gut wall or liver enzymes 2.3 Examples of drugs associated with withdrawal effects Drug Symptoms Signs Treatment Alcohol Anxiety, panic, paranoid delusions, visual and auditory hallucinations Agitation, restlessness, delirium, tremor, tachycardia, ataxia, disorientation, seizures Treat immediate withdrawal syndrome with benzodiazepines Barbiturates, benzodiazepines Similar to alcohol Similar to alcohol Transfer to long-acting benzodiazepine then gradually reduce dosage Glucocorticoids Weakness, fatigue, decreased appetite, weight loss, nausea, vomiting, diarrhoea, abdominal pain Hypotension, hypoglycaemia Prolonged therapy suppresses the hypothalamic–pituitary–adrenal axis and causes adrenal insufciency requiring glucocorticoid replacement. Withdrawal should be gradual after prolonged therapy (p. 684) Opioids Rhinorrhoea, sneezing, yawning, lacrimation, abdominal and leg cramping, nausea, vomiting, diarrhoea Dilated pupils Transfer addicts to long-acting agonist methadone Selective serotonin re-uptake inhibitors (SSRIs) Dizziness, sweating, nausea, insomnia, tremor, delirium, nightmares Tremor Reduce SSRIs slowly to avoid withdrawal effects
- 39. Principles of clinicalpharmacology 17 2 on some degree of manual dexterity and timing (see Fig. 17.23). Patients who nd these difcult may use a ‘spacer’ device to improve drug delivery. A special mode of inhaled delivery is via a nebulised solution created by using pressurised oxygen or air to break up solutions and suspensions into small aerosol droplets that can be directly inhaled from the mouthpiece of the device. Drug distribution Distribution is the process by which drug molecules transfer between the circulating blood, interstitial space and intracellular uid. This is inuenced by the drug’s molecular size and lipid solubility, the extent to which it binds to proteins in plasma, its susceptibility to drug transporters expressed on cell surfaces and its binding to its molecular target and to other cellular proteins (which can be irreversible). Most drugs diffuse passively across capillary walls down a concentration gradient into the interstitial uid until the concentration of free drug molecules in the inter- stitial uid is equal to that in the plasma. As drug molecules in the blood are removed by metabolism or excretion, the plasma concentration falls and drug molecules diffuse back from the tissue compartment into the blood until eventually all are eliminated. Note that this reverse movement of drug away from the tissues will be prevented if further drug doses are administered and absorbed into the plasma. Volume of distribution The apparent volume of distribution (Vd ) is the volume into which a drug appears to have distributed following intravenous injection. It is calcu- lated from the equation Vd = D.C0 where D is the amount of drug given and C0 is the initial plasma concen- tration (Fig. 2.4A). Drugs that are highly bound to plasma proteins may have a Vd below 10L (e.g. warfarin, aspirin), while those that diffuse into the interstitial uid but do not enter cells because they have low lipid sol- ubility may have a Vd between 10 and 30L (e.g. gentamicin, amoxicillin). It is an ‘apparent’ volume because those drugs that are lipid-soluble and highly tissue-bound may have a Vd of greater than 100L (e.g. digoxin, amitriptyline). Drugs with a larger Vd have longer half-lives (see below), take longer to reach steady state on repeated administration and are eliminated more slowly from the body following discontinuation. Drug elimination Drug metabolism Metabolism is the process by which drugs are chemically altered from a lipid-soluble form suitable for absorption and distribution to a more water-soluble form that is necessary for excretion. Some drugs, known as ‘prodrugs’, are inactive in the form in which they are administered, but are converted to an active metabolite in vivo. (‘rst-pass metabolism’). As a consequence, absorption is frequently incomplete following oral administration. The term ‘bioavailability’ describes the proportion of the dose that reaches the systemic circulation intact. Buccal and sublingual (SL). These routes have the advantage of enabling rapid absorption into the systemic circulation without the uncertainties associated with oral administration (e.g. organic nitrates for angina pectoris, triptans for migraine, opioid analgesics). Rectal (PR). The rectal mucosa is occasionally used as a site of drug administration when the oral route is compromised because of nausea and vomiting or unconsciousness (e.g. diazepam in status epilepticus). Parenteral administration These routes avoid absorption via the gastrointestinal tract and rst-pass metabolism in the liver: Intravenous (IV). The IV route enables all of a dose to enter the sys- temic circulation reliably, without any concerns about absorption or rst-pass metabolism (i.e. the dose is 100% bioavailable), and rapidly achieve a high plasma concentration. It is ideal for very ill patients when a rapid, certain effect is critical to outcome (e.g. ben- zylpenicillin for meningococcal meningitis). Intramuscular (IM). IM administration is easier to achieve than the IV route (e.g. adrenaline (epinephrine) for acute anaphylaxis), but absorption is less predictable and depends on muscle blood ow. Subcutaneous (SC). The SC route is ideal for drugs that have to be administered parenterally because of low oral bioavailability, are absorbed well from subcutaneous fat and can ideally be injected by patients themselves (e.g. insulin, heparin). Transdermal. A transdermal patch can enable a drug to be absorbed through the skin and into the circulation (e.g. oestrogens, nicotine, nitrates). Nasal. The nasal mucosa provides another potential route for absorption of some drugs with systemic action (e.g. sumatriptan, calcitonin, naloxone, testosterone, desmopressin). Other routes of administration Topical application of a drug involves direct administration to the site of action (e.g. skin, eye, ear). This has the advantage of achieving sufcient concentration at this site while minimising systemic expo- sure and the risk of adverse effects elsewhere. Inhaled (INH) administration allows drugs to be delivered directly to a target in the respiratory tree, usually the small airways (e.g. salbutamol, beclometasone). However, a signicant proportion of the inhaled dose may be absorbed from the lung or is swallowed and can reach the systemic circulation. The most common mode of delivery is the metered-dose inhaler, but its success depends I terst tial fluid Intracellular fluid Kidney Liver Parenteral Mouth Stomach Small intestine Large intestine Rectum Buccal Excretion in urine Excretion in faeces Portal venous system Intestinal wall enzymes Liver enzymes Metabolism Circulating plasma Rectal Oral Fig. 2.3 Pharmacokinetics summary. Most drugs are taken orally, are absorbed from the intestinal lumen and enter the portal venous system to be conveyed to the liver, where they may be subject to rst-pass metabolism and/or excretion in bile. Active drugs then enter the systemic circulation, from which they may diffuse (or sometimes be actively transported) in and out of the interstitial and intracellular uid compartments. Drug that remains in circulating plasma is subject to liver metabolism and renal excretion. Drugs excreted in bile may be reabsorbed, creating an enterohepatic circulation. First-pass metabolism in the liver is avoided if drugs are administered via the buccal or rectal mucosa, or parenterally (e.g. by intravenous injection).
- 40. 18 CLINICALTHERAPEUTICS AND GOOD PRESCRIBING Phase I metabolism involves oxidation, reduction or hydrolysis to make drug molecules suitable for phase II reactions or for excretion. Oxidation is by far the most common form of phase I reaction and chiey involves members of the cytochrome P450 family of membrane-bound enzymes in the endoplasmic reticulum of hepatocytes. Phase II metabolism involves combining phase I metabolites with an endogenous substrate to form an inactive conjugate that is much more water-soluble. Reactions include glucuronidation, sulphation, acetyla- tion, methylation and conjugation with glutathione. This is necessary to enable renal excretion, because lipid-soluble metabolites will simply dif- fuse back into the body after glomerular ltration (p. 617). Drug excretion Excretion is the process by which drugs and their metabolites are removed from the body. Renal excretion is the usual route of elimination for drugs or their metabolites that are of low molecular weight and sufciently water-soluble to avoid reabsorption from the renal tubule. Drugs bound to plasma pro- teins are not ltered by the glomeruli. The pH of the urine is more acidic than that of plasma, so that weakly acidic drugs (e.g. salicylates) become un-ionised and tend to be reabsorbed. Alkalination of the urine can has- ten excretion (e.g. after a salicylate overdose; p. 225). For some drugs, active secretion into the proximal tubule lumen, rather than glomerular ltration, is the predominant mechanism of excretion (e.g. methotrexate, penicillins). Faecal excretion is the predominant route of elimination for drugs with high molecular weight, including those that are excreted in the bile after conjugation with glucuronide in the liver and any drugs that are not absorbed after enteral administration. Molecules of drug or metabolite that are excreted in the bile enter the small intestine where they may, if they are sufciently lipid-soluble, be reabsorbed through the gut wall and return to the liver via the portal vein (see Fig. 2.3). This recycling between the liver, bile, gut and portal vein is known as ‘enterohepatic circulation’ and can signicantly prolong the residence of drugs in the body (e.g. digoxin, morphine, levothyroxine). Elimination kinetics The net removal of drug from the circulation results from a combination of drug metabolism and excretion and is usually described as ‘clearance’, i.e. the volume of plasma that is completely cleared of drug per unit time. For most drugs, elimination is a high-capacity process that does not become saturated, even at high dosage. The rate of elimination is, there- fore, directly proportional to the drug concentration because of the ‘law of mass action’, whereby higher drug concentrations will drive faster met- abolic reactions and support higher renal ltration rates. This results in ‘rst-order’ kinetics, when a constant fraction of the drug remaining in the circulation is eliminated in a given time and the decline in concentration over time is exponential (see Fig. 2.4A). This elimination can be described by the drug’s half-life (t1/2 ), i.e. the time taken for the plasma drug concen- tration to halve, which remains constant throughout the period of drug elimination. The signicance of this phenomenon for prescribers is that the effect of increasing doses on plasma concentration is predictable – a doubled dose leads to a doubled concentration at all time points. For a few drugs in common use (e.g. phenytoin, alcohol), elimination capacity is exceeded (saturated) within the usual dose range. This is called ‘zero-order’ kinetics. Its signicance for prescribers is that, if the rate of administration exceeds the maximum rate of elimination, the drug will accumulate progressively, leading to serious toxicity. Repeated dose regimens The goal of therapy is usually to maintain drug concentrations within the therapeutic range (see Fig. 2.2) over several days (e.g. antibiotics) or even for months or years (e.g. antihypertensives, lipid-lowering drugs, thyroid hormone replacement therapy). This goal is rarely achieved with single doses, so prescribers have to plan a regimen of repeated doses. This involves choosing the size of each individual dose and the frequency of dose administration. As illustrated in Figure 2.4B, the time taken to reach drug concentra- tions within the therapeutic range depends on the half-life of the drug. Typically, with doses administered regularly, it takes approximately 5 half-lives to reach a ‘steady state’ in which the rate of drug elimination is equal to the rate of drug administration. This applies when starting new drugs and when adjusting doses of current drugs. With appropri- ate dose selection, steady-state drug concentrations will be maintained within the therapeutic range. This is important for prescribers because it means that the effects of a new prescription, or dose titration, for a drug with a long half-life (e.g. digoxin – 36 hours) may not be known for a few days. In contrast, drugs with a very short half-life (e.g. dobutamine – 2 minutes) have to be given continuously by infusion, but reach a new steady state within minutes. Time (hours) A constant fraction of drug is cleared in unit time t1/2 = 8 hours C0 Plasma drug concentration 6 12 18 24 A Loading dose Dose Dose Dose Dose Dose Dose Dose Subtherapeutic Dose interval = 24 hours Time (days) Plasma drug concentration 1 2 3 4 5 6 Therapeutic range Adverse effects t1/2= 30 hours B Fig. 2.4 Drug concentrations in plasma following single and multiple drug dosing. the time period required for the plasma drug concentration to halve (half-life, t1/2 ) remains concentration rises if each dose is administered before the previous dose has been entirely cleared. In this example, the drug’s half-life is 30 hours, so that with daily dosing the peak, average and trough concentrations steadily increase as drug accumulates in the body (black line). Steady state is reached after approximately 5 half-lives, when the rate of elimination (the product of concentration and clearance) is equal to the rate of drug absorption (the product of rate of administration and bioavailability). The long half-life in this example means that it takes 6 days for steady state to be achieved and, for most of the rst 3 days of treatment, plasma drug concentrations are below the therapeutic range. This problem can be overcome if a larger loading dose (red line) is used to achieve steady-state drug concentrations more rapidly.
- 41. Adverse outcomes ofdrug therapy 19 2 For drugs with a long half-life, if it is unacceptable to wait for 5 half- lives until concentrations within the therapeutic range are achieved, then an initial ‘loading dose’ can be given that is much larger than the main- tenance dose and equivalent to the amount of drug required in the body at steady state. This achieves a peak plasma concentration close to the plateau concentration, which can then be maintained by successive maintenance doses. ‘Steady state’ actually involves uctuations in drug concentrations, with peaks just after administration followed by troughs just prior to the next administration. The manufacturers of medicines recommend dosing regimens that predict that, for most patients, these oscillations result in troughs within the therapeutic range and peaks that are not high enough to cause adverse effects. The optimal dose interval is a compromise between convenience for the patient and a constant level of drug expo- sure. More frequent administration (e.g. 25mg 4 times daily) achieves a smoother plasma concentration prole than 100mg once daily, but is much more difcult for patients to sustain. A solution to this need for compromise in dosing frequency for drugs with half-lives of less than 24 hours is the use of ‘modied-release’ (m/r) formulations. These allow drugs to be absorbed more slowly from the gastrointestinal tract and reduce the oscillation in plasma drug concentration prole, which is espe- cially important for drugs with a low therapeutic index (e.g. levodopa). Inter-individual variation in drug responses Prescribers have numerous sources of guidance about how to use drugs appropriately (e.g. dose, route, frequency, duration) for many conditions. However, this advice is based on average dose–response data derived from observations in many individuals. When applying this information to an individual patient, prescribers must take account of inter-individ- ual variability in response. Some of this variability is predictable and good prescribers are able to anticipate it and adjust their prescriptions accordingly to maximise the chances of benet and minimise harm. Inter- individual variation in responses also mandates that effects of treatment should be monitored (p. 35). Some inter-individual variation in drug response is accounted for by differences in pharmacodynamics. For example, the benecial natriuresis produced by the loop diuretic furosemide is often signicantly reduced at a given dose in patients with renal impairment, while delirium caused by opioid analgesics is more likely in the elderly. However, it is differences in pharmacokinetics that more commonly account for different drug responses. Examples of factors inuencing the absorption, metabolism and excretion of drugs are shown in Box 2.4. It is hoped that a signicant proportion of the inter-individual varia- tion in drug responses can be explained by studying genetic differences in single genes (‘pharmacogenetics’; Box 2.5) or the effects of multiple gene variants (‘pharmacogenomics’). The aim is to identify those patients most likely to benet from specic treatments and those most suscepti- ble to adverse effects. In this way, it may be possible to select drugs and dose regimens for individual patients to maximise the benet-to-hazard ratio (‘personalised medicine’). Adverse outcomes of drug therapy The decision to prescribe a drug always involves a judgement of the balance between therapeutic benets and risk of an adverse outcome. Both prescribers and patients tend to be more focused on the former, but a truly informed decision requires consideration of both. Adverse drug reactions Some important denitions for the adverse effects of drugs are: Adverse event. A harmful event that occurs while a patient is taking a drug, irrespective of whether the drug is suspected of being the cause. Adverse drug reaction (ADR). An unwanted or harmful reaction that is experienced following the administration of a drug or combination of drugs under normal conditions of use and is suspected to be related to the drug. An ADR will usually require the drug to be dis- continued or the dose reduced. Side-effect. Any effect caused by a drug other than the intended therapeutic effect, whether benecial, neutral or harmful. The term ‘side-effect’ is often used interchangeably with ‘ADR’, although the former usually implies an ADR that occurs during exposure to nor- mal therapeutic drug concentrations (e.g. vasodilator-induced ankle oedema). Hypersensitivity reaction. An ADR that occurs as a result of an immunological reaction and often after exposure to subtherapeutic drug concentrations. These include: (1) acute anaphylaxis (p. 183) – the result of an interaction between drug antigens and immuno- globulin E (IgE) on mast cells and basophils, resulting in a release of vasoactive biomolecules (e.g. penicillin, suxamethonium); this is also known as a type I hypersensitivity reaction. (2) ‘Anaphylactoid’ 2.4 Patient-specic factors that inuence pharmacokinetics Age Drug metabolism is low in the fetus and newborn, may be enhanced in young children, and becomes less effective with age Drug excretion falls with the age-related decline in renal function Sex Women have a greater proportion of body fat than men, increasing the volume of distribution and half-life of lipid-soluble drugs Body weight Obesity increases volume of distribution and half-life of lipid-soluble drugs Patients with higher lean body mass have larger body compartments into which drugs are distributed and may require higher doses Liver function Metabolism of most drugs depends on several cytochrome P450 enzymes that are impaired in patients with advanced liver disease Hypoalbuminaemia inuences the distribution of drugs that are highly protein- bound Kidney function Renal disease and the decline in renal function with ageing may lead to drug accumulation Gastrointestinal function Small intestinal absorption of oral drugs may be delayed by reduced gastric motility Absorptive capacity of the intestinal mucosa may be reduced in disease (e.g. Crohn’s or coeliac disease) or after surgical resection Food Food in the stomach delays gastric emptying and reduces the rate (but not usually the extent) of drug absorption Some food constituents bind to certain drugs and prevent their absorption Smoking Tar in tobacco smoke stimulates the oxidation of certain drugs Alcohol Regular alcohol consumption stimulates liver enzyme synthesis, while binge drinking may temporarily inhibit drug metabolism Drugs Drug–drug interactions cause marked variation in pharmacokinetics (see Box 2.12)
- 42. 20 CLINICALTHERAPEUTICS AND GOOD PRESCRIBING reactions – these present in a similar manner to acute anaphylaxis, but are a consequence of non-IgE-mediated degranulation of mast cells and basophils or direct complement activation (e.g. aspirin, non-steroidal anti-inammatory drugs, opiates). (3) Types II–IV hypersensitivity reactions – these occur via other mechanisms, such as antibody-dependent (IgM or IgG), immune complex-mediated or cell-mediated pathways (p. 78); examples of such reactions are listed in Box 2.6. Drug toxicity. Adverse effects of a drug that occur because the dose or plasma concentration has risen above the therapeutic range, either unintentionally or intentionally (drug overdose; see Fig. 2.2 and p. 224). Drug misuse. The misuse of recreational or therapeutic drugs that may lead to addiction or dependence, serious physiological injury (such as liver damage), psychological harm (abnormal behaviour patterns, hallucinations, memory loss) or death (p. 1240). Prevalence of ADRs ADRs are a common cause of illness, accounting in the UK for approx- imately 3% of consultations in primary care, 7% of emergency admis- sions to hospital and affecting around 15% of hospital inpatients. Many ‘disease’ presentations are eventually attributed to ADRs, emphasising the importance of always taking a careful drug history (Box 2.7). Factors 2.5 Examples of pharmacogenetic variations that inuence drug response Genetic variant Drug affected Clinical outcome Pharmacokinetic Aldehyde dehydrogenase-2 deciency Ethanol Elevated blood acetaldehyde causes facial ushing and increased heart rate in ~50% of Japanese, Chinese and other Asian populations Acetylation Isoniazid, hydralazine, procainamide Increased responses in slow acetylators, up to 50% of some populations Oxidation (CYP2D6) Nortriptyline Codeine Increased risk of toxicity in poor metabolisers Reduced responses with slower conversion of codeine to more active morphine in poor metabolisers, 10% of European populations Increased risk of toxicity in ultra-fast metabolisers, 3% of Europeans but 25% of North Africans Oxidation (CYP2C9) Warfarin Polymorphisms known to inuence dosages Oxidation (CYP2C19) Clopidogrel Proguanil Reduced enzymatic activation results in reduced antiplatelet effect Reduced efcacy with slower conversion to active cycloguanil in poor metabolisers Sulphoxidation Penicillamine Increased risk of toxicity in poor metabolisers Pseudocholinesterase deciency Suxamethonium (succinylcholine) Decreased drug inactivation leads to prolonged paralysis and sometimes persistent apnoea requiring mechanical ventilation until the drug can be eliminated by alternate pathways; occurs in 1 in 1500 people Pharmacodynamic Glucose-6-phosphate dehydrogenase (G6PD) deciency Oxidant drugs, including antimalarials (e.g. chloroquine, primaquine) Risk of haemolysis in G6PD deciency Acute intermittent porphyria Enzyme-inducing drugs Increased risk of an acute attack SLC01B1 polymorphism Statins Increased risk of rhabdomyolysis HLA-B*5701 polymorphism Abacavir Increased risk of skin hypersensitivity reaction HLA-B*5801 polymorphism Allopurinol Increased risk of rashes in Han Chinese HLA-B*1502 polymorphism Carbamazepine Increased risk of serious dermatological reactions (e.g. Stevens–Johnson syndrome) Hepatic nuclear factor 1 alpha (HNF1A) polymorphism Sulphonylureas Increased sensitivity to the blood glucose-lowering effects Human epidermal growth factor receptor 2 (HER2)- positive breast cancer cells Trastuzumab Increased sensitivity to the inhibitory effects on growth and division of the target cancer cells accounting for the rising prevalence of ADRs are the increasing age of patients, polypharmacy (higher risk of drug interactions), increasing avail- ability of over-the-counter medicines, increasing use of herbal or tradi- tional medicines and the increase in medicines available via the Internet that can be purchased without a prescription from a health-care profes- sional. Risk factors for ADRs are shown in Box 2.8. ADRs are important because they reduce quality of life for patients, reduce adherence to and therefore efcacy of benecial treatments, cause diagnostic confusion, undermine the condence of patients in their health-care professional(s) and consume health-care resources. Retrospective analysis of ADRs has shown that more than half could have been avoided if the prescriber had taken more care in anticipating the poten- tial hazards of drug therapy. For example, non-steroidal anti-inammatory drug (NSAID) use accounts for many thousands of emergency admissions, gastrointestinal bleeding episodes and a signicant number of deaths. In many cases, the patients are at increased risk due to their age, interacting drugs (e.g. aspirin, warfarin) or a past history of peptic ulcer disease. Drugs that commonly cause ADRs are listed in Box 2.9. Prescribers and their patients ideally want to know the frequency with which ADRs occur for a specic drug. Although this may be well char- acterised for more common ADRs observed in clinical trials, it is less clear for rarely reported ADRs when the total numbers of reactions and patients exposed are not known. The words used to describe frequency
- 43. Adverse outcomes ofdrug therapy 21 2 who experience type B reactions are generally ‘hyper-susceptible’ because of unpredictable immunological or genetic factors (e.g. anaphylaxis caused by penicillin, peripheral neuropathy caused by isoniazid in poor acetylators). This simple classication has shortcomings, and a more detailed clas- sication based on dose (see Fig. 2.2), timing and susceptibility (DoTS) is now used by those analysing ADRs in greater depth (Box 2.10). The AB classication can be extended as a reminder of some other types of ADR: Type C (‘chronic/continuous’) ADRs. These occur only after pro- longed continuous exposure to a drug. Examples include osteopo- rosis caused by glucocorticoids, retinopathy caused by (hydroxy) chloroquine and tardive dyskinesia caused by phenothiazines. Type D (‘delayed’) ADRs. These are delayed until long after drug exposure, making diagnosis difcult. Examples include malignancies that may emerge after immunosuppressive treatment post-trans- plantation (e.g. azathioprine, tacrolimus) and vaginal cancer occur- ring many years after exposure to diethylstilboestrol. Type E (‘end-of-treatment’) ADRs. These occur after abrupt drug withdrawal (see Box 2.3). 2.6 Examples of drug-mediated types I-IV hypersensitivity reactions1 Type I (mediated by IgE antibodies and mast cell degranulation) Acute anaphylaxis Penicillins Chemotherapy Monoclonal antibodies Neuromuscular blocking drugs Type II (mediated by IgM and IgG antibodies) Haemolytic anaemia (latency less than 7 days) Methyldopa Penicillins Cephalosporins NSAIDs Quinidine/quinine Neutropenia/agranulocytosis (latency days to weeks) Antiarrhythmics Antibiotics NSAIDs Antimalarials Antithyroid drugs Clozapine Ticlopidine Thrombocytopenia (latency 1–2 weeks) Carbamazepine Heparin Penicillins Cephalosporins NSAIDs Quinidine/quinine Thiazide diuretics Type III (mediated by immune complex deposition) Glomerulonephritis, serum sickness, vasculitis Penicillins Cephalosporins Sulphonamides Type IV (mediated by T cells) Skin eruptions, including maculopapular rash, lichenoid or pemphigoid-like reaction, drug rash with eosinophilia and systemic symptoms (DRESS), Stevens– Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)2 Carbamazepine Abacavir Trimethoprim Dapsone Drug-induced lupus Allopurinol Thiazide diuretics Hydralazine 2.7 How to take a drug history Information from the patient (or carer) Use language that patients will understand (e.g.‘medicines’ rather than ‘drugs’, which may be mistaken for drugs of abuse) while gathering the following information: Current prescribed drugs, including formulations (e.g. modied-release tablets), doses, routes of administration, frequency and timing, duration of treatment Other medications that are often forgotten (e.g. contraceptives, over-the-counter drugs, herbal remedies, vitamins) Drugs that have been taken in the recent past and reasons for stopping them Previous drug hypersensitivity reactions, their nature and time course (e.g. rash, anaphylaxis) Previous ADRs, their nature and time course (e.g. ankle oedema with amlodipine) Adherence to therapy (e.g. ‘Are you taking your medication regularly?’) Information from GP medical records and/or pharmacist Up-to-date list of medications Previous ADRs Last order dates for each medication Inspection of medicines Drugs and their containers (e.g. blister packs, bottles, vials) should be inspected for name, dosage and the number of dosage forms taken since dispensed (ADR = adverse drug reaction) can be misinterpreted by patients, but widely accepted meanings include: very common (10% or more), common (1%–10%), uncommon (0.1%–1%), rare (0.01%–0.1%) and very rare (0.01% or less). Classication of ADRs ADRs have traditionally been classied into two major groups: Type A (‘augmented’) ADRs. These are predictable from the known pharmacodynamic effects of the drug and are dose-dependent, common (detected early in drug development) and usually mild. Examples include constipation caused by opioids, hypotension caused by antihypertensives and dehydration caused by diuretics. Type B (‘bizarre’) ADRs. These are not predictable, are not obvi- ously dose-dependent in the therapeutic range, are rare (remaining undiscovered until the drug is marketed) and often severe. Patients 2.8 Risk factors for adverse drug reactions Patient factors Advanced age (e.g. low physiological reserve) Gender (e.g. ACE inhibitor-induced cough in women) Polypharmacy (e.g. drug interactions) Genetic predisposition (see Box 2.5) Hypersensitivity/allergy (e.g. β-lactam antibiotics) Diseases altering pharmacokinetics (e.g. hepatic or renal impairment) or pharmacodynamic responses (e.g. bladder instability) Adherence problems (e.g. cognitive impairment) Drug factors Steep dose–response curve (e.g. insulin) Low therapeutic index (e.g. digoxin, cytotoxic drugs) Prescriber factors Inadequate understanding of the principles of clinical pharmacology Inadequate knowledge of the patient Inadequate knowledge of the prescribed drug Inadequate instructions and warnings provided to patients Inadequate monitoring arrangements planned (ACE = angiotensin-converting enzyme) 2 See also Boxes 27.34 and 27.35. 1 Type I is often known as ‘immediate’ hypersensitivity while types II–IV are known as ‘delayed’ hypersensitivity.
- 44. 22 CLINICALTHERAPEUTICS AND GOOD PRESCRIBING A teratogen is a drug with the potential to affect the development of the fetus in the rst 10 weeks of intrauterine life (e.g. phenytoin, warfa- rin). The thalidomide disaster in the early 1960s highlighted the risk of teratogenicity and led to mandatory testing of all new drugs. Congenital defects in a live infant or aborted fetus should provoke suspicion of an ADR and a careful exploration of maternal drug exposures (including self-medication and herbal remedies). Detecting ADRs – pharmacovigilance Type A ADRs become apparent early in the development of a new drug. By the time a new drug is licensed and launched on to a possi- ble worldwide market, however, a relatively small number of patients (just several hundred) may have been exposed to it, meaning that rarer but potentially serious type B ADRs may remain undiscovered. Pharmacovigilance is the process of detecting (‘signal generation’) and evaluating ADRs in order to help prescribers and patients to be better informed about the risks of drug therapy. Drug regulatory agen- cies may respond to this information by placing restrictions on the licensed indications, reducing the recommended dose range, adding special warnings and precautions for prescribers in the product litera- ture, writing to all health-care professionals or withdrawing the product from the market. Voluntary reporting systems allow health-care professionals and patients to report suspected ADRs to the regulatory authorities. A good example is the ‘Yellow Card’ scheme that was set up in the UK in response to the thalidomide tragedy. Reports are analysed to assess the likelihood that they represent a true ADR (Box 2.11). Although vol- untary reporting is a continuously operating and effective early-warning system for previously unrecognised rare ADRs, its weaknesses include low reporting rates (only 3% of all ADRs and 10% of serious ADRs are ever reported), an inability to quantify risk (because the ratio of ADRs to prescriptions is unknown) and the inuence of prescriber awareness on likelihood of reporting (reporting rates rise rapidly following publicity about potential ADRs). More systematic approaches to collecting information on ADRs include ‘prescription event monitoring’, in which a sample of prescribers of a particular drug are issued with questionnaires concerning the clini- cal outcome for their patients and the collection of population statistics. Many health-care systems routinely collect patient-identiable data on prescriptions (a surrogate marker of exposure to a drug), health-care events (e.g. hospitalisation, operations, new clinical diagnoses) and other 2.9 Drugs that are common causes of adverse drug reactions Drug or drug class Common adverse drug reactions ACE inhibitors (e.g. lisinopril) Renal impairment Hyperkalaemia Antibiotics (e.g. amoxicillin) Nausea Diarrhoea Anticoagulants (e.g. warfarin, heparin) Bleeding Antipsychotics (e.g. haloperidol) Falls Sedation Delirium Aspirin Gastrotoxicity (dyspepsia, gastrointestinal bleeding) Benzodiazepines (e.g. diazepam) Drowsiness Falls β-blockers (e.g. atenolol) Cold peripheries Bradycardia Calcium channel blockers (e.g. amlodipine) Ankle oedema Digoxin Nausea and anorexia Bradycardia Diuretics (e.g. furosemide, bendroumethiazide) Dehydration Electrolyte disturbance (hypokalaemia, hyponatraemia) Hypotension Renal impairment Insulin Hypoglycaemia NSAIDs (e.g. ibuprofen) Gastrotoxicity (dyspepsia, gastrointestinal bleeding) Renal impairment Opioid analgesics (e.g. morphine) Nausea and vomiting Delirium Constipation (ACE = angiotensin-converting enzyme; NSAID = non-steroidal anti-inammatory drug) 2.10 DoTS classication of adverse drug reactions Category Example Dose Below therapeutic dose In the therapeutic dose range At high doses Anaphylaxis with penicillin Nausea with morphine Hepatotoxicity with paracetamol Timing With the rst dose Early stages of treatment On stopping treatment Signicantly delayed Anaphylaxis with penicillin Hyponatraemia with diuretics Benzodiazepine withdrawal syndrome Clear-cell cancer with diethylstilboestrol Susceptibility See patient factors in Box 2.8 2.11 TREND analysis of suspected adverse drug reactions Factor Key question Comment Temporal relationship What is the time interval between the start of drug therapy and the reaction? Most ADRs occur soon after starting treatment and within hours in the case of anaphylactic reactions Re-challenge What happens when the patient is re- challenged with the drug? Re-challenge is rarely possible because of the need to avoid exposing patients to unnecessary risk Exclusion Have concomitant drugs and other non- drug causes been excluded? ADR is a diagnosis of exclusion following clinical assessment and relevant investigations for non-drug causes Novelty Has the reaction been reported before? The suspected ADR may already be recognised and mentioned in the SPC approved by the regulatory authorities De-challenge Does the reaction improve when the drug is withdrawn or the dose is reduced? Most, but not all, ADRs improve on drug withdrawal, although recovery may be slow (ADR = adverse drug reaction; SPC = summary of product characteristics)
- 45. Adverse outcomes ofdrug therapy 23 2 clinical data (e.g. haematology, biochemistry). If these records can be linked, with appropriate safeguards for condentiality and data protec- tion, they may provide a much more powerful mechanism for assessing both the harms and benets of drugs. All prescribers will inevitably see patients experiencing ADRs caused by prescriptions written by themselves or their colleagues. It is important that these are recognised early. In addition to the features in Box 2.11, features that should raise suspicion of an ADR and the need to respond (by drug withdrawal, dosage reduction or reporting to the regulatory authorities) include: concern expressed by a patient that a drug has harmed them abnormal clinical measurements (e.g. blood pressure, temperature, pulse, blood glucose and weight) or laboratory results (e.g. abnor- mal liver or renal function, low haemoglobin or white cell count) while on drug therapy new therapy started that could be in response to an ADR (e.g. ome- prazole, allopurinol, naloxone) the presence of risk factors for ADRs (see Box 2.8). Drug interactions A drug interaction has occurred when the administration of one drug increases or decreases the benecial or adverse responses to another drug. Although the number of potential interacting drug com- binations is very large, only a small number are common in clinical practice. Important drug interactions are most likely to occur when the affected drug has a low therapeutic index, steep dose–response curve, high rst-pass or saturable metabolism, or a single mechanism of elimination. Mechanisms of drug interactions Pharmacodynamic interactions occur when two drugs produce additive, synergistic or antagonistic effects at the same drug target (e.g. receptor, enzyme) or physiological system (e.g. electrolyte excretion, heart rate). These are the most common interactions in clinical practice and some important examples are given in Box 2.12. 2.12 Common drug interactions Mechanism Object drug Precipitant drug Result Pharmaceutical* Chemical reaction Sodium bicarbonate Calcium gluconate Precipitation of insoluble calcium carbonate Pharmacokinetic Reduced absorption Tetracyclines Calcium, aluminium and magnesium salts Reduced tetracycline absorption Reduced protein binding Phenytoin Aspirin Increased unbound and reduced total phenytoin plasma concentration Reduced metabolism: CYP3A4 Amiodarone Grapefruit juice Cardiac arrhythmias because of prolonged QT interval (p. 418) Warfarin Clarithromycin Enhanced anticoagulation CYP2C19 Phenytoin Miconazole Phenytoin toxicity CYP2D6 Haloperidol Fluoxetine Haloperidol toxicity Xanthine oxidase Azathioprine Allopurinol Azathioprine toxicity Monoamine oxidase Catecholamines Monoamine oxidase inhibitors Hypertensive crisis due to monoamine toxicity Increased metabolism (enzyme induction) Ciclosporin St John’s wort Loss of immunosuppression Reduced renal elimination Lithium Diuretics Lithium toxicity Methotrexate NSAIDs Methotrexate toxicity Pharmacodynamic Direct antagonism at same receptor Opioids Naloxone Reversal of opioid effects used therapeutically Salbutamol Atenolol Inhibits bronchodilator effect Direct potentiation in same organ system Benzodiazepines Alcohol Increased sedation ACE inhibitors NSAIDs Increased risk of renal impairment Indirect potentiation by actions in different organ systems Digoxin Diuretics Digoxin toxicity enhanced because of hypokalaemia Warfarin Aspirin, NSAIDs Increased risk of bleeding because of gastrotoxicity and antiplatelet effects Diuretics ACE inhibitors Blood pressure reduction (may be therapeutically advantageous) because of the increased activity of the renin–angiotensin system in response to diuresis *Pharmaceutical interactions are related to the formulation of the drugs and occur before drug absorption. (ACE = angiotensin-converting enzyme; NSAID = non-steroidal anti-inammatory drug)
- 46. 24 CLINICALTHERAPEUTICS AND GOOD PRESCRIBING Pharmacokinetic interactions occur when the administration of a sec- ond drug alters the concentration of the rst at its site of action. There are numerous potential mechanisms: Absorption interactions. Drugs that either delay (e.g. anticholinergic drugs) or enhance (e.g. prokinetic drugs) gastric emptying inuence the rate of rise in plasma concentration of other drugs, but not the total amount of drug absorbed. Drugs that bind to form insoluble complexes or chelates (e.g. aluminium-containing antacids binding with ciprooxacin) can reduce drug absorption. Distribution interactions. Co-administration of drugs that compete for protein binding in plasma (e.g. phenytoin and diazepam) can increase the unbound drug concentration, but the effect is usually short-lived due to increased elimination and hence restoration of the pre-interaction equilibrium. Metabolism interactions. Many drugs rely on metabolism by different isoenzymes of cytochrome P450 (CYP) in the liver. CYP enzyme inducers (e.g. phenytoin, rifampicin) generally reduce plasma con- centrations of other drugs, although they may enhance activation of prodrugs. CYP enzyme inhibitors (e.g. clarithromycin, cimetidine, grapefruit juice) have the opposite effect. Enzyme induction effects usually take a few days to manifest because of the need to synthesise new CYP enzyme, in contrast to the rapid effects of enzyme inhibition. Excretion interactions. These primarily affect renal excretion. For example, drug-induced reduction in glomerular ltration rate (e.g. diuretic-induced dehydration, angiotensin-converting enzyme (ACE) inhibitors, NSAIDs) can reduce the clearance and increase the plasma concentration of many drugs, including some with a low therapeutic index (e.g. digoxin, lithium, aminoglycoside antibiotics). Less commonly, interactions may be due to competition for a com- mon tubular organic anion transporter (e.g. methotrexate excretion may be inhibited by competition with NSAIDs). Avoiding drug interactions Drug interactions are increasing as patients are prescribed more medi- cines (polypharmacy). Prescribers can avoid the adverse consequences of drug–drug interactions by taking a careful drug history (see Box 2.7) before prescribing additional drugs, only prescribing for clear indications and taking special care when prescribing drugs with a narrow therapeu- tic index (e.g. warfarin). When prescribing an interacting drug is una- voidable, good prescribers will seek further information and anticipate the potential risk. This will allow them to provide special warnings for the patient and arrange for monitoring, either of the clinical effects (e.g. coagulation tests for warfarin) or of plasma concentration (e.g. digoxin). Medication errors A medication error is any preventable event that may lead to inappropri- ate medication use or patient harm while the medication is in the control of the health-care professional or patient. Errors may occur in prescrib- ing, dispensing, preparing solutions, administration or monitoring. Many ADRs are considered in retrospect to have been ‘avoidable’ with more care or forethought; in other words, an adverse event considered by one prescriber to be an unfortunate ADR might be considered by another to be a prescribing error. Medication errors are very common. Several thousand medication orders are dispensed and administered each day in a medium-sized hospital. Recent UK studies suggest that 7%–9% of hospital prescrip- tions contain an error, and most are written by junior doctors. Common prescribing errors in hospitals include omission of medicines (especially failure to prescribe regular medicines at the point of admission or dis- charge, i.e. ‘medicines reconciliation’), dosing errors, unintentional pre- scribing and poor use of documentation (Box 2.13). Most prescription errors result from a combination of failures by the individual prescriber and the health-service systems in which they work (Box 2.14). Health-care organisations increasingly encourage reporting of errors within a ‘no-blame culture’ so that they can be subject to ‘root cause analysis’ using human error theory (Fig. 2.5). Prevention is tar- geted at the factors in Box 2.14 and can be supported by prescribers communicating and cross-checking with colleagues (e.g. when calculat- ing doses adjusted for body weight, or planning appropriate monitoring after drug administration). Prescription errors may also be reduced by clinical pharmacist support (e.g. to check the patient’s previous medica- tions and current prescriptions) and electronic prescribing (which avoids errors due to illegibility or serious dosing mistakes and may be combined with a clinical decision support system to take account of patient char- acteristics and drug history, and provide warnings of potential contrain- dications and drug interactions). Responding when an error is discovered All prescribers will make errors. When they do, their rst duty is to pro- tect the patient’s safety. This will involve a clinical review and the taking of any steps that will reduce harm (e.g. remedial treatment, monitoring, recording the event in the notes, informing colleagues). Patients should be informed if they have been exposed to potential harm. For errors that do not reach the patient, it is the prescriber’s duty to report them, so that others can learn from the experience and take the opportunity to reect on how a similar incident might be avoided in the future. 2.13 Hospital prescribing errors Error type Approximate % of total Omission on admission 30 Underdose 11 Overdose 8 Strength/dose missing 7 Omission on discharge 6 Administration times incorrect/missing 6 Duplication 6 Product or formulation not specied 4 Incorrect formulation 4 No maximum dose 4 Unintentional prescribing 3 No signature 2 Clinical contraindication 1 Incorrect route 1 No indication 1 Intravenous instructions incorrect/missing 1 Drug not prescribed but indicated 1 Drug continued for longer than needed 1 Route of administration missing 1 Start date incorrect/missing 1 Risk of drug interaction < 0.5 Controlled drug requirements incorrect/missing < 0.5 Daily dose divided incorrectly < 0.5 Signicant allergy < 0.5 Drug continued in spite of adverse effects < 0.5 Premature discontinuation < 0.5 Failure to respond to out-of-range drug level < 0.5
- 47. Drug regulation andmanagement 25 2 2.14 Causes of prescribing errors Systems factors Working hours of prescribers (and others) Patient throughput Professional support and supervision by colleagues Availability of information (medical records) Design of prescription forms Distractions Availability of decision support Checking routines (e.g. clinical pharmacy) Reporting and reviewing of incidents Prescriber factors Knowledge Clinical pharmacology principles Drugs in common use Therapeutic problems commonly encountered Knowledge of workplace systems Skills Taking a good drug history Obtaining information to support prescribing Communicating with patients Numeracy and calculations Prescription writing Attitudes Coping with risk and uncertainty Monitoring of prescribing Checking routines Planned action Prescribing Intended action Correct action Intended outcome Unintended action Lapse Slip Wrong plan selected (Causes include poor training and lack of experience) Correct plan known but not executed (Causes include workload, time pressures, distractions) Prescription not as intended Prescriber unaware Prescription incomplete or forgotten Prescriber may remember Violation Mistake Prescription as intended but written based on the wrong principles or lack of knowledge Prescriber unaware Deliberate deviations from standard practice Prescriber aware Fig. 2.5 Human error theory. Unintended errors may occur because the prescriber fails to complete the prescription correctly (a slip; e.g. writes the dose in ‘mg’ not ‘micrograms’) or forgets part of the action that is important for success (a lapse; e.g. forgets to co-prescribe folic acid with methotrexate); prevention requires the system to provide appropriate checking routines. Intended errors occur when the prescriber acts incorrectly due to lack of knowledge (a mistake; e.g. prescribes atenolol for a patient with known severe asthma because of ignorance about the contraindication); prevention must focus on training the prescriber. Drug regulation and management Given the powerful benecial and potentially adverse effects of drugs, the production and use of medicines are strictly regulated (e.g. by the Food and Drug Administration in the United States, Medicines and Healthcare Products Regulatory Agency in the UK, and Central Drugs Standard Control Organisation in India). Regulators are responsible for licensing medicines, monitoring their safety (pharmacovigilance), approving clinical trials, and inspecting and maintaining standards of drug development and manufacture. In addition, because of the high costs of drugs and their adverse effects, health-care services must prioritise their use in light of the evidence of their benet and harm, a process referred to as ‘medicines management’. Drug development and marketing Naturally occurring products have been used to treat illnesses for thousands of years and some remain in common use today. Examples include morphine from the opium poppy (Papaver somniferum), dig- italis from the foxglove (Digitalis purpurea), curare from the bark of a variety of species of South American trees, and quinine from the bark of the Cinchona species. Although plants and animals remain a source of discovery, the majority of new drugs come from drug dis- covery programmes that aim to identify small-molecule compounds with specic interactions with a molecular target that will induce a predicted biological effect. The usual pathway for development of these small molecules includes: identifying a plausible molecular target by investigating pathways in dis- ease; screening a large library of compounds for those that interact with the molecular target in vitro; conducting extensive medicinal chemistry to optimise the properties of lead compounds; testing efcacy and toxicity of these compounds in vitro and in animals; and undertaking a clinical development programme (Box 2.15). This process typically takes longer than 10 years and may cost up to US$2 billion. Manufacturers have a dened period of exclusive marketing of the drug while it remains pro- tected by an original patent, typically 10–15 years, during which time they must recoup the costs of developing the drug. Meanwhile, com- petitor companies will often produce similar ‘me too’ drugs of the same class. Once the drug’s patent has expired, ‘generic’ manufacturers may step in to produce cheaper formulations of the drug. Paradoxically, if a generic drug is produced by only one manufacturer, the price may actu- ally rise, sometimes substantially. 2.15 Clinical development of new drugs Phase I Healthy volunteers (20–80) These involve initial single-dose, ‘rst-into-man’ studies, followed by repeated-dose studies. They aim to establish the basic pharmacokinetic and pharmacodynamic properties, and short-term safety Duration: 6–12 months Phase II Patients (100–200) These investigate clinical effectiveness (‘proof of concept’), safety and dose– response relationship, often with a surrogate clinical endpoint, in the target patient group to determine the optimal dosing regimen for larger conrmatory studies Duration: 1–2 years Phase III Patients (100s–1000s) These are large, expensive clinical trials that conrm safety and efcacy in the target patient population, using relevant clinical endpoints. They may be placebo-controlled studies or comparisons with other active compounds Duration: 1–2 years Phase IV Patients (100s–1000s) These are undertaken after the medicine has been marketed for its rst indication to evaluate new indications, new doses or formulations, long-term safety or cost-effectiveness
- 48. 26 CLINICALTHERAPEUTICS AND GOOD PRESCRIBING New therapeutic agents The traditional approach of targeting membrane-bound receptors and enzymes with small molecules (see Box 2.2) is now giving way to drug development that focuses on new targets, such as complex second- messenger systems, cytokines, nucleic acids and cellular networks (Box 2.16). These require the development of novel therapeutic agents, which are typically large molecules (e.g. human recombinant antibod- ies) manufactured by biological processes (‘biologics’) (Fig. 2.6). These present new challenges for ‘translational medicine’, the discipline of con- verting scientic discoveries into a useful medicine with a well-dened benet–risk prole, and also for health-care providers and prescribers. Manufacturers There are multiple challenges at every stage of the development and quality assurance of high-quality biological products. These include the initial molecular cloning process, development of clone expres- sion by stable cell lines, purication and characterisation procedures, performing post-translation modications, ensuring chemical stability, deploying novel sensitive bio-analytical methods and meeting strin- gent regulatory expectations. There are also new hurdles to overcome in the clinical development phase, including denition of the clinical indication with linked inclusion and exclusion criteria, study design and appropriate comparator product, selecting the appropriate ther- apeutic dose based on interpretation of pharmacokinetic/pharma- codynamic (PK/PD) data, and addressing specic safety concerns (notably immunogenicity) that arise after exposure to large biological molecules. Health services Biological drugs are often much more expensive than conventional synthetic molecules because of the complex manufacturing process outlined above, but also because they often have much narrower indi- cations for use based on specic molecular proling of the recipients. This means that the development costs have to be recouped from a rel- atively smaller patient group. After the patent for the originator product expires, other manufacturers may develop similar products (‘biosimi- lars’) that have the same pharmacological actions, but are not com- pletely identical because of inevitable differences that arise during a complex manufacturing process (e.g. glycosylation). For that reason, ‘biosimilars’ are not considered to be ‘generic’ medications, although they are usually considerably cheaper than the originator product. Nevertheless, the use of expensive biological agents is subject to par- ticular scrutiny with regard to cost-effectiveness and health services may put additional requirements in place prior to access (e.g. failure of conventional treatments). Prescribers For prescribers there are some important considerations when assessing the balance of benecial and adverse effects of biologics, for example, the use of recombinant antibodies for autoimmune inammatory conditions. Drugs such as iniximab or adalimumab carry a signicantly increased risk of infection when compared to classical disease-modifying anti-rheu- matic drugs (cDMARDs) and this risk is increased by age, co-morbidities and concomitant use of other immunosuppressant drugs (e.g. gluco- corticoids). Patients should be protected with appropriate vaccinations (e.g. inuenza, pneumococcus) and treatment is contra-indicated in the presence of active infection (e.g. hepatitis B, tuberculosis). The increased immunogenicity of large biological molecules has two important conse- quences. First, there is an increased chance of immediate and delayed hypersensitivity reactions (see Box 2.6). Second, the development of anti- drug antibodies can precipitate loss of effect. A recent Cochrane review of exposure to nine commonly used biologics for up to 5 years concluded that there was a 5% absolute increase in all adverse effects combined, a 1% absolute increase in risk of serious infection, but little or no increased risk of cancer or other serious outcomes. Licensing new medicines New drugs are given a ‘market authorisation’, based on the evidence of quality, safety and efcacy presented by the manufacturer. The regulator not only will approve the drug, but also will take great care to ensure that the accompanying information reects the evidence that has been presented. The summary of product characteristics (SPC), or ‘label’, provides detailed information about indications, dosage, adverse effects, warnings and monitoring requirements. If approved, drugs can be made available with different levels of restriction: Controlled drug (CD). These drugs are subject to strict legal controls on supply and possession, usually due to their abuse potential (e.g. opioid analgesics). Prescription-only medicine (PoM). These are available only from a pharmacist and can be supplied only if prescribed by an appropriate practitioner. Pharmacy (P). These are available only from a pharmacist, but can be supplied without a prescription. General sales list (GSL). These medicines may be bought ‘over the counter’ (OTC) from any shop and without a prescription. Although the regulators take great care to agree the exact indica- tions for prescribing a medicine, based on the evidence provided by the manufacturer, there are some circumstances in which prescribers may 2.16 Novel therapeutic alternatives to conventional small-molecule drugs Approaches Therapeutic indications Challenges Monoclonal antibodies Targeting of receptors or other molecules with relatively specic antibodies Cancer Chronic inammatory diseases (e.g. rheumatoid arthritis, inammatory bowel disease) Selectivity of action Complex manufacturing process Small interfering RNA (siRNA) Inhibition of gene expression Macular degeneration Delivery to target Gene therapy Delivery of modied genes that supplement or alter host DNA Cystic brosis Cancer Cardiovascular disease Delivery to target Adverse effects of delivery vector (e.g. virus) Stem cell therapy Stem cells differentiate and replace damaged host cells Parkinson’s disease Spinal cord injury Ischaemic heart disease Delivery to target Immunological compatibility Long-term effects unknown
- 49. Drug regulation andmanagement 27 2 Monoclonal antibodies e.g. infliximab, adalimumab 150000 Da Small-molecule drugs e.g. allopurinol 136 Da Other proteins e.g. interferons, enzymes, cytokines 10000 – 500000 Da A B Polypeptides e.g. insulin, glucagon 5000 – 50000 Da α β 7 20 7 19 s s s s s s Blood products e.g. red blood cells, white cells, platelets 1000000000000 Da C D Gene therapies e.g. alipogene tiparvovec 1000000 Da Antisense oligonucleotides e.g. nusinersin, inotersin 10000 Da mRNA E F Cell therapy e.g. CAR-T cells, embryonic stem cells 1000000000000 Da Vaccines e.g. Haemophilus, polio 50000000 Da G H Fig. 2.6 The mechanism of action and molecular weight of various types of biologic therapies. Cell therapies include injection of cells that replace damaged cells (e.g. embryonic stem cells) or manipulated immune cells that are targeted Vaccines are used to stimulate the immune system to respond to and remember specic antigens associated with viral or bacterial infections. (CAR-T cells = chimeric antigen recipient T cells; Da = Daltons; mRNA = messenger ribonucleic acid; TNF = tumour necrosis factor) direct its use outside the terms stated in the SPC (‘off-label’ prescribing). Common situations where this might occur include prescribing outside the approved age group (e.g. prescribing for children) or using an alter- native formulation (e.g. administering a medicine provided in a solid form as an oral solution). Other important examples might include prescribing for an indication for which there are no approved medicines or where all of the approved medicines have caused unacceptable adverse effects. Occasionally, medicines may be prescribed when there is no marketing authorisation in the country of use. Examples include when a medicine licensed in another country is imported for use for an individual patient (‘unlicensed import’) or when a patient requires a specic preparation of a medicine to be manufactured (‘unlicensed special’). When prescribing is ‘off-label’ or ‘unlicensed’, there is an increased requirement for pre- scribers to be able to justify their actions and to inform and agree the decision with the patient. Drug marketing The marketing activities of the pharmaceutical industry are well resourced and are important in the process of recouping the massive costs of drug development. In some countries, such as the United States, it is possible to promote a new drug by direct-to-consumer advertising, although this is illegal in the UK and countries of the European Union. A major focus is on promotion to prescribers via educational events, sponsorship of meetings, advertisements in journals, involvement with opinion leaders and direct contact by company representatives. Such largesse has the potential to cause signicant conicts of interest and might tempt pre- scribers to favour one drug over another, even in the face of evidence on effectiveness or cost-effectiveness. Managing the use of medicines Many medicines meet the three key regulatory requirements of quality, safety and efcacy. Although prescribers are legally entitled to prescribe any of them, it is desirable to limit the choice so that treatments for spe- cic diseases can be focused on the most effective and cost-effective options, prescribers (and patients) gain familiarity with a smaller number of medicines, and pharmacies can concentrate stocks on them. The process of ensuring optimal use of available medicines is known as ‘medicines management’ or ‘quality use of medicines’. It involves careful evaluation of the evidence of benet and harm from using the medicine, an assessment of cost-effectiveness and support for pro- cesses to implement the resulting recommendations. These activities usually involve both national (e.g. National Institute for Health and Care Excellence (NICE) in the UK) and local organisations (e.g. drug and ther- apeutics committees).
- 50. 28 CLINICALTHERAPEUTICS AND GOOD PRESCRIBING Evaluating evidence Drugs are often evaluated in high-quality randomised controlled trials, the results of which can be considered in systematic reviews (Fig. 2.7). Ideally, data are available not only for comparison with placebo, but also for ‘head-to-head’ comparison with alternative therapies. Trials are con- ducted in selected patient populations and so may not be representative of every clinical scenario; therefore, extrapolation to individual patients is not always straightforward. Other subtle bias may be introduced because of the sources of funding (e.g. pharmaceutical industry) and the interests of the investigators in being involved in research that has a ‘positive’ impact. These biases may be manifest in the way the trials are conducted or in how they are interpreted or reported. A common exam- ple of the latter is the difference between relative and absolute risk of clin- ical events reported in prevention trials. If a clinical event is encountered in the placebo arm at a rate of 1 in 50 patients (2%), but only 1 in 100 patients (1%) in the active treatment arm, then the impact of treatment can be described as either a 50% relative risk reduction or 1% absolute risk reduction. Although the former sounds more impressive, it is the latter that is of more importance to the individual patient. It means that the number of patients that needed to be treated (NNT) for 1 to benet (compared to placebo) was 100. This illustrates how large clinical trials of new medicines can produce highly statistically signicant and impressive relative risk reductions and still predict a very modest clinical impact. Evaluating cost-effectiveness New drugs often represent an incremental improvement over the current standard of care, but are usually more expensive. Health-care budgets are limited in every country and so it is impossible to fund all new medicines. This means that very difcult nancial decisions have to be taken with due regard to the principles of ethical justice. The main approach taken is cost-effectiveness analysis (CEA), where a comparison is made between the relative costs and outcomes of different courses of action. CEA is usu- ally expressed as a ratio where the denominator is a gain in health and the numerator is the cost associated with the health gain. A major challenge is to compare the value of interventions for different clinical outcomes. One method is to calculate the quality-adjusted life years (QALYs) gained if the new drug is used rather than standard treatment. This analysis involves estimating the ‘utility’ of various health states between 1 (perfect health) and 0 (dead). If the additional costs and any savings are known, then it is possible to derive the incremental cost-effectiveness ratio (ICER) in terms of cost/QALY. These principles are exemplied in Box 2.17. There are, however, inherent weaknesses in this kind of analysis: it usually depends on modelling future outcomes well beyond the duration of the clinical trial data; it assumes that QALYs gained at all ages are of equivalent value; and the appropriate standard care against which the new drug should be compared is often uncertain. These pharmacoeconomic assessments are challenging and resource-intensive, and are undertaken at national level in most coun- tries, e.g. in the UK by NICE. Implementing recommendations Many recommendations about drug therapy are included in clinical guide- lines written by an expert group after systematic review of the evidence. Guidelines provide recommendations rather than obligations for prescribers and are helpful in promoting more consistent and higher-quality prescrib- ing. They are often written without concern for cost-effectiveness, however, and may be limited by the quality of available evidence. Guidelines cannot anticipate the extent of the variation between individual patients who may, for example, have unexpected contraindications to recommended drugs or choose different priorities for treatment. When deviating from respected national guidance, prescribers should be able to justify their practice. Additional recommendations for prescribing are often implemented locally or imposed by bodies responsible for paying for health care. Most health-care units have a drug and therapeutics committee (or equivalent) comprised of medical staff, pharmacists and nurses, as well as manag- ers (because of the implications of the committee’s work for governance and resources). This group typically develops local prescribing policy and guidelines, maintains a local drug formulary and evaluates requests to use new drugs. The local formulary contains a more limited list than any national formulary (e.g. British National Formulary) because the latter lists all licensed medicines that can be prescribed legally, while the former contains only those that the health-care organisation has approved for local use. The local committee may also be involved, with local special- ists, in providing explicit protocols for management of clinical scenarios. Prescribing in practice Decision-making in prescribing Prescribing should be based on a rational approach to a series of chal- lenges (see Box 2.1). Odds ratio Favours treatment 0.1 0.2 0.5 1 2 5 10 Favours placebo Fig. 2.7 Systematic review of the evidence from randomised controlled clinical trials. This forest plot shows the effect of warfarin compared with placebo on the likelihood of stroke in patients with atrial brillation in ve randomised controlled trials that passed the quality criteria required for inclusion in a meta- analysis. For each trial, the purple box is proportionate to the number of participants. The tick marks show the mean odds ratio and the black lines indicate its 95% condence intervals. Note that not all the trials showed statistically signicant effects (i.e. the condence intervals cross 1.0). However, the meta-analysis, represented by the black diamond, conrms a highly signicant statistical benet. The overall odds ratio is approximately 0.4, indicating a mean 60% risk reduction with warfarin treatment in patients with the characteristics of the participants in these trials. 2.17 Cost-effectiveness analysis A clinical trial lasting 2 years compares two interventions for the treatment of colon cancer: Treatment A: standard treatment, cost £1000/year, oral therapy Treatment B: new treatment, cost £6000/year, monthly intravenous infusions, often followed by a week of nausea. The new treatment (B) signicantly increases the average time to progression (18 months versus 12 months) and reduces overall mortality (40% versus 60%). The health economist models the survival curves from the trial in order to undertake a cost–utility analysis and concludes that: Intervention A: allows an average patient to live for 2 extra years at a utility 0.7 = 1.4 QALYs (cost £2000) Intervention B: allows an average patient to live for 3 extra years at a utility 0.6 = 1.8 QALYs (cost £18000). The health economists conclude that treatment B provides an extra 0.4 QALYs at an extra cost of £16000, meaning that the ICER = £40000/QALY. They recommend that the new treatment should not be funded on the basis that their threshold for cost acceptability is £30000/QALY. (ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life year)
- 51. Prescribing in practice 29 2 Making a diagnosis Ideally, prescribing should be based on a conrmed diagnosis but, in reality, many prescriptions are based on the balance of probability, taking into account the differential diagnosis (e.g. proton pump inhibitors for post-prandial retrosternal discomfort). Establishing the therapeutic goal The goals of treatment are usually clear, particularly when relieving symp- toms (e.g. pain, nausea, constipation). Sometimes the goal is less obvi- ous to the patient, especially when aiming to prevent future events (e.g. ACE inhibitors to prevent hospitalisation and extend life in chronic heart failure). Prescribers should be clear about the therapeutic goal against which they will judge success or failure of treatment. It is also important to establish that the value placed on this goal by the prescriber is shared by the patient (concordance). Choosing the therapeutic approach For many clinical problems, drug therapy is not absolutely mandated. Having taken the potential benets and harms into account, prescribers must consider whether drug therapy is in the patient’s interest and is preferred to no treatment or one of a range of alternatives (e.g. physio- therapy, psychotherapy, surgery). Assessing the balance of benet and harm is often complicated and depends on various features associated with the patient, disease and drug (Box 2.18). Choosing a drug For most common clinical indications (e.g. type 2 diabetes, depression), more than one drug is available, often from more than one drug class. Although prescribers often have guidance about which represents the rational choice for the average patient, they still need to consider whether this is the optimal choice for the individual patient. Certain factors may inuence the choice of drug: Absorption Patients may nd some formulations easier to swallow than others or may be vomiting and require a drug available for parenteral administration. Distribution Distribution of a drug to a particular tissue sometimes dictates choice (e.g. tetracyclines and rifampicin are concentrated in the bile, and linco- mycin and clindamycin in bones). Metabolism Drugs that are extensively metabolised should be avoided in severe liver disease (e.g. opioid analgesics). Excretion Drugs that depend on renal excretion for elimination (e.g. digoxin, amino- glycoside antibiotics) should be avoided in patients with impaired renal function if suitable alternatives exist. Efcacy Prescribers normally choose drugs with the greatest efcacy in achieving the goals of therapy (e.g. proton pump inhibitors rather than H2 -receptor antagonists). It may be appropriate, however, to compromise on efcacy if other drugs are more convenient, safer to use or less expensive. Avoiding adverse effects Prescribers should be wary of choosing drugs that are more likely to cause adverse effects (e.g. cephalosporins rather than alternatives for patients allergic to penicillin) or worsen coexisting conditions (e.g. β-blockers as treatment for angina in patients with asthma). Features of the disease This is most obvious when choosing antibiotic therapy, which should be based on the known or suspected sensitivity of the infective organism. Severity of disease The choice of drug should be appropriate to disease severity (e.g. par- acetamol for mild pain, morphine for severe pain). Coexisting disease This may be either an indication or a contraindication to therapy. Hypertensive patients might be prescribed a β-blocker if they also have left ventricular impairment, but not if they have asthma. Avoiding adverse drug interactions Prescribers should avoid giving combinations of drugs that might inter- act, either directly or indirectly (see Box 2.12). Patient adherence to therapy Prescribers should choose drugs with a simple dosing schedule or eas- ier administration (e.g. the ACE inhibitor lisinopril once daily rather than captopril 3 times daily for hypertension). Cost Prescribers should choose the cheaper drug (e.g. a generic or biosimilar) if two drugs are of equal efcacy and safety. Even if cost is not a concern for the individual patient, it is important to remember that unnecessary expendi- ture will ultimately limit choices for other prescribers and patients. Sometimes a more costly drug may be appropriate (e.g. if it yields improved adherence). Genetic factors There are already a small number of examples where genotype inu- ences the choice of drug therapy (see Box 2.5). Choosing a dosage regimen Prescribers have to choose a dose, route and frequency of administra- tion (dosage regimen) to achieve a steady-state drug concentration that provides sufcient exposure of the target tissue without producing toxic effects. Manufacturers draw up dosage recommendations based on average observations in many patients, but the optimal regimen that will maximise the benet to harm ratio for an individual patient is never cer- tain. Rational prescribing involves treating each prescription as an exper- iment and gathering sufcient information to amend it if necessary. There are some general principles that should be followed, as described below. Dose titration Prescribers should generally start with a low dose and titrate this slowly upwards as necessary. This cautious approach is particularly important if the patient is likely to be more sensitive to adverse pharmacodynamic effects (e.g. delirium or postural hypotension in the elderly), if there may be altered pharmacokinetic handling (e.g. renal or hepatic impairment) and when using drugs with a low therapeutic index (e.g. benzodiazepines, lithium, digoxin). However, there are some exceptions. Some drugs must achieve therapeu- tic concentration quickly because of the clinical circumstance (e.g. antibiot- ics, glucocorticoids, carbimazole). When early effect is important, but there may be a delay in achieving steady state because of a drug’s long half-life (e.g. digoxin, warfarin, amiodarone), an initial loading dose is given prior to establishing the appropriate maintenance dose (see Fig. 2.4). 2.18 Factors to consider when balancing benets and harms of drug therapy Seriousness of the disease or symptom Efcacy of the drug Seriousness of potential adverse effects Likelihood of adverse effects Efcacy of alternative drugs or non-drug therapies Safety of alternative drugs or non-drug therapies
- 52. 30 CLINICALTHERAPEUTICS AND GOOD PRESCRIBING If adverse effects occur, the dose should be reduced or an alternative drug prescribed; in some cases, a lower dose may sufce if it can be combined with another synergistic drug (e.g. the immunosuppressant azathioprine reduces glucocorticoid requirements in patients with inam- matory disease). It is important to remember that the shape of the dose– response curve (see Fig. 2.2) means that higher doses may produce little added therapeutic effect and might increase the chances of toxicity. Route There are many reasons for choosing a particular route of administration (Box 2.19). Frequency Frequency of doses is usually dictated by a manufacturer’s recommen- dation. Less frequent doses are more convenient for patients, but result in greater uctuation between peaks and troughs in drug concentration (see Fig. 2.4). This is relevant if the peaks are associated with adverse effects (e.g. dizziness with antihypertensives) or the troughs are associ- ated with troublesome loss of effect (e.g. anti-Parkinsonian drugs). These problems can be tackled either by splitting the dose or by employing a modied-release formulation, if available. Timing For many drugs the time of administration is unimportant. There are occasionally pharmacokinetic or therapeutic reasons, however, for giving drugs at particular times (Box 2.20). Formulation For some drugs there is a choice of formulation, some for use by different routes. Some are easier to ingest, particularly by children (e.g. elixirs). The formulation is important when writing repeat prescriptions for drugs with a low therapeutic index that come in different formulations (e.g. lithium, phenytoin, theophylline). Even if the prescribed dose remains constant, an alternative formulation may differ in its absorption and bioavailabil- ity, and hence plasma drug concentration. These are examples of the small number of drugs that should be prescribed by specic brand name rather than ‘generic’ international non-proprietary name (INN). Duration Some drugs require a single dose (e.g. thrombolysis post-myocardial infarction), while for others the duration of the course of treatment is cer- tain at the outset (e.g. antibiotics). For most, the duration will be largely at the prescriber’s discretion and will depend on response and disease progression (e.g. analgesics, antidepressants). For many, the treatment will be long-term (e.g. insulin, antihypertensives, levothyroxine). Involving the patient Patients should, whenever possible, be engaged in making choices about drug therapy. Their beliefs and expectations affect the goals of therapy and help in judging the acceptable benet/harm balance when selecting treatments. Very often, patients may wish to defer to the pro- fessional expertise of the prescriber. Nevertheless, they play key roles in adherence to therapy and in monitoring treatment, not least by providing early warning of adverse events. It is important for them to be provided with the necessary information to understand the choice that has been made, what to expect from the treatment, and any measurements that must be undertaken (Box 2.21). A major drive to include patients has been the recognition that up to half of the drug doses for chronic preventative therapy are not taken. This is often termed ‘non-compliance’, but is more appropriately called ‘non-adherence’, to reect a less paternalistic view of the doctor–patient relationship; it may or may not be intentional. Non-adherence to the dose regimen reduces the likelihood of benets to the patient and can be costly in terms of wasted medicines and unnecessary health-care episodes. An important reason may be lack of concordance with the prescriber about the goals of treatment. A more open and shared decision-making process might resolve any misunderstandings at the outset and foster improved adherence, as well as improved satisfaction with health-care services and condence in prescribers. Considerable efforts are now made to help patients to access the reliable information they require to engage more fully with clinicians. Patient-focused websites and leaets provided by national services, local health-care providers and charities are increasingly supplementing the Patient Information Leaet (PIL) approved by the regu- latory authorities and supplied with all medicines. Fully engaging patients in shared decision-making is sometimes constrained by various factors, such as limited consultation time, language barriers and challenges in communicating complex numerical data. Writing the prescription The culmination of the planning described above is writing an accurate and legible prescription so that the drug will be dispensed and adminis- tered as planned (see ‘Writing prescriptions’ below). Monitoring treatment effects Rational prescribing involves monitoring for the benecial and adverse effects of treatment so that the balance remains in favour of a positive outcome (see ‘Monitoring drug therapy’ below). Stopping drug therapy It is also important to review long-term treatment at regular intervals to assess whether continued treatment is required. Elderly patients are keen to reduce their medication burden and are often prepared to compromise on the original goals of long-term preventative therapy to achieve this. 2.19 Factors inuencing the route of drug administration Reason Example Only one route possible Dobutamine (IV) Gliclazide (oral) Patient adherence Phenothiazines and thioxanthenes (2 weekly IM depot injections rather than daily tablets, in schizophrenia) Poor absorption Furosemide (IV rather than oral, in severe heart failure) Rapid action Haloperidol (IM rather than oral, in acute behavioural disturbance) Vomiting Phenothiazines (PR or buccal rather than oral, in nausea) Avoidance of rst-pass metabolism Glyceryl trinitrate (SL, in angina pectoris) Certainty of effect Amoxicillin (IV rather than oral, in acute chest infection) Direct access to the site of action (avoiding unnecessary systemic exposure) Bronchodilators (INH rather than oral, in asthma) Local application of drugs to skin, eyes etc. Ease of access Diazepam (PR, if IV access is difcult in status epilepticus) Adrenaline (epinephrine) (IM, if IV access is difcult in acute anaphylaxis) Comfort Morphine (SC rather than IV in terminal care) (IM = intramuscular; INH = by inhalation; IV = intravenous; PR = per rectum; SC = subcutaneous; SL = sublingual)
- 53. Prescribing in practice 31 2 Prescribing in special circumstances Prescribing for patients with renal disease Patients with renal impairment are identied by a low estimated glomer- ular ltration rate (eGFR <60mL/min/1.73m2 ), based on their serum cre- atinine, age, sex and ethnic group (see Box 18.1). This group includes a large proportion of elderly patients. If a drug (or its active metabolites) is eliminated predominantly by the kidneys, it will tend to accumulate and so the maintenance dose must be reduced. For some drugs, renal impairment makes patients more sensitive to their adverse pharmacody- namic effects. Examples of drugs that require extra caution in patients with renal disease are listed in Box 2.22. Prescribing for patients with hepatic disease The liver has a large capacity for drug metabolism and hepatic insuf- ciency has to be advanced before drug dosages need to be modi- ed. Patients who may have impaired metabolism include those with jaundice, ascites, hypoalbuminaemia, malnutrition or encephalopathy. Hepatic drug clearance may also be reduced in acute hepatitis, in hepatic congestion due to cardiac failure and in the presence of intra- hepatic arteriovenous shunting (e.g. in hepatic cirrhosis). There are no good tests of hepatic drug-metabolising capacity or of biliary excre- tion, so dosage should be guided by the therapeutic response and careful monitoring for adverse effects. The presence of liver disease also increases the susceptibility to adverse pharmacological effects of drugs. Some drugs that require extra caution in patients with hepatic disease are listed in Box 2.22. Prescribing for older patients The issues around prescribing in old age are discussed in Box 2.23. Prescribing for women who are pregnant or breastfeeding Prescribing in pregnancy should be avoided if possible to minimise the risk of adverse effects in the fetus. Drug therapy in pregnancy may, however, be required either for a pre-existing problem (e.g. epilepsy, asthma, hypothyroidism) or for problems that arise during pregnancy (e.g. morning sickness, anaemia, prevention of neural tube defects, gestational diabetes, hypertension). About 35% of women take drug 2.20 Factors inuencing the timing of drug therapy Drug Recommended timing Reasons Diuretics (e.g. furosemide) Once in the morning Night-time diuresis undesirable Statins (e.g. simvastatin) Once at night HMG CoA reductase activity is greater at night Antidepressants (e.g. amitriptyline) Once at night Allows adverse effects to occur during sleep Salbutamol Before exercise Reduces symptoms in exercise-induced asthma Glyceryl trinitrate When required Relief of acute symptoms only Paracetamol Regular nitrate therapy (e.g. isosorbide mononitrate) Eccentric dosing regimen (e.g. twice daily at 8 a.m. and 2 p.m.) Reduces development of nitrate tolerance by allowing drug-free period each night Aspirin With food Minimises gastrotoxic effects Alendronate Once in the morning before breakfast, sitting upright Minimises risk of oesophageal irritation Tetracyclines 2 hours before or after food or antacids Divalent and trivalent cations chelate tetracyclines, preventing absorption Hypnotics (e.g. temazepam) Once at night Maximises therapeutic effect and minimises daytime sedation Antihypertensive drugs (e.g. amlodipine) Once in the morning Blood pressure is higher during the daytime (HMG CoA = 3-hydroxy-3-methylglutaryl-coenzyme A) 2.21 What patients need to know about their medicines* Knowledge Comment The reason for taking the medicine Reinforces the goals of therapy How the medicine works How to take the medicine May be important for the effectiveness (e.g. inhaled salbutamol in asthma) and safety (e.g. alendronate for osteoporosis) of treatment What benets to expect May help to support adherence or prompt review because of treatment failure What adverse effects might occur Discuss common and mild effects that may be transient and might not require discontinuation Mention rare but serious effects that might inuence the patient’s consent Precautions that improve safety Explain symptoms to report that might allow serious adverse effects to be averted, monitoring that will be required and potentially important drug–drug interactions When to return for review This will be important to enable monitoring *Many medicines are provided with patient information leaets, which the patient should be encouraged to read.
- 54. 32 CLINICALTHERAPEUTICS AND GOOD PRESCRIBING therapy at least once during pregnancy and 6% take drug therapy during the rst trimester (excluding iron, folic acid and vitamins). The most commonly used drugs are simple analgesics, antibacterial drugs and antacids. Some considerations when prescribing in pregnancy are listed in Box 2.24. Drugs that are excreted in breast milk may cause adverse effects in the baby. Prescribers should always consult the SPC for each drug or a relia- ble formulary when treating a pregnant woman or breastfeeding mother. Writing prescriptions A prescription is a means by which a prescriber communicates the intended plan of treatment to the pharmacist who dispenses a med- icine and to a nurse or patient who administers it. It should be pre- cise, accurate, clear and legible. The two main kinds of prescription are those written, dispensed and administered in hospital and those written in primary care (in the UK by a GP), dispensed at a community pharmacy and self-administered by the patient. The information sup- plied must include: the date the identication details of the patient the name of the drug the formulation the dose the frequency of administration the route and method of administration the amount to be supplied (primary care only) instructions for labelling (primary care only) the prescriber’s signature. Prescribing in hospital Although primary care prescribing is increasingly electronic, many hos- pital prescriptions continue to be based around the prescription and administration record (the ‘drug chart’) (Fig. 2.8). A variety of charts are in use and prescribers must familiarise themselves with the local version. Most contain the following sections: Basic patient information: will usually include name, age, date of birth, hospital number and address. These details are often ‘lled in’ using a sticky addressograph label, but this increases the risk of serious error. Previous adverse reactions/allergies: communicates important patient safety information based on a careful drug history and/or the medical record. Other medicines charts: notes any other hospital prescription doc- uments that contain current prescriptions being received by the patient (e.g. anticoagulants, insulin, oxygen, uids). Once-only medications: for prescribing medicines to be used infrequently, such as single-dose prophylactic antibiotics and other pre-operative medications. 2.22 Some drugs that require extra caution in patients with renal or hepatic disease Kidney disease Liver disease Pharmacodynamic effects enhanced ACE inhibitors and ARBs (renal impairment, hyperkalaemia) Metformin (lactic acidosis) Spironolactone (hyperkalaemia) NSAIDs (impaired renal function) Sulphonylureas (hypoglycaemia) Insulin (hypoglycaemia) Warfarin (increased anticoagulation because of reduced clotting factor synthesis) Metformin (lactic acidosis) Chloramphenicol (bone marrow suppression) NSAIDs (gastrointestinal bleeding, uid retention) Sulphonylureas (hypoglycaemia) Benzodiazepines (coma) Pharmacokinetic handling altered (reduced clearance) Aminoglycosides (e.g. gentamicin) Vancomycin Other antibiotics (e.g. ciprooxacin) Digoxin Lithium Atenolol Allopurinol Cephalosporins Methotrexate Opioids (e.g. morphine) Phenytoin Rifampicin Propranolol Warfarin Diazepam Lidocaine Opioids (e.g. morphine) (ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; NSAID = non- steroidal anti-inammatory drug) 2.23 Prescribing in old age Reduced drug elimination: partly due to impaired renal function. Increased sensitivity to drug effects: notably in the brain (leading to sedation or delirium) and as a result of comorbidities. More drug interactions: largely as a result of polypharmacy. Lower starting doses and slower dose titration: often required, with careful monitoring of drug effects. Drug adherence: may be poor because of cognitive impairment, difculty swallowing (dry mouth) and complex polypharmacy regimens. Supplying medicines in pill organisers (e.g. dosette boxes or calendar blister packs), providing automatic reminders, and regularly reviewing and simplifying the drug regimen can help. Some drugs that require extra caution, and their mechanisms Digoxin: increased sensitivity of Na+ /K+ pump; hypokalaemia due to diuretics; renal impairment favours accumulation→increased risk of toxicity. Antihypertensive drugs: reduced baroreceptor function→increased risk of postural hypotension. Antidepressants, hypnotics, sedatives, tranquillisers: increased sensitivity of the brain; reduced metabolism→increased risk of toxicity. Warfarin: increased tendency to falls and injury and to bleeding from intra- and extracranial sites; increased sensitivity to inhibition of clotting factor synthesis→increased risk of bleeding. Amitriptyline, diltiazem, lidocaine, metoprolol, morphine, propranolol, theophylline: metabolism reduced→increased risk of toxicity. Non-steroidal anti-inammatory drugs: poor renal function→increased risk of renal impairment; susceptibility to gastrotoxicity→increased risk of upper gastrointestinal bleeding. 2.24 Prescribing in pregnancy Teratogenesis: a potential risk, especially when drugs are taken between 2 and 8 weeks of gestation (4–10 weeks from last menstrual period). Common teratogens include retinoids (e.g. isotretinoin), cytotoxic drugs, angiotensin- converting enzyme inhibitors, antiepileptics (e.g. sodium valproate) and warfarin. If there is inadvertent exposure, then the timing of conception should be established, counselling given and investigations undertaken for fetal abnormalities. Adverse fetal effects in late gestation: e.g. tetracyclines may stain growing teeth and bones; sulphonamides displace fetal bilirubin from plasma proteins, potentially causing kernicterus; opioids given during delivery may be associated with respiratory depression in the neonate. Altered maternal pharmacokinetics: extracellular uid volume and Vd increase. Plasma albumin falls but other binding globulins (e.g. for thyroid and steroid hormones) increase. Glomerular ltration increases by approximately 70%, enhancing renal clearance. Placental metabolism contributes to increased clearance, e.g. of levothyroxine and glucocorticoids. The overall effect is a fall in plasma concentration of many drugs. In practice Avoid any drugs unless the risk:benet analysis is in favour of treating (usually the mother). Use drugs for which there is some record of safety in humans. Use the lowest dose for the shortest time possible. Choose the least harmful drug if alternatives are available.
- 55. Prescribing in practice 33 2 Regular medications: for prescribing medicines to be taken for a number of days or continuously, such as a course of antibiotics or antihypertensive drugs. ‘As required’ medications: for prescribing for symptomatic relief, usually to be administered at the discretion of the nursing staff (e.g. antiemetics, analgesics). Prescribers should be aware of the risks of prescription error (Box 2.25 and see Box 2.14), ensure they have considered the rational basis for their prescribing decision and then follow the guidance illustrated in Figure 2.8 in order to write the prescription. It is a basic principle that a prescription will be followed by a judgement as to its success or failure and any appropriate changes made (e.g. altered dosage, discontinuation or substitution). Hospital discharge (‘to take out’) medicines Most patients will be prescribed a short course of their medicines at discharge. This prescription is particularly important because it usually informs future therapy at the point of transfer of prescribing responsibility to primary care. Great care is required to ensure that this list is accurate. It is particularly important to ensure that any hospital medicines that should be stopped are not included and that those intended to be administered for a short duration only are clearly iden- tied. It is also important for any signicant ADRs experienced in hos- pital to be recorded and any specic monitoring or review identied. Prescribing in primary care Most of the considerations above are equally applicable to primary care (GP) prescriptions. In many health-care systems, community prescrib- ing is electronic, making issues of legibility irrelevant and often providing basic decision support to limit the range of doses that can be written and highlight potential drug interactions. Important additional issues more rel- evant to GP prescribing are: OTHER MEDICINES CHARTS CODES FOR NON-ADMINISTRATION OF PRESCRIBED MEDICINE PREVIOUS ADVERSE REACTIONS (This must be completed before prescribing on this chart) Hospital number: (Attach printed label here) D.O.B.: Weight: Date Date Time Medicine (approved name) Dose Route Time given Given by Prescriber – sign and print If a dose is not administered as prescribed, intial and enter a code in the column with a circle drawn round the code according to the reason as shown below. Inform the responsible doctor of the appropriate timescale. 1. Patient refuses 2. Patient not present 3. Medicines not available – CHECK ORDERED 4. Asleep/drowsy 5. Administration route not available – CHECK FOR ALTERNATIVE 6. Vomiting/nausea 7. Time varied on doctor’s instructions 8. Once-only/as-required medicine given 9. Dose withheld on doctor’s instructions 10. Possible adverse reaction/side-effect Type of chart Medicine Description of reaction Completed by Date Height: If rewritten, date: DISCHARGE PRESCRIPTION PRESCRIPTION AND ADMINISTRATION RECORD Standard Chart ONCE-ONLY MEDICINES Date completed:– Completed by:– A B Fig. 2.8 Example of a hospital prescription and administration record (‘drug chart’). Front page. The correct identication of the patient is critical to reducing the risk of an administration error. This page also clearly identies other prescriptions charts in use and previous adverse reactions to drugs to minimise the risk of repeated exposure. Note also the codes employed by the nursing staff to indicate reasons why drugs may not have been administered. The patient’s name and date of birth should be written on ‘Once-only medicines’ This area is used for prescribing medicines that are unlikely to be repeated on a regular basis. Note that the prescriber has written the names of all drugs legibly in block capitals. The generic international non-proprietary name (INN) should be used in preference to the brand name (e.g. write ‘SIMVASTATIN’, not ‘ZOCOR’). The only exceptions are when variation occurs in the properties of alternative branded formulations (e.g. modied-release preparations of drugs such as lithium, theophylline, phenytoin and nifedipine) or when the drug is a combination product with no generic name (e.g. Kliovance®). The only acceptable abbreviations for drug dose units are ‘g’ and ‘mg’. ‘Units’ (e.g. of insulin or heparin) and ‘micrograms’ must always be written in full, never as ‘U’ or ‘µg’ (nor ‘mcg’, nor ‘ug’). For liquid preparations write the dose in mg; ‘mL’ can be written only for a combination product (e.g. Gaviscon liquid) or if the strength is not expressed in weight (e.g. adrenaline (epinephrine) 1 in 1000). Use numbers/gures (e.g. 1 or ‘one’) to denote use of a sachet/enema but avoid prescribing numbers of tablets without specifying their strength. Always include the dose of inhaled drugs in addition to stating numbers of ‘puffs’, as strengths can vary. Widely accepted abbreviations for route of administration are: intravenous – ‘IV’; intramuscular – ‘IM’; subcutaneous – ‘SC’; sublingual – ‘SL’; per rectum – ‘PR’; per vaginam – ‘PV’; nasogastric – ‘NG’; inhaled – ‘INH’; and topical – ‘TOP’. ‘ORAL’ is preferred to per oram – ‘PO’. Care should be taken in specifying ‘RIGHT’ or ‘LEFT’ for eye and ear drops. The prescriber should sign and print their name clearly so that they can be identied by colleagues. The prescription should be dated and have an administration time. The nurse who administered the prescription has signed to conrm that the dose has been administered. (Continues overleaf)
- 56. 34 CLINICALTHERAPEUTICS AND GOOD PRESCRIBING REGULAR MEDICINES AS-REQUIRED THERAPY Drug (approved name) Dose Date Time 6 8 12 14 18 22 6 8 12 14 18 22 6 8 12 14 18 22 Prescriber–sign and print Notes Start date Pharmacy Route Drug (approved name) Dose Prescriber–sign and print Notes Start date Pharmacy Route Drug (approved name) Dose and frequency Prescriber–sign and print Start date Route Date Time Dose Initials Date Time Dose Initials Drug (approved name) Dose and frequency Route Date Time Dose Initials Date Time Dose Initials Drug (approved name) Dose Prescriber–sign and print Notes Start date Pharmacy Route C D Fig. 2.8, cont’d ‘Regular medicines’. This area is used for prescribing medicines that are going to be given regularly. In addition to the name, dose and route, a frequency of administration is required for each medicine. Widely accepted Latin abbreviations for dose frequency are: once daily – ‘OD’; twice daily – ‘BD’; 3 times daily – ‘TDS’; 4 times daily – ‘QDS’; as required – ‘PRN’; in the morning – ‘OM’ (omni mane); at night – ‘ON’ (omni nocte); and immediately – ‘stat’. The hospital chart usually requires specic times to be identied for regular medicines that coincide with nursing drug rounds and these can be circled. If treatment is for a known time period, cross off subsequent days when the medicine is not required. The ‘notes’ box can be used to communicate additional important information (e.g. whether a medicine should be taken with food, type of inhaler device used, and anything else that the drug dispenser should know). State here the times for peak/trough plasma levels for drugs requiring therapeutic monitoring. Prescriptions should be discontinued by drawing a vertical line at the point of discontinuation, horizontal lines through the remaining days on the chart, and diagonal lines through the drug details and administration boxes. This action should be signed and dated and a supplementary note written to explain it (e.g. describing any adverse effect). In this example, amlodipine has been discontinued because of ankle oedema. There is room for the ward pharmacist to sign to indicate that the prescription has been reviewed and that a supply of the medicine is available. The administration boxes allow the nurse to sign to conrm that the dose has been given. Note that these boxes also allow for recording of reasons for non-administration (in this example ‘2’ indicates that the patient was not present on the ward at the time) and the prevention of ‘As-required medicines’. These prescriptions leave the administration of the drug to the discretion of the nursing staff. The prescription must describe clearly the indication, frequency, minimal time interval between doses, and maximum dose in any 24-hour period (in this case, the maximum daily dose of paracetamol is 4g). Formulation. The prescription needs to carry information about the formulation for the dispensing pharmacist (e.g. tablets or oral suspension). Amount to be supplied. A pharmacist will organise this in hospital. Elsewhere it must be specied either as the precise number of tab- lets or as the duration of treatment. Creams and ointments should be specied in grams and lotions in mL. Controlled drugs. Prescriptions for ‘controlled’ drugs (e.g. opioid analgesics, with potential for drug abuse) are subject to additional legal requirements. In the UK, they must contain the address of the patient and prescriber (not necessary on most hospital forms), the form and the strength of the preparation, and the total quantity of the preparation/number of dose units in both words and gures. ‘Repeat prescriptions’. A large proportion of GP prescribing involves ‘repeat prescriptions’ for chronic medication. These are often gen- erated automatically, although the prescriber remains responsible for regular review and for ensuring that the benet-to-harm ratio remains favourable.
- 57. Prescribing in practice 35 2 Monitoring drug therapy Prescribers should measure the effects of the drug, both benecial and harmful, to inform decisions about dose titration (up or down), discontinu- ation or substitution of treatment. Monitoring can be achieved subjectively by asking the patient about symptoms or, more objectively, by measuring a clinical effect, which may be possible to assess by clinical examination (e.g. eczematous rash), physiological measurement (e.g. blood pressure, pulse oximetry), imaging (e.g. chest X-ray, CT scan) or laboratory tests (e.g. haemoglobin, INR (International Normalised Ratio)). Alternatively, if the phar- macodynamic effects of the drug are difcult to assess, the plasma drug concentration may be measured, if this is closely related to the effect of the drug (see Fig. 2.2). Rational prescribing ultimately rests on continuous monitoring of the balance between the risks and benets of drug therapy. Common examples are ACE inhibitors (negative impact on renal function versus blood pressure-lowering), cancer chemotherapy (bone marrow suppression versus radiological tumour regression) and disease-modifying anti-rheumatic drugs (liver toxicity versus anti-inammatory effect). Advances in therapeutics have also led to increasing complexity of ongoing monitoring requirements. The recognition that hospital specialist clinics cannot take on the responsibility for monitoring of all chronic disease therapy has led to the development of ‘shared care protocols’ that aim to share monitoring activ- ities between specialists and primary care physicians with the aim of max- imising efcient use of health-care resources and convenience for patients. Clinical and surrogate endpoints Ideally, clinical endpoints are measured directly and the drug dosage titrated to achieve the therapeutic goal and avoid toxicity (e.g. control of ventricular rate in a patient with atrial brillation, monitoring anticoagulation using INR). Sometimes this is impractical because the clinical endpoint is a future event (e.g. prevention of myocardial infarction by statins or resolution of a chest infection with antibiotics); in these circumstances, it may be possible to select a ‘surrogate’ endpoint that will predict success or failure. This may be an intermediate step in the pathophysiological process (e.g. serum choles- terol as a surrogate for risk of myocardial infarction) or a measurement that follows the pathophysiology, even if it is not a key factor in its progression (e.g. serum C-reactive protein as a surrogate for resolution of inammation in chest infection, TSH as a surrogate for adequate replacement of levo- thyroxine). Such surrogates are sometimes termed ‘biomarkers’. Plasma drug concentration The following criteria must be met to justify routine monitoring by plasma drug concentration: Clinical endpoints and other pharmacodynamic (surrogate) effects are difcult to monitor. The relationship between plasma concentration and clinical effects is predictable. The therapeutic index is low. For drugs with a high therapeutic index, any variability in plasma concentrations is likely to be irrele- vant clinically. Some examples of drugs that full these criteria are listed in Box 2.26. Measurement of plasma concentration may be useful in planning adjustments of drug dose and frequency of administration; to explain an inadequate therapeutic response (by identifying subtherapeutic con- centration or incomplete adherence); to establish whether a suspected ADR is likely to be caused by the drug; and to assess and avoid potential drug interactions. Timing of samples in relation to doses The concentration of drug rises and falls during the dosage interval (see Fig. 2.4B). Measurements made during the initial absorption and 2.25 High-risk prescribing moments Trying to amend an active prescription (e.g. altering the dose/timing) – always avoid and start again Writing up drugs in the immediate presence of more than one prescription chart or set of notes – avoid Allowing one’s attention to be diverted in the middle of completing a prescription – avoid Prescribing ‘high-risk’ drugs (e.g. anticoagulants, opioids, insulin, sedatives) – ask for help if necessary Prescribing parenteral drugs – take care Rushing prescribing (e.g. in the midst of a busy ward round) – avoid Prescribing unfamiliar drugs – consult the formulary and ask for help if necessary Transcribing multiple prescriptions from an expired chart to a new one – take care to review the rationale for each medicine Writing prescriptions based on information from another source such as a referral letter (the list may contain errors and some of the medicines may be the cause of the patient’s illness) – review the justication for each as if it is a new prescription Writing up ‘to take out’ drugs (because these will become the patient’s regular medication for the immediate future) – take care and seek advice if necessary Calculating drug doses – ask a colleague to perform an independent calculation or use approved electronic dose calculators Prescribing sound-alike or look-alike drugs (e.g. chlorphenamine and chlorpromazine) – take care 2.26 Drugs commonly monitored by plasma drug concentration Drug Half-life (hrs)* Comment Digoxin 36 Steady state takes several days to achieve. Samples should be taken 6hrs post dose. Measurement is useful to conrm the clinical impression of toxicity or non-adherence but clinical effectiveness is better assessed by ventricular heart rate. Risk of toxicity increases progressively at concentrations >1.5µg/L, and is likely at concentrations >3.0µg/L (toxicity is more likely in the presence of hypokalaemia) Gentamicin 2 Measure pre-dose trough concentration (should be <1mg/L) to ensure that accumulation (and the risk of nephrotoxicity and ototoxicity) is avoided; see Fig. 6.18 Lithium 24 Steady state takes several days to achieve. Samples should be taken 12hrs post dose. Target range 0.4–1mmol/L Phenytoin 24 Measure pre-dose trough concentration (should be 10–20mg/L) to ensure that accumulation is avoided. Good correlation between concentration and toxicity. Concentration may be misleading in the presence of hypoalbuminaemia Theophylline (oral) 6 Steady state takes 2–3 days to achieve. Samples should be taken 6hrs post dose. Target concentration is 10–20mg/L but its relationship with bronchodilator effect and adverse effects is variable Vancomycin 6 Measure pre-dose trough concentration (should be 10–15mg/L) to ensure clinical efcacy and that accumulation and the risk of nephrotoxicity are avoided *Half-lives vary considerably with different formulations and between patients.
- 58. 36 CLINICALTHERAPEUTICS AND GOOD PRESCRIBING distribution phases are unpredictable because of the rapidly changing concentration, so samples are usually taken at the end of the dosage interval (a ‘trough’ or ‘pre-dose’ concentration). This measurement is normally made in steady state, which usually takes 5 half-lives to achieve after the drug is introduced or the dose changed (unless a loading dose has been given). Interpreting the result A target range is provided for many drugs, based on average thresh- olds for therapeutic benet and toxicity. Inter-individual variability means that these can be used only as a guide. For instance, in a patient who describes symptoms that could be consistent with toxicity, but has a drug concentration in the top half of the target range, toxic effects should still be suspected. Another important consideration is that some drugs are heavily protein-bound (e.g. phenytoin), but only the unbound drug is pharmacologically active. Patients with hypoalbuminaemia may, there- fore, have a therapeutic or even toxic concentration of unbound drug, despite a low ‘total’ concentration. Further information Websites bnf.org The British National Formulary (BNF) is a key reference resource for UK NHS prescribers, with a list of licensed drugs, chapters on prescribing in renal failure, liver disease, pregnancy and during breastfeeding, and appendices on drug interactions cochrane.org The Cochrane Collaboration is a leading international body that provides evidence-based reviews (around 7000 so far) evidence.nhs.uk NHS Evidence provides a wide range of health information relevant to delivering quality patient care icp.org.nz The Interactive Clinical Pharmacology site is designed to increase understanding of principles in clinical pharmacology medicines.org.uk/emc/ The electronic medicines compendium (emc) contains up-to-date, easily accessible information about medicines licensed by the UK Medicines and Healthcare Products Regulatory Agency (MHRA) and the European Medicines Agency (EMA) nice.org.uk The UK National Institute for Health and Care Excellence makes recommendations to the UK NHS on new and existing medicines, treatments and procedures who.int/health-topics/medicines The World Health Organization Essential Medicines and Pharmaceutical Policies
- 59. Multiple Choice Questions 2.1.Which of the following drugs for type 2 diabetes acts on a transporter protein? A. Gliclazide B. Dapagliozin C. Metformin hydrochloride D. Pioglitazone E. Sitagliptin Answer: B. Dapagliozin is a sodium-glucose co-transporter 2 inhibitor that is indicated for the treatment of type 2 diabetes mellitus. Dapagliozin improves glycaemic control by inhibiting glucose re-absorption in the proximal tubule of the nephron leading to excretion of excess glucose in the urine (glycosuria). 2.2. Which of the following is a prodrug that depends on hepatic metabolism for conversion to its active form? A. Amlodipine B. Clopidogrel C. Metoprolol D. Simvastatin E. Tramadol Answer: B. Clopidogrel binds specically and irreversibly to the platelet P2RY12 purinergic receptor to inhibit ADP-mediated platelet activation and aggregation. Clopidogrel is a prodrug that is absorbed in the intestine and activated in the liver. The conversion of clopidogrel to its active metabolite involves two sequential oxidation reactions that involve vari- ous cytochrome P450 isoforms (CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4/5). 2.3. A 52-year-old man who is being treated with azathioprine 150mg orally daily to maintain remission from Crohn’s disease presents to hospital with severe pancytopenia. Which of his other current medicines (listed below) is most likely to have interacted with azathioprine to cause this adverse drug reaction? A. Allopurinol 200mg orally daily B. Atorvastain 20mg orally daily C. Indapamide 2.5mg orally daily D. Metronidazole 400mg orally three times daily E. Omeprazole 20mg orally daily Answer: A. Allopurinol inhibits the enzyme xanthine oxidase (XO), which is one of the three enzymes responsible for inactivating 6-mercaptopurine, its active purine metabolite. Normally, XO is needed to convert the purine base hypoxanthine to xanthine and then xanthine to uric acid. Allopurinol is a structural analogue of hypoxanthine and binds to XO, thereby inhib- iting its effect on purine metabolism. 2.4. Which of the following regular medicines is most likely to require a dose reduction in a patient who develops chronic renal impairment (chronic kidney disease stage 3)? A. Bendroumethiazide 2.5mg orally daily B. Digoxin 125micrograms orally daily C. Fluoxetine 20mg orally daily D. Simvastatin 20mg orally nightly E. Verapamil hydrochloride m/r 120mg orally daily Answer: B. Digoxin is mainly eliminated by renal excretion and there is a risk of toxicity if the dosage is not reduced as renal function deteriorates. Bendroumethiazide becomes less effective as renal function deterior- ates but does not require a dose reduction (unless there is evidence that dehydration is a contributory factor). Simvastatin should be used with caution if the eGFR falls below 30mL/min/1.73m2 . Verapamil is eliminated by hepatic metabolism. Fluoxetine does not require dose adjustment. 2.5. Which of the following aspects of a new drug is not considered by drug regulators but considered by heath-care providers (e.g. a hospital drug and therapeutics committee)? A. Manufacturing standards B. Safety prole C. Efcacy in treating the clinical indication D. Cost-effectiveness E. Patient information Answer: D. The role of national drug regulatory authorities is to ensure that any new medicine meets minimum acceptable standards of quality, safety and efcacy prior to being granted a market authorisation. It is not the role of the regulator to assess cost-effectiveness which is devolved to national or local health technology assessments that may compare the new drug with other available treatment options.
- 60. Clinical genetics 3 K Tatton-Brown Thefundamental principles of genomics 38 The packaging of genes: DNA, chromatin and chromosomes 38 From DNA to protein 38 Non-coding RNA 40 Cell division, differentiation and migration 40 Cell death, apoptosis and senescence 41 Genomics, health and disease 41 Classes of genetic variant 41 Consequences of genomic variation 42 Normal genomic variation 45 Constitutional genetic disease 45 Somatic genetic disease 49 Interrogating the genome: the changing landscape of genomic technologies 50 Looking at chromosomes 50 Looking at genes 50 Genomics and clinical practice 52 Genomics and health care 52 Genomics in infectious disease 55 Treatment of genetic disease 56 Ethics in a genomic age 56
- 61. 38 CLINICALGENETICS We have entered a genomic era. Powerful new technologies are driving forward transformational change in health care. Genetic sequencing has evolved from the targeted sequencing of a single gene to the parallel sequencing of multiple genes. In addition to improving the chances of identifying a genetic cause of rare diseases, these technologies are increasingly directing therapies and, in the future, are likely to be used in the diagnosis and prevention of common diseases such as diabetes. In this chapter we explore the fundamentals of genomics, the basic prin- ciples underlying these new genomic technologies and how the data generated can be applied safely for patient benet. We will review the use of genomic technology across a breadth of medical specialties, including obstetrics, paediatrics, oncology and infectious disease, and consider how health care is being transformed by these new genomic technolo- gies. Finally, we will consider the ethical impact that these technologies are likely to have, both for the individual and for their wider family. The fundamental principles of genomics The packaging of genes: DNA, chromatin and chromosomes Genes are functional units encoded in double-stranded deoxyribonucleic acid (DNA), packaged as chromosomes and located in the nucleus of the cell: a membrane-bound compartment found in all cells except erythro- cytes and platelets (Fig. 3.1). DNA consists of a linear sequence of just four bases: adenine (A,) cytosine (C), thymine (T) and guanine (G.) It forms a ‘double helix’, a twisted ladder-like structure formed from two comple- mentary strands of DNA joined by hydrogen bonds between bases on the opposite strand that can form only between a C and a G base and an A and a T base. It is this feature of DNA that enables faithful DNA replica- tion and is the basis for many of the technologies designed to interrogate the genome: when the DNA double helix ‘unzips’, one strand can act as a template for the creation of an identical strand. A single copy of the human genome comprises approximately 3.1 billion base pairs of DNA, wound around proteins called histones. The unit consisting of 147 base pairs wrapped around four different histone proteins is called the nucleosome. Sequences of nucleosomes (resembling a string of beads) are wound and packaged to form chroma- tin: tightly wound, densely packed chromatin is called heterochromatin and open, less tightly wound chromatin is called euchromatin. The chromatin is nally packaged into the chromosomes. Humans are diploid organisms: the nucleus contains two copies of the genome, visible microscopically as 23 chromosome pairs (known as the karyo- type). Chromosomes 1 through to 22 are known as the autosomes and consist of identical chromosome pairs. The 23rd ‘pair’ of chromosomes are the two sex chromosomes: females have two X chromosomes and males an X and Y chromosome. A normal female karyotype is therefore written as 46,XX and a normal male is 46,XY. From DNA to protein Genes are functional elements on the chromosome that are capable of transmitting information from the DNA template via the production of messenger ribonucleic acid (mRNA) to the production of proteins. The human genome contains over 20000 genes, although many of these are inactive or silenced in different cell types, reecting the varia- ble gene expression responsible for cell-specic characteristics. The central dogma is the pathway describing the basic steps of protein production: transcription, splicing, translation and protein modication (Fig. 3.2). Although this is now recognised as an over-simplication (con- trary to this linear relationship, a single gene will often encode many different proteins), it remains a useful starting point to explore protein production. Transcription: DNA to messenger RNA Transcription describes the production of ribonucleic acid (RNA) from the DNA template. For transcription to commence, an enzyme called RNA polymerase binds to a segment of DNA at the start of the gene: the pro- moter. Once bound, RNA polymerase moves along one strand of DNA, producing an RNA molecule complementary to the DNA template. In protein-coding genes this is known as messenger RNA (mRNA). A DNA sequence close to the end of the gene, called the polyadenylation signal, acts as a signal for termination of the RNA transcript (Fig. 3.3). DNA helix Histones Chromatin Chromosome Normal female karyotype Nucleosome A T G A C G G A T T A C T G C C T A Fig. 3.1 The packaging of DNA, genes and chromosomes. From bottom to top: the double helix and the complementary DNA bases; chromatin; and a normal female chromosome pattern – the karyotype. DNA 5’CGATTC3’ 3’GCTAAG5’ 5’CGAUUC3’ N_ArgPhe_C RNA Protein Transcription Translation Fig. 3.2 The central dogma of protein production. Double-stranded DNA as a template for single-stranded RNA, which codes for the production of a peptide chain of amino acids. Each of these chains has an orientation. For DNA and RNA, this is 5 to 3 . For peptides, this is N-terminus to C-terminus.
- 62. The fundamental principlesof genomics 39 3 RNA differs from DNA in three main ways: RNA is single-stranded. The sugar residue within the nucleotide is ribose, rather than deoxyribose. It contains uracil (U) in place of thymine (T). The activity of RNA polymerase is regulated by transcription fac- tors. These proteins bind to specic DNA sequences at the promoter or to enhancer elements that may be many thousands of base pairs away from the promoter; a loop in the chromosomal DNA brings the enhancer close to the promoter, enabling the bound proteins to interact. The human genome encodes more than 1200 different tran- scription factors. Mutations (now more frequently referred to as gene variants) within transcription factors, promoters and enhancers can cause disease. For example, the blood disorder alpha-thalassaemia is usually caused by gene deletions (see Box 3.4). However, it can also result from a variant in an enhancer located more than 100000 base pairs (bp) from the α-globin gene promoter, leading to greatly reduced transcription. Gene activity, or expression, is inuenced by a number of complex interacting factors, including the accessibility of the gene promoter to transcription factors. DNA can be modied by the addition of a methyl group to cytosine molecules (methylation). If DNA methylation occurs in promoter regions, transcription is silenced, as methyl cytosines are usually not available for transcription factor binding. A second mecha- nism determining promoter accessibility is the structural conguration of chromatin. In open chromatin, called euchromatin, gene promoters are accessible to RNA polymerase and transcription factors; therefore it is transcriptionally active. This contrasts with heterochromatin, which is densely packed and transcriptionally silent. The chromatin conguration is determined by modications (such as methylation or acetylation) of specic amino acid residues of histone protein tails. Modications of DNA and histone protein tails are termed epigenetic (‘epi-’ meaning ‘above’ the genome), as they do not alter the primary sequence of the DNA code but have biological signicance in chromo- somal function. Abnormal epigenetic changes are increasingly recognised as important events in the progression of cancer, allowing expression of normally silenced genes that result in cancer cell de-differentiation and proliferation. They also afford therapeutic targets. For instance, the his- tone deacetylase inhibitor vorinostat has been successfully used to treat cutaneous T-cell lymphoma, due to the re-expression of genes that had previously been silenced in the tumour. These genes encode transcrip- tion factors that promote T-cell differentiation as opposed to proliferation, thereby causing tumour regression. RNA splicing, editing and degradation Transcription produces an RNA molecule that is a copy of the whole gene, termed the primary or nascent transcript. This nascent transcript then undergoes splicing, whereby regions not required to make pro- tein (the intronic regions) are removed while those segments that are necessary for protein production (the exonic regions) are retained and rejoined. Splicing is a highly regulated process that is carried out by a multimeric protein complex called the spliceosome. Following splicing, the mRNA molecule is exported from the nucleus and used as a template for pro- tein synthesis. Many genes produce more than one form of mRNA (and thus protein) by a process termed alternative splicing, in which different combinations of exons are joined together. Different proteins from the same gene can have entirely distinct functions. For example, in thyroid C cells the calcitonin gene produces mRNA encoding the osteoclast inhib- itor calcitonin, but in neurons the same gene produces an mRNA with a different complement of exons via alternative splicing that encodes a neurotransmitter, calcitonin-gene-related peptide. Protein product N-term C-term cap Messenger RNA (mRNA) Messenger RNA (mRNA) AAAAA tRNAs Ribosome Nuclear membrane Primary RNA transcript Spliceosome RNA export to cytoplasm cap cap AAAAA PolyA tail 3'UTR 5'UTR Nuclear pore AAAAA Splicing Transcription 3' 5' 3' Sense strand Enhancer Transcription factors RNA polymerase II Exon 1 Intron 2 Intron 1 Exon 2 Exon 3 Exon 1 Exon 2 Exon 3 Promoter Nucleolus Nuclear membrane Gene A Gene B Gene C Active gene RNA Nucleus Translation Fig. 3.3 RNA synthesis and its translation into protein. Gene transcription involves binding of RNA polymerase II to the promoter of genes being transcribed with other proteins (transcription factors) that regulate the transcription rate. The primary RNA transcript is a copy of the whole gene and includes both introns and exons, but the introns are removed within the nucleus by splicing and the exons are joined to form the messenger RNA (mRNA). Prior to export from the nucleus, a methylated guanosine nucleotide is added to the 5 end of the RNA (‘cap’) and a string of adenine nucleotides is added to the 3 (‘polyA tail’). This protects the RNA from degradation and facilitates transport into the cytoplasm. In the cytoplasm, the mRNA binds to ribosomes and forms a template for protein production. (tRNA = transfer RNA; UTR = untranslated region)
- 63. 40 CLINICALGENETICS Translation and protein production Following splicing, the segment of mRNA containing the code that directs synthesis of a protein product is called the open reading frame (ORF). The inclusion of a particular amino acid in the protein is specied by a codon composed of three contiguous bases. There are 64 different codons with some redundancy in the system: 61 codons encode one of the 20 amino acids, and the remaining three codons – UAA, UAG and UGA (known as stop codons) – cause termination of the growing polypeptide chain. ORFs in humans most commonly start with the amino acid methionine. All mRNA molecules have domains before and after the ORF called the 5 untranslated region (UTR) and 3 UTR, respectively. The start of the 5 UTR contains a cap structure that protects mRNA from enzymatic degradation, and other elements within the 5 UTR are required for efcient translation. The 3 UTR also contains elements that regulate efciency of translation and mRNA stability, including a stretch of adenine bases known as a polyA tail (see Fig. 3.3). The mRNAs then leave the nucleus via nuclear pores and associate with ribosomes, the sites of protein production (see Fig. 3.3). Each ribo- some consists of two subunits (40S and 60S), which comprise non-cod- ing rRNA molecules (see Fig. 3.9) complexed with proteins. During translation, a different RNA molecule known as transfer RNA (tRNA) binds to the ribosome. The tRNAs deliver amino acids to the ribosome so that the newly synthesised protein can be assembled in a stepwise fashion. Individual tRNA molecules bind a specic amino acid and ‘read’ the mRNA ORF via an ‘anticodon’ of three nucleotides that is comple- mentary to the codon in mRNA (see Fig. 3.3). A proportion of ribosomes is bound to the membrane of the endoplasmic reticulum (ER), a complex tubular structure that surrounds the nucleus. Proteins synthesised on these ribosomes are translocated into the lumen of the ER, where they undergo folding and processing. From here, the protein may be transferred to the Golgi apparatus, where it under- goes post-translational modications, such as glycosylation (covalent attachment of sugar moieties), to form the mature protein that can be exported into the cytoplasm or packaged into vesicles for secretion. The clinical importance of post-translational modication of proteins is shown by the severe developmental, neurological, haemostatic and soft tissue abnormalities that are associated with the many different congenital dis- orders of glycosylation. Post-translational modications can also be dis- rupted by the synthesis of proteins with abnormal amino acid sequences. For example, the most common CFTR gene variant that causes cystic brosis (ΔF508) results in an abnormal protein that cannot be exported from the ER and Golgi (see Box 3.4). Non-coding RNA Approximately 4500 genes in humans encode non-coding RNAs (ncRNA) rather than proteins. There are various categories of ncRNA, including transfer RNA (tRNA), ribosomal RNA (rRNA), ribozymes and microRNA (miRNA). The miRNAs, which number over 1000, have a role in post-translational gene expression: they bind to mRNAs, typically in the 3 UTR, promoting target mRNA degradation and gene silenc- ing. Together, miRNAs affect over half of all human genes and have important roles in normal development, cancer and common degen- erative disorders. This is the subject of considerable research interest at present. Cell division, differentiation and migration In normal tissues, molecules such as hormones, growth factors and cytokines provide the signal to activate the cell cycle: a controlled pro- gramme of biochemical events that culminates in cell division. In all cells of the body, except the gametes (the sperm and egg cells, also known as the germ line), mitosis completes cell division, resulting in two diploid daughter cells. In contrast, the sperm and eggs cells com- plete cell division with meiosis, resulting in four haploid daughter cells (Fig. 3.4). The stages of cell division in the non-germ-line, somatic cells are shown below: Cells not committed to mitosis are said to be in G0 Cells committed to mitosis must go through the preparatory phase of interphase consisting of G1 , S and G2 G1 (rst gap): synthesis of the cellular components necessary to complete cell division S (synthesis): DNA replication producing identical copies of each chromosome called the sister chromatids Egg Sperm Father Mother Meiotic cell divisions 1st polar bodies 2nd polar body DNA replication Sister chromatids Homologous pairing Swapping of genetic material between homologues: Recombination Individual chromosome pair (homologues) Non-disjunction of chromosomes is a common error in human meiosis, resulting in trisomy of individual chromosomes or uniparental disomy (both chromosomes from single parent) Fig. 3.4 Meiosis and gametogenesis: the main chromosomal stages of meiosis in both males and females. A single homologous pair of chromosomes is represented in different colours. The nal step is the production of haploid germ cells. Each round of meiosis in the male results in four sperm cells; in the female, however, only one egg cell is produced, as the other divisions are sequestered on the periphery of the mature egg as peripheral polar bodies.
- 64. Genomics, health anddisease 41 3 G2 (second gap): repair of any errors in the replicated DNA before proceeding to mitosis. Mitosis (M) consists of four phases: Prophase: the chromosomes condense and become visible, the centrioles move to opposite ends of the cell and the nuclear membrane disappears. Metaphase: the centrioles complete their migration to opposite ends of the cell and the chromosomes – consisting of two identical sister chromatids – line up at the equator of the cell. Anaphase: spindle bres attach to the chromosome and pull the sister chromatids apart. Telophase: the chromosomes decondense, the nuclear membrane reforms and two daughter cells – each with 46 chromosomes – are formed. The progression from one phase to the next is tightly controlled by cell-cycle checkpoints. For example, the checkpoint between G2 and mitosis ensures that all damaged DNA is repaired prior to segregation of the chromosomes. Failure of these control processes is a crucial driver in the pathogenesis of cancer, as discussed on page 130. Meiosis is a special, gamete-specic, form of cell division (see Fig. 3.4). Like mitosis, meiosis consists of four phases (prophase, metaphase, anaphase and telophase) but differs from mitosis in the following ways: It consists of two separate cell divisions known as meiosis I and meiosis II. It reduces the chromosome number from the diploid to the haploid number via a tetraploid stage, i.e. from 46 to 92 (MI S) to 46 (MI M) to 23 (MII M) chromosomes, so that when a sperm cell fertilises the egg, the resulting zygote will return to a diploid, 46, chromosome complement. This reduction to the haploid number occurs at the end of meiosis II. The 92 chromosome stage consists of 23 homologous pairs of sister chromatids, which then swap genetic material, a process known as recombination. This occurs at the end of MI prophase and ensures that the chromosome that a parent passes to his or her offspring is a mix of the chromosomes that the parent inherited from his or her own mother and father. The individual steps in meiotic cell division are similar in males and females. However, the timing of the cell divisions is very different. In females, meiosis begins in fetal life but does not complete until after ovu- lation. A single meiotic cell division can thus take more than 40 years to complete. As women become older, the separation of chromosomes at meiosis II becomes less efcient. That is why the risk of trisomies (p. 42) due to non-disjunction grows greater with increasing maternal age. In males, meiotic division does not begin until puberty and contin- ues throughout life. In the testes, both meiotic divisions are completed in a matter of days. Cell death, apoptosis and senescence With the exception of stem cells, human cells have only a limited capac- ity for cell division. The Hayick limit is the number of divisions a cell population can go through in culture before division stops and enters a state known as senescence. This ‘biological clock’ is of great interest in the study of the normal ageing process. Rare human diseases associ- ated with premature ageing, called progeric syndromes, have been very helpful in identifying the importance of DNA repair mechanisms in senes- cence. For example, in Werner syndrome, a DNA helicase (an enzyme that separates the two DNA strands) is mutated, leading to failure of DNA repair and premature ageing. A distinct mechanism of cell death is seen in apoptosis, or programmed cell death. Apoptosis is an active process that occurs in normal tissues and plays an important role in development, tissue remodelling and the immune response. The signal that triggers apoptosis is specic to each tissue or cell type. This signal activates enzymes, called caspases, which actively destroy cellular components, including chromosomal DNA. This degradation results in cell death, but the cellular corpse contains characteristic vesicles called apoptotic bodies. The corpse is then recognised and removed by phagocytic cells of the immune system, such as macrophages, in a manner that does not provoke an inammatory response. A third mechanism of cell death is necrosis. This is a pathological pro- cess in which the cellular environment loses one or more of the compo- nents necessary for cell viability. Hypoxia is probably the most common cause of necrosis. Genomics, health and disease Classes of genetic variant There are many different classes of variation in the human genome, cat- egorised by the size of the DNA segment involved and/or by the mecha- nism giving rise to the variation. Nucleotide substitutions The substitution of one nucleotide for another is the most common type of genomic variation. This is caused by misincorporation of a nucleotide during DNA synthesis or by chemical modication of the base. When these substitutions occur within ORFs of a protein-coding gene, they are further classied into: synonymous – resulting in a change in the codon without altering the amino acid non-synonymous (also known as a missense variant) – resulting in a change in the codon and the encoded amino acid stop gain (or nonsense variant) – introducing a premature stop codon and resulting in truncation of the protein splicing – disruption of normal splicing and therefore most frequently occurring at the junctions between an intron and an exon. These different types of gene variants are illustrated in Box 3.1 and examples are shown in Figs. 3.5 and 3.6. Insertions and deletions One or more nucleotides may be inserted or lost in a DNA sequence, resulting in an insertion/deletion (indel) variant (see Box 3.1 and Fig. 3.5). If a multiple of three nucleotides is involved, this is in-frame. If an indel change affects one or two nucleotides within the ORF of a protein-coding gene, this can have serious consequences because the triple nucleotide sequence of the codons is disrupted, resulting in a frameshift variant. The effect on the gene is typically severe because the amino acid sequence is totally disrupted. Simple tandem repeat variants Variations in the length of simple tandem repeats of DNA are thought to arise as the result of slippage of DNA during meiosis and are termed microsatellite (small) or minisatellite (larger) repeats. These repeats are unstable and can expand or contract in different generations. This instability is proportional to the size of the original repeat, in that longer repeats tend to be more unstable. Many microsatellites and minisat- ellites occur in introns or in chromosomal regions between genes and have no obvious adverse effects. However, some genetic diseases are caused by microsatellite repeats that result in duplication of amino acids within the affected gene product or affect gene expression (Box 3.2).
- 65. 42 CLINICALGENETICS 3.1 Classes of genetic variant The classes of genetic variant can be illustrated using the sentence ‘THE FAT FOX WAS ILL COS SHE ATE THE OLD CAT’ Synonymous Silent polymorphism with no amino acid change THE FAT FOX WAS ILL COS SHE ATE THE OLD KAT where the C is replaced with a K but the meaning remains the same Non-synonymous Causing an amino acid change THE FAT BOX WAS ILL COS SHE ATE THE OLD CAT where the F of FOX is replaced by B and the original meaning of the sentence is lost Stop-gain (also called a nonsense variant) Causing the generation of a premature stop codon THE CAT where the F of FAT is replaced by a C, generating a premature stop codon Indel Where the bases are either inserted or deleted; disruption of the reading frame is dependent on the number of bases inserted or deleted THE FAT FOX WAS ILL ILL COS SHE ATE THE OLD CAT where the insertion of three bases results in maintenance of the reading frame THE FAT FOX WAW ASI LLC OSS HEA TET HEO LDC AT where the insertion of two bases results in disruption of the reading frame Fig. 3.5 Different types of mutation affecting coding exons. Normal Silent polymorphism (no amino acid change) Missense variant causing Lys–Gln amino acid change ‘G’ insertion causing frameshift variant Nonsense variant causing premature termination codon A B C D E mosaic distribution) does not occur, but Turner syndrome, in which there is monosomy for the X chromosome, affects approximately 1 in 2500 live births (Box 3.3). Large insertions or deletions of chromosomal DNA also occur and are usually associated with a learning disability and/or congenital malforma- tions. Such structural chromosomal anomalies usually arise as the result of one of two different processes: non-homologous end-joining non-allelic homologous recombination. Random double-stranded breaks in DNA are a necessary process in meiotic recombination and also occur during mitosis at a predictable rate. The rate of these breaks is dramatically increased by exposure to ionising radiation. When such breaks take place, they are usually repaired accu- rately by DNA repair mechanisms within the cell. However, in a proportion of breaks, segments of DNA that are not normally contiguous will be joined (‘non-homologous end-joining’). If the joined fragments are from different chromosomes, this results in a translocation. If they are from the same chromosome, this will result in either inversion, duplication or deletion of a chromosomal fragment (Fig. 3.7). Large insertions and deletions may be cytogenetically visible as chromosomal deletions or duplications. If the anomalies are too small to be detected by microscopy, they are termed microdeletions and microduplications. Many microdeletion syndromes have been described and most result from non-allelic homologous recom- bination between repeats of highly similar DNA sequences, which leads to recurrent chromosome anomalies – and clinical syndromes – occurring in unrelated individuals (see Fig. 3.7 and Box 3.3). Consequences of genomic variation The consequence of an individual genomic variant depends on many factors, including the variant type, the nature of the gene product and the position of the variant in the protein. Variants can have profound or subtle effects on gene and cell function. Variations that have profound effects are responsible for ‘classical’ genetic diseases, whereas those with sub- tle effects may contribute to the pathogenesis of common disease where there is a genetic component, such as diabetes. Neutral variants have no effect on quality or type of protein produced. Copy number variations Variation in the number of copies of an individual segment of the genome from the usual diploid (two copies) content can be categorised by the size of the segment involved. Rarely, individuals may gain (trisomy) or lose (monosomy) a whole chromosome. Such numerical chromosome anom- alies most commonly occur by a process known as non-disjunction, where pairs of homologous chromosomes do not separate at meio- sis II (p. 40). Common trisomies include Down syndrome (trisomy 21), Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13). Monosomy of the autosomes (present in all the cells, as opposed to in a
- 66. Genomics, health anddisease 43 3 Fig. 3.6 Splice-site variants. result, splicing no longer occurs, leading to read-through of the mRNA into the intron, which contains a premature termination codon downstream of the variant. Normal Splice-site variant Splice donor site Exon Exon Intron Exon Exon Intron Intron removed by splicing Splice acceptor site mRNA ‘reads through’ intron Abnormal protein with premature stop codon A B 3.2 Diseases associated with triplet and other repeat expansions* Repeat No. of repeats Gene Gene location Inheritance Normal Mutant Coding repeat expansion Huntington’s disease [CAG] 6–34 >35 Huntingtin 4p16 AD Spinocerebellar ataxia (type 1) [CAG] 6–39 >40 Ataxin 6p22–23 AD Spinocerebellar ataxia (types 2, 3, 6, 7) [CAG] Various Various Various Various AD Dentatorubral-pallidoluysian atrophy [CAG] 7–25 >49 Atrophin 12p12–13 AD Machado–Joseph disease [CAG] 12–40 >67 MJD 14q32 AD Spinobulbar muscular atrophy [CAG] 11–34 >40 Androgen receptor Xq11–12 XL recessive Non-coding repeat expansion Myotonic dystrophy [CTG] 5–37 >50 DMPK-3 UTR 19q13 AD Friedreich’s ataxia [GAA] 7–22 >200 Frataxin-intronic 9q13 AR Progressive myoclonic epilepsy [CCCCGCCCCGCG]4–8 2–3 >25 Cystatin B-5 UTR 21q AR Fragile X mental retardation [CGG] 5–52 >200 FMR1–5 UTR Xq27 XL dominant Fragile site mental retardation 2 (FRAXE) [GCC] 6–35 >200 FMR2 Xq28 XL, probably recessive *The triplet repeat diseases fall into two major groups: those with disease stemming from expansion of [CAG]n repeats in coding DNA, resulting in multiple adjacent glutamine residues (polyglutamine tracts), and those with non-coding repeats. The latter tend to be longer. Unaffected parents usually display ‘pre-mutation’ allele lengths that are just above the normal range. (AD/AR = autosomal dominant/recessive; UTR = untranslated region; XL = X-linked) Loss-of-function variants result in loss or reduction in the normal protein function. Whole-gene deletions are the archetypal loss-of- function variants but stop-gain or indel variants (early in the ORF), missense variants affecting a critical domain and splice-site variants can also result in loss of protein function. Gain-of-function variants result in a gain of protein function. They are typically non-synonymous variants that alter the protein structure, leading to activation/alteration of its normal function through causing either an interaction with a novel substrate or a change in its normal function. Dominant negative variants are the result of non-synonymous sub- stitutions or in-frame deletions/duplications but may also, less fre- quently, be caused by triplet repeat expansions. Dominant negative variants are heterozygous changes that result in the production of an abnormal protein that interferes with the normal functioning of the wild-type protein.
- 67. 44 CLINICALGENETICS 3.3 Chromosome and contiguous gene disorders Disease Locus Incidence Clinical features Numerical chromosomal abnormalities Down syndrome (trisomy 21) 47,XY,+21 or 47,XX+21 1 in 800 Characteristic facies, IQ usually <50, congenital heart disease, reduced life expectancy Edwards syndrome (trisomy 18) 47,XY,+18 or 47,XX,+18 1 in 6000 Early lethality, characteristic skull and facies, frequent malformations of heart, kidney and other organs Patau syndrome (trisomy 13) 47,XY,+13 or 47, XX,+13 1 in 15000 Early lethality, cleft lip and palate, polydactyly, small head, frequent congenital heart disease Klinefelter syndrome 47,XXY 1 in 1000 Phenotypic male, infertility, gynaecomastia, small testes XYY 47,XYY 1 in 1000 Usually asymptomatic, some impulse control problems Triple X syndrome 47,XXX 1 in 1000 Usually asymptomatic, may have reduced IQ Turner syndrome 45,X 1 in 5000 Phenotypic female, short stature, webbed neck, coarctation of the aorta, primary amenorrhoea Recurrent deletions, microdeletions and contiguous gene defects Di George/velocardiofacial syndrome 22q11.2 1 in 4000 Cardiac outow tract defects, distinctive facial appearance, thymic hypoplasia, cleft palate and hypocalcaemia. Major gene seems to be TBX1 (cardiac defects and cleft palate) Prader–Willi syndrome 15q11–q13 1 in 15000 Distinctive facial appearance, hyperphagia, small hands and feet, distinct behavioural phenotype. Imprinted region, deletions on paternal allele in 70% of cases Angelman syndrome 15q11–q13 1 in 15000 Distinctive facial appearance, absent speech, electroencephalogram (EEG) abnormality, characteristic gait. Imprinted region, deletions on maternal allele encompassing UBE3A Williams syndrome 7q11.23 1 in 10000 Distinctive facial appearance, supravalvular aortic stenosis, learning disability and infantile hypercalcaemia. Major gene for supravalvular aortic stenosis is elastin Smith–Magenis syndrome 17p11.2 1 in 25000 Distinctive facial appearance and behavioural phenotype, self-injury and rapid eye movement (REM) sleep abnormalities. Major gene seems to be RAI1 Fig. 3.7 Chromosomal analysis and structural chromosomal disorders. acrocentric if the centromere is at the end. The bands of each chromosome are given a number, starting at the centromere and working out along the short (p) arm and long (q) arm. Translocations and inversions are balanced structural chromosome anomalies where no genetic material is missing but it is in the wrong order. Translocations can be divided into reciprocal (direct swap of chromosomal material between non-homologous chromosomes) and Robertsonian (fusion of acrocentric chromosomes). Deletions and duplications can also occur due to non-allelic homologous recombination (illustrated in part B). Deletions are classied as interstitial if they lie within a chromosome, and terminal if the terminal region of the chromosome is affected. Duplications can be either in tandem (where the duplicated fragment is inserted next to the region that is duplicated and orientated in the correct direction) or inverted (where the duplicated fragment is in the wrong direction). (N = normal; A = allelic homologous recombination, can occur (right panel), resulting in a deletion on one chromosome and a duplication in the homologous chromosome. The error is induced by tandem repeats in the DNA sequences (green), which can misalign and bind to each other, thereby ‘fooling’ the DNA into thinking the pairing prior to recombination is correct. Chromosome 9 Cen p 23 21 12 12 21.1 21.3 21.2 31 33 34.2 q Cen p N N A N A N A N A N A N A A 13 (sa) (st) 11.2 12 21 23 24.2 31 32.2 q Metacentric Acrocentric Chromosome 14 Reciprocal translocation Robertsonian translocation Inversions Interstitial Terminal Tandem Inverted Mechanism underlying recurrent deletions and duplication: non-allelic homologous recombination How structural chromosomal anomalies are described Deletions Duplications B A Recombination Normal pairing Abnormal pairing between DNA repeats Deletion Duplication 1 1 1 2 1 2 1 2 2 2 2 DNA repeat Maternal chromosome Paternal chromosome 1 1 2 1 2
- 68. Genomics, health anddisease 45 3 Normal genomic variation We each have 3–5 million variants in our genome, occurring approxi- mately every 300 bases. These variants are mostly polymorphisms, aris- ing in more than 1% of the population; they have no or subtle effects on gene and cell function, and are not associated with a high risk of disease. Polymorphisms can occur within exons, introns or the intergenic regions that comprise 98%–99% of the human genome. Each of the classes of genetic variant discussed in this chapter (Box 3.1) is present in the genome as a common polymorphism. However, the most frequent is the single nucleotide polymorphism, or SNP (pronounced ‘snip’), describing the substitution of a single base. Polymorphisms and common disease The protective and detrimental polymorphisms associated with common disease have been identied primarily through genome-wide association studies (GWAS, p. 52) and are the basis for many direct-to-consumer tests that purport to determine individual risk proles for common diseases or traits such as cardiovascular disease, diabetes and even male-pattern baldness! An example is the polymorphism in the gene SLC2A9 that not only explains a signicant proportion of the normal population variation in serum urate concentration but also predisposes ‘high-risk’ allele carriers to the development of gout. However, the current reality is that, until we have a more comprehensive understanding of the full genomic landscape and knowledge of the complete set of detrimental and protective poly- morphisms, we cannot accurately assess risk. Evolutionary selection Genetic variants play an important role in evolutionary selection, with advantageous variants resulting in positive selection via improved reproductive tness, and variations that decrease reproductive tness becoming excluded through evolution. Given this simple paradigm, it would be tempting to assume that common variants are all advan- tageous and all rare variants are pathogenic. Unfortunately, it is often difcult to classify any common variant as either advantageous or dele- terious – or, indeed, neutral. Variants that are advantageous in early life and thus enhance reproductive tness may be deleterious in later life. There may be variants that are advantageous for survival in particular conditions (e.g. famine or pandemic) that may be disadvantageous in more benign circumstances by causing a predisposition to obesity or autoimmune disorders. Constitutional genetic disease Familial genetic disease is caused by constitutional variants, which are inherited through the germ line. However, different variants in the same gene can have different consequences, depending on the genetic mech- anism underlying that disease. About 1% of the human population car- ries constitutional pathogenic variants that cause disease. Constructing a family tree The family tree – or pedigree – is a fundamental tool of the clinical geneticist, who will routinely take a three-generation family history, on both sides of the family, enquiring about details of all medical conditions in family members, consanguinity, dates of birth and death, and any history of pregnancy loss or infant death. The basic symbols and nomenclature used in drawing a pedigree are shown in Fig. 3.8 Fig. 3.8 Drawing a pedigree and patterns of inheritance. inheritance (see text for details). SB Male Clinically affected Deceased individual (with age at death) Separated Consanguinity Clinically affected, several diagnoses Carrier Positive pre- symptomatic test Monozygotic twins Dizygotic twins Stillbirth (with gestation) Termination Miscarriage (with gestation) Unknown sex Female Partners Recessive inheritance Dominant inheritance Mitochondrial DNA disorder X-linked recessive inheritance Transmission to 50% of offspring independent of gender Consanguinity Affected males related through unaffected females Both sexes affected but only inherited through female meiosis I II III IV I II III IV I II III IV V I II III IV 1 1 1 2 2 3 4 2 3 4 5 6 1 2 3 4 1 1 1 2 2 3 4 2 3 4 5 6 3 6 7 5 6 7 8 1 1 1 2 2 3 4 2 3 4 5 6 1 2 3 4 1 1 1 2 2 3 4 2 3 4 5 6 1 2 3 4 d. 50 y 30 wk SB 39 wk 16 wk A B
- 69. 46 CLINICALGENETICS Patterns of disease inheritance Autosomal dominant inheritance Take some time to draw out the following pedigree: Anne is referred to Clinical Genetics to discuss her personal history of colon cancer (she was diagnosed at the age of 46 years) and family history of colon/endometrial cancer: her mother was diagnosed with endometrial cancer at the age of 60 years and her cousin through her healthy maternal aunt was diagnosed with colon cancer in her fties. Both her maternal grandmother and grandfather died of ‘old age’. There is no family history of note on her father’s side of the family. He has one brother and both his parents died of old age, in their eighties. Anne has two healthy daughters, aged 12 and 14 years, and a healthy full sister. This family history is typical of an autosomal dominant condition (see Fig. 3.8): in this case, a colon/endometrial cancer susceptibility syn- drome known as Lynch syndrome, associated with disruption of one of the mismatch repair genes: MSH2, MSH6, MLH1 and PMS2 (see Ch. 23 and Box 3.11). Features of an autosomal dominant pedigree include: There are affected individuals in each generation (unless the patho- genic variant has arisen de novo, i.e. for the rst time in an affected individual). However, variable penetrance and expressivity can inuence the number of affected individuals and the severity of dis- ease in each generation. Penetrance is dened as the proportion of individuals bearing a mutated allele who develop the disease phe- notype. The variant is said to be fully penetrant if all individuals who inherit a variant develop the disease. Expressivity describes the level of severity of each aspect of the disease phenotype. Males and females are usually affected in roughly equal numbers (unless the clinical presentation of the condition is gender-specic, such as an inherited susceptibility to breast and/or ovarian cancer). The offspring risk for an individual affected with an autosomal domi- nant condition is 1 in 2 (or 50%). This offspring risk is true for each preg- nancy, since half the affected individual gametes (sperm or egg cells) will contain the affected chromosome/gene and half will contain the normal chromosome/gene. There is a long list of autosomal dominant conditions, some of which are shown in Box 3.4 Autosomal recessive inheritance As above, take some time to draw a pedigree representing the following: Mr and Mrs Kent, a non-consanguineous couple, are referred because their son, Jamie, had severe neonatal liver disease. Included among the many investigations that the paediatric hepatologist under- took was testing for α1 -antitrypsin deciency (Box 3.5). Jamie was shown to have the PiZZ phenotype. Testing conrmed both parents as carriers with PiMZ phenotypes. In the family, Jamie has an older sister who has no medical problems. Mr Kent is one of four children with two brothers and a sister and Mrs Kent has a younger brother. Both sets of grandparents are alive and well. There is no family history of α1 -an- titrypsin deciency. This family history is characteristic of an autosomal recessive disor- der (see Fig. 3.8), where both alleles of a gene must be mutated before the disease is manifest in an individual; an affected individual inherits one mutant allele from each of their parents, who are therefore healthy carriers for the condition. An autosomal recessive condition might be suspected in a family where: Males and females are affected in roughly equal proportions. Parents are blood-related; this is known as consanguinity. Where there is consanguinity, the variant are usually homozygous, i.e. the same mutant allele is inherited from both parents. Individuals within one sibship in one generation are affected and so the condition can appear to have arisen ‘out of the blue’. 3.4 Genetic conditions dealt with by clinicians in other specialties Name of condition Gene Reference Autosomal dominant conditions Autosomal dominant polycystic kidney disease (ADPKD) PKD1 (85%), PKD2 (15%) p. 579 Box 18.28 Tuberous sclerosis TSC1 TSC2 p. 1114 Marfan syndrome FBN1 p. 445 Long QT syndrome KCNQ1 p. 418 Brugada syndrome SCN5A p. 418 Neurobromatosis type 1 NF1 p. 1185 Box 28.76 Neurobromatosis type 2 NF2 p. 1185 Box 28.76 Hereditary spherocytosis ANK1 p. 956 Vascular Ehlers–Danlos syndrome (EDS type 4) COL3A1 p. 980 Hereditary haemorrhagic telangiectasia ENG, ALK1, GDF2 p. 980 Osteogenesis imperfecta COL1A1, COL1A2 p. 1058 Charcot–Marie–Tooth disease PMP22, MPZ, GJB1 p. 1193 Hereditary neuropathy with liability to pressure palsies PMP22 Autosomal recessive conditions Familial Mediterranean fever MEFV p. 76 Mevalonic aciduria (mevalonate kinase deciency) MVK p. 76 Autosomal recessive polycystic kidney disease (ARPKD) PKHD1 Box 18.28 Kartagener syndrome (primary ciliary dyskinesia) DNAI1 Box 17.30 Cystic brosis CFTR1 p. 510 Box 17.30 p. 854 Pendred syndrome SLC26A4 p. 667 Congenital adrenal hyperplasia-21 hydroxylase deciency CYP21A p. 689 Box 20.27 Haemochromatosis HFE p. 906 Wilson’s disease ATP7B p. 907 Alpha-1-antitrypsin deciency SERPINA1 p. 908 Gilbert syndrome UGT1A1 p. 908 Benign recurrent intrahepatic cholestasis ATP8B1 p. 912 Alpha-thalassaemia HBA1, HBA2 p. 962 Beta-thalassaemia HBB p. 962 Sickle cell disease HBB p. 960 Spinal muscular atrophy SMN1 p. 1171 X-linked conditions Alport syndrome COL4A5 Box 18.28 p. 577 Primary agammaglobulinaemia BTK p. 74 Haemophilia A (factor VIII deciency) F8 p. 981 Haemophilia B (factor IX deciency) F9 p. 984 Duchenne muscular dystrophy DMD p. 1196 Box 28.90
- 70. Genomics, health anddisease 47 3 Examples of some autosomal recessive conditions, discussed else- where in this book, are shown in Box 3.4 X-linked inheritance The following is an exemplar of an X-linked recessive pedigree (see Fig. 3.8): Edward has a diagnosis of Duchenne muscular dystrophy (DMD, Box 3.6). His parents had suspected the diagnosis when he was 3 years old because he was not yet walking and there was a family history of DMD: Edward’s maternal uncle had been affected and died at the age of 24 years. Edward’s mother has no additional siblings. After Edward demonstrated a very high creatinine kinase level, the paediatrician also requested genetic testing, which identied a deletion of exons 2–8 of the dystrophin gene. Edward has a younger, healthy sister and grandparents on both sides of the family are well, although the maternal grandmother has recently developed a cardiomyopathy. Edward’s father has an older sister and an older brother who are both well. Genetic diseases caused by variants on the X chromosome have spe- cic characteristics: X-linked diseases are mostly recessive and predominantly affect males who carry the mutant allele. This is because males have only one X chromosome, whereas females have two (see Fig. 3.1). Occasionally, female carriers may exhibit signs of an X-linked dis- ease due to a phenomenon called skewed X-inactivation. All female embryos, at about 100 cells in size, stably inactivate one of their two X chromosomes in each cell. Where this inactivation is random, approximately 50% of the cells will express the genes from one X chromosome and 50% of cells will express genes from the other. Where there is a mutant gene, there is often skewing away from the associated X chromosome, resulting in an unaffected female carrier. However, if, by chance, there is a disproportionate inactivation of the normal X chromosome with skewing towards the mutant allele, then an affected female carrier may be affected (albeit more mildly than males). The gene can be transmitted from female carriers to their sons: in families with an X-linked recessive condition, there are often a num- ber of affected males related through unaffected females. Affected males cannot transmit the condition to their sons (but all their daughters would be carriers). The risk of a female carrier having an affected child is 25% or half of her male offspring. Mitochondrial inheritance The mitochondrion is the main site of energy production within the cell. Mitochondria arose during evolution via the symbiotic associa- tion with an intracellular bacterium. They have a distinctive structure with functionally distinct inner and outer membranes. Mitochondria produce energy in the form of adenosine triphosphate (ATP). ATP is mostly derived from the metabolism of glucose and fat (Fig. 3.9). Glucose cannot enter mitochondria directly but is rst metabolised to pyruvate via glycolysis. Pyruvate is then imported into the mito- chondrion and metabolised to acetyl-co-enzyme A (acetyl-CoA). Fatty acids are transported into the mitochondria following conjugation with carnitine and are sequentially catabolised by a process called β-oxida- tion to produce acetyl-CoA. The acetyl-CoA from both pyruvate and fatty acid oxidation is used in the citric acid (Krebs) cycle – a series of enzymatic reactions that produces CO2 , the reduced form of nico- tinamide adenine dinucleotide (NADH) and the reduced form of avine adenine dinucleotide (FADH2 ). Both NADH and FADH2 then donate electrons to the respiratory chain. Here these elections are transferred via a complex series of reactions, resulting in the formation of a pro- ton gradient across the inner mitochondrial membrane. The gradient is used by an inner mitochondrial membrane protein, ATP synthase, to produce ATP, which is then transported to other parts of the cell. Dephosphorylation of ATP is used to produce the energy required for many cellular processes. 3.5 Alpha-1-antitrypsin deciency Inheritance pattern Autosomal recessive Genetic cause Two common variants in the SERPINA1 gene: p.Glu342Lys and p.Glu264Val Prevalence 1 in 1500–3000 of European ancestry Clinical presentation Variable presentation from neonatal period through to adulthood Neonatal period: prolonged jaundice with conjugated hyperbilirubinaemia or (rarely) liver disease Adulthood: pulmonary emphysema and/or cirrhosis. Rarely, the skin disease, panniculitis, develops Disease mechanism SERPINA1 encodes α1 -antitrypsin, which protects the body from the effects of neutrophil elastase. The symptoms of α1 -antitrypsin deciency result from the effects of this enzyme attacking normal tissue Disease variants M variant: if an individual has normal SERPINA1 genes and produces normal levels of α1 -antitrypsin, they are said to have an M variant S variant: p.Glu264Val variant results in α1 -antitrypsin levels reduced to about 40% of normal Z variant: p.Glu342Lys variant results in very little α1 -antitrypsin PiZZ: individuals who are homozygous for the p.Glu342Lys variant are likely to have α1 -antitrypsin deciency and the associated symptoms PiZS: individuals who are compound heterozygous for p.Glu342Lys and p.Glu264Val are likely to be affected, especially if they smoke, but usually to a milder degree 3.6 Duchenne muscular dystrophy Inheritance pattern X-linked recessive Genetic cause Deletions/variants encompassing/within the DMD (dystrophin) gene located at Xp21 Prevalence 1 in 3000–4000 live male births Clinical presentation Delayed motor milestones Speech delay Grossly elevated creatine kinase levels (in the thousands) Ambulation is usually lost between the ages of 7 and 13 years Lifespan is reduced, with a mean age of death, usually from respiratory failure, in the mid-twenties Cardiomyopathy affects almost all boys with Duchenne muscular dystrophy and some female carriers Disease mechanism DMD encodes dystrophin, a major structural component of muscle Dystrophin links the internal cytoskeleton to the extracellular matrix Disease variants Becker muscular dystrophy, although a separate disease, is also caused by variants in the dystrophin gene In Duchenne muscular dystrophy, there is no dystrophin protein, whereas in Becker muscular dystrophy there is a reduction in the amount or alteration in the size of the dystrophin protein Approximately 1 in 4 children born to carriers of an autosomal reces- sive condition will be affected. The offspring risk for carrier parents is therefore 25% and the chances of an unaffected child, with an affected sibling, being a carrier is 2/3.
- 71. 48 CLINICALGENETICS L strand H strand Outer membrane Inner membrane NADH NAD I II III Q Cyt C IV NADH FADH2 Fatty acid β-oxidation cycle Citric acid (Krebs) cycle H+ e 2e FADH2 FADH2 Lactate Pyruvate PDH Acetyl-CoA Glucose 22 tRNAs NADH dehydrogenase 7 subunits Cytochrome B/C oxidase 4 subunits 2 ribosomal RNA subunits 2 ATP synthase subunits Intragenic DNA Inner membrane Cristae Matrix Outer membrane FFA CPT I CPT II Carnitine Carnitine-FA ester C A B FFA FAD 2H+ H2O O2 ATP ADP + Pi H+ H+ ATP synthase Carnitine e e e Fig. 3.9 Mitochondria. The membranes create two compartments: the inter-membrane compartment, which plays a crucial role in the electron transport chain, and the inner compartment (or matrix), which contains mitochondrial DNA and the enzymes responsible for the citric acid (Krebs) cycle and the fatty acid β contains several copies of a circular double-stranded DNA molecule, which has a non-coding region, and a coding region that encodes the genes responsible for energy production, conjugated to carnitine by carnitine-palmityl transferase type 1 (CPT I) and, once inside the matrix, are unconjugated by CPT II to release free fatty acids (FFA). These are broken down by the β-oxidation cycle to produce acetyl-co-enzyme A (acetyl-CoA). Pyruvate can enter the mitochondrion directly and is metabolised by pyruvate dehydrogenase (PDH) to produce acetyl-CoA. The acetyl-CoA enters the Krebs cycle, leading to the production of NADH and avine adenine dinucleotide (reduced form) (FADH2 ), which are used by proteins in the electron transport chain to generate a hydrogen ion gradient across the inter-membrane compartment. Reduction of NADH and FADH2 by proteins I and II, respectively, releases electrons (e), and the energy released is used to pump protons into the inter-membrane compartment. Coenzyme Q10 /ubiquinone (Q) is an intensely hydrophobic electron carrier that is mobile within the inner membrane. As electrons are exchanged between proteins in the chain, more protons are pumped across the membrane, until the electrons reach complex IV (cytochrome oxidase), which uses the energy to reduce oxygen to water. The hydrogen ion gradient is used to produce ATP by the enzyme ATP synthase, which consists of a proton channel and catalytic sites for the synthesis of ATP from ADP. When the channel opens, hydrogen ions enter the matrix down the concentration gradient, and energy is released that is used to make ATP. (ATP = adenosine triphosphate; NADH = the reduced form of nicotinamide adenine dinucleotide) energy production, e.g. most forms of Leigh syndrome (although Leigh syndrome may also be caused by a mitochondrial gene variant). The inheritance of mtDNA disorders is characterised by transmis- sion from females, but males and females generally are equally affected (see Fig. 3.8). Unlike the other inheritance patterns mentioned above, mitochondrial inheritance has nothing to do with meiosis but reects the fact that mitochondrial DNA is transmitted by oöcytes: sperm do not contribute mitochondria to the zygote. Mitochondrial disorders tend to be variable in penetrance and expressivity within families, and this is mostly accounted for by the fact that only a proportion of multiple mtDNA molecules within mitochondria contain the causal variant (the degree of mtDNA heteroplasmy). Each mitochondrion contains 2–10 copies of a 16-kilobase (kB) dou- ble-stranded circular DNA molecule (mtDNA). This mtDNA contains 13 protein-coding genes, all involved in the respiratory chain, and the ncRNA genes required for protein synthesis within the mitochondria (see Fig. 3.9). The mutational rate of mtDNA is relatively high due to the lack of protection by chromatin. Several mtDNA diseases characterised by defects in ATP production have been described. Mitochondria are most numerous in cells with high metabolic demands, such as muscle, retina and the basal gan- glia, and these tissues tend to be the ones most severely affected in mito- chondrial diseases (Box 3.7). There are many other mitochondrial diseases that are caused by pathogenic variants in nuclear genes, which encode proteins that are then imported into the mitochondrion and are critical for
- 72. Genomics, health anddisease 49 3 be active while the maternally inherited may be silenced, or vice versa. Variants within imprinted loci lead to an unusual pattern of inheritance where the phenotype is manifest only if inherited from the parent who contributes the transcriptionally active allele. Examples of imprinting dis- orders are given in Box 3.8 Somatic genetic disease Somatic variants are not inherited but instead occur during post-zygotic mitotic cell divisions at any point from embryonic development to late adult life. An example of this phenomenon is polyostotic brous dysplasia (McCune–Albright syndrome), in which a somatic variant in the GS alpha gene causes constitutive activation of downstream signalling, resulting in focal lesions in the skeleton and endocrine dysfunction. The most important example of human disease caused by somatic var- iants is cancer (see Ch. 7). Here, ‘driver mutations’ occur within genes that are involved in regulating cell division or apoptosis, resulting in abnormal cell growth and tumour formation. The two general categories of cancer-caus- ing variant are gain-of-function variants in growth-promoting genes (onco- genes) and loss-of-function variants in growth-suppressing genes (tumour suppressor genes). Whichever mechanism is acting, most tumours require an initiating variant in a single cell that can then escape from normal growth controls. This cell replicates more frequently or fails to undergo programmed death, resulting in clonal expansion. As the size of the clone increases, one or more cells may acquire additional variants that confer a further growth advantage, leading to proliferation of these subclones, which may ultimately result in aggressive metastatic cancer. The cell’s complex self-regulating machinery means that more than one variant is usually required to produce a malignant tumour (see Fig. 7.3). For example, if a variant results in acti- vation of a growth factor gene or receptor, then that cell will replicate more frequently as a result of autocrine stimulation. However, this mutant cell will still be subject to normal cell-cycle checkpoints to promote DNA integrity in its progeny. If additional variants in the same cell result in defective cell-cycle checkpoints, however, it will rapidly accumulate further genomic variants, which may allow completely unregulated growth and/or separation from its matrix and cellular attachments and/or resistance to apoptosis. As cell growth becomes increasingly dysregulated, cells de-differentiate, lose their response to normal tissue environment and cease to ensure appropriate mitotic chromosomal segregation. These processes combine to generate the classical malignant characteristics of disorganised growth, variable levels of differentiation and numerical and structural chromosome abnormalities. An increase in somatic variant rate can occur on exposure to external muta- gens, such as ultraviolet light or cigarette smoke, or if the cell has defects in DNA repair systems. Cancer is thus a disease that affects the fundamental processes of molecular and cell biology. 3.7 The structure of the respiratory chain complexes and the diseases associated with their dysfunction Complex Enzyme nDNA subunits1 mtDNA subunits2 Diseases I NADH dehydrogenase 38 7 MELAS, MERRF bilateral striatal necrosis, LHON, myopathy and exercise intolerance, parkinsonism, Leigh syndrome, exercise myoglobinuria, leucodystrophy/myoclonic epilepsy II Succinate dehydrogenase 4 0 Phaeochromocytoma, Leigh syndrome III Cytochrome bc1 complex 10 1 Parkinsonism/MELAS, cardiomyopathy, myopathy, exercise myoglobinuria, Leigh syndrome IV Cytochrome c oxidase 10 3 Sideroblastic anaemia, myoclonic ataxia, deafness, myopathy, MELAS, MERRF mitochondrial encephalomyopathy, motor neuron disease-like, exercise myoglobinuria, Leigh syndrome V ATP synthase 14 2 Leigh syndrome, NARP, bilateral striatal necrosis 1 nDNA subunits. 2 mtDNA subunits = number of different protein subunits in each complex that are encoded in the nDNA and mtDNA, respectively. (ATP = adenosine triphosphate; LHON = Leber hereditary optic neuropathy; MELAS = myopathy, encephalopathy, lactic acidosis and stroke-like episodes; MERRF = myoclonic epilepsy and ragged red bres; mtDNA = mitochondrial DNA; NADH = the reduced form of nicotinamide adenine dinucleotide; NARP = neuropathy, ataxia and retinitis pigmentosa; nDNA = nuclear DNA) 3.8 Imprinting disorders Disorder Locus Genes Notes Beckwith–Wiedemann syndrome 11p15 CDKN1C, IGF2, H19 Increased growth, macroglossia, hemihypertrophy, abdominal wall defects, ear lobe pits/creases and increased susceptibility to developing childhood tumours Prader–Willi syndrome 15q11–q13 SNRPN, Necdin and others Obesity, hypogonadism and learning disability. Lack of paternal contribution (due to deletion of paternal 15q11–q13, or inheritance of both chromosome 15q11–q13 regions from the mother) Angelman syndrome (AS) 15q11–q13 UBE3A Severe mental retardation, ataxia, epilepsy and inappropriate laughing bouts. Due to loss-of-function variants in the maternal UBE3A gene. The neurological phenotype results because most tissues express both maternal and paternal alleles of UBE3A, whereas the brain expresses predominantly the maternal allele Pseudohypoparathyroidism 20q13 GNAS1 Inheritance of the variant from the mother results in hypocalcaemia, hyperphosphataemia, raised parathyroid hormone (PTH) levels, ectopic calcication, obesity, delayed puberty and shortened 4th and 5th metacarpals (the syndrome known as Albright hereditary osteodystrophy, AHO). When the gene variant is inherited from the father, PTH, calcium and phosphate levels are normal but the other features are present. These differences are due to the fact that, in the kidney (the main target organ through which PTH regulates serum calcium and phosphate), the paternal allele is silenced and the maternal allele is expressed, whereas both alleles are expressed in other tissues Imprinting Several chromosomal regions (loci) have been identied where gene expression is inherited in a parent-of-origin-specic manner; these are called imprinted loci. Within these loci the paternally inherited gene may
- 73. 50 CLINICALGENETICS Interrogating the genome: the changing landscape of genomic technologies Looking at chromosomes The analysis of metaphase chromosomes by light microscopy was the mainstay of clinical cytogenetic analysis for decades, the aim being to detect gain or loss of whole chromosomes (aneuploidy) or large chromo- somal segments (>4 million bp). More recently, genome-wide microarrays (array comparative genomic hybridisation or array CGH) have replaced chromosome analysis, allowing rapid and precise detection of segmental gain or loss of DNA throughout the genome (see Box 3.3). Microarrays consist of grids of multiple wells containing short DNA sequences (refer- ence DNA) that are complementary to known sequences in the genome. Patient and reference DNA are each labelled with a coloured uorescent dye (generally, patient DNA is labelled with a green uorescent dye and reference DNA with a red uorescent dye) and added to the microar- ray grid. Where there is an equal quantity of patient and reference DNA bound to the spot, this results in yellow uorescence. Where there is too much patient DNA (representing a duplication of a chromosome region), the spot will be greener; it will be more red (appears orange) where there is 2:1 ratio of the control:patient DNA (representing heterozygous dele- tion of a chromosome region; Fig. 3.10). Array CGH and other array-based approaches can detect small chro- mosomal deletions and duplications. They are also generally more sen- sitive than conventional karyotyping at detecting mosaicism (where there are two or more populations of cells, derived from a single fertilised egg, with different genotypes). However, array-based approaches will not detect balanced chromosome rearrangements where there is no loss or gain of genes/chromosome material, such as balanced reciprocal trans- locations, or a global increase in copy number, such as triploidy. The widespread use of array-based approaches has brought a num- ber of challenges for clinical interpretation, including the identication of copy number variants (CNVs) of uncertain clinical signicance, CNVs of variable penetrance and incidental ndings. A CNV of uncertain clinical signicance describes a loss or gain of chromosome material where there are insufcient data to conclude whether or not it is associated with a learning disability and/or medical problems. While this uncertainty can be difcult to prepare families for and can be associated with consider- able anxiety, it is likely that there will be greater clarity in the future as we generate larger CNV datasets. A CNV of variable penetrance, also known as a neurosusceptibility locus, describes a chromosome deletion or duplication associated with a lower threshold for manifesting a learning disability or autistic spectrum disorder. CNVs of variable penetrance are therefore identied at greater frequencies among individuals with a learning disability and/or autistic spectrum disorder than in the general population. The current under- standing is that additional modifying factors (genetic, environmental or stochastic) must inuence the phenotypic expression of these neurosus- ceptibility loci. Finally, an incidental CNV nding describes a deletion or duplication encompassing a gene or genes that are causative of a phenotype or risk unrelated to the presenting complaint. For instance, if, through the array CGH investigation for an intellectual disability, a deletion encompassing the BRCA1 gene were identied, this would be considered an incidental nding. Looking at genes Gene amplication: polymerase chain reaction The polymerase chain reaction (PCR) is a fundamental laboratory tech- nique that amplies targeted sections of the human genome for fur- ther analyses – most commonly, DNA sequencing. The method utilises thermal cycling: repeated cycles of heating and cooling allow the initial separation of double-stranded DNA into two single strands (known as denaturation), each of which serves as a template during the subsequent replication step, guided by primers designed to anneal to a specic genomic region. This cycle of heating/cooling and denaturation/replica- tion is repeated many times, resulting in the exponential amplication of DNA between primer sites (Fig. 3.11). Gene sequencing In the mid-1970s, a scientist called Fred Sanger pioneered a DNA sequencing technique (‘Sanger sequencing’) that determined the pre- cise order and nucleotide type (thymine, cytosine, adenine and guanine) in a molecule of DNA. Modern Sanger sequencing uses uorescently labelled, chain-terminating nucleotides that are sequentially incorporated into the newly synthesised DNA, generating multiple DNA chains of dif- fering lengths. These DNA chains are subject to capillary electrophoresis, which separates them by size, allowing the fragments to be ‘read’ by a laser and producing a sequence chromatogram that corresponds to the target sequence (Fig. 3.12). Although transformative, Sanger sequencing was difcult and costly to scale, as exemplied by the Human Genome Project, which took 12 years to sequence the entire human genome at a cost approaching 3 billion US$. Recently, DNA sequencing has been transformed again by a group of technologies collectively known as ‘next-generation sequencing’ (NGS; Fig. 3.13). This refers to a family of post-Sanger sequencing technologies that utilise the same ve basic principles: Library preparation: DNA samples are fragmented (by enzyme cleavage or ultrasound) and then modied with a custom adapter sequence. Amplication: the library fragment is amplied to produce DNA clus- ters, each originating from a single DNA fragment. Each cluster will act as a single sequencing reaction. Capture: if an entire genome is being sequenced, this step will not be included. The capture step is required if targeted resequencing is necessary, such as for a panel gene test or an exome (Box 3.9). CGH Patient DNA Label DNA with different fluorescent dyes Mix equimolar amounts of labelled DNA Apply DNA mix to glass slide with high-density array of different DNA probes with known location in the human genome Patient/control ratio = 0.5:1 → deletion of patient DNA Patient/control ratio = 1.5:1 → duplication of patient DNA Patient/control ratio = 1:1 → normal Normal control DNA Fig. 3.10 Detection of chromosome abnormalities by comparative genomic hybridisation (CGH). Deletions and duplications are detected by looking for deviation from the 1:1 ratio of patient and control DNA in a microarray. Ratios in excess of 1 indicate duplications, whereas ratios below 1 indicate deletions.
- 74. Interrogating the genome:the changing landscape of genomic technologies 51 3 Sequencing: each DNA cluster is simultaneously sequenced and the data from each captured; this is known as a ‘read’ and is usu- ally between 50 and 300 bases long (see Box 3.10 for a detailed description of the three most commonly used sequencing methods: synthesis, ligation and ion semiconductor sequencing). Alignment and variant identication: specialised software analyses read sequences and compare the data to a reference template. This is known as ‘alignment’ or ‘mapping’ and, although there are approximately 3 billion bases in the human genome, allows the remarkably accurate determination of the genomic origin where a read consists of 25 nucleotides or more. Variants are identied as differences between the read and the reference genome. For instance, if there is a different nucleotide in half the reads at a given position compared to the reference genome, this is likely to repre- sent a heterozygous base substitution. The number of reads that align at a given point is called the ‘depth’ or ‘coverage’. The higher the read depth, the more accurate the variant call. However, in gen- eral, a depth of 30 or more reads is generally accepted as producing diagnostic-grade results. Rather than sequencing only one small section of DNA at a time, NGS allows the analysis of many hundreds of thousands of DNA strands in a single experiment and so is also commonly referred to as multiple parallel sequencing technology. Today’s NGS machines can sequence the entire human genome in a single day at a cost of less than 1000 US$. NGS capture Although we now have the capability to sequence the entire genome in a single experiment, whole-genome sequencing is not always the optimal use of NGS. NGS capture refers to the ‘pull-down’ of a targeted region of the genome and may constitute several to several hundred genes associated with a given phenotype (a gene panel), the exons of all known coding genes (an exome), or the exons of all coding genes known to be associated with disease (a clinical exome). Each of these targeted resequencing approaches is associated with a number of advantages and disadvantages (see Box 3.9). In order for NGS to be used for opti- mal patient benet, it is essential for the clinician to have a good under- standing of which test is the best one to request in any given clinical presentation. Challenges of NGS technologies Genomic technologies are transforming the way that we practise med- icine, and ever faster and cheaper DNA sequencing offers increasing opportunities to prevent, diagnose and treat disease. However, genomic technologies are not without their challenges: for instance, storing the enormous quantities of data generated by NGS. While the A, C, T and G of our genomic code could be stored on the memory of a smartphone, huge computers, able to store several petabytes of data (where 1 peta- byte is 1 million gigabytes of data), are required to store the information needed to generate each individual’s genome. Even if we can store and handle these huge datasets successfully, we then need to be able to sift through the millions of normal variants to identify the single (or, rarely, several) pathogenic, disease-causing variant. While this can, to an extent, be achieved through the application of com- plex algorithms, these take time and considerable expertise to develop and are not infallible. Furthermore, even after these data have been sifted by bioinforma- ticians, it is highly likely that clinicians will be left with some variants for which there are insufcient data to enable their denitive categorisation as either pathogenic or non-pathogenic. This may be because we simply do not know enough about the gene, because the particular variant has not previously been reported and/or it is identied in an unaffected par- ent. These variants must be interpreted with caution and, more usually, their interpretation will require input from a genetics expert in the con- text of the clinical presentation, where an ‘innocent until proven guilty’ approach is often adopted. Cool ~60°C DNA sample DNA strands separate Primers bind to DNA DNA replicated Heat 95°C Heat 95°C Cool ~60°C Repeat cycles 20–30 times 108 107 106 105 104 103 102 10 0 5 10 15 PCR cycles Exponential amplification of DNA between primer sites DNA molecules 20 25 30 DNA strands separate Primers bind to DNA Cycle no. 1 DNA replicated Heat ~72°C Heat ~72°C Polymerase + dNTPs Primers Cycle no. 2 Fig. 3.11 The polymerase chain reaction (PCR). PCR involves adding a tiny amount of the patient’s DNA to a reaction containing primers (short oligonucleotides 18–21bp in length, which bind to the DNA anking the region of interest) and deoxynucleotide phosphates (dATP, dCTP, dGTP, dTTP), which are used to synthesise new DNA and a heat-stable polymerase. The reaction mix is rst heated to 95°C, which causes the double-stranded DNA molecules to separate. The reaction is then cooled to 50–60°C, which allows the primers to bind to the target DNA. The reaction is then heated to 72°C, at which point the polymerase starts making new DNA strands. These cycles are repeated 20–30 times, resulting in exponential amplication of the DNA fragment between the primer sites. The resulting PCR products can then be used for further analysis – most commonly, DNA sequencing (see Fig. 3.12).
- 75. 52 CLINICALGENETICS Finally, if we are to interrogate the entire genome or even the exome, it is foreseeable that we will routinely identify ‘incidental’ or secondary ndings – in other words, ndings not related to the initial diagnostic question. Whether or not to report these incidental ndings is a topic of much debate in the UK, although there is growing support to feedback incidental ndings where there is an intervention that could slow or halt development/progress of the associated disease. Uses of NGS NGS is now frequently used, within diagnostic laboratories, to identify base substitutions and indels (although the latter were initially problem- atic). The current NGS challenge is to detect large deletions or duplica- tions spanning several hundreds or thousands of bases and therefore exceeding any single read copy number variants and triplet repeat dis- orders such as those that cause Huntington’s disease, myotonic dys- trophy and fragile X syndrome, although techniques to detect both are improving (see Box 3.2). Increasingly, however, disorders caused by both copy number variants and triplet repeat expansions are being diagnosed using sophisticated computational methods. Additional potential uses of NGS include detection of balanced and unbalanced translocations and mosaicism: NGS has proved remarkably sensitive at detecting the latter when there is high read coverage for a given region. Of note, however, NGS is still not able to interrogate the epigenome and so will not iden- tify conditions caused by a disruption of imprinting, such as Beckwith– Wiedemann, Silver–Russell, Angelman and Prader–Willi syndromes (see Boxes 3.8 and 3.2). Third-generation sequencing Increasingly, third-generation or single-molecule sequencing is entering the diagnostic arena. As with next- or second-generation sequencing, a number of different platforms are commercially available. One of the most successful is SMRT technology (single-molecule sequencing in real time), developed by Pacic Biosciences. This system utilises a sin- gle-stranded DNA molecule (as compared to the amplied clusters used in NGS), which acts as a template for the sequential incorporation, using a polymerase, of uorescently labelled nucleotides. As each complemen- tary nucleotide is added, the uorescence (and therefore the identity of the nucleotide) is recorded before it is removed and another nucleotide is added. A key advantage of third-generation sequencing is the long length of the read it generates: in the region of 10–15 kilobases. It is also cheaper than NGS, as fewer reagents are required. Given these inherent advan- tages, third-generation sequencing is likely to supersede NGS in the near future. Given the confusion surrounding the terminology of NGS and third-generation sequencing, these technologies are increasingly referred to as ‘massively parallel sequencing’. Genomics and clinical practice Genomics and health care Genomics in rare neurodevelopmental disorders Although, by denition, the diagnosis of a rare disorder is made infre- quently, rare diseases, when considered together, affect about 3 million people in the UK, the majority of whom are children. NGS has trans- formed the ability to diagnose individuals affected by a rare disease. Whereas previously, when we were restricted to the sequential analysis of single genes, a clinician would need to make a clinical diagnosis in order to target testing, NGS allows the interrogation of multiple genes in a single experiment. This might be done through a gene panel, a clinical exome or an exome (see Box 3.9 and p. 51), and has increased the diagnostic yield in neurodevelopmental disorders to 35%–50%. Not only does the identication of the genetic cause of a rare disorder potentially provide families with answers, prognostic information and the opportu- nity to meet and derive support from other affected families but also it can provide valuable information for those couples planning further chil- dren and wishing to consider prenatal testing in the future. Genomics and common disease Most common disorders are determined by interactions between a num- ber of genes and the environment. In this situation, the genetic contribu- tion to disease is termed polygenic. Until recently, very little progress had been made in identifying the genetic variants that predispose to com- mon disorders, but this has been changed by the advent of genome- wide association studies. A GWAS typically involves genotyping many (>500000) genetic markers (SNPs) spread across the genome in a large group of individuals with the disease and in controls. By comparing the SNP genotypes in cases and controls, it is possible to identify regions of the genome, and therefore genes, more strongly associated with a given Capillary electrophoresis Largest fragments migrate slowest Smallest fastest Laser fluorescence detector ddTTP ddCTP ddATP ddGTP DNA sample PCR DNA sequence chromatogram Key Fragments detected by laser fluorescence New DNA molecules terminated by incorporation of ddNTP Polymerase + ddNTPs Primers Fig. 3.12 Sanger sequencing of DNA, which is very widely used in DNA diagnostics. This is performed using polymerase chain reaction (PCR)-amplied fragments of DNA corresponding to the gene of interest. The sequencing reaction is carried out with a combination dNTP and uorescently labelled di-deoxy-dNTP (ddATP, ddTTP, ddCTP and ddGTP), which become incorporated into the newly synthesised DNA, causing termination of the chain at that point. The reaction products are then subject to capillary electrophoresis and the different-sized fragments are detected by a laser, producing a sequence chromatogram that corresponds to the target DNA sequence.
- 76. Genomics and clinicalpractice 53 3 SNP prole and therefore more likely to contribute to the disease under study. Increasingly there is a move to develop disease-specic polygenic risk scores (PRS) in order to stratify individual risk and determine person- alised management strategies. Whilst not yet in mainstream practice, it is likely that PRS will be integrated into clinical management in the next few years. Genomics and obstetrics Prenatal genetic testing may be performed where a pregnancy is consid- ered at increased risk of being affected with a genetic condition, either because of the ultrasound/biochemical screening results or because of the family history. While invasive tests, such as amniocentesis and chorionic villus sampling, have been the mainstay of prenatal diagnosis for many years, they are increasingly being superseded by non-invasive CCGATATCTAGCTTA ATATCTAGC CG TAGC TATCTAGC CCG TAGCTAGCTTA 1 Library preparation 2 Cluster amplification Genomic DNA Fragmentation Adapter ligation Flow cell Amplification 3 Sequencing Reads Reference genome 4 Alignment and variant interpretation G T A C A A Fig. 3.13 Sequencing by synthesis as used in the Illumina system. (1) Library preparation: DNA is fragmented and specialist adapters are ligated to the fragmented ends. (2) Cluster amplication: the library is loaded to a ow cell and the adapters hybridise to the ow-cell surface. Each bound fragment is hybridised. (3) Sequencing. (4) Alignment and variant interpretation: reads are aligned to a reference sequence using complex software and differences between reference and case genomes are identied. 3.9 The advantages and disadvantages of whole-genome sequencing,whole-exome sequencing and gene panels Test Advantages Disadvantages Whole-genome sequencing (WGS) The most comprehensive analysis of the genome available More even coverage of genes, allowing better identication of dosage abnormalities Will potentially detect all gene variants, including intronic variants More expensive to generate and store Will detect millions of variants in non-coding DNA, which can be very difcult to interpret Associated with a greater risk of identifying incidental ndings Shallow sequencing (few reads per gene) and so less sensitive and less able to detect mosaicism Whole-exome sequencing (WES) Cheaper than whole- genome sequencing Analysis is not restricted to only those genes known to cause a given condition Fewer variants detected than in WGS and so easier interpretation Deeper sequencing than WGS increases sensitivity and detection of mosaicism Less even coverage of the genome and so dosage abnormalities are more difcult to detect Less comprehensive analysis (1%–2% of the genome) than WGS Increased risk of identifying incidental ndings over targeted gene sequencing Gene panels Cost-effective Very deep sequencing, increasing the chances of mosaicism being detected Fewer variants detected and so data easier to interpret As analysis is restricted to known genes, the likelihood of a variant being pathogenic is greatly increased Will only detect variation in genes known to cause a given condition Difcult to add new genes to the panel as they are discovered testing of cell-free fetal DNA (cffDNA), originating from placental tropho- blasts and detectable in the maternal circulation from 4–5 weeks’ gesta- tion; it is present in sufcient quantities for testing by 9 weeks. Non-invasive prenatal testing (NIPT): the sequencing and quantica- tion, using NGS, of cffDNA chromosome-specic DNA sequences to identify trisomy 13, 18 or 21. The accuracy of NIPT in detecting pregnancy-specic aneuploidy approaches 98%. A false-negative result can occur when there is too little cffDNA (possibly due to early gestation or high maternal body mass index) or when aneuploidy has arisen later in development and is conned to the embryo and not represented in the placenta. False positives can occur with conned placental mosaicism (describing aneuploidy in the pla- centa, not the fetus) or with an alternative cause of aneuploidy in the maternal circulation, such as cell-free tumour DNA.
- 77. 54 CLINICALGENETICS 3.11 Inherited cancer predisposition syndromes Syndrome name Gene Associated cancers Additional clinical features Birt–Hogg–Dubé syndrome FLCN Renal tumour (oncocytoma, chromophobe (and mixed), renal cell carcinoma) Fibrofolliculoma Trichodiscoma Pulmonary cysts Breast/ovarian hereditary susceptibility BRCA1 BRCA2 Breast carcinoma Ovarian carcinoma Pancreatic carcinoma Prostate carcinoma Cowden syndrome PTEN Breast carcinoma Thyroid carcinoma Endometrial carcinoma Macrocephaly Intellectual disability/autistic spectrum disorder Trichilemmoma Acral keratosis Papillomatous papule Thyroid cyst Lipoma Haemangioma Intestinal hamartoma Gorlin syndrome/basal cell naevus syndrome PTCH1 Basal cell carcinoma Medulloblastoma Odontogenic keratocyst Palmar or plantar pits Falx calcication Rib abnormalities (e.g. bid, fused or missing ribs) Macrocephaly Cleft lip/palate Li–Fraumeni syndrome TP53 Sarcoma (e.g. osteosarcoma, chondrosarcoma, rhabdomyosarcoma) Breast carcinoma Brain cancer (esp. glioblastoma) Adrenocortical carcinoma Brain 3.10 Next-generation sequencing methods Sequencing by synthesis (Fig. 3.13) The most frequently used NGS method Used in Illumina systems (commonly used in diagnostic laboratories) Uses uorescently labelled, terminator nucleotides that are sequentially incorporated into a growing DNA chain Library DNA samples (fragmented DNA anked by DNA adapter sequences) are anchored to a ow cell by hybridisation of the DNA adapter sequence to probes on the ow- cell surface Amplication occurs by washing the ow cell in a mixture containing all four uorescently labelled terminator nucleotides: A, C, T and G Once the nucleotide, complementary to the rst base of the DNA template, is incorporated, no further nucleotides can be added until the mixture is washed away The nucleotide terminator is shed and the newly incorporated nucleotide reverts to a regular, non-uorescent nucleotide that can be extended The process is then repeated with the incorporation of a second base etc. Sequencing by synthesis is therefore space- and time-dependent: a sensor will detect the order of uorescent emissions for each spot on the plate (representing the cluster) and determine the sequence for that read Sequencing by ligation Used in SOLiD systems Uses DNA ligase rather than DNA polymerase (as is used in sequencing by synthesis) and short oligonucleotides (as opposed to single nucleotides) Library DNA samples are washed in a mixture containing oligonucleotide probes representing 4–16 dinucleotide sequences. Only one nucleotide in the probe is uorescently labelled The complementary oligo probes will hybridise, using DNA ligase, to the target sequence, initially at a primer annealed to the anchor site and then progressively along the DNA strand After incorporation of each probe, uorescence is measured and the dye is cleaved off Eventually, a new strand is synthesised (composed of a series of the oligo probes) A new strand is then synthesised but is offset by one nucleotide The process is repeated a number of times (5 rounds in the SOLiD system), providing overlapping templates that are analysed and a composite of the target sequence determined Ion semiconductor sequencing When a nucleotide is incorporated into a growing DNA strand, a hydrogen ion is released that can be detected by an alteration in the pH of the solution. This hydrogen ion release forms the basis of ion semiconductor sequencing Each amplied DNA cluster is located above a semiconductor transistor, capable of detecting differences in the pH of the solution The DNA cluster is washed in a mixture containing only one type of nucleotide If the correct nucleotide, complementary to the next base on the DNA template, is in the mixture and incorporated, a hydrogen ion is released and detected If a homopolymer (sequence of two or more identical nucleotides) is present, this will be detected as a decrease in pH proportionate to the number of identical nucleotides in the sequence
- 78. Genomics and clinicalpractice 55 3 Syndrome name Gene Associated cancers Additional clinical features Lynch syndrome/hereditary non-polyposis colon cancer MLH1 MSH2 MSH6 PMS2 Colorectal carcinoma (majority right-sided) Endometrial carcinoma Gastric carcinoma Cholangiocarcinoma Ovarian carcinoma (esp. mucinous) Multiple endocrine neoplasia 1 MEN1 Parathyroid tumour Endocrine pancreatic tumour Anterior pituitary tumour Lipoma Facial angiobroma Multiple endocrine neoplasia 2a and 2b (formerly known as type 2 and 3, respectively) RET Medullary thyroid tumour Phaeochromocytoma Parathyroid tumour Polyposis, familial adenomatous (FAP) APC Colorectal adenocarcinoma (FAP is characterised by thousands of polyps from the second decade; without colectomy, malignant transformation of at least one of these polyps is inevitable) Duodenal carcinoma Hepatoblastoma Desmoid tumour Congenital hypertrophy of the retinal pigment epithelium (CHRPE) Polyposis, MYH-associated MYH (MUTYH) Colorectal adenocarcinoma Duodenal adenocarcinoma Retinoblastoma, familial RB1 Retinoblastoma Osteosarcoma 3.11 Inherited cancer predisposition syndromes Non-invasive prenatal diagnosis (NIPD): the identication of a fetal single-gene defect that either has been paternally inherited or has arisen de novo and so is not identiable in the maternal genome. Examples of conditions that are currently amenable to NIPD include achondroplasia and the craniosynostoses. Increasingly, however, NIPD is being used for autosomal recessive conditions such as cystic brosis, where parents are carriers for different gene variants and research is under way to perform more agnostic fetal gene sequencing through whole-exome or whole-genome sequencing. Where a genetic diagnosis is known in a family, a couple may opt to undertake pre-implantation genetic diagnosis (PGD). PGD is used as an adjunct to in vitro fertilisation and involves the genetic testing of a single cell from a developing embryo, prior to implantation. Genomics and oncology Until recently, individuals were stratied to genetic testing if they pre- sented with a personal and/or family history suggestive of an inherited cancer predisposition syndrome (Box 3.11). Relevant clinical information included the age of cancer diagnosis and number/type of tumours. For example, the diagnosis of bilateral breast cancer in a woman in her thir- ties with a mother who had ovarian cancer in her forties is suggestive of BRCA1/2-associated familial breast/ovarian cancer. In many familial cancer syndromes, somatic gene variants act together with an inherited variant to cause specic cancers (p. 49). Familial cancer syndromes may be due to germ-line loss-of-function variants in tumour suppressor genes encoding DNA repair enzymes or proto-oncogenes. At the cellular level, loss of one copy of a tumour suppressor gene does not have any func- tional consequences, as the cell is protected by the remaining normal copy. However, a somatic variant affecting the normal allele is likely to occur in one cell at some point during life, resulting in complete loss of tumour suppressor activity and a tumour developing by clonal expansion of that cell. This two-hit mechanism (one inherited, one somatic) for can- cer development is known as the Knudson hypothesis. It explains why tumours may not develop for many years (or ever) in some members of these cancer-prone families. In DNA repair diseases, the inherited vari- ants increase the somatic mutation rate. Autosomal dominant variants in genes encoding components of specic DNA repair systems are relatively common causes of familial colon cancer and breast cancer (e.g. BRCA1). Increasingly, genetics is moving into the mainstream, becoming inte- grated into routine oncological care as new gene-specic treatments are introduced. Testing for a genetic predisposition to cancer is therefore mov- ing from the domain of clinical genetics, where it has informed diagnosis, cascade treatment and screening/prophylactic management, to oncology, where it is informing the immediate management of the patient following cancer diagnosis. This is exemplied by BRCA1 and BRCA2 (BRCA1/2)- related breast cancer. Previously, women with a pathogenic variant in either the BRCA1 or BRCA2 gene would have received similar rst-line chemotherapy to women with a sporadic breast cancer without a known genetic association. More recently, it has been shown that BRCA1/2 muta- tion-positive tumours are sensitive to poly ADP ribose polymerase (PARP) inhibitors. PARP inhibitors block the single-strand break-repair pathway. In a BRCA1/2 mutation-positive tumour – with compromised double-strand break repair – the additional loss of the single-strand break-repair pathway will drive the cell towards apoptosis. Indeed, PARP inhibitors have been shown to be so effective at destroying BRCA1/2 mutation-positive tumour cells, and with such minimal side-effects, that BRCA1/2 gene testing is increasingly determining patient management. It is likely, with a growing understanding of the genomic architecture of tumours, increasing acces- sibility of NGS and an expanding portfolio of gene-directed therapies, that testing for many of the other inherited cancer susceptibility genes will, in time, move into the mainstream. Genomics in infectious disease NGS technologies are also transforming infectious disease. Given that a microbial genome can be sequenced within a single day at a current cost of less than 100US$, microbiologists are able to identify a causa- tive microorganism and target effective treatment rapidly and accurately. Moreover, microbial genome sequencing enables the effective surveil- lance of infections to reduce and prevent transmission. Finally, an under- standing of the microbial genome will drive the development of vaccines and antibiotics, essential in an era characterised by increasing microbial resistance to established antibiotic agents.
- 79. 56 CLINICALGENETICS Treatment of genetic disease Pharmacogenomics Pharmacogenomics is the science of dissecting the genetic determi- nants of drug kinetics and effects using information from the human genome. For more than 50 years it has been appreciated that poly- morphic variants within genes can affect individual responses to some drugs, such as loss-of-function variants in CYP2D6 that cause hyper- sensitivity to debrisoquine, an adrenergic-blocking medication formerly used for the treatment of hypertension, in 3% of the population. This gene is part of a large family of highly polymorphic genes encoding cytochrome P450 proteins, mostly expressed in the liver, which deter- mine the metabolism of a host of specic drugs. Polymorphisms in the CYP2D6 gene also determine codeine activation, while those in the CYP2C9 gene affect warfarin inactivation. Polymorphisms in these and other drug metabolic genes determine the persistence of drugs and, therefore, should provide information about dosages and toxicity. With the increasing use of NGS, genetic testing for assessment of drug response is seldom employed routinely, but in the near future it may be possible to predict the best specic drugs and dosages for individual patients based on genetic proling: so-called ‘personalised medicine’. An example is the enzyme thiopurine methyltransferase (TPMT), which catabolises azathioprine, a drug that is used in the treatment of auto- immune diseases and in cancer chemotherapy. Genetic screening for polymorphic variants of TPMT can be useful in identifying patients who have increased sensitivity to the effects of azathioprine and who can be treated with lower doses than normal. Gene therapy and genome editing Replacing or repairing mutated genes (gene therapy) is challenging in humans. Retroviral-mediated ex vivo replacement of the defective gene in bone marrow cells for the treatment of severe combined immune de- ciency syndrome has been successful. The major problems with clinical use of virally delivered gene therapy have been oncogenic integration of the exogenous DNA into the genome and severe immune response to the virus. Other therapies for genetic disease include PTC124, a compound that can ‘force’ cells to read through a nonsense variant that results in a premature termination codon in an ORF with the aim of producing a near-normal protein product. This therapeutic approach could be applied to any genetic disease caused by nonsense variants. The most exciting development in genetics for a generation has been the discovery of accurate, efcient and specic techniques to enable editing of the genome in cells and organisms. This technology is known as CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats and CRISPR-associated) genome editing. It is likely that ex vivo correction of genetic disease will become commonplace over the next few years. In vivo correction is not yet possible and will take much longer to become part of clinical practice. Induced pluripotent stem cells and regenerative medicine Adult stem-cell therapy has been in wide use for decades in the form of bone marrow transplantation. The identication of adult stem cells for other tissues, coupled with the ability to purify and maintain such cells in vitro, now offers exciting therapeutic potential for other diseases. It was recently discovered that many different adult cell types can be trans-dif- ferentiated to form cells (induced pluripotent stem cells or iPS cells) with almost all the characteristics of embryonal stem cells derived from the early blastocyst. In mammalian model species, such cells can be taken and used to regenerate differentiated tissue cells, such as in heart and brain. They have great potential both for the development of tissue mod- els of human disease and for regenerative medicine. Pathway medicine The ability to manipulate pathways that have been altered in genetic disease has tremendous therapeutic potential for Mendelian disease, but a rm understanding of both disease pathogenesis and drug action at a biochemical level is required. An exciting example has been the dis- covery that the vascular pathology associated with Marfan syndrome is due to the defective brillin molecules causing up-regulation of trans- forming growth factor (TGF)-β signalling in the vessel wall. Losartan is an antihypertensive drug that is marketed as an angiotensin II receptor antagonist. However, it also acts as a partial antagonist of TGF-β signalling and is effective in preventing aortic dilatation in a mouse model of Marfan syndrome, showing promising effects in early human clinical trials. Ethics in a genomic age As genomic technology is increasingly moving into mainstream clinical practice, it is essential for clinicians from all specialties to appreciate the complexities of genetic testing and consider whether genetic testing is the right thing to do in a given clinical scenario. To exemplify the ethical considerations associated with genetic testing, it may be helpful to think about them in the context of a clinical scenario. As you read the scenario, try to think what counselling/ethical issues might arise: A 32-year-old woman is referred to discuss BRCA2 testing; she is currently pregnant with her second child (she already has a 2-year-old daughter) and has an identical twin sister. Her mother, a healthy 65-year- old with Ashkenazi Jewish ancestry, participated in direct-to-consumer testing (DCT) for ‘a bit of fun’ and a BRCA2 gene variant – common in the Ashkenazi Jewish population – was identied. There is no signicant cancer family history of note. Consider the following issues: Pre-symptomatic/predictive testing: this describes testing for a known familial gene variant in an unaffected individual (compared with diagnostic testing, where genetic testing is undertaken in an affected individual). Although this could be considered for the unaffected patient, in the current scenario any testing would also have implications for her identical twin sister. This needs to be fully explored with the patient and her sister prior to testing. There is also the potential issue of predictive testing in the patient’s rst child. A fundamental tenet in clinical genetics is that predictive genetic testing should be avoided in childhood for adult-onset conditions. This is because, if no benet to the patient is accrued through childhood testing, it is better to retain the child’s right to decide for herself, when she is old enough, whether she wishes to participate in genetic testing or not. Prenatal testing: the principles behind predictive genetic testing in childhood can be extended to prenatal testing, i.e. if a pregnancy is being continued, a baby should not be tested for an adult-on- set condition that cannot be prevented or treated in childhood. However, prenatal testing itself is hugely controversial and there is much debate as to how severe a condition should be to justify prenatal diagnosis, which would determine ongoing pregnancy decisions. DCT: while DCT can be interesting and empowering for individuals wishing to nd out more about their genetic backgrounds, it also has several drawbacks. Perhaps the main one is that, unlike face-to-face genetic counselling (which usually precedes any genetic testing, certainly where there are serious health implications for the individ- ual and their family, such as is associated with BRCA1/2 variants), DCT is undertaken in isolation with no direct access to professional support. Furthermore, in addition to some (common) single-gene variants, such as the founder BRCA1/2 variants frequently identied in the Ashkenazi Jewish population and discussed in this example, current DCT packages utilise a series of SNPs to determine an overall risk prole; they evaluate the number of detrimental and
- 80. Further information 57 3 protective SNPs for a given disease. However, given that only a minority of the risk SNPs have so far been characterised, this is often inaccurate. Individuals may be falsely reassured that they are not at increased risk of a genetic condition despite a family history suggesting otherwise, resulting in inadequate surveillance and/or management. The ethical considerations listed in this clinical scenario give just a a- vour of some of the issues frequently encountered in clinical genetics. They are not meant to be an exhaustive summary and whole textbooks and meetings are devoted to the discussion of hugely complex ethical issues in genetics. However, a guiding principle is that, although each counselling situation will be unique with specic communication and eth- ical challenges, a genetic result is permanent and has implications for the whole family, not just the individual. Where possible, therefore, an informed decision regarding genetic testing should be taken by a com- petent adult following counselling by an experienced and appropriately trained clinician. Further information Books and journal articles Alberts B, Bray D, Hopkin K, etal. Essential cell biology, 4th edn. New York: Garland Science; 2013. Firth H, Hurst JA. Oxford desk reference: clinical genetics. Oxford: Oxford University Press; 2005. Read A, Donnai D. New clinical genetics, 2nd edn. Banbury: Scion; 2010. Strachan T, Read A. Human molecular genetics, 4th edn. New York: Garland Science; 2010. Websites bsgm.org.uk British Society for Genetic Medicine; has a report on genetic testing of children. decipher.sanger.ac.uk Excellent, comprehensive genomic database. ensembl.org Annotated genome databases from multiple organisms. futurelearn.com/courses/the-genomics-era Has a Massive Open Online Course on genomics, for which the author of the current chapter is the lead educator . genome.ucsc.edu Excellent source of genomic information. ncbi.nlm.nih.gov Online Mendelian Inheritance in Man (OMIM). ncbi.nlm.nih.gov/books/NBK1116/ Gene Reviews: excellent US-based source of information about many rare genetic diseases. orpha.net/consor/cgi-bin/index.php Orphanet: European-based database on rare disease.
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- 82. Multiple Choice Questions 3.1.Which of the following best describes a missense or non- synonymous variant? A. A base substitution that results in the introduction of a premature stop codon B. A base substitution that results in a different codon and different amino acid C. The deletion of two bases that results in a shift of reading frame and the introduction of a downstream premature stop codon D. A base substitution that introduces a cryptic splice site E. A base substitution that results in a different codon but same amino acid Answer: B. The most common type of genomic variation is the substitution of one nucleotide for another, caused by either misincorporation of a nucleotide during DNA synthesis or chemical modication of the base. If a nucleo- tide substitution occurs within the open reading frame of a protein-coding gene it will affect a codon within that gene. A missense/non-synonymous variant refers to a nucleotide substitution in which the effect on the codon in which it occurs is to cause it to encode a different amino acid. 3.2. Approximately how many genes are there in the average human genome? A. 2000 B. 20000 C. 200000 D. 2000000 E. 20000000 Answer: B. The human genome contains over 20 000 genes. Many of these are inactive or silenced in different cell types, reecting the variable gene expression responsible for cell-specic characteristics. 3.3. Which of the following is a cardinal feature of an X-linked recessive disorder? A. Male-to-male transmission B. Affected individuals in each generation. C. Increased frequency in consanguineous unions D. Predominantly males affected E. There is characteristically highly variable penetrance and expressivity in the same family Answer: D. In X-linked recessive diseases females who carry a copy of the mutant allele on one of their X chromosomes (unaffected carriers) will pass the allele on to 50% of their offspring. Only the male offspring will be affected, because they have only one X chromosome. The female offspring will be carriers, as they will inherit a ‘normal’ X chromosome from their fathers. The overall risk of a female carrier having an affected child is therefore 25%, or half of her male offspring. Male-to-male transmission of an X-linked recessive condition does not occur because fathers will pass on their Y chromosome to their sons (not the X chromosome with mutant allele). The presence of affected individuals in each generation is a characteristic feature of autosomal dominant inheritance with full penetrance, in which half of the offspring of an affected parent will be affected irrespective of their sex. Increased frequency in consanguineous unions would suggest an autosomal recessive disorder, because the chance of both the female and the male parent carrying the same mutant allele would be increased by consan- guinity. Highly variable penetrance and expressivity in the same family is a feature of mitochondrial disorders. 3.4. Which type of genomic variant will an array comparative genomic hybridisation (CGH) best detect? A. A balanced chromosome translocation B. A frameshift variant C. A 2 MB deletion D. A missense variant E. An essential splice variant Answer: C. Array CGH allows rapid and precise detection of segmental gain or loss of DNA throughout the genome. Microarrays consist of grids of multiple wells containing short DNA sequences (reference DNA) that are comple- mentary to known sequences in the genome. Patient and reference DNA are each labelled with a coloured uorescent dye (generally, patient DNA is labelled with a green uorescent dye and reference DNA with a red u- orescent dye) and added to the microarray grid. Where there is an equal quantity of patient and reference DNA bound to the spot, this results in yellow uorescence. Where there is too much patient DNA (representing a duplication of a chromosome region), the spot will be greener; and it will be more red (appears orange) where there is a 2:1 ratio of the control:patient DNA (representing heterozygous deletion of a chromosome region). Array CGH can detect small chromosomal deletions and duplications and is also more sensitive than conventional karyotyping at detecting mosaicism. However, array CGH and other array-based approaches will not detect balanced chromosome rearrangements where there is no loss or gain of genes/chromosome material, such as balanced reciprocal translocations, or a global increase in copy number, such as triploidy. In addition, an array CGH will not detect small insertions/deletions or single nucleotide substitutions. 3.5. Which of the following is an imprinted condition? A. Huntington’s disease B. Patau syndrome C. Neurobromatosis type 1 D. Pseudohypoparathyroidism E. Alpha-1-antitrypsin deciency Answer: D. Several chromosomal regions (loci) have been identied where gene expression is inherited in a parent-of-origin-specic manner; these are called imprinted loci. Within these loci the paternally inherited gene may be active while the maternally inherited may be silenced, or vice versa. Variants within imprinted loci lead to an unusual pattern of inheritance where the phenotype is manifest only if inherited from the parent who contributes the transcriptionally active allele. Pseudohypoparathyroidism (PHP) is caused by the maternal inher- itance of a GNAS1 variant (located at 20q13) and is characterised by hypocalcaemia, hyperphosphataemia, raised parathyroid hormone (PTH) levels, ectopic calcication, obesity, delayed puberty and short- ened 4th and 5th metacarpals (the syndrome also known as Albright hereditary osteodystrophy, AHO). When the gene variant is inherited from the father, PTH, calcium and phosphate levels are normal but the other (skeletal) features are present and the condition is known as pseudpseu- dohypoparathyroidism (PPHP). GNAS1 encodes Gsα which is primar- ily expressed from the maternal allele in the kidney, pituitary, thyroid and gonadal cells (and their disruption is the cause of the biochemical defects) whereas both alleles are expressed in other tissues (responsible for the skeletal features). Therefore where a GNAS1 variant is maternally inherited the individual will have both biochemical and skeletal features (PHP) but where it is paternally inherited they will not have the biochem- ical features (PPHP).
- 83. Clinical immunology 4 SL Johnston Functionalanatomy and physiology 60 The innate immune system 60 The adaptive immune system 65 The inammatory response 67 Acute inammation 67 Chronic inammation 69 Laboratory features of inammation 69 Presenting problems in immune disorders 70 Recurrent infections 70 Intermittent fever 71 Anaphylaxis 72 Immune deciency 72 Primary phagocyte deciencies 72 Complement pathway deciencies 73 Primary antibody deciencies 73 Primary T-lymphocyte deciencies 75 Secondary immune deciencies 75 Periodic fever syndromes 76 Amyloidosis 77 Autoimmune disease 78 Allergy 80 Angioedema 82 Pregnancy and the immune system 84 Transplantation and graft rejection 84 Transplant rejection 84 Complications of transplant immunosuppression 85 Organ donation 85 Tumour immunology 85
- 84. 60 CLINICALIMMUNOLOGY The immune system has evolved to identify and destroy pathogens while minimising damage to host tissue. Despite the ancient observa- tion that recovery from an infectious disease frequently results in pro- tection against that condition, the existence of the immune system as a functional entity was not recognised until the end of the 19th century. More recently, it has become clear that the immune system not only protects against infection but also regulates tissue repair following injury, and when dysregulated, governs the responses that can lead to auto- immune and auto-inammatory diseases. Dysfunction or deciency of the immune response can lead to a wide variety of diseases that may potentially involve every organ system in the body. The aim of this chapter is to provide a general understanding of the immune system, how it contributes to human disease and how manipu- lation of the immune system can be put to therapeutic use. A review of the key components of the immune response is followed by sections that illustrate the clinical presentation of the most common forms of immune dysfunction: immune deciency, inammation, autoimmunity and allergy. More detailed discussion of individual conditions can be found in the relevant organ-specic, emergency and critical care medicine chapters Functional anatomy and physiology The immune system consists of an intricately linked network of lymphoid organs, cells and proteins that are strategically placed to protect against infection (Fig. 4.1). Immune defences are normally categorised into the innate immune response, which provides immediate protection against an invading pathogen, and the adaptive or acquired immune response, which takes more time to develop but confers exquisite specicity and long-lasting protection. Innate and adaptive immunity do not work in iso- lation, but rather in concert, largely driven by cytokines produced by the specic immune cell populations. The innate immune system Innate defences against infection include anatomical barriers, phagocytic cells, soluble molecules such as complement and acute phase proteins, and natural killer cells. The innate immune system recognises generic microbial structures present on non-mammalian tissue and can be mobi- lised within minutes. A specic stimulus will elicit essentially identical responses in different individuals, in contrast with adaptive antibody and T-cell responses, which vary greatly between individuals. Physical barriers The tightly packed keratinised cells of the skin physically limit coloni- sation by microorganisms. The hydrophobic oils that are secreted by sebaceous glands further repel water and microorganisms, and micro- bial growth is inhibited by the skin's low pH and low oxygen tension. Sweat also contains lysozyme, an enzyme that destroys the structural integrity of bacterial cell walls; ammonia, which has antibacterial prop- erties; and several antimicrobial peptides such as defensins. Similarly, the mucous membranes of the respiratory, gastrointestinal and geni- tourinary tracts provide a physical barrier to infection. Secreted mucus traps invading pathogens, and immunoglobulin A (IgA), generated by the adaptive immune system, prevents bacteria and viruses attaching to and penetrating epithelial cells. As in the skin, lysozyme and antimi- crobial peptides within mucosal membranes directly kill invading path- ogens, and lactoferrin acts to starve invading bacteria of iron. Within the respiratory tract, cilia directly trap pathogens and contribute to removal of mucus, assisted by physical manœuvres such as sneez- ing and coughing. In the gastrointestinal tract, hydrochloric acid and salivary amylase chemically destroy bacteria, while normal peristal- sis and induced vomiting or diarrhoea assist clearance of invading organisms. Adenoids Lymph nodes Tonsils Thoracic duct Spleen Bone marrow Liver Appendix Germinal centre Proliferating B cells after antigen exposure Afferent lymph Paracortex T cells Dendritic cells Cortex B cells in primary lymphoid follicles Efferent lymph Medulla Plasma cells Sinuses with macrophages Blood vessels Capsule Lymph node section Lymphatics Neutrophil Eosinophil Cells of the innate immune system Natural killer cell Basophil Mast cell Monocyte Macrophage T lymphocyte Cells of the adaptive immune system Antigen-presenting cell B lymphocyte Thymus Peyer’s patches in small intestine Fig. 4.1 Anatomy of the immune system.
- 85. Functional anatomy andphysiology 61 4 The microbiome, which is made up of endogenous commensal bacteria, provides an additional constitutive defence against infection. Approximately 1014 bacteria normally reside at epithelial surfaces in symbiosis with the human host. They compete with pathogenic microorganisms for scarce resources, including space and nutrients, and produce fatty acids and bactericidins that inhibit the growth of many pathogens. In addition, recent research has demonstrated that commensal bacteria help to shape the immune response by inducing specic regulatory T cells within the intestine. Eradication of the normal ora with broad-spectrum antibiotics commonly results in opportunistic infection by organisms such as Clostridioides dif- cile, which rapidly colonise an undefended ecological niche. These constitutive barriers are highly effective, but if external defences are breached by a wound or pathogenic organism, the specic soluble proteins and cells of the innate immune system are activated. Phagocytes Phagocytes (‘eating cells’) are specialised cells that ingest and kill microorganisms, scavenge cellular and infectious debris, and produce inammatory molecules that regulate other components of the immune system. They include neutrophils, monocytes and macrophages, and are particularly important for defence against bacterial and fungal infections. Phagocytes express a wide range of surface receptors, including pattern recognition receptors (PRRs), which recognise pathogen-associated molecular patterns (PAMPs) on invading microorganisms, allowing their identication. The PRRs include Toll-like receptors, nucleotide oligom- erisation domain (NOD) protein-like receptors and mannose receptors, whereas the PAMPs they recognise are molecular motifs not present on mammalian cells, including bacterial cell wall components, bacterial DNA and viral double-stranded RNA. Interaction between the PRRs and their PAMPs leads to activation of nuclear factor kappa B (NFκB), which stim- ulates expression of pro-inammatory genes, and of nucleotide-binding oligomerisation domain (NOD)-like receptor proteins (NLRP), which form complexes with other intracellular proteins to form the inammasome (Fig. 4.2). The inammasome results in activation of interleukin-1 beta (IL-1β), which is excreted extracellularly and plays a key pathogenic role in familial fever syndromes (p. 76) and acute gout (Ch. 26). While phago- cytes can recognise microorganisms through PRRs alone, engulfment of microorganisms is greatly enhanced by opsonisation. Opsonins include acute phase proteins produced by the liver, such as C-reactive protein and complement component C3b. Antibodies generated by the adaptive immune system also act as opsonins. They bind both to the pathogen and to phagocyte receptors, acting as a bridge between the two to facili- tate phagocytosis (see Fig. 4.2). This is followed by intracellular pathogen destruction and downstream activation of pro-inammatory genes, result- ing in the generation of pro-inammatory cytokines as discussed below. Neutrophils Neutrophils, also known as polymorphonuclear leucocytes, are derived from the bone marrow and circulate freely in the blood. They are short- lived cells with a half-life of 6hours, and are produced at the rate of 1011 cells daily. Their functions are to kill microorganisms, to facilitate rapid transit of cells through tissues and to amplify the immune response non-specically. These functions are mediated by enzymes contained in granules, which also provide an intracellular milieu for the killing and degradation of microorganisms. Two main types of granule are recognised: primary or azurophil gran- ules, and the more numerous secondary or specic granules. Primary granules contain myeloperoxidase and other enzymes important for intracellular killing and digestion of ingested microbes. Secondary gran- ules are smaller and contain lysozyme, collagenase and lactoferrin, which can be released into the extracellular space. Enzyme production is increased in response to infection, which is reected by more intense granule staining on microscopy, known as ‘toxic granulation’. Microbes C3b Antibody C-reactive protein Fc receptor Pattern recognition receptors NOD-like receptors Microbial DNA Microbial RNA Microbial proteins Pathogen- associated molecular patterns LPS Peptidoglycans Crystals NFκB NFκB Lysosome C3b receptor Phagocytic cell Pro-inflammatory gene expression Pro-IL-1β IL-1β NLRP NLRP expression Inflammasome Fig. 4.2 Phagocytosis and opsonisation. Phagocytosis of microbes can be augmented by several opsonins, such as C-reactive protein, antibodies and complement fragments like C3b, which enhance the ability of phagocytic cells to engulf microorganisms and destroy them. Phagocytes also recognise components of microbes, such as lipopolysaccharide, peptidoglycans, DNA and RNA, collectively known as pathogen-associated molecular patterns (PAMPs). These activate pattern recognition receptors (PRRs), such as Toll-like receptors and nucleotide oligomerisation domain (NOD)-like receptors, which promote inammatory gene expression through the nuclear factor kappa B (NFκB) pathway. Uric acid and other crystals can also promote inammation through the NOD pathway. (IL = interleukin; LPS = lipopolysaccharide; NLRP = nucleotide-binding oligomerisation domain (NOD)-like receptor proteins)
- 86. 62 CLINICALIMMUNOLOGY Changes in damaged or infected cells trigger local production of inammatory molecules and cytokines. These cytokines stimulate the production and maturation of neutrophils in the bone marrow, and their release into the circulation. Neutrophils are recruited to specic sites of infection by chemotactic agents, such as interleukin 8 (IL-8), and by acti- vation of local endothelium. Up-regulation of cellular adhesion molecules on neutrophils and the endothelium also facilitates neutrophil migration. The transit of neutrophils through the blood stream is responsible for the rise in neutrophil count that occurs in early infection. Once present within infected tissue, activated neutrophils seek out and engulf invading micro- organisms. These are initially enclosed within membrane-bound vesicles, which fuse with cytoplasmic granules to form the phagolysosome. Within this protected compartment, killing of the organism occurs through a combination of oxidative and non-oxidative killing. Oxidative killing, also known as the respiratory burst, is mediated by the nicotinamide adenine dinucleotide phosphate (NADPH)–oxidase enzyme complex, which con- verts oxygen into reactive oxygen species such as hydrogen peroxide and superoxide that are lethal to microorganisms. The myeloperoxidase enzyme within neutrophils produces hypochlorous acid, which is a pow- erful oxidant and antimicrobial agent. Non-oxidative (oxygen-independ- ent) killing occurs through the release of bactericidal enzymes into the phagolysosome. Each enzyme has a distinct antimicrobial spectrum, providing broad coverage against bacteria and fungi. An additional, recently identied form of neutrophil-mediated killing is neutrophil extracellular trap (NET) formation. Activated neutrophils can release chromatin with granule proteins such as elastase to form an extracellular matrix that binds to microbial proteins. This can immobilise or kill microorganisms without requiring phagocytosis. The process of phagocytosis and NET formation (NETosis) depletes neutrophil glycogen reserves and is followed by neutrophil death. As the cells die, their con- tents are released and lysosomal enzymes degrade collagen and other components of the interstitium, causing liquefaction of closely adjacent tissue. The accumulation of dead and dying neutrophils results in the formation of pus, which, if extensive, may lead to abscess formation. Monocytes and macrophages Monocytes are the precursors of tissue macrophages. They are pro- duced in the bone marrow and enter the circulation, where they con- stitute about 5% of leucocytes. From the blood stream they migrate to peripheral tissues, where they differentiate into tissue macrophages and reside for long periods. Specialised populations of tissue macrophages include Kupffer cells in the liver, alveolar macrophages in the lung, mesan- gial cells in the kidney, and microglial cells in the brain. Macrophages, like neutrophils, are capable of phagocytosis and killing of microorganisms but also play an important role in the amplication and regulation of the inammatory response (Box 4.1). They are particularly important in tissue surveillance and constantly survey their immediate surroundings for signs of tissue damage or invading organisms. Dendritic cells Dendritic cells are specialised antigen-presenting cells that are present in tissues in contact with the external environment, such as the skin and mucosal membranes. They can also be found in an immature state in the blood. They sample the environment for foreign particles and, once activated, carry microbial antigens to regional lymph nodes, where they interact with T cells and B cells to initiate and shape the adaptive immune response. Cytokines Cytokines are signalling proteins produced by cells of the immune sys- tem and a variety of other cell types. More than 100 have been identied. Cytokines have complex and overlapping roles in cellular communication and regulation of the immune response. Subtle differences in cytokine production, particularly at the initiation of an immune response, can have a major impact on outcome. Cytokines bind to specic receptors on target cells and activate downstream intracellular signalling pathways, ultimately leading to changes in gene transcription and cellular func- tion. Two important signalling pathways are illustrated in Figure 4.3. The nuclear factor kappa B (NFκB) pathway is activated by tumour necrosis factor (TNF), by other members of the TNF superfamily such as receptor activator of nuclear kappa B ligand (RANKL), and by the Toll-like recep- tors and NOD-like receptors (see Fig. 4.2). In the case of TNF superfamily members, receptor binding causes the inhibitor of kappa B kinase (IKK) complex of three proteins to be recruited to the receptor by binding TNF receptor-associated proteins (TRAF). This activates IKK, which in turn leads to phosphorylation of the inhibitor of nuclear factor kappa B pro- tein (IκB), causing it to be degraded by the proteasome, allowing NFκB to translocate to the nucleus and activate gene transcription. The Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway is involved in transducing signals downstream of many cytokine receptors, including those for IL-2, IL-6 and interferon-gamma (IFN-γ). On receptor binding, JAK proteins are recruited to the intracellular por- tion of the receptor and are phosphorylated. These in turn phosphorylate STAT proteins, which translocate to the nucleus and activate gene tran- scription, altering cellular function. The function and disease associations of several important cytokines are shown in Box 4.2. Cytokine inhibitors are now routinely used in the treatment of autoimmune diseases, most of which are monoclonal antibodies to cytokines or their receptors. In addition, small-molecule inhibitors have been developed that inhibit the intracellular signalling pathways used by cytokines. These include the Janus kinase inhibitors tofacitinib, baracitinib and upadacitinib and l- gotinib which are used in the treatment of various inammatory rheu- matic diseases and inammatory bowel disease, and the tyrosine kinase inhibitor imatinib, which is used in chronic myeloid leukaemia and other haematological malignancies. Integrins Integrins are transmembrane proteins that play important roles in cell–cell and cell–matrix interactions. They are expressed on lymphocytes as well as a variety of other cell types and mediate attachment of cells to the endothelium and the extracellular matrix, affecting cell migration and sig- nal transduction. Their role in autoimmune disease has been extensively studied and therapeutic agents are now being developed which modify binding of integrins to their targets. For example, natalizumab is a mono- clonal antibody which targets the a4 integrin which is expressed on lym- phocytes. Natalizumab prevents α4β1 integrin binding to VCAM-1 and the α4β7 integrin binding to MAdCAM-1 resulting in an anti-inammatory 4.1 Functions of macrophages Amplication of the inammatory response Stimulate the acute phase response (through production of IL-1 and IL-6) Activate vascular endothelium (IL-1, TNF-α) Stimulate neutrophil maturation and chemotaxis (IL-1, IL-8) Stimulate monocyte chemotaxis Killing of microorganisms Phagocytosis Microbial killing through oxidative and non-oxidative mechanisms Clearance, resolution and repair Scavenging of necrotic and apoptotic cells Clearance of toxins and other inorganic debris Tissue remodelling (elastase, collagenase, matrix proteins) Down-regulation of inammatory cytokines Wound healing and scar formation (IL-1, platelet-derived growth factor, broblast growth factor) Link between innate and adaptive immune systems Activate T cells by presenting antigen in a recognisable form T cell-derived cytokines increase phagocytosis and microbicidal activity of macrophages in a positive feedback loop (IL = interleukin; TNF = tumour necrosis factor)
- 87. Functional anatomy andphysiology 63 4 effect. It is an effective treatment for multiple sclerosis, which works by preventing immune cells from entering the central nervous system by interfering with lymphocyte binding the α4β1 integrin. This treatment is not without risk, however, since there are reports of progressive multifo- cal leucoencephalopathy (PML) in MS treated patients, as a result of JC virus infection of the central nervous system. Similarly, vedolizumab, a monoclonal antibody directed against the α4/β7 integrin, is an effective treatment for Crohn’s disease and ulcerative colitis which works selec- tively by preventing lymphocytes entering gut endothelium by inhibiting the interaction with MAdCAM-1. Complement The complement system comprises a group of more than 20 tightly reg- ulated, functionally linked proteins that act to promote inammation and eliminate invading pathogens. Complement proteins are produced in the liver and are present in inactive form in the circulation. When the comple- ment system is activated, it sets in motion a rapidly amplied biological cascade analogous to the coagulation cascade. There are three mechanisms by which the complement cascade can be activated (Fig. 4.4): The alternate pathway is triggered directly by binding of C3 to bac- terial cell-wall components, such as lipopolysaccharide of Gram- negative bacteria and teichoic acid of Gram-positive bacteria. The classical pathway is initiated when two or more IgM or IgG antibody molecules bind to antigen. The associated conformational change exposes binding sites on the antibodies for the rst protein in the classical pathway, C1, which is a multiheaded molecule that can bind up to six antibody molecules. Once two or more ‘heads’ of a C1 molecule are bound to antibody, the classical cascade is trig- gered. An important inhibitor of the classical pathway is C1 inhibitor (C1inh), as illustrated in Figure 4.4 The lectin pathway is activated when mannose-binding lectin inter- acts with microbial cell surface carbohydrates. This directly stimu- lates the classical pathway at the level of C4, bypassing the need for immune complex formation. Activation of complement by any of these pathways results in activation of C3. This in turn activates the nal common pathway, in which the com- plement proteins C5–C9 assemble to form the membrane attack complex (MAC). This can puncture the cell wall, leading to osmotic lysis of target cells. JAK JAK inhibitor Response genes Response genes Proteasome JAK Cytokines Cytokine receptor P P P P P STAT STAT P P STAT STAT DNA TNF TNF receptor TRAF IκB P IκB NFκB NFκB IKKκ IKKα IKKβ IFN-γ IL-6 IL-2 Fig. 4.3 Cytokines signalling pathways and the immune response. Cytokines regulate the immune response through binding to specic receptors that activate a variety of intracellular signalling pathways, two of which are shown. Members of the tumour necrosis factor (TNF) superfamily and the Toll-like receptors and NOD-like receptors (see Fig. 4.2) signal through the nuclear factor kappa B (NFκB) pathway. Several other cytokines, including IL-2, IL-6 and interferons, employ the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway to regulate cellular function (see text for more details). (IFN, interferon; IκB = inhibitor of kappa B; IKK = I kappa B kinase; IL=interleukin; P = phosphorylation of the signalling protein; TRAF = tumour necrosis factor receptor-associated factor) Smooth muscle contraction Activation of cells Vascular permeability Lysis of bacteria Membrane attack complex (MAC) Opsonisation of bacteria Direct activation Lectin pathway Mannose- binding lectin Classical pathway Antibody–antigen complexes Alternate pathway C4 C2 C3 C3a C1inh C5a C5 C3b C5b C6 C7 C8 C1 C9 Fig. 4.4 The complement pathway. The classical pathway is activated by binding of antigen–antibody complexes to C1 but is blocked by C1 inhibitor (C1inh), whereas mannose-binding lectins, which are macromolecules that bind to carbohydrates on the surface of various microorganisms, activate the pathway by binding C4. Bacteria can directly activate the pathway through C3, which plays a pivotal role in complement activation through all three pathways.
- 88. 64 CLINICALIMMUNOLOGY There are a number of control proteins within the complement system that prevent activation on host cells, thereby preventing host cell damage, some of which are membrane bound, others soluble, such as C1 inhibi- tor. Factor H is an important example in control of the alternate pathway, CD59 and decay accelerating factor (DAF) are important in the terminal complement pathway. Deciencies in factor H can lead to atypical haemo- lytic uraemic syndrome and failure of binding of CD59 and DAF due to deciency in the anchoring glycosylphosphatidylinositol on red blood cells can lead to paroxysmal nocturnal haemoglobulinuria as a result of comple- ment-mediated haemolysis. A monoclonal antibody directed against the central complement molecule C5, eculizumab, has been developed for therapeutic use in these conditions. Invasive infection, including menin- gococcal sepsis, has been reported with eculizumab therapy, highlighting the importance of the complement system in preventing such infections. 4.2 Important cytokines in the regulation of the immune response Cytokine Source Actions Biologic therapies Interferon-alpha (IFN-α) T cells and macrophages Antiviral activity Activates NK cells, CD8+ T cells and macrophages Recombinant IFN-α used in hepatitis C and some malignancies Interferon-gamma (IFN-γ) T cells and NK cells Increases antimicrobial activity of macrophages Regulates cytokine production by T cells and macrophages Interferon-γ used in chronic granulomatous disease Tumour necrosis factor alpha (TNF-α) Macrophages, NK cells and others, including T cells Pro-inammatory Increases expression of other cytokines and adhesion molecules Causes apoptosis of some target cells Directly cytotoxic TNF-α inhibitors used in rheumatoid arthritis, inammatory bowel disease, psoriasis and many other inammatory conditions Interleukin-1 (IL-1) Macrophages and neutrophils Stimulates neutrophil recruitment, fever, and T-cell and macrophage activation as part of the inammatory response IL-1 inhibitors used in systemic juvenile rheumatoid arthritis, periodic fever syndromes and acute gout Interleukin-2 (IL-2) CD4+ T cells Stimulates proliferation and differentiation of antigen-specic T lymphocytes IL-2 inhibitors used in the treatment of transplant rejection Interleukin-4 (IL-4) CD4+ T cells Stimulates maturation of B and T cells, and production of IgE antibody Antibodies to IL-4 receptor used in severe atopic dermatitis Interleukin-5 (IL-5) CD4+ T cells, mast cells, eosinophils and basophils Growth and differentiation factor for B cells and eosinophils Antibodies to IL-5 or the IL-5 receptor used in treatment refractory eosinophilic asthma and more recently anti-IL-5 antibodies used in eosinophilic vasculitis Interleukin-6 (IL-6) Monocytes and macrophages Stimulates neutrophil recruitment, fever, and T-cell and macrophage activation as part of the inammatory response, stimulates maturation of B cells into plasma cells Antibodies to IL-6 receptor used in rheumatoid arthritis and giant cell arteritis Interleukin-12 (IL-12) Monocytes and macrophages Stimulates IFN-γ and TNF-α release by T cells Activates NK cells Antibody to p40 subunit of IL-12 used in psoriasis and psoriatic arthritis Interleukin-17 (IL-17) Th17 cells (T helper), NK cells, NK-T cells Pro-inammatory cytokine Involved in mucosal immunity and control of extracellular pathogens, synergy with IL-1 and TNF Antibody to IL-17 used in psoriasis, psoriatic arthritis and ankylosing spondylitis Interleukin-22 (IL-22) Th17 cells Induction of epithelial cell proliferation and antimicrobial proteins in keratinocytes Interleukin-23 (IL-23) Activated macrophages and dendritic cells in peripheral tissues Pro-inammatory cytokine, proliferation of Th17 T cells with induction of IL-17 Antibody to IL-23 used in psoriasis, psoriatic arthritis and inammatory bowel disease (IgE = immunoglobulin E; NK = natural killer) This step is particularly important in the defence against encapsulated bacteria such as Neisseria spp. and Haemophilus inuenzae. Complement fragments generated by activation of the cascade can also act as opsonins, rendering microorganisms more susceptible to phagocytosis by macrophages and neutrophils (see Fig. 4.2). In addi- tion, they are chemotactic agents, promoting leucocyte trafcking to sites of inammation. Some fragments act as anaphylotoxins, binding to complement receptors on mast cells and triggering release of histamine, which increases vascular permeability. The products of complement acti- vation also help to target immune complexes to antigen-presenting cells, providing a link between the innate and the adaptive immune systems. Finally, activated complement products dissolve the immune complexes that triggered the cascade, minimising bystander damage to surrounding tissues.
- 89. Functional anatomy andphysiology 65 4 Mast cells and basophils Mast cells and basophils are bone marrow-derived cells that play a cen- tral role in allergic disorders. Mast cells reside predominantly in tissues exposed to the external environment, such as the skin and gut, while basophils circulate in peripheral blood and are recruited into tissues in response to inammation. Both contain large cytoplasmic granules that enclose vasoactive substances such as histamine (see Fig. 4.14). Mast cells and basophils express IgE receptors on their cell surface, which bind IgE antibody. On encounter with specic antigen, the cell is triggered to release histamine and other mediators present within the granules and to synthesise additional mediators, including leukotrienes, prostaglandins and cytokines. An inammatory cascade is initiated that increases local blood ow and vascular permeability, stimulates smooth muscle contraction and increases secretion at mucosal surfaces. Natural killer cells Natural killer (NK) cells are large granular lymphocytes that play a major role in defence against tumours and viruses. They exhibit features of both the adaptive and the innate immune systems in that they are morpho- logically similar to lymphocytes and recognise similar ligands, but they are not antigen-specic and cannot generate immunological memory. NK cells express a variety of cell surface receptors, some of which are stim- ulatory and others inhibitory. The effects of inhibitory receptors normally predominate. These recognise human leucocyte antigen (HLA) molecules that are expressed on normal nucleated cells, preventing NK cell-medi- ated attack, whereas the stimulatory receptors recognise molecules that are expressed primarily when cells are damaged. This allows NK cells to remain tolerant to healthy cells but not to damaged ones. When cells become infected by viruses or undergo malignant change, expression of HLA class I molecules on the cell surface can be down-regulated. This is an important mechanism by which these cells then evade adaptive T-lymphocyte responses. In this circumstance, however, NK cell defences becomes important, as down-regulation of HLA class I abrogates the inhibitory signals that normally prevent NK activation. The net result is NK attack on the abnormal target cell. NK cells can also be activated by bind- ing of antigen–antibody complexes to surface receptors. This physically links the NK cell to its target in a manner analogous to opsonisation and is known as antibody-dependent cellular cytotoxicity (ADCC). Activated NK cells can kill their targets in various ways. They secrete pore-forming proteins such as perforin into the membrane of the target cell, and proteolytic enzymes called granzymes into the target cell, which cause apoptosis. In addition, NK cells produce a variety of cytokines such as TNF-α and IFN-γ, which have direct antiviral and anti-tumour effects. The adaptive immune system If the innate immune system fails to provide effective protection against an invading pathogen, the adaptive immune system is mobilised (see Fig. 4.1). This has three key characteristics: It has exquisite specicity and can discriminate between very small differences in molecular structure. It is highly adaptive and can respond to an almost unlimited number of molecules. It possesses immunological memory, and changes consequent to initial activation by an antigen allow a more effective immune response on subsequent encounters. There are two major arms of the adaptive immune response. Humoral immunity involves the production of antibodies by B lymphocytes, and cellular immunity involves the activation of T lymphocytes, which syn- thesise and release cytokines that affect other cells, as well as directly killing target cells. These interact closely with each other and with the components of the innate immune system to maximise effectiveness of the immune response. Lymphoid organs The primary lymphoid organs are involved in lymphocyte development. They include the bone marrow, where T and B lymphocytes differentiate from haematopoietic stem cells and where B lymphocytes also mature, and the thymus, the site of T-cell maturation (see Fig. 4.1). After matu- ration, lymphocytes migrate to the secondary lymphoid organs. These include the spleen, lymph nodes and mucosa-associated lymphoid tis- sue. These trap and concentrate foreign substances and are the major sites of interaction between naïve lymphocytes and microorganisms. The thymus The thymus is a bi-lobed structure in the anterior mediastinum, and is organised into cortical and medullary areas. The cortex is densely pop- ulated with immature T cells, which migrate to the medulla to undergo selection and maturation. The thymus is most active in the fetal and neo- natal period, and involutes after puberty. Failure of thymic development is associated with profound T-cell immune deciency but surgical removal of the thymus in childhood (usually during major cardiac surgery) is not associated with signicant immune dysfunction. The spleen The spleen is the largest of the secondary lymphoid organs. It is highly effective at ltering blood and is an important site of phagocytosis of senescent erythrocytes, bacteria, immune complexes and other debris, and of antibody synthesis. It is important for defence against encap- sulated bacteria, and asplenic individuals are at risk of overwhelming Streptococcus pneumoniae and H. inuenzae infection (see Box 4.5). Lymph nodes These are positioned to maximise exposure to lymph draining from sites of external contact, and are highly organised (see Fig. 4.1). The cortex contains primary lymphoid follicles, which are the site of B-lymphocyte interactions. When B cells encounter antigen, they undergo intense proliferation, forming germinal centres. The paracortex is rich in T lymphocytes and dendritic cells. The medulla is the major site of antibody-secreting plasma cells. Within the medulla there are many sinuses, which contain large numbers of macrophages. Mucosa-associated lymphoid tissue Mucosa-associated lymphoid tissue (MALT) consists of diffusely distrib- uted lymphoid cells and follicles present along mucosal surfaces. It has a similar function to the more organised, encapsulated lymph nodes. They include the tonsils, adenoids and Peyer's patches in the small intestine. Lymphatics Lymphoid tissue is connected by a network of lymphatics, with three major functions: lymphatics provide access to lymph nodes, return inter- stitial uid to the venous system and transport fat from the small intestine to the blood stream (see Fig. 19.12). The lymphatics begin as blind- ending capillaries, which come together to form lymphatic ducts, enter- ing and leaving regional lymph nodes as afferent and efferent ducts, respectively. They eventually coalesce and drain into the thoracic duct and left subclavian vein. Lymphatics may be either deep or supercial, and follow the distribution of major blood vessels. Humoral immunity Humoral immunity is mediated by B lymphocytes, which differentiate from haematopoietic stem cells in the bone marrow. Their major functions are to produce antibody and interact with T cells, but they are also involved in antigen presentation. Mature B lymphocytes can be found in the bone marrow, lymphoid tissue, spleen and, to a lesser extent, the blood stream. They express a unique immunoglobulin receptor on their cell surface, the B-cell receptor, which binds to soluble antigen targets (Fig. 4.5).
- 90. 66 CLINICALIMMUNOLOGY Encounters with antigen usually occur within lymph nodes. If provided with appropriate cytokines and other signals from nearby T lymphocytes, anti- gen-specic B cells respond by rapidly proliferating in a process known as clonal expansion (see Fig. 4.5). This is accompanied by a highly complex series of genetic rearrangements known as somatic hypermutation, which generates B-cell populations that express receptors with greater afnity for antigen than the original. These cells differentiate into either long-lived memory cells, which reside in the lymph nodes, or plasma cells, which pro- duce antibody. Memory cells allow production of a more rapid and more effective response on subsequent exposure to that pathogen. Immunoglobulins Immunoglobulins (Ig) play a central role in humoral immunity. They are solu- ble proteins produced by plasma cells and are made up of two heavy and two light chains (Fig. 4.6). The heavy chain determines the antibody class or isotype, such as IgG, IgA, IgM, IgE or IgD. Subclasses of IgG and IgA also occur. The antigen is recognised by the antigen-binding regions (Fab ) of both heavy and light chains, while the consequences of antibody bind- ing are determined by the constant region of the heavy chain (Fc ) (Box4.3). Antibodies have several functions. They facilitate phagocytosis by acting as opsonins (see Fig. 4.2) and facilitate cell killing by cytotoxic cells, par- ticularly NK cells by antibody-dependent cellular cytotoxicity. Binding of antibodies to antigen can trigger activation of the classical complement pathway (see Fig. 4.4). In addition, antibodies can directly neutralise the biological activity of their antigen target. This is a particularly important feature of IgA antibodies, which act predominantly at mucosal surfaces. The humoral immune response is characterised by immunological memory, in which the antibody response to successive exposures to an antigen is qualitatively and quantitatively improved from the rst expo- sure. When a previously unstimulated or ‘naïve’ B lymphocyte is acti- vated by antigen, the rst antibody to be produced is IgM, which appears in the serum after 5–10 days. Depending on additional stimuli provided by T lymphocytes, other antibody classes (IgG, IgA and IgE) are pro- duced 1–2 weeks later. If the memory B cell is subsequently re-exposed to the same antigen, the lag time between exposure and production of antibody is decreased to 2–3 days, the amount of antibody produced is increased, and the response is dominated by IgG antibodies of high afn- ity. Furthermore, in contrast to the initial antibody response, secondary antibody responses do not require additional input from T lymphocytes. This allows the rapid generation of highly specic responses on re-expo- sure to a pathogen and is an important mechanism in vaccine efcacy. Cellular immunity Cellular immunity is mediated by T lymphocytes, which play important roles in defence against viruses, fungi and intracellular bacteria. They also play an important immunoregulatory role, by orchestrating and regulating the responses of other components of the immune system. T-lymphocyte precursors differentiate from haematopoietic stem cells in the bone marrow and are exported to the thymus when they are still immature (see Fig. 4.1). Individual T cells express a unique receptor that is highly specic for a single antigen. Within the thymus T cells undergo a process of stringent selection to ensure that autoreactive cells are destroyed. Mature T lymphocytes leave the thymus and expand to pop- ulate other organs of the immune system. It has been estimated that an individual possesses 107 –109 T-cell clones, each with a unique T-cell receptor, ensuring at least partial coverage for any antigen encountered. Unlike B cells, T cells cannot recognise intact protein antigens in their native form. Instead, the protein must be broken down into component pep- tides by antigen-presenting cells for presentation to T lymphocytes in asso- ciation with HLA molecules on the antigen-presenting cell surface (Fig. 4.7). This process is known as antigen processing and presentation, and it is the complex of peptide and HLA together that is recognised by individual T cells. The structure of HLA molecules varies widely between individuals. Since each HLA molecule has the capacity to present a subtly different peptide repertoire to T lymphocytes, this ensures enormous diversity in recognition of antigens by the T-cell population. All nucleated cells have the capacity to process and present antigens, but cells with specialised antigen-presenting functions include dendritic cells, macrophages and B lymphocytes. These cells carry additional co-stimulatory molecules, such as CD80 and CD86, providing the necessary ‘second signal’ for full T-cell activation (Fig. 4.8). Mechanisms also exist to inhibit activation of T-cells. One of the most impor- tant is the programmed cell death 1 (PD-1) pathway. The PD1 receptor is expressed on lymphocytes and inhibits lymphocyte activation when bound by its ligand (PDL-1) which is a molecule expressed on antigen-present- ing cells, endothelial; cells and come tumour cells (Fig. 4.8). Monoclonal antibodies which inhibit this interaction are important treatments for certain types of cancer (see tumour immunology later in this chapter). T lymphocytes can be divided into two subgroups on the basis of function and recognition of HLA molecules. These are designated CD4+ and CD8+ T cells, according to the ‘cluster of differentiation’ (CD) antigen number of key proteins expressed on their cell surface. CD8+ T lymphocytes These cells recognise antigenic peptides in association with HLA class I molecules (HLA-A, HLA-B, HLA-C). They kill infected cells directly Variable region (Fab) Constant region (Fc) Light chain Heavy chain Fig. 4.6 The structure of an immunoglobulin (antibody) molecule. The variable region is responsible for antigen binding, whereas the constant region can interact with immunoglobulin receptors expressed on immune cells. T-helper cell Immunoglobulin receptor Antigen CD40L CD40 TCR HLA B-cell activation B cell Clonal expansion Plasma cells Antibodies Memory B cells IL-4 IL-5 Fig. 4.5 B-cell activation. Activation of B cells is initiated through binding of an antigen with the immunoglobulin receptor on the cell surface. For activation to proceed, an interaction with T-helper cells is also required, providing additional signals through binding of CD40 ligand (CD40L) to CD40; an interaction between the T-cell receptor (TCR) and processed antigenic peptides presented by human leucocyte antigen (HLA) molecules on the B-cell surface; and cytokines released by the T-helper cells. Fully activated B cells undergo clonal expansion with differentiation towards plasma cells that produce antibody. Following activation, memory cells are generated that allow rapid antibody responses when the same antigen is encountered on a second occasion. (IL = interleukin)
- 91. The inflammatory response 67 4 through the production of pore-forming molecules such as perforin and release of digesting enzymes triggering apoptosis of the target cell, and are particularly important in defence against viral infection. CD4+ T lymphocytes These cells recognise peptides presented on HLA class II molecules (HLA-DR, HLA-DP and HLA-DQ) and have mainly immunoregulatory functions. They produce cytokines and provide co-stimulatory signals that support the activation of CD8+ T lymphocytes and assist the pro- duction of mature antibody by B cells. In addition, their close interaction with phagocytes determines cytokine production by both cell types. CD4+ lymphocytes can be further subdivided into subsets on the basis of the cytokines they produce: Th1 (T-helper) cells typically produce IL-2, IFN-γ and TNF-α, and support the development of delayed-type hypersensitivity responses. Th2 cells typically produce IL-4, IL-5, IL-10 and IL-13, and promote allergic responses. T-regulatory cells (T-regs) are a further subset of specialised CD4+ lymphocytes that are important in actively suppressing activation of other cells and preventing autoimmune disease. They produce cytokines such as TGF-β and IL-10. Th17 cells are pro-inammatory cells dened by their production of IL-17. They are related to regulatory T cells. Th17 cells have a key role in defence against extracellular bacteria and fungi. They also have a role in the development of autoimmune disease. T-cell activation is regulated by a balance between co-stimulatory mol- ecules, the second signal required for activation, and inhibitory molecules that down-regulate T-cell activity. One such inhibitory molecule, CTLA4, has been harnessed therapeutically in the form of abatacept, which is a fusion protein comprised of the Fc fragment of immunoglobulin linked to CTLA4. This is used to inhibit T-cell activation in rheumatoid arthritis and solid organ transplantation. The inammatory response Inammation is the response of tissues to injury or infection, and is nec- essary for normal repair and healing. This section focuses on the general principles of the inammatory response and its multisystem manifesta- tions. The role of inammation in specic diseases is discussed in many other chapters of this book. Acute inammation Acute inammation is the result of rapid and complex interplay between the cells and soluble molecules of the innate immune system. The clas- sical external signs include heat, redness, pain and swelling (Fig. 4.9). The inammatory process is initiated by local tissue injury or infection. Damaged epithelial cells produce cytokines and antimicrobial peptides, causing early inltration of phagocytic cells. Production of leukotrienes, 4.3 Classes and properties of antibody Antibody Concentration in adult serum Complement activation* Opsonisation Presence in external secretions Other properties IgG 6.0–16.0g/L IgG1 +++ IgG2 + IgG3 +++ IgG1 ++ IgG3 ++ ++ Four subclasses: IgG1, IgG2, IgG3, IgG4 Distributed equally between blood and extracellular uid, and transported across placenta IgG2 is particularly important in defence against polysaccharides antigens IgA 1.5–4.0g/L – – ++++ Two subclasses: IgA1, IgA2 Highly effective at neutralising toxins Particularly important at mucosal surfaces IgM 0.5–2.0g/L ++++ + Highly effective at agglutinating pathogens IgE 0.003–0.04g/L – – – Majority of IgE is bound to mast cells, basophils and eosinophils Important in allergic disease and defence against parasite infection IgD Not detected – – – Function in B-cell development *Activation of the classical pathway, also called ‘complement xation’. (IgG = immunoglobulin) CD80/86 CD28 T cell T-cell proliferation T-cell effector function Pathogen PAMP PAMP internalised by PRR and degraded in lysosome PRR APC CD4/CD8 TCR Processed antigenic peptide HLA Antigenic peptide IL-2 positive feedback Co-stimulation T-cell activation Fig. 4.7 Antigen presentation. For T-cell activation, antigen has to be processed via antigen-presenting cells (APC). Pathogens, bearing pathogen-associated molecular patterns (PAMPs) on their surface, are recognised by pattern recognition receptors (PRRs) on the APC. Following endocytosis, the pathogen is broken down intracellularly. Antigenic peptides are then loaded onto human leucocyte antigens (HLA), also known as major histocompatibility complexes (MHC), and presented at the APC surface. The combination of peptide and HLA is then recognised by the T-cell receptor (TCR). For T-cell activation, a second, co-stimulatory signal is required through binding of CD80 or CD86 on the APC to CD28 on the T cell (see also Fig.4.8). (CD28 and CD80/86 = co-stimulatory molecules; IL = interleukin)
- 92. 68 CLINICALIMMUNOLOGY prostaglandins, histamine, kinins, anaphylotoxins and inducible nitric oxide synthase also occurs within inamed tissue. These mediators cause vasodilatation and increased vascular permeability, causing traf- cking of uid and cells into the affected tissue. In addition, pro-inam- matory cytokines, such as IL-1, TNF-α and IL-6 produced at the site of injury, are released systemically and act on the hypothalamus to cause fever, and on the liver to stimulate production of acute phase proteins. The acute phase response The acute phase response refers to the production of a variety of proteins by the liver in response to inammatory stimuli. These proteins have a wide range of activities. Circulating levels of C-reactive protein (CRP) and serum amyloid A may be increased 100- to 1000-fold, contributing to host defence and stimulating repair and regeneration. Fibrinogen plays an essential role in wound healing, and α1 -antitrypsin and α1 -antichymotrypsin control the pro-inammatory cascade by neutralising the enzymes pro- duced by activated neutrophils, preventing widespread tissue destruction. In addition, antioxidants such as haptoglobin and manganese superoxide dismutase scavenge for oxygen free radicals, while increased levels of iron- binding proteins such as ferritin and lactoferrin decrease the iron available for uptake by bacteria. Immunoglobulins are not acute phase proteins but are often increased in chronic inammation. Septic shock Septic shock is the clinical manifestation of overwhelming inammation. It is characterised by excessive production of pro-inammatory cytokines by macrophages, causing hypotension, hypovolaemia and tissue oedema. In addition, uncontrolled neutrophil activation causes release of proteases and oxygen free radicals within blood vessels, damaging the vascular endothelium and further increasing capillary permeability. Direct activation of the coagulation pathway combines with endothelial cell disruption to form clots within the damaged vessels. The clinical con- sequences include cardiovascular collapse, acute respiratory distress syndrome, disseminated intravascular coagulation, multi-organ failure and often death. Septic shock most frequently results from infection with Gram-negative bacteria, because lipopolysaccharide produced by these organisms is particularly effective at activating the inammatory cascade. Early recognition and appropriate early intervention can improve patient outcome. More details on the diagnosis and management of septic shock are provided in Chapter 9. Resolution of inammation Resolution of an inammatory response is crucial for normal healing. This involves active down-modulation of inammatory stimuli and repair CD80/CD86 CD80/CD86 CD4+ Th2 cells B-cell activation IL-4, IL-5, IL-10, IL-13 Th1 cells Pro-inflammatory TNF-α, IFN-γ Th17 cells Mucosal immunity Pro-inflammatory IL-17 Regulatory T cells Memory T cells Fas ligand TNF-α, IFN-γ Direct cell killing CD8+ Anti-inflammatory IL-10, TGF-β PD-L1 Tumour cell Proliferation HLA TCR T-cell activation Antigenic peptide PD-1 CTLA4 CD28 CD4/CD8 Antigen-presenting cell IL-2 Fig. 4.8 T-cell activation. Activation of T cells is initiated when an antigenic peptide bound to a human leucocyte antigen (HLA) molecule on antigen-presenting cells interacts with the T-cell receptor expressed by T lymphocytes. Additional signals are required for T-cell activation, however. These include binding of the co-stimulatory molecules CD80 and CD86 with CD28 on the T cell, and interleukin 2 (IL-2), which is produced in an autocrine manner by T cells that are undergoing activation. Other molecules are present that can inhibit T-cell activation, however, including cytotoxic T-lymphocyte-associated protein 4 (CTLA4), which competes with CD28 for binding to CD80 and CD86; and PD-1, which, by binding PD-L1, is also inhibitory. Following activation, T cells proliferate and, depending on their subtype, have various functions with distinct patterns of cytokine production, as indicated. Memory cells are also generated that can mount a rapid immune response on encountering the same antigen. (IFN-γ = interferon-gamma; IL = interleukin; PD-1 = programmed cell death 1; PD-L1 = programmed death ligand 1; TCR = T-cell receptor; TGF-β = transforming growth factor beta; TNF-α = tumour necrosis factor alpha)
- 93. The inflammatory response 69 4 of bystander damage to local tissues. Extravasated neutrophils undergo apoptosis and are phagocytosed by macrophages, along with the remains of microorganisms. Macrophages also synthesise collagenase and elastase, which break down local connective tissue and aid in the removal of debris. Normal tissue homeostasis is also associated with reversion of parenchymal cells to a non-inammatory phenotype. Macrophage-derived cytokines, including transforming growth factor-beta (TGF-β) and plate- let-derived growth factor, stimulate broblasts and promote the synthesis of new collagen, while angiogenic factors stimulate new vessel formation. Chronic inammation In most instances, the development of an active immune response results in clearance and control of the inammatory stimulus and res- olution of tissue damage. Failure of this process may result in chronic inammation, with signicant associated bystander damage, known as hypersensitivity responses. Persistence of microorganisms can result in ongoing accumulation of neutrophils, macrophages and activated T lym- phocytes within the lesion. If this is associated with local deposition of brous tissue, a granuloma may form. Granulomas are characteristic of tuberculosis and leprosy (Hansen's disease), in which the microorgan- ism is protected by a robust cell wall that shields it from killing, despite phagocytosis. Laboratory features of inammation Inammation is associated with changes in many laboratory investi- gations. Leucocytosis is common, and reects the transit of activated neutrophils and monocytes to the site of infection. The platelet count may also be increased. The most widely used laboratory measure of acute inammation is CRP. Circulating levels of many other acute phase reactants, including brinogen, ferritin and complement components, are also increased in response to acute inammation, while albumin levels are reduced. Chronic inammation is frequently associated with a nor- mocytic normochromic anaemia. C-reactive protein C-reactive protein (CRP) is an acute phase reactant synthesised by the liver, which opsonises invading pathogens. Circulating concentrations of CRP increase within 6hours of the start of an inammatory stimulus. Serum con- centrations of CRP provide a direct biomarker of acute inammation and, because the serum half-life of CRP is 18hours, levels fall promptly once the inammatory stimulus is removed. Sequential measurements are useful in monitoring disease activity (Box 4.4). For reasons that remain unclear, some diseases are associated with only minor elevations of CRP despite Hypothalamus: Change in temperature set point Fever Sweating Neuro-endocrine and autonomic stress responses Flushing ↑Respiratory rate ↑Heart rate, flow murmur Adrenal release of glucocorticoids and catecholamines Release of insulin from pancreas Bone marrow: ↑Production and mobilisation of neutrophils Vasodilatation ↑Local vascular permeability Neutrophils + Macrophages Inflammatory mediators and cytokines Tissue damage Bacteria Local infection Skin rupture Phagocytosis Cytokine production Vasodilatation ↑Local vascular permeability ↑Leucocyte influx Headache Delirium Anorexia Low blood pressure Liver: ↑Synthesis of acute phase proteins Enlarged draining lymph nodes Ascending lymphangitis Local cellulitis Pain Redness Swelling Nail Fig. 4.9 Clinical features of acute inammation. In this example, the response is to a penetrating injury and infection of the foot.
- 94. 70 CLINICALIMMUNOLOGY unequivocal evidence of active inammation. These include systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis and leukaemia. An important practical point is that if the CRP is raised in these conditions, it suggests intercurrent infection rather than disease activity. Since the CRP is a more sensitive early indicator of the acute phase response, it is gener- ally used in preference to the erythrocyte sedimentation rate (ESR). If both ESR and CRP are used, any discrepancy should be resolved by assessing the individual determinants of the ESR, which are discussed below. Erythrocyte sedimentation rate The ESR is an indirect measure of inammation. It measures how fast erythrocytes fall through plasma, which is determined by the composi- tion of plasma proteins and the morphology of circulating erythrocytes. These factors govern the propensity of red cells to aggregate, the major determinant of the ESR. Erythrocytes are inherently negatively charged, which prevents them from clumping together in the blood stream. Since plasma proteins such as brinogen and immunoglobulins are posi- tively charged, increased concentrations of these proteins neutralise an increase in plasma protein concentrations neutralises the negative charge of erythrocytes, overcoming their inherent repulsive forces and causing them aggregate, resulting in rouleaux formation. Rouleaux have a higher mass-to-surface area ratio than single red cells, and therefore sediment faster. The most common reason for an increased ESR is an acute phase response, which causes an increase in the concentration of acute phase proteins, including CRP. However, other conditions that do not affect acute phase proteins may alter the composition and concen- tration of other plasma proteins (see Box 4.4). For example, immuno- globulins comprise a signicant proportion of plasma proteins but do not participate in the acute phase response. Thus any condition that causes an increase in serum immunoglobulins will increase the ESR without a corresponding increase in CRP. In addition, abnormal red cell morphol- ogy can make rouleaux formation impossible. For these reasons, an inappropriately low ESR occurs in spherocytosis and sickle-cell anaemia. Plasma viscosity Plasma viscosity is another surrogate measure of plasma protein concen- tration. Like the ESR, it is affected by the concentration of large plasma proteins, including brinogen and immunoglobulins. It is not affected by properties of erythrocytes and is generally considered to be more reliable than the ESR as a marker of inammation. Presenting problems in immune disorders Recurrent infections Infections can occur in otherwise healthy individuals but recurrent infec- tion raises suspicion of an immune deciency. Depending on the compo- nent of the immune system affected, the infections may involve bacteria, viruses, fungi or protozoa, as summarised in Box 4.5. T-cell deciencies can involve pathogens from all groups. Aetiology Infections secondary to immune deciency occur because of defects in the number or function of phagocytes, B cells, T cells or complement, as described later in this chapter. Clinical assessment Clinical features that may indicate immune deciency are listed in Box 4.6. Frequent or severe infections, or ones caused by unusual organisms or at unusual sites, are typical of immune deciency. Investigations Initial investigations should include full blood count and white cell differ- ential, CRP, renal and liver function tests, urine dipstick, serum immu- noglobulins with protein electrophoresis, and HIV testing. Additional microbiological tests, virology and imaging are required to identify the causal organism and localise the site of infection, as outlined in Box 4.7. If primary immune deciency is suspected on the basis of initial investi- gations, more specialised tests should be considered, as summarised in Box 4.8 Management If an immune deciency is suspected but has not yet been formally char- acterised, patients should not receive live vaccines because of the risk of vaccine-induced disease. Further management depends on the underly- ing cause and details are provided later. 4.4 Conditions commonly associated with abnormal C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR) Condition Consequence Effect on CRP1 Effect on ESR2 Acute bacterial, fungal or viral infection Stimulates acute phase response Increased (range 50–150mg/L; in severe infections may be > 300mg/L) Increased Necrotising bacterial infection Stimulates profound acute inammatory response Greatly increased (may be > 300mg/L) Increased Chronic bacterial or fungal infection Localised abscess, bacterial endocarditis or tuberculosis Stimulates acute and chronic inammatory response with polyclonal increase in immunoglobulins, as well as increased acute phase proteins Increased (range 50–150mg/L) Increased disproportionately to CRP Acute inammatory diseases Crohn's disease, polymyalgia rheumatica, inammatory arthritis Stimulates acute phase response Increased (range 50–150mg/L) Increased Systemic lupus erythematosus, Sjögren syndrome, ulcerative colitis Chronic inammatory response Normal Increased Multiple myeloma Monoclonal increase in serum immunoglobulin without acute inammation Normal Increased Pregnancy, old age, end-stage renal disease Increased brinogen Normal Moderately increased 1 Reference range <5mg/L. 2 Reference range: adult males <10mm/hr, adult females <3–15mm/hr.
- 95. Presenting problems inimmune disorders 71 4 Intermittent fever Intermittent fever has a wide differential diagnosis, including recurrent infection, malignancy and certain rheumatic disorders, such as Still's dis- ease, vasculitis and SLE but a familial fever syndrome is a potential cause. Aetiology Familial fever syndromes are genetic disorders caused by mutations in genes responsible for regulating the inammatory response. The symptoms are caused by activation of intracellular signalling pathways involved in the regulation of inammation, with over-production of pro-in- ammatory cytokines such as IL-1. Clinical assessment A full clinical history and physical examination should be performed, pay- ing attention to the patient's ethnic background and any family history of a similar disorder. If this assessment shows no evidence of underly- ing infection, malignancy or a rheumatic disorder and there is a positive 4.6 Warning signs of primary immune deciency* In children In adults ≥ 4 new ear infections within 1 year ≥ 2 new ear infections within 1 year ≥ 2 serious sinus infections within 1 year ≥ 2 new sinus infections within 1 year, in the absence of allergy ≥ 2 months on antibiotics with little effect Recurrent viral infections ≥ 2 pneumonias within 1 year ≥ 1 pneumonia per year for more than 1 year Failure of an infant to gain weight or grow normally Chronic diarrhoea with weight loss Recurrent deep skin or organ abscesses Recurrent deep skin or organ abscesses Persistent thrush in mouth or elsewhere on skin after infancy Persistent thrush or fungal infection on skin or elsewhere Need for intravenous antibiotics to clear infections Recurrent need for intravenous antibiotics to clear infections ≥ 2 deep-seated infections such as sepsis, meningitis or cellulitis Infection with atypical mycobacteria A family history of primary immune deciency A family history of primary immune deciency *The presence of two or more of the listed features may indicate the presence of an underlying primary immunodeciency. ©Jeffrey Modell Foundation 4.5 Immune deciencies and common patterns of infection Phagocyte deciency Complement deciency Antibody deciency T-lymphocyte deciency Bacteria Staphylococcus aureus Pseudomonas aeruginosa Serratia marcescens Burkholderia cenocepacia Nocardia Mycobacterium tuberculosis Atypical mycobacteria Neisseria meningitidis Neisseria gonorrhoeae Haemophilus inuenzae Streptococcus pneumoniae Haemophilus inuenzae Streptococcus pneumoniae Staphylococcus aureus Mycobacterium tuberculosis Atypical mycobacteria Fungi Candida spp. Aspergillus spp. – – Candida spp. Aspergillus spp. Pneumocystis jirovecii Viruses – – Cytomegalovirus (CMV) Enteroviruses Epstein–Barr virus (EBV) Herpes zoster virus Human papillomavirus Human herpesvirus 8 Protozoa Giardia lamblia Toxoplasma gondii Cryptosporidia 4.7 Initial investigations in suspected immune deciency Test Value Comment Full blood count Full white cell differential May dene pathway for further investigation Acute phase reactants Help determine presence of active infection Serum immunoglobulins Detection of antibody deciency Serum protein electrophoresis Detection of paraprotein May be the cause of immune paresis; paraprotein should be excluded prior to diagnosis of primary antibody deciency Serum free light chains/Bence Jones proteins Detection of paraprotein Human immunodeciency virus (HIV) test To exclude HIV as cause of secondary immune deciency Imaging according to history and examination ndings Detection of active infection/end-organ damage To support treatment decisions
- 96. 72 CLINICALIMMUNOLOGY family history and early age at onset, then the likelihood of a familial fever syndrome is increased. Investigations Blood should be taken for a full blood count, measurement of ESR and CRP, and assessment of renal and liver function. Serum ferritin should be checked, as very high levels support the diagnosis of Still's disease. Blood and urine cultures should also be performed, along with an auto- immune screen that includes measurement of antinuclear antibodies and consideration of antineutrophil cytoplasmic antibodies to check for evidence of SLE or vasculitis, respectively. Imaging may be required to exclude occult infection. If these investigations provide no evidence of infection or another cause, then genetic analysis should be considered to conrm the diagnosis of a familial fever syndrome. Negative genetic testing does not, however, entirely exclude a periodic fever syndrome. Management Symptomatic management with non-steroidal anti-inammatory drugs (NSAIDs) should be initiated, pending the results of investigations. If the response to NSAIDs is inadequate, glucocorticoids can be tried, pro- vided that infection has been excluded. If a familial fever syndrome is conrmed, then denitive therapy should be initiated, depending on the underlying diagnosis, as discussed later in this chapter (p. 76). Anaphylaxis Anaphylaxis is a potentially life-threatening, systemic allergic reaction characterised by circulatory collapse, bronchospasm, laryngeal stridor, often associated with angioedema, and urticaria. The risk of death is increased in patients with pre-existing asthma, particularly if this is poorly controlled, and in situations where treatment with adrenaline (epineph- rine) is delayed. Further details are provided in the ‘Presenting problems in acute medicine’ section in Chapter 9 Immune deciency The consequences of immune deciency include recurrent infection, autoimmunity as a result of immune dysregulation, and increased sus- ceptibility to malignancy, especially malignancy driven by viral infec- tions such as Epstein–Barr virus. Immune deciency may arise through intrinsic defects in immune function but is much more commonly due to secondary causes, including infection, drug therapy, malignancy and ageing. This section gives an overview of primary immune de- ciencies. More than a hundred such deciencies have been described, most of which are genetically determined and present in childhood or adolescence. The presentation of immune deciency depends on the component of the immune system that is defective (see Box 4.5). There is considerable overlap and redundancy in the immune network, however, and some diseases do not fall easily into this classication. Primary phagocyte deciencies Primary phagocyte deciencies typically present with recurrent bacterial and fungal infections, which may involve unusual sites. Affected patients require aggressive management of infections, including intravenous anti- biotics and surgical drainage of abscesses, and long-term prophylaxis with antibacterial and antifungal agents. The most important examples are illustrated in Figure 4.10 and discussed below. Chronic granulomatous disease This is caused by mutations in genes that encode NADPH oxidase enzymes, which results in failure of oxidative killing. The defect leads to susceptibility to catalase-positive organisms such as Staphylococcus aureus, Burkholderia cenocepacia and Aspergillus. Intracellular killing of mycobacteria in macrophages is also impaired. Infections most com- monly involve the lungs, lymph nodes, soft tissues, bone, skin and uri- nary tract, and are characterised histologically by granuloma formation. Most cases are X-linked Leucocyte adhesion deciencies These very rare disorders of phagocyte migration occur because of fail- ure to express adhesion molecules on the surface of leucocytes, result- ing in their inability to exit the blood stream. The most common cause is loss-of-function mutations affecting the ITGB2 gene, which encodes the integrin β-2 chain, a component of the adhesion molecule LFA1. They are characterised by recurrent bacterial infections but sites of infection lack evidence of neutrophil inltration, such as pus formation. Peripheral blood neutrophil counts may be very high during acute infection because of the failure of mobilised neutrophils to exit blood vessels. Specialised tests show reduced or absent expression of adhesion molecules on neutrophils. 4.8 Specialist investigations in suspected immune deciency Test Value Comment Complement (C3/C4/CH50/AP50) Investigation of recurrent pyogenic bacterial infection Inherited complement deciency likely to give low/ absent results on functional assays Test vaccination Determination of functional humoral immune response Helpful in patients with borderline low or normal immunoglobulins but conrmed recurrent infection Neutrophil function Investigation of recurrent invasive bacterial and fungal infection, especially with catalase-positive organisms Respiratory burst low/absent in chronic granulomatous disease Investigation of leucocyte adhesion deciency Leucocytosis with absent CD11a, b, c expression Lymphocyte immunophenotyping (by ow cytometry) Determination of specic lymphocyte subsets, T cell, B cell, NK cell May dene specic primary immune deciency, e.g. absent B cells in X-linked agammaglobulinaemia Lymphocyte proliferation Determination of lymphocyte proliferation in response to mitogenic stimulation Poor responses seen in certain T-cell immune deciencies Cytokine production To determine T-cell immune function in response to antigen stimulation; limited availability, not routine Can be helpful, for example, in investigation of atypical mycobacterial infection Genetic testing Under specialist supervision when specic primary immune deciency suspected May conrm genetic cause, with implications for family members and future antenatal testing (NK = natural killer)
- 97. Immune deficiency 73 4 Defects in cytokines and cytokine receptors Mutations of the genes encoding cytokines such as IFN-γ, IL-12, IL-23 or their receptors result in failure of intracellular killing by macrophages, and affected individuals are particularly susceptible to mycobacterial infections. Complement pathway deciencies Loss-of-function mutations have been identied in almost all the com- plement pathway proteins (see Fig. 4.4). While most complement de- ciencies are rare, mannose-binding lectin deciency is common and affects about 5% of the northern European population, many of whom are asymptomatic (see below). Clinical features Patients with deciency in complement proteins can present in differ- ent ways. In some cases, the presenting feature is recurrent infection with encapsulated bacteria, particularly Neisseria spp., reecting the importance of the membrane attack complex in defence against these organisms. However, genetic deciencies of the classical complement pathway (C1, C2 and C4) also present with an increased risk of auto- immune disease, particularly SLE. Individuals with mannose-binding lectin deciency have an increased incidence of bacterial infections if subjected to an additional cause of immune compromise, such as pre- mature birth or chemotherapy. The signicance of this condition has been debated, however, since population studies have shown no overall increase in infectious disease or mortality in patients with this disorder. Deciency of the regulatory protein Cl inhibitor is not associated with recurrent infection but causes recurrent angioedema. Investigations Screening for complement deciencies usually involves specialised func- tional tests of complement-mediated haemolysis. These are known as the CH50 (classical haemolytic pathway 50) and AP50 (alternative path- way 50) tests. If abnormal, haemolytic tests are followed by measure- ment of individual complement components. Management Patients with complement deciencies should be vaccinated with meningococcal, pneumococcal and H. inuenzae B vaccines to boost their adaptive immune responses. Lifelong prophylactic penicillin to prevent meningococcal infection is recommended, as is early access to acute medical assessment in the event of infection. Patients should also carry a MedicAlert or similar. At-risk family members should be screened for complement deciencies with functional complement assays. The management of C1 esterase deciency is discussed elsewhere. Primary antibody deciencies Primary antibody deciencies occur as the result of abnormalities in B-cell function, as summarised in Figure 4.11. They are characterised by recurrent bacterial infections, particularly of the respiratory and gas- trointestinal tract. The most common causative organisms are encap- sulated bacteria such as Streptococcus pneumoniae and H. inuenzae. These disorders usually present in infancy, when the protective benet of placental transfer of maternal immunoglobulin has waned. The most important causes are discussed in more detail below. Neutrophils traverse endothelium through binding of LFA1 to ICAM1 Normal Primary phagocyte deficiency Leucocyte adhesion deficiency Neutrophils cannot traverse endothelium due to defects in ITGB2, a component of LFA1 Chronic granulomatous disease Cytokines activate macrophages Destruction of microorganisms through NADPH oxidase-mediated killing Cytokine defects LFA1 IL-23 IL-12 IFN-γ Phagocytes cannot be activated due to defects in cytokines or their receptors Microorganisms cannot be destroyed in lysosomes due to NADPH oxidase deficiency IL-23 IL-12 IFN-γ IL-23 IL-12 IFN-γ ICAM1 Fig. 4.10 Normal phagocyte function and mechanisms of primary phagocyte deciency. Under normal circumstances, neutrophils traverse the endothelium to enter tissues by the cell surface molecule lymphocyte function-associated antigen 1 (LFA1), which binds to intercellular adhesion molecule 1 (ICAM1) on endothelium. In order for macrophages to engulf and kill microorganisms, they need to be activated by cytokines and also require nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate free radicals. Primary phagocyte deciencies can occur as the result of leucocytes being unable to traverse endothelium due to defects in LFA1, because of mutations in cytokines or their receptors, or because of defects in NADPH oxidase. (IFN-γ = interferon-gamma; IL = interleukin)
- 98. 74 CLINICALIMMUNOLOGY X-linked agammaglobulinaemia This rare X-linked disorder is caused by mutations in the BTK gene, which encodes Bruton tyrosine kinase, a signalling protein that is required for B-cell development. Affected males present with severe bacterial infec- tions during infancy. There is a marked reduction in B-cell numbers and immunoglobulin levels are low or undetectable. Management is with immunoglobulin replacement therapy and antibiotics to treat infections. Selective IgA deciency This is the most common primary antibody deciency, affecting 1:600 northern Europeans. Although IgA deciency is usually asymptomatic with no clinical sequelae, about 30% of individuals experience recurrent mild respiratory and gastrointestinal infections. The diagnosis can be conrmed by measurement of IgA levels, which are low or undetectable (< 0.05g/L). In some patients, there is a compensatory increase in serum IgG levels. Specic treatment is generally not required. Common variable immune deciency Common variable immune deciency (CVID) is characterised by low serum IgG levels and failure to make antibody responses to exoge- nous pathogens. It is a heterogeneous adult-onset primary immune deciency, the underlying cause is unknown in most cases, although genetic mutations have been identied in a minority of patients. The presentation is with recurrent infections, and bronchiectasis is a recog- nised complication. Paradoxically, antibody-mediated autoimmune dis- eases, such as idiopathic thrombocytopenic purpura and autoimmune haemolytic anaemia, are common in CVID. It is also associated with an increased risk of malignancy, particularly lymphoproliferative disease. Specic antibody deciency This is a poorly characterised condition resulting in defective anti- body responses to polysaccharide antigens. Some patients are also decient in the antibody subclasses IgG2 and IgG4, and this con- dition was previously called IgG subclass deciency. There is over- lap between specic antibody deciency, IgA deciency and CVID, and some patients may progress to a more global antibody deciency over time. Investigations Serum immunoglobulins (Box 4.9) should be measured in conjunction with protein and urine electrophoresis to exclude secondary causes of hypogammaglobulinaemia, and B- and T-lymphocyte subsets should be measured. Specic antibody responses to known pathogens should be assessed by measuring IgG antibodies against tetanus, H. inuen- zae and Strep. pneumoniae (most patients will have been exposed to these antigens through infection or immunisation). If specic antibody levels are low, immunisation with the appropriate killed vaccine should Failure of lymphocyte precursors: Severe combined immune deficiency Stem cells Lymphoid progenitors Bone marrow Failure of production of IgG antibodies: Common variable immune deficiency Specific antibody deficiency IgM-producing B cells Failure of B-cell maturation: X-linked agammaglobulinaemia Immature B cells IgG IgE IgA Plasma cells Failure of IgA production: Selective IgA deficiency Fig. 4.11 B lymphocytes and primary antibody deciencies (green boxes). (Ig = immunoglobulin) 4.9 Investigation of primary antibody deciencies Selective IgA deciency Normal Often elevated Absent Normal Normal Normal Not applicable* Common variable immune deciency Normal or low Low Low or absent Low or absent Variable Variable No antibody response Specic antibody deciency Normal Normal Normal Normal Normal Normal No antibody response to polysaccharide antigens *Test immunisation is not usually performed in IgA deciency but some patients may have impaired responses.
- 99. Immune deficiency 75 4 be followed by repeat antibody measurement 6–8 weeks later; failure to mount a response indicates a signicant defect in antibody produc- tion. These functional tests have generally superseded IgG subclass quantitation. Management The mainstay of treatment in most patients with antibody deciency is immunoglobulin replacement therapy. Human normal immunoglobulin (Box 4.10) is derived from plasma from hundreds of donors and contains IgG antibodies to a wide variety of common organisms. Replacement immunoglobulin may be administered either intravenously or subcutane- ously, with the aim of maintaining trough IgG levels (the IgG level just prior to an infusion) within the normal range. This has been shown to mini- mise progression of end-organ damage and improve clinical outcome. Patients with antibody deciencies also require aggressive treatment of infections when they occur; prophylactic antibiotics may be indicated. Treatment may be self-administered and is life-long. Benets of immu- nisation are limited because of the defect in IgG antibody production, but patients may derive some T cell benet from vaccination. As with all primary immune deciencies, live vaccines should be avoided. Primary T-lymphocyte deciencies These are a group of diseases characterised by recurrent viral, proto- zoal and fungal infections (see Box 4.5). Many T-cell deciencies are also associated with defective antibody production because of the impor- tance of T cells in providing help for B cells. These disorders generally present in childhood. Several causes of T-cell deciency are recognised. These are summarised in Figure 4.12 and discussed in more detail below. DiGeorge syndrome This results from failure of development of the third and fourth phary- ngeal pouches, and is usually caused by a deletion of chromosome 22q11. The immune deciency is accounted for by failure of thymic development; however, the immune deciency can be very heterogene- ous. Affected patients can have very low numbers of circulating T cells despite normal development in the bone marrow. It is associated with multiple developmental anomalies, including congenital heart disease, hypoparathyroidism, tracheo-oesophageal stulae, cleft lip and palate. Bare lymphocyte syndromes These very rare disorders are caused by mutations in a variety of genes that regulate expression of HLA molecules or their transport to the cell surface. If HLA class I molecules are affected, CD8+ lymphocytes fail to develop normally, while absent expression of HLA class II molecules affects CD4+ lymphocyte maturation. In addition to recurrent infections, failure to express HLA class I is associated with systemic vasculitis caused by uncontrolled activation of NK cells. Severe combined immune deciency Severe combined immune deciency (SCID) results from mutations in a number of genes that regulate lymphocyte development, with fail- ure of T-cell maturation, with or without accompanying B- and NK-cell maturation. The most common cause is X-linked SCID, resulting from loss-of-function mutations in the interleukin-2 receptor gamma (IL2RG) gene. The gene product is a component of several interleukin receptors, including those for IL-2, IL-7 and IL-15, which are absolutely required for T-cell and NK development. This results in T-cell-negative, NK-cell- negative, B-cell-positive SCID. Another cause is deciency of the enzyme adenosine deaminase (ADA), which causes lymphocyte death due to accumulation of toxic purine metabolites intracellularly, resulting in T-cell-negative, B-cell-negative and NK-cell-negative SCID. The absence of an effective adaptive immune response causes recur- rent bacterial, fungal and viral infections soon after birth. Stem cell trans- plantation (SCT) is the treatment option of rst choice. Gene therapy has been approved for treatment of ADA deciency when there is no suitable donor for SCT, has been used successfully in X-linked SCID and is under investigation for a number of other causes of SCID. Investigations The principal tests for T-lymphocyte deciencies are a total lymphocyte count and quantitation of individual lymphocyte subpopulations. Serum immunoglobulins should also be measured. Second-line, functional tests of T-cell activation and proliferation may be indicated. Patients in whom T-lymphocyte deciencies are suspected should be tested for HIV infec- tion. Genetic testing to identify the underlying cause is usually under- taken following specialist referral. Management PatientswithT-celldecienciesshouldbeconsideredforanti-Pneumocystis and antifungal prophylaxis, and require aggressive management of infec- tions when they occur. Immunoglobulin replacement is indicated for asso- ciated defective antibody production. Stem cell transplantation or gene therapy may be appropriate in some disorders. Where a family history is known and antenatal testing conrms a specic defect, stem cell therapy prior to recurrent invasive infection can improve outcome. Autoimmune lymphoproliferative syndrome This rare disorder is caused by failure of normal lymphocyte apoptosis, most commonly due to mutations in the FAS gene, which encodes Fas, a signalling protein that regulates programmed cell death in lymphocytes. This results in massive accumulation of autoreactive T cells, which cause autoimmune-mediated anaemia, thrombocytopenia and neutropenia. Other features include lymphadenopathy, splenomegaly and a variety of other autoimmune diseases. Susceptibility to infection is increased because of the neutropenia. Secondary immune deciencies Secondary immune deciencies are much more common than primary immune deciencies and occur when the immune system is compromised by external factors (Box 4.11). Common causes include infections, such as HIV and measles, and cytotoxic and immunosuppressive drugs, par- ticularly those used in the management of transplantation, autoimmunity and cancer. Physiological immune deciency occurs at the extremes of 4.10 Types of immunoglobulin preparations for therapeutic use Normal human Immunoglobulin Derived from multiple plasma donors and provides passive immunity to those unable to produce immunoglobulin, be that as a result of primary or secondary antibody deciency. Immunoglobulin replacement therapy provides short-term protection, lasting for the duration of the passively transferred antibodies, IgG having a half-life of approximately 21 days. Treatment is therefore required on an ongoing basis Hyperimmune globulin Concentrated antibody products, initially derived from animal sources (diphtheria and tetanus anti-toxins), but more recently of human origin, developed for the prevention of a number of infectious diseases, including rabies as post-exposure treatment, hepatitis B and varicella zoster virus as post-exposure prophylaxis and cytomegalovirus as prophylaxis in patients on immune suppressive therapy, particularly transplant recipients Convalescent plasma Convalescent plasma derived from individual donors with high antibody levels against certain pathogens following recovery from natural infection, recently under investigation for the treatment of epidemic/pandemic infection, such as Ebola virus infection and more recently COVID-19, where clinical trials of ABO-compatible convalescent plasma for severe COVID-19 pneumonia have to date proved disappointing, possibly as a result of such intervention being given too late in the course of infection.
- 100. 76 CLINICALIMMUNOLOGY life; the decline of the immune response in the elderly is known as immune senescence (Box 4.12). Management of secondary immune deciency is described in the relevant chapters on infectious diseases (Ch. 13), HIV (Ch. 14), haematological disorders (Ch. 25) and oncology (Ch. 7). Periodic fever syndromes These rare disorders are characterised by recurrent episodes of fever and organ inammation, associated with an elevated acute phase response. Familial Mediterranean fever Familial Mediterranean fever (FMF) is the most common of the familial periodic fevers, predominantly affecting Mediterranean people, including Arabs, Turks, Sephardic Jews and Armenians. It results from mutations of the MEFV gene, which encodes a protein called pyrin that regulates neutro- phil-mediated inammation by indirectly suppressing the production of IL-1. FMF is characterised by recurrent painful attacks of fever associated with peritonitis, pleuritis and arthritis, which last for a few hours to 4 days and are associated with markedly increased CRP levels. Symptoms resolve com- pletely between episodes. Most individuals have their rst attack before the age of 20. The major complication of FMF is AA amyloidosis (see below). Colchicine signicantly reduces the number of febrile episodes in 90% of patients but is ineffective during acute attacks. Anti-cytokine therapy block- ing IL-1, for example anakinra or the monoclonal antibody canakinumab, can be effective for patients with colchicine refractory symptoms. Mevalonate kinase deciency Mevalonate kinase deciency, previously known as hyper-IgD syndrome, is an autosomal recessive disorder that causes recurrent attacks of fever, abdominal pain, diarrhoea, lymphadenopathy, arthralgia, skin lesions and aphthous ulceration. Most patients are from Western Europe, particularly the Netherlands and northern France. It is caused by loss-of-function mutations in the gene encoding mevalonate kinase, which is involved in the metabolism of cholesterol. It remains unclear why this causes an inammatory periodic fever. Serum IgD and IgA levels may be persistently elevated, and CRP levels are increased during acute attacks. Standard anti-inammatory drugs, including colchicine and glucocorticoids, are ineffective in suppressing the attacks but IL-1 inhibitors, such as ana- kinra, and TNF inhibitors, such as etanercept, may improve symptoms and can induce complete remission in some patients. TNF receptor-associated periodic syndrome TNF receptor-associated periodic syndrome (TRAPS) also known as Hibernian fever, is an autosomal dominant syndrome caused by muta- tions in the TNFRSF1A gene. The presentation is with recurrent attacks of Failure of lymphocyte precursors: Severe combined immune deficiency Stem cells Lymphoid progenitors Bone marrow Failure of expression of HLA molecules: Bare lymphocyte syndromes Failure of thymic development: DiGeorge syndrome Proliferation and maturation of thymocytes Export of mature T lymphocytes to periphery T-lymphocyte activation and effector function Apoptotic cell death Failure of apoptosis: Autoimmune lymphoproliferative syndromes Thymus Failure of cytokine production: Cytokine deficiencies Fig. 4.12 T-lymphocyte function and dysfunction (green boxes). (HLA = human leucocyte antigen) 4.11 Causes of secondary immune deciency Physiological Ageing Prematurity Pregnancy Infection HIV infection Measles Mycobacterial infection Iatrogenic Immunosuppressive therapy Antineoplastic agents Glucocorticoids Stem cell transplantation Radiation injury Antiepileptic agents Malignancy B-cell malignancies including leukaemia, lymphoma and myeloma Solid tumours Thymoma Biochemical and nutritional disorders Malnutrition Renal insufciency/dialysis Diabetes mellitus Specic mineral deciencies (iron, zinc) Other conditions Burns Asplenia/hyposplenism
- 101. Amyloidosis 77 4 fever,arthralgia, myalgia, serositis and rashes. Attacks may be prolonged for 1 week or more. During a typical attack, laboratory ndings include neutrophilia, increased CRP and elevated IgA levels. The diagnosis can be conrmed by low serum levels of the soluble type 1 TNF receptor and by mutation screening of the TNFRSF1A gene. As in FMF, the major com- plication is amyloidosis, and regular screening for proteinuria is advised. Acute episodes respond to systemic glucocorticoids. Therapy with IL-1 inhibitors, such as anakinra, can be effective in preventing attacks. Cryopyrin-associated periodic syndrome (CAPS) This disorder includes three phenotypes: familial cold auto-inammatory syndrome, Muckle–Wells syndrome and neonatal-onset multisystem inammatory disease. CAPS results from gain of function mutation of the NLRP3 gene coding cryopyrin, which forms part of the inammas- ome. Defects lead to overproduction of IL-1, resulting in the inammatory manifestations. Treatments are now targeted at the IL-1 pathway. Amyloidosis Amyloidosis is the name given to a group of acquired and hereditary dis- orders characterised by the extracellular deposition of insoluble proteins. Pathophysiology Amyloidosis is caused by deposits consisting of brils of the specic pro- tein involved, linked to glycosaminoglycans, proteoglycans and serum amyloid P. Protein accumulation may be localised or systemic, and the clinical manifestations depend on the organ(s) affected. Amyloid diseases are classied by the aetiology and type of protein deposited (Box 4.13). Clinical features The clinical presentation may be with nephrotic syndrome, cardiomyopa- thy or peripheral neuropathy. Amyloidosis should always be considered as a potential diagnosis in patients with these disorders when the cause is unclear. Investigations The diagnosis is established by biopsy, which may be of an affected organ, rectum or subcutaneous fat. The pathognomonic histological fea- ture is apple-green birefringence of amyloid deposits when stained with Congo red dye and viewed under polarised light. Immunohistochemical staining can identify the type of amyloid bril present. Quantitative scin- tigraphy with radiolabelled serum amyloid P is a valuable tool in deter- mining the overall load and distribution of amyloid deposits. Management The aims of treatment are to support the function of affected organs and, in acquired amyloidosis, to prevent further amyloid deposition through treatment of the primary cause. When the latter is possible, regression of existing amyloid deposits may occur. 4.12 Immune senescence T-cell responses: decline, with reduced delayed-type hypersensitivity responses. Antibody production: decreased for many exogenous antigens. Although autoantibodies are frequently detected, autoimmune disease is less common. Response to vaccination: reduced; 30% of healthy older people may not develop protective immunity after inuenza vaccination. Allergic disorders and transplant rejection: less common. Susceptibility to infection: increased; community-acquired pneumonia by threefold and urinary tract infection by 20-fold. Latent infections, including tuberculosis and herpes zoster, may be reactivated. Manifestations of inammation: may be absent, with lack of pyrexia or leucocytosis. Secondary immune deciency: common. 4.13 Causes of amyloidosis Disorder Pathological basis Predisposing conditions Other features Acquired systemic amyloidosis Reactive (AA) amyloidosis Increased production of serum amyloid A as part of prolonged or recurrent acute inammatory response Chronic infection (tuberculosis, bronchiectasis, chronic abscess, osteomyelitis) Chronic inammatory diseases (untreated rheumatoid arthritis, familial Mediterranean fever) 90% of patients present with non-selective proteinuria or nephrotic syndrome Light chain amyloidosis (AL) Increased production of monoclonal light chain Monoclonal gammopathies, including myeloma, benign gammopathies and plasmacytoma Restrictive cardiomyopathy, peripheral and autonomic neuropathy, carpal tunnel syndrome, proteinuria, spontaneous purpura, amyloid nodules and plaques Macroglossia occurs rarely but is pathognomonic Prognosis is poor Dialysis- associated (Aβ2 M) amyloidosis Accumulation of circulating β2 -microglobulin due to failure of renal catabolism in kidney failure Renal dialysis Carpal tunnel syndrome, chronic arthropathy and pathological fractures secondary to amyloid bone cyst formation Manifestations occur 5–10 years after the start of dialysis Senile systemic amyloidosis Normal transthyretin protein deposited in tissues Age > 70 years Feature of normal ageing (affects > 90% of 90-year-olds) Usually asymptomatic Hereditary systemic amyloidosis > 20 forms of hereditary systemic amyloidosis Production of protein with an abnormal structure that predisposes to amyloid bril formation. Most commonly due to mutations in transthyretin gene Autosomal dominant inheritance Peripheral and autonomic neuropathy, cardiomyopathy Renal involvement unusual 10% of gene carriers are asymptomatic throughout life FCPS Single Best Question
- 102. 78 CLINICALIMMUNOLOGY Autoimmune disease Autoimmunity can be dened as the presence of immune responses against self-tissue. This may be a harmless phenomenon, identied only by the presence of low-titre autoantibodies or autoreactive T cells. However, if these responses cause signicant organ damage, autoim- mune diseases occur. These are a major cause of chronic morbidity and disability, affecting up to 1 in 30 adults at some point during life. Pathophysiology Autoimmune diseases result from the failure of immune tolerance, the pro- cess by which the immune system recognises and accepts self-tissue. Central immune tolerance occurs during lymphocyte development, when T and B lymphocytes that recognise self-antigens are eliminated before they develop into fully immunocompetent cells. This process is most active in fetal life but continues throughout life as immature lymphocytes are gen- erated. Some autoreactive cells inevitably evade deletion and escape into the circulation, however, and are controlled through peripheral tolerance mechanisms. Peripheral immune tolerance mechanisms include the sup- pression of autoreactive cells by regulatory T cells; the generation of func- tional hyporesponsiveness (anergy) in lymphocytes that encounter antigen in the absence of the co-stimulatory signals that accompany inammation; and cell death by apoptosis. Autoimmune diseases develop when self-re- active lymphocytes escape from these tolerance mechanisms. Multiple genetic and environmental factors contribute to the devel- opment of autoimmune disease. Autoimmune diseases are much more common in women than in men, for reasons that remain unclear. Many are associated with genetic variations in the HLA loci, reecting the impor- tance of HLA genes in shaping lymphocyte responses. Other important susceptibility genes include those determining cytokine activity, co-stimu- lation (the expression of second signals required for full T-cell activation; see Figs. 4.7 and 4.8) and cell death. Many of the same gene variants under- lie multiple autoimmune disorders, reecting their common pathogenesis (Box 4.14). Even though some of these associations are the strongest that have been identied in complex genetic diseases, they have very limited predictive value and are generally not useful in determining management of individual patients. Several environmental factors may be associated with autoimmunity in genetically predisposed individuals, including infection, cigarette smoking and hormone levels. The most widely studied of these is infection, as occurs in acute rheumatic fever following streptococcal infec- tion or reactive arthritis following bacterial infection. Several mechanisms have been invoked to explain the autoimmunity that occurs after an infec- tious trigger. These include cross-reactivity between proteins expressed by the pathogen and the host (molecular mimicry), such as Guillain–Barré syndrome and Campylobacter infection; release of sequestered antigens from tissues that are damaged during infections that are not usually visi- ble to the immune system; and production of inammatory cytokines that overwhelm the normal control mechanisms that prevent bystander dam- age. Occasionally, autoimmune disease may be an adverse effect of drug treatment. For example, metabolic products of the anaesthetic agent hal- othane can bind to liver enzymes, resulting in a structurally novel protein that is recognised as a foreign antigen by the immune system. This can provoke the development of autoantibodies and activated T cells, which can cause hepatic necrosis. Clinical features The clinical presentation of autoimmune disease is highly variable. Autoimmune diseases can be classied by organ involvement or by the predominant mechanism responsible for tissue damage. The Gell and Coombs classication of hypersensitivity is the most widely used, and distinguishes four types of immune response that result in tissue damage (Box 4.15). Type I hypersensitivity is relevant in allergy but is not associated with autoimmune disease. Type II hypersensitivity causes injury to a single tissue or organ and is mediated by specic autoantibodies. Type III hypersensitivity results from deposition of immune complexes, which initiates activation of the classical complement cascade, as well as recruitment and activation of phagocytes and CD4+ lymphocytes. The site of immune complex deposition is determined by the relative amount of antibody, size of the immune complexes, nature of the 4.14 Association of specic gene polymorphisms with autoimmune diseases Gene Function Diseases HLA complex Key determinants of antigen presentation to T cells Most autoimmune diseases PTPN22 Regulation of T- and B-cell receptor signalling Rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus CTLA4 Important co- stimulatory molecule that transmits inhibitory signals to T cells Rheumatoid arthritis, type 1 diabetes IL23R Cytokine-mediated control of T cells Inammatory bowel disease, psoriasis, ankylosing spondylitis TNFRSF1A Control of tumour necrosis factor network Multiple sclerosis ATG5 Autophagy Systemic lupus erythematosus 4.15 Gell and Coombs classication of hypersensitivity diseases Type Mechanism Example of disease in response to exogenous agent Example of autoimmune disease Type I Immediate hypersensitivity IgE-mediated mast cell degranulation Allergic disease None described Type II Antibody- mediated Binding of cytotoxic IgG or IgM antibodies to antigens on cell surface causes cell killing ABO blood transfusion reaction Hyperacute transplant rejection Autoimmune haemolytic anaemia Idiopathic thrombocytopenic purpura Goodpasture's disease Type III Immune complex- mediated IgG or IgM antibodies bind soluble antigen to form immune complexes that trigger classical complement pathway activation Serum sickness Farmer's lung Systemic lupus erythematosus Cryoglobulinaemia Type IV Delayed type Activated T cells, and phagocytes Acute cellular transplant rejection Nickel hypersensitivity Type 1 diabetes Hashimoto's thyroiditis
- 103. Autoimmune disease 79 4 antigen and local haemodynamics. Generalised deposition of immune complexes gives rise to systemic diseases such as SLE. Type IV hypersensitivity is mediated by activated T cells and mac- rophages, which together cause tissue damage. Investigations Autoantibodies Many autoantibodies have been identied and are used in the diagnosis and monitoring of autoimmune diseases, as discussed elsewhere in this book. Antibodies can be quantied either by titre (the maximum dilution of the serum at which the antibody can be detected) or by concentra- tion in standardised units using an enzyme-linked immunosorbent assay (ELISA) in which the antigen is used to coat microtitre plates to which the patient's serum is added (Fig. 4.13A). Immunoblotting (Fig. 4.13B) can also be employed for autoantibody detection as well as qualitative tests in which the pattern of immunouorescence staining is recorded (Fig. 4.13C). Antibody testing can also be performed using Luminex technology. In this case multiple test antigens are individually bound to red and infra-red uorescently labelled polystyrene or paramagnetic beads. Each antigen-coated bead is coated with a unique proportion of red and infrared dyes. The patient sample is incubated with these beads and if antibodies are present in the sample these will bind to the test anti- gens coating the beads. After washing to remove unbound antibodies, a third uorescent dye is added and the sample is processed through a dual laser Luminex analyser, which can detect the unique spectral sig- natures arising from beads coated with different test antigens allowing detection of multiple antibodies present in a single patient sample. Complement Measurement of complement components can be useful in the evalu- ation of immune complex-mediated diseases. Classical complement pathway activation leads to a decrease in circulating C4 levels and is A B C Antibodies bind to target Target antigen Wash Detection of bound antibody Quantitate on plate reader Target antigen Wash Nucleolar Homogenous Speckled P-ANCA Fig. 4.13 Autoantibody testing. plates to which patient serum is added. If autoantibodies are present, these bind to the target antigen on the microtitre plate. The amount of bound antibody is quantitated autoantibodies by immunoblotting. Test strips are coated with puried antigens in parallel lines. The strips are incubated with patient serum or plasma and controls. After washing to remove unbound antibody, strips are incubated with enzyme-conjugated alkaline phosphatase-labelled anti-human IgG. After washing and addition of a chromogenic substrate, an enzyme-mediated colour reaction develops. After a nal wash, the strips are dried and any observed banding pattern is scanned for band intensity against an electronic template. The black bars on the strip separate the antigens being tested. Positive results are seen as vertical grey lines below the test antigen and the intensity of staining corresponds to the concentration of antibody in the patient’s serum. The strength of staining is expressed both as a number and as a grade from + (weak) to +++ (strong). Note that all strips contain an internal quality control (marked as Ko or Co), to ensure the assay has worked. In the example shown, the patient sample was positive for of indirect immunouorescence staining. In this assay, patient serum is added to cell substrate and a secondary antibody is added with a uorescent label to detect any bound antibody. If antibodies are present, they are detected as bright green staining using a uorescence microscope. Different antinuclear antibody patterns may be seen in different types of connective tissue disease using a HEp2 or HEp2000 (human epithelial cell line) as substrate (see Ch. 26). Immunouorescence can be undertaken using different substrates, according to the autoantibody under investigation. An antinucleolar ANA can be seen in systemic sclerosis, a homogenous ANA can be seen in SLE and a speckled ANA can be seen in SLE or Sjögren syndrome. In the context of small vessel vasculitis, the tissue substrate is ethanol-xed neutrophils. Two main staining patterns of anti- neutrophil cytoplasmic antibodies (ANCA) are clinically relevant, cytoplasmic and perinuclear, seen in granulomatosis with polyangiitis and microspcopic polyangiitis (see Ch. 26), the autoantibodies recognising proteinase 3 and myeloperoxidase respectively. (B and C, Nucleolar and Homogenous) Courtesy of Juliet Dunphy, Biomedical Scientist, Royal United Hospital Bath, UK; (C, Speckled and P-ANCA) Courtesy of Mr Richard Brown, Clinical Scientist in Immunology, Southwest Pathology Services, UK
- 104. 80 CLINICALIMMUNOLOGY often also associated with decreased C3 levels. Serial measurement of C3 and C4 can be helpful as a surrogate measure of disease activity in conditions such as SLE. Cryoglobulins Cryoglobulins are antibodies that can be directed against other immuno- globulins, which form immune complexes that precipitate in the cold. They can lead to type III hypersensitivity reactions, with typical clinical manifes- tations including purpuric rash, often of the lower extremities, arthralgia and peripheral neuropathy. Cryoglobulins are classied into three types, depending on the properties of the immunoglobulin involved (Box 4.16). Testing for cryoglobulins requires the transport of a serum specimen to the laboratory at 37°C. Cryoglobulins should not be confused with cold agglutinins; the latter are autoantibodies specically directed against the I/i antigen on the surface of red cells, which can cause intravascular haemol- ysis in the cold (p. 958). Management The management of autoimmune disease depends on the organ sys- tem involved and further details are provided elsewhere in this book. In general, treatment of autoimmune diseases involves the use of gluco- corticoids and immunosuppressive agents, which are increasingly used in combination with biologic agents targeting disease-specic cytokines and their receptors. Not all conditions require immune suppression, how- ever. For example, the management of coeliac disease involves dietary gluten withdrawal, while autoimmune hypothyroidism requires appropri- ate thyroxine supplementation. Allergy Allergic diseases are a common and increasing cause of illness, affecting between 15% and 20% of the population at some time. They comprise a range of disorders from mild to life-threatening and affect many organs. Atopy is the tendency to produce an exaggerated IgE immune response to otherwise harmless environmental substances, while an allergic dis- ease can be dened as the clinical manifestation of this inappropriate IgE immune response. Pathophysiology The immune system does not normally respond to the many environ- mental substances to which it is exposed on a daily basis. In allergic indi- viduals, however, an initial exposure to a normally harmless exogenous substance (known as an allergen) triggers the production of specic IgE antibodies by activated B cells. These bind to high-afnity IgE receptors on the surface of mast cells, a step that is not itself associated with clin- ical sequelae. However, re-exposure to the allergen binds to and cross- links membrane-bound IgE, which activates the mast cells, releasing a variety of vasoactive mediators (the early phase response; Fig. 4.14 and see Chapter 9). This type I hypersensitivity reaction forms the basis of an allergic reaction, which can range from sneezing and rhinorrhea to anaphylaxis (Box 4.17). In some individuals, the early phase response is followed by persistent activation of mast cells, manifest by ongoing swelling and local inammation. This is known as the late phase reac- tion and is mediated by mast cell metabolites, basophils, eosinophils and macrophages. Long-standing or recurrent allergic inammation may give rise to a chronic inammatory response characterised by a complex inltrate of macrophages, eosinophils and T lymphocytes, in addition to mast cells and basophils. Once this has been established, inhibition of mast cell mediators with antihistamines is clinically ineffective in isolation. Mast cell activation may also be non-specically triggered through other signals, such as neuropeptides, anaphylotoxins and bacterial peptides. The increasing incidence of allergic diseases is largely unexplained but one widely held theory is the ‘hygiene hypothesis’. This proposes that infections in early life are critically important in maturation of the immune response and bias the immune system against the development of allergies; the high prevalence of allergic disease is the penalty for the decreased exposure to infection that has resulted from improvements in sanitation and health care. Genetic factors also contribute strongly to the development of allergic diseases. A positive family history is com- mon in patients with allergy, and genetic association studies have iden- tied a wide variety of predisposing variants in genes controlling innate immune responses, cytokine production, IgE levels and the ability of the epithelial barrier to protect against environmental agents. The expression of a genetic predisposition is complex; it is governed by environmental factors, such as pollutants and cigarette smoke, and the incidence of bacterial and viral infection. 4.16 Classication of cryoglobulins Type I Type II Type III Immunoglobulin (Ig) isotype and specicity Isolated monoclonal IgM paraprotein with no particular specicity Immune complexes formed by monoclonal IgM paraprotein directed towards constant region of IgG Immune complexes formed by polyclonal IgM or IgG directed towards constant region of IgG Prevalence 25% 25% 50% Disease association Lymphoproliferative disease, especially Waldenström macroglobulinaemia Infection, particularly hepatitis C; lymphoproliferative disease Infection, particularly hepatitis C; autoimmune disease, including rheumatoid arthritis and systemic lupus erythematosus Symptoms Hyperviscosity: Raynaud's phenomenon Acrocyanosis Retinal vessel occlusion Arterial and venous thrombosis Small-vessel vasculitis: Purpuric rash Arthralgia Neuropathy Cutaneous ulceration, hepatosplenomegaly, glomerulonephritis, Raynaud's phenomenon Small-vessel vasculitis: Purpuric rash, arthralgia Cutaneous ulceration hepatosplenomegaly, glomerulonephritis Raynaud's phenomenon Protein electrophoresis Monoclonal IgM paraprotein Monoclonal IgM paraprotein No monoclonal paraprotein Rheumatoid factor Negative Strongly positive Strongly positive Complement Usually normal Decreased C4 Decreased C4 Serum viscosity Raised Normal Normal
- 105. Allergy 81 4 Clinicalfeatures Common presentations of allergic disease are shown in Box 4.17. Those that affect the respiratory system and skin are discussed in more detail in Chapters 17 and 27, respectively. Here we focus on general principles of the approach to the allergic patient and some specic allergies. The management of acute anaphylaxis is discussed in Chapter 9 Insect venom allergy Local non-IgE-mediated reactions to insect stings are common and may cause extensive swelling around the site lasting up to 7 days. These usually do not require specic treatment. Toxic reactions to venom after multiple (50–100) simultaneous stings may mimic anaphylaxis. In addi- tion, exposure to large amounts of insect venom frequently stimulates the production of IgE antibodies, and thus may be followed by allergic reactions to single stings. Allergic IgE-mediated reactions vary from mild to life-threatening. Antigen-specic immunotherapy (desensitisation; see below) with bee or wasp venom can reduce the incidence of recurrent anaphylaxis from 50% to 60% to approximately 10%, but requires 3–5 years of treatment or more. Peanut allergy Peanut allergy is the most common food-related allergy. More than 50% of patients present before the age of 3 years and some individuals react to their rst known exposure to peanuts, thought to result from sensi- tisation to arachis oil in topical creams. Peanuts are ubiquitous in the Western diet, and every year up to 25% of peanut-allergic individuals experience a reaction as a result of inadvertent exposure. Birch oral allergy syndrome This syndrome is characterised by the combination of birch pollen hay fever and local oral symptoms, including itch and angioedema, after con- tact with certain raw fruits, raw vegetables and nuts. Cooked fruits and vegetables are tolerated without difculty. It is due to shared or cross- reactive allergens that are destroyed by cooking or digestion, and can be conrmed by skin-prick testing using fresh fruit. Severe allergic reactions are unusual. Diagnosis When assessing a patient with a complaint of allergy, it is important to identify what the patient means by the term, as up to 20% of the UK population describe themselves as having a food allergy; in fact, less than 1% have true allergy, as dened by an IgE-mediated hypersensi- tivity reaction conrmed on double-blind challenge. The nature of the symptoms should be established and specic triggers identied, along with the predictability of a reaction, and the time lag between exposure to a potential allergen and onset of symptoms. An allergic reaction usually occurs within minutes of exposure and provokes predictable, reproduc- ible symptoms such as angioedema, urticaria and wheezing. Specic enquiry should be made about other allergic symptoms, past and pres- ent, and about a family history of allergic disease. Potential allergens in the home and workplace should be identied. A detailed drug history should always be taken, including details of adherence to medication, possible adverse effects and the use of over-the-counter or complemen- tary therapies. Investigations Skin-prick tests Skin-prick testing is a key investigation in the assessment of patients suspected of having allergy. A droplet of diluted standardised allergen is placed on the forearm and the skin is supercially punctured through the droplet with a sterile lancet. Positive and negative control mate- rial must be included in the assessment. After 15minutes, a positive response is indicated by a local weal and are response 2mm or more larger than the negative control. A major advantage of skin-prick test- ing is that the patient can clearly see the results, which may be useful in gaining adherence to avoidance measures. Disadvantages include the remote risk of a severe allergic reaction, so resuscitation facilities should be available. Results are unreliable in patients with extensive skin disease. Antihistamines inhibit the magnitude of the response and should be discontinued for at least 3 days before testing; low-dose glu- cocorticoids do not inuence test results. A number of other prescribed medicines can also lead to false-negative results, including amitriptyline and risperidone. B B B T T B B B B Allergen T and B cells IgE antibody IgE receptor Mast cell Histamine, tryptase and vasoactive peptides A B C Fig. 4.14 Type I (immediate) hypersensitivity response. mast cells. This cross-linking of the IgE triggers mast cell activation with release of vasoactive mediators. 4.17 Clinical manifestations of allergy Dermatological Urticaria Atopic eczema if chronic Allergic contact eczema Angioedema Respiratory Asthma Atopic rhinitis Ophthalmological Allergic conjunctivitis Gastrointestinal Food allergy Other Anaphylaxis Drug allergy Allergy to insect venom
- 106. 82 CLINICALIMMUNOLOGY Specic IgE tests An alternative to skin-prick testing is the quantitation of IgE directed against the suspected allergen. The sensitivity and specicity of specic IgE tests (previously known as radioallergosorbent tests, RAST) are lower than those of skin-prick tests. However, IgE tests may be very useful if skin testing is inappropriate, such as in patients taking antihistamines or those with severe skin disease or dermatographism. They can also be used to test for cross-reactivity – for example, with multiple insect venoms, where component-resolved diagnostics, using recombinant allergens, is now increasingly used rather than crude allergen extract. Component resolved diagnostics (CRD) is a more recent development in allergic investigation. CRD uses puried native or recombinant aller- gens to detect specic IgE directed against individual allergenic mole- cules. CRD can discriminate genuine sensitisation from sensitisation due to cross reactivity and in some cases can be used in risk stratication. For example, in patients with hazelnut allergy, the clinical features can be mild and most consistent with the oral allergy syndrome rather than primary nut allergy, in which case CRD may conrm specic IgE to Cor a1, a birch pollen homologue, hence the association with the oral allergy syndrome, whereas patients with primary hazelnut allergy positive for Cor a9 or Cor a14 tend to have more severe allergy. Severity of reaction in peanut allergy can also be associated with specic Ara h allergens, which are present in peanuts. Such risk stratication can impact on patient management, for example, identifying patients who may require an adrenaline auto-injector. Supervised exposure to allergen Tests involving supervised exposure to an allergen (allergen challenge) are usually performed in specialist centres on carefully selected patients, and include bronchial provocation testing, nasal challenge, and food or drug challenge. These may be particularly useful in the investigation of occupational asthma or food allergy. Patients can be considered for chal- lenge testing when skin tests and/or IgE tests are negative, as they can be helpful in ruling out allergic disease. Mast cell tryptase Measurement of serum mast cell tryptase is extremely useful in investi- gating a possible anaphylactic event. Ideally, measurements should be made at the time of the reaction following appropriate resuscitation, and 3hours and 24 hours later. The basis of the test is the fact that circulat- ing levels of mast cell degranulation products rise dramatically to peak 1–2hours after a systemic allergic reaction. Tryptase is the most stable of these and is easily measured in serum. Serum total IgE Serum total IgE measurements are not routinely indicated in the investi- gation of allergic disease, other than to aid in the interpretation of specic IgE results, as false-positive specic IgEs are common in patients with atopy, who often have a high total IgE level. Although atopy is the most common cause of an elevated total IgE in developed countries, there are many other causes, including parasitic and helminth infections, lym- phoma, drug reactions and eosinophilic granulomatosis with polyangiitis (previously known as Churg–Strauss vasculitis). Normal total IgE levels do not exclude allergic disease. Eosinophilia Peripheral blood eosinophilia is common in atopic individuals but lacks specicity. Eosinophilia of more than 20% or an absolute eosinophil count over 1.5×109 /L should initiate a search for a non-atopic cause, such as eosinophilic granulomatosis with polyangiitis or parasitic infection. Management Several approaches can be deployed in the management of allergic indi- viduals, as discussed below. Avoidance of the allergen This is indicated in all cases and should be rigorously attempted, with the advice of specialist dietitians and occupational physicians as necessary. Antihistamines Antihistamines are useful in the management of allergy as they inhibit the effects of histamine on tissue H1 receptors. Long-acting, non-sedating preparations are particularly useful for prophylaxis. Glucocorticoids These are highly effective in allergic disease, and if used topically, adverse effects can be minimised. Sodium cromoglicate Sodium cromoglicate stabilises the mast cell membrane, inhibiting release of vasoactive mediators. It is effective as a prophylactic agent in asthma and allergic rhinitis but has no role in management of acute attacks. It is poorly absorbed and therefore generally ineffective in the management of food allergies. Antigen-specic immunotherapy This involves the sequential administration of increasing doses of aller- gen extract over a prolonged period of time. The mechanism of action is not fully understood but it is highly effective in the prevention of insect venom anaphylaxis and of allergic rhinitis secondary to grass pollen allergy. The traditional route of administration is by subcutaneous injec- tion, which carries a risk of anaphylaxis and should be performed only in specialised centres. Sublingual immunotherapy is also increasingly used. Clinical studies to date do not support the use of allergen immu- notherapy for food hypersensitivity, although this is an area of active investigation. Omalizumab Omalizumab is a monoclonal antibody directed against IgE; it inhibits the binding of IgE to mast cells and basophils. It is licensed for treatment of refractory chronic spontaneous urticaria and also for severe persistent allergic asthma that has failed to respond to standard therapy. The dose and frequency are determined by baseline IgE (measured before the start of treatment) and body weight. It is under investigation for allergic rhinitis but not yet approved for this indication. Adrenaline (epinephrine) Adrenaline given by injection in the form of a pre-loaded self-injectable device can be life-saving in the acute management of anaphylaxis (see Ch. 9). Angioedema Angioedema is an episodic, localised, non-pitting swelling of submucous or subcutaneous tissues. Pathophysiology The causes of angioedema are summarised in Box 4.18. It may be a manifestation of allergy or non-allergic degranulation of mast cells in response to drugs and toxins. In these conditions the main cause is mast cell degranulation with release of histamine and other vasoactive media- tors. In hereditary angioedema, the cause is C1 inhibitor deciency, which leads to increased local release of bradykinin. Angiotensin-converting enzyme (ACE) inhibitor-induced angioedema also occurs as the result of increased bradykinin levels due to inhibition of its breakdown. Clinical features Angioedema is characterised by soft-tissue swelling that most frequently affects the face (Fig. 4.15) but can also affect the extremities and gen- italia. Involvement of the larynx or tongue may cause life-threatening respiratory tract obstruction, and oedema of the intestinal mucosa may cause abdominal pain and distension. Investigations Differentiating the mechanism of angioedema is important in determin- ing the most appropriate treatment. A clinical history of allergy or drug
- 107. Angioedema 83 4 exposurecan give clues to the underlying diagnosis. If no obvious trigger can be identied, measurement of complement C4 is useful in differenti- ating hereditary and acquired angioedema from other causes. If C4 levels are low, further investigations should be initiated to look for evidence of C1 inhibitor deciency. Management Management depends on the underlying cause. Angioedema associated with allergen exposure generally responds to antihistamines and gluco- corticoids. Following acute management of angioedema secondary to drug therapy, drug withdrawal should prevent further attacks, although ACE inhibitor-induced angioedema can continue for a limited period post drug withdrawal. Management of angioedema associated with C1 inhib- itor deciency is discussed below. Hereditary angioedema Hereditary angioedema (HAE), also known as inherited C1 inhibitor de- ciency, is an autosomal dominant disorder caused by decreased produc- tion or activity of C1 inhibitor protein. This complement regulatory protein inhibits spontaneous activation of the classical complement pathway (see Fig. 4.4). It also acts as an inhibitor of the kinin cascade, activation of which increases local bradykinin levels, giving rise to local pain and swelling. Clinical features The angioedema in HAE may be spontaneous or triggered by local trauma or infection. Multiple parts of the body may be involved, especially the face, extremities, upper airway and gastrointestinal tract. Oedema of the intestinal wall causes severe abdominal pain and many patients with undiagnosed HAE undergo exploratory laparotomy. The most important complication is laryngeal obstruction, often associated with minor dental procedures, which can be fatal. Episodes of angioedema are self-limiting and usually resolve within 48 hours. Patients with HAE generally present in adolescence but may go undiagnosed for many years. A family history can be identied in 80% of cases. HAE is not associated with allergic diseases and is specically not associated with urticaria. Investigations Acute episodes are accompanied by low C4 levels; a low C4 during an episode of angioedema should therefore trigger further investigation. The diagnosis can be conrmed by measurement of C1 inhibitor levels and function. Management Severe acute attacks should be treated with plasma-derived or recombi- nant C1 inhibitor or the bradykinin receptor antagonist icatibant. Anabolic 4.18 Types of angioedema Allergic reaction to specic trigger Idiopathic angioedema Hereditary angioedema ACE-inhibitor associated angioedema Pathogenesis IgE-mediated degradation of mast cells Non-IgE-mediated degranulation of mast cells C1 inhibitor deciency, with resulting increased local bradykinin concentration Inhibition of breakdown of bradykinin Key mediator Histamine Histamine Bradykinin Bradykinin Prevalence Common Common Rare autosomal dominant disorder 0.1%–0.2% of patients treated with ACE inhibitors Clinical features Usually associated with urticaria History of other allergies common Follows exposure to specic allergen, in food, animal dander or insect venom Usually associated with urticaria May be triggered by physical stimuli such as heat, pressure or exercise Dermatographism common Occasionally associated with underlying infection or thyroid disease Not associated with urticaria or other features of allergy Does not cause anaphylaxis May cause life-threatening respiratory tract obstruction Can cause severe abdominal pain Not associated with urticaria Does not cause anaphylaxis Usually affects the head and neck, and may cause life- threatening respiratory tract obstruction Can occur years after the start of treatment Investigations Specic IgE tests or skin- prick tests Specic IgE tests and skin- prick tests often negative Hypothyroidism should be excluded Complement C4 (invariably low in acute attacks) C1 inhibitor levels No specic investigations Treatment Allergen avoidance Antihistamines Antihistamines are mainstay of treatment and prophylaxis Unresponsive to antihistamines Anabolic steroids C1 inhibitor concentrate or icatibant for acute attacks ACE inhibitor should be discontinued ARBs should be avoided if possible unless there is a strong indication Associated drug reactions Specic drug allergies NSAIDs Opioids, radiocontrast media ACE inhibitors, ARBs (ACE = angiotensin-converting enzyme; ARBs = angiotensin II receptor blockers; IgE = immunoglobulin E; NSAIDs = non-steroidal anti-inammatory drugs) B A Fig. 4.15 Angioedema. From Helbert M. Flesh and bones of immunology. Edinburgh: Churchill Livingstone, Elsevier Ltd; 2006.
- 108. 84 CLINICALIMMUNOLOGY steroids, such as danazol, can be used to prevent attacks and act by increasing endogenous production of complement proteins, but is limited by treatment toxicity. Tranexamic acid can be helpful as prophylaxis in some patients. C1 inhibitor concentrate can also be used as prophylaxis, for example for surgical or dental intervention. Patients can be taught to self-administer therapy and should be advised to carry a MedicAlert or similar. More recently, a humanised monoclonal antibody which inhibits plasma kallikrein activity, limiting the production of bradykinin, has been developed for the prevention of recurrent attacks in patients with C1 inhibitor deciency. This is not licensed for acute attacks. Acquired C1 inhibitor deciency This rare disorder is clinically indistinguishable from HAE but presents in late adulthood. It is associated with autoimmune and lymphoprolif- erative diseases. Most cases are due to the development of autoan- tibodies to C1 inhibitor, but the condition can also be caused by autoantibodies that activate C1. Treatment of the underlying disorder may induce remission of angioedema. As with HAE, a low C4 is seen during acute episodes. Pregnancy and the immune system Major adaptations occur in the immune system during pregnancy so that the mother does not mount an immune response to the developing fetus. These adaptations can inuence the risk and severity of certain infectious diseases such as varicella pneumonia (see p. 1271) as well as the activity of some autoimmune diseases. Some considerations for the development and management of immunological diseases during pregnancy and breastfeeding are summarised in Box 4.19 Transplantation and graft rejection Transplantation provides the opportunity for denitive treatment of end- stage organ disease. The major complications are graft rejection, drug toxicity and infection consequent to immunosuppression. Transplant survival continues to improve, as a result of the introduction of less toxic immunosuppressive agents and increased understanding of the pro- cesses of transplant rejection. Stem cell transplantation and its compli- cations are discussed in more detail in Chapter 25 Transplant rejection Solid organ transplantation inevitably stimulates an aggressive immune response by the recipient, unless the transplant is between monozygotic twins. The type and severity of the rejection response is determined by the genetic disparity between the donor and recipient, the immune sta- tus of the host and the nature of the tissue transplanted (Box 4.20). The most important genetic determinant is the difference between donor and recipient HLA proteins. The extensive polymorphism of these proteins means that donor HLA antigens are almost invariably recognised as for- eign by the recipient immune system, unless an active attempt has been made to minimise incompatibility. Hyperacute rejection results in rapid and irreversible destruction of the graft (see Box 4.20). It is mediated by pre-existing recipient antibodies against donor HLA antigens, which arise as a result of previous exposure through transplantation, blood transfusion or pregnancy. It is very rarely seen in clinical practice, as the use of screening for anti-HLA antibodies and pre-transplant cross-match- ing ensures the prior identication of such recipient–donor incompatibility. Acute cellular rejection is the most common form of graft rejection. It is mediated by activated T lymphocytes and results in deterioration in graft function. If allowed to progress, it may cause fever, pain and tenderness over the graft. It is usually amenable to increased immu- nosuppressive therapy. Acute vascular rejection is mediated by antibody formed de novo after transplantation. It is more curtailed than the hyperacute response because of the use of intercurrent immunosuppression but it is also associated with reduced graft survival. Aggressive immu- nosuppressive therapy is indicated and physical removal of antibody through plasmapheresis may be indicated in severe causes. Not all post-transplant anti-donor antibodies cause graft damage; their consequences are determined by specicity and ability to trigger other immune components, such as the complement cascade. 4.19 Immunological diseases in pregnancy Allergic disease Maternal dietary restrictions during pregnancy or lactation: current evidence does not support these for prevention of allergic disease. Breastfeeding for at least 4 months: prevents or delays the occurrence of atopic dermatitis, cow's milk allergy and wheezing in early childhood, as compared with feeding formula milk containing intact cow's milk protein. Autoimmune disease Suppressed T-cell-mediated immune responses in pregnancy: may suddenly reactivate post-partum. Some autoimmune diseases may improve during pregnancy but are immediately after delivery. Systemic lupus erythematosus (SLE) is an exception, however, as it is prone to exacerbation in pregnancy or the puerperium. Passive transfer of maternal antibodies: can mediate autoimmune disease in the fetus and newborn, including SLE, Graves' disease and myasthenia gravis. Antiphospholipid syndrome (p. 987): an important cause of fetal loss, intrauterine growth restriction and pre-eclampsia. HIV in pregnancy: see p. 367. 4.20 Classication of transplant rejection Type Time Pathological ndings Mechanism Treatment Hyperacute rejection Minutes to hours Thrombosis, necrosis Pre-formed antibody to donor antigens results in complement activation (type II hypersensitivity) None – irreversible graft loss Acute cellular rejection 5–30 days Cellular inltration CD4+ and CD8+ T cells (type IV hypersensitivity) Increase immunosuppression Acute vascular rejection 5–30 days Vasculitis Antibody and complement activation Increase immunosuppression Chronic allograft failure > 30 days Fibrosis, scarring Immune and non-immune mechanisms Minimise drug toxicity, control hypertension and hyperlipidaemia
- 109. Tumour immunology 85 4 Chronic allograft failure, also known as chronic rejection, is a major cause of graft loss. It is associated with proliferation of transplant vascular smooth muscle, interstitial brosis and scarring. The pathogenesis is poorly understood but contributing factors include immunological damage caused by subacute rejection, hypertension, hyperlipidaemia and chronic drug toxicity. Investigations Pre-transplantation testing HLA typing determines an individual's HLA polymorphisms and facili- tates donor–recipient matching. Potential transplant recipients are also screened for the presence of anti-HLA antibodies. The recipient is excluded from receiving a transplant that carries these alleles. Donor–recipient cross-matching is a functional assay that directly tests whether serum from a recipient (which potentially contains anti-do- nor antibodies) is able to bind and/or kill donor lymphocytes. It is specic to a prospective donor–recipient pair and is done immediately prior to transplantation. A positive cross-match is a contraindication to trans- plantation because of the risk of hyperacute rejection. Post-transplant biopsy: C4d staining C4d is a fragment of the complement protein C4 (see Fig. 4.4). Deposition of C4d in graft capillaries indicates local activation of the classical complement pathway and provides evidence of antibody-me- diated damage. This is useful in the early diagnosis of vascular rejection. Complications of transplant immunosuppression Transplant recipients require indenite treatment with immunosuppres- sive agents. In general, two or more immunosuppressive drugs are used in synergistic combination in order to minimise adverse effects (Box 4.21). The major complications of long-term immunosuppression are infection and malignancy. The risk of some opportunistic infections may be minimised through the use of prophylactic medication, such as ganciclovir for cytomegalovirus prophylaxis and trimethoprim–sulfameth- oxazole for Pneumocystis prophylaxis. Immunisation with killed vaccines is appropriate, although the immune response may be curtailed. Live vaccines should not be given. The increased risk of malignancy arises because T-cell suppression results in failure to control viral infections associated with malignant transformation. Virus-associated tumours include lymphoma (associated with Epstein–Barr virus), Kaposi's sarcoma (associated with human her- pesvirus 8) and skin tumours (associated with human papillomavirus). Immunosuppression is also linked with a small increase in the incidence of common cancers not associated with viral infection (such as lung, breast and colon cancer), reecting the importance of T cells in anti-can- cer surveillance. Organ donation The major problem in transplantation is the shortage of organ donors. Cadaveric organ donors are usually previously healthy individuals who experience brainstem death, frequently as a result of road trafc acci- dents or cerebrovascular events. Even if organs were obtained from all potential cadaveric donors, though, their numbers would be insufcient to meet current demands. An alternative is the use of living donors. Altruistic living donation, usually from close relatives, is widely used in renal transplantation. Living organ donation is inevitably associated with some risk to the donor and it is highly regulated to ensure appropriate appreciation of the risks involved. Because of concerns about coercion and exploitation, non-altruistic organ donation (the sale of organs) is ille- gal in most countries. Tumour immunology Surveillance by the immune system is critically important in monitor- ing and removing damaged and mutated cells as they arise. The abil- ity of the immune system to kill cancer cells effectively is inuenced by tumour immunogenicity and specicity. Many cancer antigens are poorly expressed and specic antigens can mutate, either sponta- neously or in response to treatment, which can result in evasion of immune responses. In addition, the inhibitory pathways that are used to maintain self-tolerance and limit collateral tissue damage during anti- microbial immune responses can be co-opted by cancerous cells to evade immune destruction. Recognition and understanding of these immune checkpoint pathways has led to the development of a number of new treatments for cancers that are otherwise refractory to treat- ment. Immune checkpoint blockade enhances anti-tumour immunity by blocking down-regulators of immune activation. Immune check- point inhibitors targeting CTLA-4, PD1 and PD-L1, such as ipilimimab, nivolumab, and pembrolizumab, have shown benet in a number of tumour types, including melanoma, non-small cell lung cancer, urothe- lial cancers, colorectal malignancy and classic Hodgkin’s lymphoma. These agents can, however, have serious inammatory side effects, with immune-related adverse events most commonly involving the skin, liver, endocrine and gastrointestinal tracts, which may be treat- ment limiting. The effects of the different agents vary, with lung and thyroid involvement being more common with anti-PD1 therapy, colitis and hypophysitis being more common with anti-CTLA-4 therapy, with 4.21 Immunosuppressive drugs used in transplantation Drug Mechanism of action Major adverse effects Anti-proliferative agents Azathioprine, mycophenolate mofetil Inhibit lymphocyte proliferation by blocking DNA synthesis May be directly cytotoxic at high doses Increased susceptibility to infection Leucopenia Hepatotoxicity Calcineurin inhibitors Ciclosporin, tacrolimus Inhibit T-cell signalling; prevent lymphocyte activation; block cytokine transcription Increased susceptibility to infection Hypertension Nephrotoxicity Diabetogenic (especially tacrolimus) Gingival hypertrophy, hirsutism (ciclosporin) Glucocorticoids Decrease phagocytosis and release of proteolytic enzymes; decrease lymphocyte activation and proliferation; decrease cytokine production; decrease antibody production Increased susceptibility to infection Multiple other complications Anti-thymocyte globulin (ATG) Antibodies to cell surface proteins deplete or block T cells Profound non-specic immunosuppression Increased susceptibility to infection Basiliximab Monoclonal antibody directed against CD25 (IL-2Rα chain), expressed on activated T cells Increased susceptibility to infection Gastrointestinal side- effects Belatacept Selectively inhibits T-cell activation through blockade of CD80/CD86 Increased susceptibility to infection and malignancy Gastrointestinal side- effects Hypertension Anaemia/leucopenia
- 110. 86 CLINICALIMMUNOLOGY anti-CTLA-4 therapy-related events often being more severe. However, patients who have had a favourable response to immune checkpoint blockade but discontinue as a result of immune-related adverse events may maintain their anti-tumour response. Glucocorticoids are consid- ered rst line therapy for these side effects, with additional immune suppression if required. The development of autoimmunity reects the importance of these pathways in the control of self-tolerance. Another recent advance is CAR-T cell therapy, in which genetically engineered, chimaeric antigen receptor T cells are specically developed for an individual patient, with effective reprogramming of the patient’s immune cells, which are then used to target their cancer. This has been applied to certain otherwise treatment-refractory haematological malig- nancies (Ch. 25). Not only is it a very expensive treatment, but cytokine storm and subsequent antibody deciency are predictable side effects of the CAR T-cell therapies directed at B-cell antigens, requiring manage- ment in their own right. Further information Websites allergy.org.au An Australasian site providing information on allergy, asthma and immune diseases. allergyuk.org UK site for patients and health-care professionals. anaphylaxis.org.uk Provides information and support for patients with severe allergies. info4pi.org A US site managed by the non-prot Jeffrey Modell Foundation, which provides extensive information about primary immune deciencies . niaid.nih.gov National Institute of Allergy and Infectious Diseases: provides useful information on a variety of allergic diseases, immune deciency syndromes and autoimmune diseases.
- 111. Multiple Choice Questions 4.1.In the investigation of allergy, which of the following statements are correct? A. Mast cell tryptase is labile in serum and therefore not a useful biomarker of mast cell activation B. Measurement of total IgE is not useful C. Component resolved diagnostics can have predictive value in some food allergies D. Skin testing is not affected by antihistamine medication E. Some antidepressant medications can lead to false-negative skin test results Answer: C and E. Mast cell tryptase is stable in serum, making it a particularly con- venient biomarker of mast cell activation. A total IgE can be helpful in atopic patients as a high total level can be associated with false-positive specic IgEs. Component resolved diagnostics uses puried native or recombinant allergens to detect specic IgE directed against individual allergenic molecules. CRD can discriminate genuine sensitisation from sensitisation due to cross reactivity and in some cases can be used in risk stratication, having predictive value, such as in peanut and some nut allergy. A number of medications, including certain antidepressant classes, can have antihistamine properties and thereby interfere with skin testing. Patients should be advised to discontinue interacting medica- tions in advance of testing. 4.2. Which of the following are required for naïve T-cell activation? A. Antigen processing by antigen-presenting cells B. Antigenic peptide presentation by pattern recognition receptors C. HLA class 1 for CD4 T cells D. Co-stimulatory molecules E. Intracellular T-cell signalling Answer: A, D and E. Unlike B cells, which recognise native antigen, T cells require antigen processing through professional antigen-presenting cells, with presenta- tion of antigenic peptide by self-HLA molecules expressed at the APC surface. The Ag–HLA complex then interacts with the T-cell receptor. Pattern recognition receptors are expressed by phagocytic cells and recognise pathogen-associated molecular patterns on invading micro- organisms. They do not present antigen to T cells. CD4 T cells recognise antigenic peptide presented by HLA class II molecules; CD8 T cells rec- ognise antigenic peptide presented by HLA class I molecules. A second signal, known as co-stimulation, is required for naïve T-cell activation. Downstream intracellular T cells signalling then drives T-cell proliferation. 4.3. Which of the following statements are correct regarding T-cell populations? A. CD4 T cells kill virally infected cells through production of pore- forming molecules such as perforin and release of enzymes triggering apoptosis of the target cell B. CD8 T cells are important in defence against viral infection C. Th1 (T-helper) cells typically produce IL-2, IFN γ and TNF-α D. T regs are regulatory CD4 T cells that promote activation of other cells and augment autoimmune disease E. Th-17 cells are pro-inammatory cells that produce IL-17 and have a key role in defence against extracellular bacteria and fungi Answer: B, C and E. CD8 T cells, not CD4 T cells, kill infected cells directly through the production of pore-forming molecules such as perforin and release of enzymes triggering apoptosis of the target cell. CD8 T cells are particu- larly important in defence against viral infection. Th1 (T-helper) cells typ- ically produce IL-2, IFN-γ and TNF-α, and support the development of delayed-type hypersensitivity responses. T-regulatory cells (T regs) are a subset of specialised CD4+ lymphocytes important in actively suppress- ing activation of other cells and preventing autoimmune disease. They produce cytokines such as TGF-beta and IL-10. Th17 cells are pro-in- ammatory cells dened by their production of IL-17. They have a key role in defence against extracellular bacteria and fungi. They also have a role in the development of autoimmune disease. 4.4. In tumour immunology, which of the following statements are correct? A. NK cells have an important role in immune surveillance B. Tumour cells reliably express HLA molecules to allow immune recognition by T cells C. Immune checkpoint blockade includes anti-CTLA and anti-PD1 pathways D. Autoimmune disease is a recognised complication of immune checkpoint blockade in tumour therapy E. Tumour progression occurs rapidly if immune checkpoint blockade is withdrawn Answer: A, C and D. NK cells have an important role in tumour surveillance especially as tumour cells lose their HLA expression, thereby allowing NK cell activa- tion. Loss of HLA expression is one of the mechanisms by which tumours can evade T-cell immunity. Immune checkpoint blockade includes anti- bodies directed at the normally downregulatory pathways, thereby allow- ing immune cells to be active against the tumour. Some patients maintain the anti-tumour effect of immune checkpoint blockade despite treatment withdrawal in the event of drug toxicity. 4.5. In the context of organ transplantation, which of the following statements are correct? A. The major complications are graft rejection, drug toxicity and infection B. HLA incompatibility does not have a bearing on transplant outcome C. Acute cellular rejection is predominantly mediated by activated B cells D. Post-transplantation, failure to control viral infections associated with malignant transformation leads to an increased risk of malignancy E. Co-stimulatory blockade has no role in post-transplant immune suppression Answer: A and D. The major complications of transplantation are graft rejection, drug toxicity and infection consequent to immunosuppression. Solid organ transplantation stimulates an aggressive immune response by the recip- ient, unless the transplant is between monozygotic twins. The most important genetic determinant is the difference between donor and recipient HLA proteins. The polymorphism of these proteins means that donor HLA antigens are almost invariably recognised as foreign by the recipient immune system, unless an active attempt has been made to minimise incompatibility. Acute cellular rejection is mediated by activated T lymphocytes and results in deterioration in graft function. The risk of
- 112. post-transplant malignancy arisesbecause T-cell suppression results in failure to control viral infections associated with malignant transforma- tion, e.g. lymphoma associated with Epstein–Barr virus, Kaposi's sar- coma associated with human herpesvirus 8 and skin tumours associated with human papillomavirus. Co-stimulatory blockade, using the CTLA-4 fusion protein belatacept, with high afnity for CD80/86 on T cells, selec- tively inhibits T-cell activation and has a role in post-transplant immune suppression.
- 113. Population health and epidemiology 5 HCampbell DA McAllister Global burden of disease and underlying risk factors 88 Life expectancy 88 Global causes of death and disability 88 Risk factors underlying disease 88 Social determinants of health 89 The hierarchy of systems – from molecules to ecologies 89 The life course 89 Preventive medicine 89 Principles of screening and immunisation 90 Screening 90 Immunisation 91 Epidemiology 91 Understanding causes and effect 91 Mendelian randomisation 91 Health data/informatics 94 Management of epidemics 95
- 114. 88 POPULATIONHEALTH AND EPIDEMIOLOGY The UK Faculty of Public Heath denes public health as ‘The science and art of promoting and protecting health and well-being, preventing ill-health and prolonging life through the organised efforts of society’. This recognises that there is a collective responsibility for the health of the population which requires partnerships between government, health services and other partners to promote and protect health and prevent disease. Population health has been dened as ‘the health outcomes of a group of individuals, including the distribution of such outcomes within the group’. Medical doctors can play a role in all these efforts to improve health both as part of their clinical work but also through supporting broader actions to improve public health. Global burden of disease and underlying risk factors The Global Burden of Disease (GBD) exercise was initiated by the World Bank in 1992, with rst estimates appearing in the World Development Report in 1993. Regular updated estimates have been published since that time together with projections of future disease burden. The aim of the exercise was to produce reliable and internally consistent estimates of disease burden for all diseases and injuries and to assess their physi- ological, behavioural and social risk factors so that this information could be made available to health workers, researchers and policy-makers. The GBD exercise adopted the metric ‘disability life year’ or DALY to describe population health. This combines information about prema- ture mortality in a population (measured as Years of Life Lost from an ‘expected’ life expectancy) and years of life lived with disability (Years of Life lived with Disability (YLD), which is weighted by a severity factor). The International Classication of Disease (ICD) rules, which assign one cause to each death, are followed. All estimates are presented by age and sex groups and by regions of the world. Many countries now also report their own national burden of disease data. Life expectancy Global life expectancy at birth increased from 61.7 years in 1980 to 73.0 years in 2017, an increase of about 0.3 years per calendar year. This change is due to a substantial fall in child mortality (mainly due to com- mon infections) partly offset by rises in mortality from adult conditions such as diabetes and chronic kidney disease. Some areas have not shown these increases in life expectancy in men, often due to war and interpersonal violence. Global causes of death and disability Box 5.1 shows a ranked list of the major causes of global deaths in 2019. Communicable, maternal, neonatal and nutritional causes accounted for about one-quarter of deaths worldwide – down from about one-third in 1990. In contrast, deaths from non-communicable diseases are increas- ing in importance and now account for about two-thirds of all deaths globally,: including about 18.5 million from cardiovascular disease (ischae- mic heart disease and stroke), 10 million from cancer and about 4 million from chronic respiratory diseases. The age standardised death rates for most diseases globally are falling. However, despite this, the numbers of deaths from many diseases are rising due to global population growth and the change in age structure of the population to older ages and this is placing an increasing burden on health systems. For a few con- ditions (e.g. HIV/AIDS, diabetes mellitus and chronic kidney disease) age-standardised death rates continue to rise. Within this overall pattern, signicant regional variations exist – for example, communicable, mater- nal, neonatal and nutritional causes still account for about two-thirds of premature mortality in sub-Saharan Africa. GBD also provides estimates of disability from disease (Box 5.2). This has raised awareness of the importance of conditions like depression and other common mental health conditions, low back and neck pain and other musculo-skeletal conditions, and asthma, which account for a relatively large disease burden but relatively few deaths. This in turn has resulted in greater health policy priority given to these conditions. Since the policy focus in national health systems is increasingly on keeping people healthy rather than only on reducing premature deaths it is impor- tant to have measures of these health outcomes. It is important to recognise that although these estimates represent the best overall picture of burden of disease globally, they are based on limited and imperfect data. Nevertheless, the quality of data underlying the estimates and the modelling processes are improving steadily over time and provide an increasingly robust basis for evidence-based health planning and priority setting. Risk factors underlying disease Box 5.3 shows a ranked list of the main risk factors underlying GBD in 2019 and how this ranking has changed over the past 29 years. A number of key insights have been identied in this, the most recent, GBD exercise: Socio-demographic development has been progressing steadily since 1990 but it has increased faster in countries with the highest socio-demographic development index and thus gaps have been widening. 5.1 Global causes of death – top 15 ranked causes 2019 [rank in 1990] 1. Cardiovascular disease [1] 2. Neoplasms [2] 3. Chronic respiratory [6] 4. Respiratory infections and TB [3] 5. Diabetes and CKD [10] 6. Digestive diseases [8] 7. Neurological disorders [15] 8. Maternal and neonatal [15] 9. Unintentional injuries [9] 10. Enteric infections [5] 11. Transport injuries [13] 12. Self harm and violence [12] 13. Other non-communicable diseases [11] 14. HIV/AIDS and STIs [17] 15. NTDs and malaria [14] (CKD = chronic kidney disease; TB = tuberculosis; STIs = sexually transmitted infections; NTDs = neglected tropical diseases) From GBD 2019. https://vizhub.healthdata.org/gbd-compare/. 5.2 Global disability – top 15 ranked causes 2019 [rank in 1990]* 1. Musculoskeletal disorders [1] 2. Mental disorders [2] 3. Other non-communicable diseases [3] 4. Sense organ diseases [5] 5. Neurological disorders [4] 6. Diabetes and CKD [12] 7. Skin diseases [7] 8. Unintentional injuries [8] 9. Nutritional deciencies [6] 10. Cardiovascular diseases [11] 11. Chronic respiratory diseases [9] 12. Substance use [13] 13. Maternal and neonatal conditions [17] 14. Transport injuries [16] 15. Digestive diseases [15] *By years of life lived with disability (YLD). (CKD = chronic kidney disease) From GBD 2019. https://vizhub.healthdata.org/gbd-compare/.
- 115. Social determinants ofhealth 89 5 5.4 ‘Hierarchy of systems’ applied to ischaemic heart disease Level in the hierarchy Example of effect Molecular ApoB mutation causing hypercholesterolaemia Cellular Foam cells accumulate in vessel wall Tissue Atheroma and thrombosis of coronary artery Organ Ischaemia and infarction of myocardium System Cardiac failure Person Limited exercise capacity, impact on employment Family Passive smoking, diet Community Shops and leisure opportunities Population Prevalence of obesity Society Policies on smoking, screening for risk factors Ecology Agriculture inuencing fat content in diet Health systems need to transform to be better able to respond to the changing pattern of NCDs and disabilities. The Millennium Development Goal (MDG) programme from 2000 to 2015 has led to faster progress in reducing deaths from maternal, child and neonatal conditions/TB/HIV/malaria but this level of atten- tion now needs to be directed at NCDs. Public health is not giving sufcient priority to important global risk factors which are increasing over time, such as high blood pressure, high fasting glucose, high BMI, ambient particulate matter pollution and drug and alcohol use. There are many challenges resulting from the change in global population pyramid structures, which have become inverted over recent decades and now pose many health, nancial and political challenges. Social determinants of health Health emerges from a highly complex interaction between a person’s genetic background and environmental factors (aspects of the physical, biological (microbes), built and social environments and also distant inu- ences such as the global ecosystem) (Fig. 5.1). The hierarchy of systems – from molecules to ecologies Inuences on health exist at many levels and extend beyond the individual to include the family, community, population and ecology. Box 5.4 shows an example of this for determinants of coronary heart disease and demon- strates the importance of considering not only the disease process in a patient but also its context. Health care is not the only determinant – and is usually not the major determinant – of health status in the population. The concept of ‘global health’ recognises the global dimension of health prob- lems, whether these be, for example, emerging or pandemic infections or global economic inuences on health internationally. The life course The determinants of health operate over the whole lifespan. Values and behaviours acquired during childhood and adolescence have a pro- found inuence on educational outcomes, job prospects and risk of disease. These can have a strong inuence, for example, on whether a young person takes up a damaging behaviour like smoking, risky sexual activity and drug misuse. Inuences on health can even operate before birth. Low birth weight can lead to higher risk hypertension and type 2 diabetes in young adults and of cardiovascular disease in mid- dle age. It has been suggested that under-nutrition during middle to late gestation permanently ‘programmes’ cardiovascular and metabolic responses. This ‘life course’ perspective highlights the cumulative effect (through each stage of life) on health of exposures to illness, adverse environmen- tal conditions and behaviours that damage health. Preventive medicine The complexity of the interactions between physical, social and eco- nomic determinants of health means that successful prevention is often difcult. Moreover, the life course perspective illustrates that it may be necessary to intervene early in life or even before birth, to prevent impor- tant disease in later life. Successful prevention is likely to require many interventions across the life course and at several levels in the hierarchy of systems. The examples below illustrate this principle. 5.3 Global risk factors – top 10 ranked causes 2019 [rank in 1990]* 1. High blood pressure [7] 2. Smoking/second hand smoke exposure [5] 3. High fasting blood glucose [11] 4. Low birth weight [2] 5. High BMI [16] 6. Short gestation [3] 7. Ambient particulate matter pollution [13] 8. High LDL cholesterol [14] 9. Alcohol use [15] 10. Household air pollution [4] From GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 2020; 396:1204–1222. M acro-econom y, politics, culture, global forces Other neighbourhoods, other regions People Age, sex and hereditary factors L festyle W o r k p l a y D i e t p h y s i c a l a c tivity S o c a l c a p i t a l Community N e t w o r k s W e a t h c r e a t i o n Loca economy M a r k e t s B u d n g s p l a c e s Environment A i r w a t er l a n d C m a t e c h a n g e Globa ecosystem B o d v e r s i t y Fig. 5.1 Hierarchy of systems that inuence population health. Adapted from an original model by Whitehead M, Dahlgren G. What can be done about inequalities in health? Lancet 1991; 338:1059–1063 *Risk factors ranked by % of burden of disease they cause. (BMI = body mass index; LDL = low density lipoprotein)
- 116. 90 POPULATIONHEALTH AND EPIDEMIOLOGY Alcohol Alcohol use is an increasingly important risk factor underlying global bur- den of disease (see Box 5.3). Reasons for increasing rates of alcohol- related harm vary by place and time but include the falling price of alcohol (in real terms), increased availability and cultural change fostering higher levels of consumption. Public, professional and governmental concern has now led to a minimum price being charged for a unit of alcohol, tightening of licensing regulations and curtailment of some promotional activity in many countries. However, even more aggressive public health measures will be needed to reverse the levels of harm in the population. The approach for individual patients suffering adverse effects of alcohol is described on pages 892 and 1240. Smoking Smoking is also one of the top three risk factors underlying global bur- den of disease (see Box 5.3). It is responsible for a substantial major- ity of cases of lung cancer and chronic obstructive pulmonary disease (COPD), and most smokers die either from these respiratory diseases or from ischaemic heart disease. Smoking also causes cancers of the upper respiratory and gastrointestinal tracts, pancreas, bladder and kidney, and increases risks of peripheral vascular disease, stroke and peptic ulcer- ation. Maternal smoking is an important cause of fetal growth retarda- tion. Moreover, there is increasing evidence that passive (‘second hand’) smoking has adverse effects on cardiovascular and respiratory health. The decline in smoking rates in many high-income countries has been achieved not only by warning people of the health risks but also increased taxation of tobacco, banning of advertising, banning of smoking in public places and support for smoking cessation to maintain a decline in smok- ing rates. However, smoking rates remain high in many poorer areas and are increasing amongst young women. In many low-income countries, tobacco companies have found new markets and rates are rising. There is a complex hierarchy of systems that interact to cause smokers to initiate and maintain their habit. At the molecular and cellular levels, nic- otine acts on the nervous system to create dependence and acts to main- tain the smoking habit. There are also strong inuences at the personal and social level, such as young female smokers being motivated to ‘stay thin’ or ‘look cool’ and peer pressure. Other important inuences in the wider environment include cigarette advertising, with the advertising budget of the tobacco industry being much greater than that of health services. Strategies to help individuals quit smoking (such as nicotine replacement therapy, anti-smoking advice and behavioural support) are cost-effective and form an important part of the overall anti-tobacco strategy. Obesity Obesity is an increasingly important risk factor underlying global burden of disease (see Box 5.3). The weight distribution of almost the whole population is shifting upwards – the slim are becoming less slim while the overweight and obese are becoming more so. In the UK, this translates into a 1-kilogram increase in weight per adult per year (on average over the adult population). The current obesity epidemic cannot be explained simply by individual behaviour and poor choice but also requires an understanding of the obesogenic environment that encourages people to eat more and exercise less. This includes the availability of cheap and heavily marketed energy-rich foods, the increase in labour-saving devices (e.g. elevators and remote controls) and the increase in passive transport (cars as opposed to walking, cycling, or walking to public trans- port hubs). To combat the health impact of obesity, therefore, we need to help those who are already obese but also develop strategies that impact on the whole population and reverse the obesogenic environment. Poverty and afuence The adverse health and social consequences of poverty are well doc- umented: high birth rates, high death rates and short life expectancy. Typically, with industrialisation, the pattern changes: low birth rates, low death rates and longer life expectancy. Instead of infections, chronic conditions such as heart disease dominate in an older population. Adverse health consequences of excessive afuence are also becoming apparent. Despite experiencing sustained economic growth for the last 50 years, people in many high-income countries are not growing any happier and the litany of socioeconomic problems – crime, congestion, inequality, mental health problems – persists. Many countries are now experiencing a ‘double burden’. They have large populations still living in poverty who are suffering from problems such as diarrhoea and malnutrition, alongside afuent populations (often in cities) who suffer from chronic illness such as diabetes and heart disease. Atmospheric pollution Emissions from industry, power plants and motor vehicles of sulphur oxides, nitrogen oxides, respirable particles and metals are severely pol- luting cities and towns in Asia, Africa, Latin America and Eastern Europe. Increased death rates from respiratory and cardiovascular disease occur in vulnerable adults, such as those with established respiratory disease and older people, while children experience an increase in bronchitic symptoms. Low-income countries also suffer high rates of respiratory disease as a result of indoor pollution caused mainly by heating and cooking combustion. Carbon dioxide and global warming Climate change is arguably the world’s most important environmental health issue. A combination of increased production of carbon dioxide and habitat destruction, both caused primarily by human activity, seems to be the main cause. The temperature of the globe is rising, climate is being affected, and if the trend continues, sea levels will rise and rainfall patterns will be altered so that both droughts and oods will become more common. These have already claimed millions of lives during the past 20 years and have adversely affected the lives of many more. The economic costs of property damage and the impact on agriculture, food supplies and prosperity have also been substantial. The health impacts of global warming will also include changes in the geographical range of some vector-borne infectious diseases. Currently, politicians can- not agree on an effective framework of actions to tackle the problem. Meanwhile, the industrialised world continues with lifestyles and levels of waste that are beyond the planet’s ability to sustain. Principles of screening and immunisation Screening Screening is the application of a screening test to a large number of asymptomatic people with the aim of reducing morbidity or mortality from a disease. WHO have identied a set of (Wilson and Jungner) cri- teria to guide health systems in deciding when it is appropriate to imple- ment screening programmes. The essential criteria are: Is the disease an important public health problem? Is there a suitable screening test available? Is there a recognisable latent or early stage? Is there effective treatment for the disease at this stage which improves prognosis? A suitable screening test is one that is cheap, acceptable, easy to perform, safe and gives a valid result in terms of sensitivity and specic- ity. Screening programmes should always be evaluated in trials so that robust evidence is provided in favour of their adoption. These evaluations are prone to several biases – self-selection bias, lead-time bias and length
- 117. Epidemiology 91 5 bias– and these need to be accounted for in the analysis. Examples of large-scale screening programmes in the UK include breast, colorectal and cervical cancer national screening programmes (https://www.gov. uk/topic/population-screening-programmes) and a number of screening tests carried out in pregnancy and in the newborn, such as the: diabetic eye screening programme fetal anomaly screening programme infectious diseases in pregnancy screening programme newborn and infant physical examination screening programme newborn blood spot screening programme newborn hearing screening programme sickle-cell anaemia and thalassaemia screening programme. These are illustrated in Figure 5.2 Problems with screening include: over-diagnosis (of a disease that would not have come to clinical attention on its own or would not have led to death) false reassurance diversion of resources from investments that could control the dis- ease more cost-effectively. Immunisation Immunisation can confer immunity to specic infectious diseases and be either passive (through injected antibodies, such as the monoclo- nal palivizimab against respiratory syncytial virus (RSV) infection given to premature infants) or active (through administration of a vaccine). Immunisation invokes antibody and/or cell-mediated immunity and can lead to both short- and longer-term protection in the person who is vaccinated. Immunisation has also been used to eradicate a dis- ease such as occurred in the smallpox eradication programme and is currently being targeted in the polio eradication programme. As well as direct effects of vaccination a number of indirect effects can occur – such as protection of individuals who are vaccinated through altering disease transmission leading to ‘herd immunity’; or reduction of antibiotic resistance through selective reduction of pneumococcal serogroups that are associated with antibiotic resistance. The UK immunisation schedule is described in detail and regularly updated in the UK government publication ‘Immunisation against infectious dis- ease’ (Green Book). Epidemiology Epidemiologists study disease in free-living humans, seeking to describe patterns of health and disease and to understand how different expo- sures cause or prevent disease (Box 5.5). Chronic diseases and risk factors (e.g. smoking, obesity etc.) are often described in terms of their prevalence. A prevalence is simply a proportion, for example the preva- lence of diabetes among people aged 80 and older in developed coun- tries is around 10%. Events such as deaths, hospitalisations and rst occurrences of a dis- ease are described using incidence rates, so, for example, if there are 100 new cases of a disease in a single year in a population of 1000, the incidence rate is 105 per 1000 person-years. The rate is 105 rather than 100 because the denominator is person-time, the sum of the total ‘exposed’ time for the population, which in this example is 950 per- son-years. Person-time is the sum of the total ‘exposed’ time for the population and in this example is 950 person-years. The reason the per- son-time is less than 1000 is that 100 people experienced the event. These 100 people are assumed to have had an event, on average, half- way through the time-period, removing 100 ×0.5 person-years from the exposure-time (as it is not possible to have a rst occurrence of a disease twice). A similar measure to the incidence rate is the cumulative incidence or risk, which is the number of new cases as a proportion of the total people at risk at the beginning of the exposure time. If in the example above the same 1000 people were observed for a year (i.e. with no one joining or leaving the group) then the one-year risk is 10% (100/1000). The time-period should always be specied for risks. These rates and proportions are used to describe how diseases (and risk factors) vary according to time, person and place. Temporal varia- tion may occur seasonally; for example, malaria occurs in the wet sea- son but not the dry, or as longer-term ‘secular’ trends, e.g. malaria may re-emerge due to drug resistance. Person comparisons include age, sex, socio-economic status, employment, and lifestyle characteristics. Place comparisons include the local environment (e.g. urban versus rural) and international comparisons. Understanding causes and effect Epidemiological research complements that based on animal, cell and tissue models, the ndings of which do not always translate to humans. For example, only a minority of drug discoveries from laboratory research are found to be effective when tested in people. However, differentiating causes from mere non-causal associations is a considerable challenge for epidemiology. This is because while labora- tory researchers can directly manipulate conditions to isolate and under- stand causes, such approaches are impossible in free-living populations. Epidemiologists have developed a different approach, based around a number of study designs (Box 5.6). Of these, the clinical trial is closest to the laboratory experiment. An early example of a clinical trial is shown in Figure 5.3, along with ‘effect measures’ which are used to quantify the difference in rates and risks. In clinical trials, patients are usually randomly allocated to treatments so that, on average, groups are similar apart from the intervention of interest. Nevertheless, for any particular trial, especially a small trial, the laws of probability mean that differences can and do occur by chance. Poorly designed or executed trials can also limit comparability between groups. Allocation may not truly be random (e.g. because of inadequate concealment of the randomisation sequence), and there may be system- atic differences (biases) in the way people allocated to different groups are treated or studied. Such biases also occur in observational epidemiological study designs, such as cohort, case–control and cross-sectional studies (see Box 5.6). These designs are also much more subject to the problem of confounding than are randomised trials. Confounding is where the relationship between an exposure and out- come of interest is confused by the presence of some other causal factor. For example, coffee consumption may be associated with lung cancer because smoking is commoner among coffee-drinkers. Here, smoking is said to confound the association between coffee and lung cancer. Despite these limitations, for most causes of diseases, randomised controlled trials are not feasible because of ethical, or more often prac- tical, considerations. Epidemiologists therefore seek to minimise bias and confounding by good study design and analysis. Epidemiologists subsequently make causal inferences by balancing the probability that an observed association has been caused by chance, bias and/or con- founding against the alternative probability that the relationship is causal. This weighing-up requires an understanding of the frequency and impor- tance of different sources of bias and confounding as well as the scien- tic rationale of the putative causal relationship. It was this approach, collectively and over a number of years, that settled the fact that smoking causes lung cancer, and, subsequently, heart disease. Mendelian randomisation Mendelian randomisation (MR) is a method to study whether the rela- tionship between a (modiable) risk factor and a disease may be causal. It uses genetic variation in a gene that inuences the level of the risk factor under consideration and studies the impact of this variation on
- 118. 92 POPULATIONHEALTH AND EPIDEMIOLOGY Blood for sickle cell and thalassaemia Commence folic acid Pre-conception Antenatal Newborn Blood for haemoglobin, group, rhesus and antibodies as early as possible, or as soon as a woman arrives for care, including labour Blood for syphilis, hepatitis B, HIV and rubella susceptibility as early as possible, or at any stage of the pregnancy, including labour Re-offer screening for infectious diseases if initially declined For babies of hepatitis B-positive mothers, give hepatitis B vaccination ± immunoglobulin within 24 hrs* Repeat haemoglobin and antibodies 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 +1 +2 +3 +4 +5 +6 Birth Key Week Blood for T21, T18 and T13 (combined test) Blood for T21 (quadruple test) Newborn physical examination by 72 hrs Newborn blood spot screens (ideally on day 5) for: sickle cell disease (SCD), cystic fibrosis (CF), congenital hypothyroidism (CHT) and inherited metabolic diseases (PKU, MCADD, MSUD, IVA, GA1 and HCU) Note that babies who missed the screen can be tested up to 1 year (except CF offered up to 8 weeks) Early pregnancy scan to support T21, T18 and T13 screening Women with type 1 or type 2 diabetes are offered diabetic eye (DE) screening annually. In pregnancy women with type 1 or type 2 diabetes are offered a DE screen when they first present for care Give screening information as soon as possible Give and discuss newborn screening information Follow-up DE screen for women with type 1 or 2 diabetes found to have diabetic retinopathy Further DE screen for women with type 1 or 2 diabetes Detailed ultrasound scan for structural abnormalities, including T18 and T13 Newborn hearing screen Infant physical examination at 6–8 weeks Fetal anomaly (Down syndrome/T21, Edwards syndrome/T18, Patau syndrome/T13, and fetal anomaly ultrasound) Sickle cell and thalassaemia Newborn and infant physical examination Newborn blood spot Infectious diseases in pregnancy Diabetic eye Newborn hearing Fig. 5.2 UK NHS pregnancy and newborn screening programmes. Antenatal and newborn screening timeline. *To stop mother-to-baby transmission of infection follow up all infection screens in pregnancy that are positive: carry out paediatric assessment and follow-up of mothers who are found to be HIV-positive or had syphilis treatment in pregnancy; and if mothers are found to be susceptible to rubella then offer the mother MMR vaccination postnatally and refer to GP for second dose. (GA1 = glutaric aciduria type 1; HCU = homocystinuria; IVA = isovaleric acidaemia; MCADD = medium-chain acyl-CoA dehydrogenase deciency; MSUD = maple syrup urine deciency; PKU = phenylketonuria) Based on Version 8.4, January 2019. Gateway Ref: 20144696. www.gov.uk/phe/screening.
- 119. Epidemiology 93 5 diseaserisk (see Fig. 5.4 for an example). The genetic variant (or mul- tiple variants or genetic risk score) is used as an instrumental variable under certain assumptions. MR investigates the effect of differences in the risk factor level through the life course which have been deter- mined by the genetic variants. This approach uses observational data to test a proposed causal relationship and to estimate the size of effect. Guidelines such as STROBE-MR have been published for the proper conduct of these studies and analytic software packages are now avail- able which contain a range of methods and tools. The selection of the most appropriate method depends on the research question and the data structure. The MR approach requires very large sample sizes to have sufcient power and very large databases of genetic and health data such as UK Biobank are often used. MR can be conducted using either individual level data or summary data from genome-wide association studies (GWAS); and data from one study (one sample) or two studies with the variant–risk factor association measure from one and the risk factor– outcome association from the other (two sample). Correct interpretation of MR results is challenging and multiple ana- lytic methods are often employed. This includes methods to detect and adjust for pleiotropy (having more than one effect) which is a common problem in data interpretation. The strength of the conclusions depends on the degree to which instrumental variable assumptions are met and the level of consistency of ndings across different methods. MR has proven useful in both identifying new causal relationships or conrming trial results but also in redirecting research interest away from relation- ships that have been shown not to be causal. MR can be considered 5.5 Calculation of risk using descriptive epidemiology Prevalence The ratio of the number of people with a longer-term disease or condition at a specied time, to the number of people in the population who are at risk Incidence The number of events (new cases or episodes) occurring in the population at risk during a dened period of time Attributable risk The difference between the risk (or incidence) of disease in exposed and non- exposed populations Attributable fraction The ratio of the attributable risk to the incidence Relative risk The ratio of the risk (or incidence) in the exposed population to the risk (or incidence) in the non-exposed population 5.6 Epidemiological study designs Design Description Example Clinical trial Enrols a sample from a population and compares outcomes after randomly allocating patients to an intervention The Medical Research Council (MRC) streptomycin trial – demonstrated effectiveness of streptomycin in tuberculosis Cohort Enrols a sample from a population and compares outcomes according to exposures The Framingham Study – identied risk factors for cardiovascular disease Case–control Enrols cases with an outcome of interest and controls without that outcome, and compares exposures between the groups Doll and Hill’s study on smoking and carcinoma of the lung (BMJ 1950, 2) demonstrated that smoking caused lung cancer Cross-sectional Enrols a cross-section (sample) of people from the population of interest. Obtains data on exposures and outcomes World Health Organization Demographic and Health Survey. Captures risk factor data in a uniform way across many countries Enrolled 107 patients with tuberculosis Effect measures Risk ratio (relative risk, RR) Odds ratio (OR) Absolute risk reduction (ARR) Relative risk reduction (RRR) Number needed to treat to prevent one death (NNT= 1/ARR) Random allocation Streptomycin 55 patients Bed rest 52 patients Follow-up and count deaths Events 4 Risk 7.3% Odds 0.068 Events 15 Risk 28.8% Odds 0.224 0.25 0.30 21.6% 74.8% 4.6 Fig. 5.3 An example of a clinical trial: streptomycin versus bed rest in tuberculosis. Both prevalences and risks are, in fact, proportions and are therefore frequently expressed as odds. The reasons for doing so are beyond the scope of this text. Genotype group B Population LDL-C lower LDL-C unchanged CV event rate lower CV event rate unchanged Random allocation of alleles Genotype group A Fig. 5.4 Mendelian randomisation. An example showing comparison of a conventional trial with a Mendelian randomisation study. (CV = cardiovascular; LDL-C = low-density lipoprotein cholesterol) Adapted with permission from Bennett DA, Holmes MV. Heart 2017; 103:1400–1407.
- 120. 94 POPULATIONHEALTH AND EPIDEMIOLOGY to provide further evidence for or against a causal relationship but care should be taken in interpretation of the size of the expected impact from an intervention. Health data/informatics As patients pass through health and social care systems, data are recorded concerning their family background, lifestyle and disease states, which is of potential interest to health-care organisations seek- ing to deliver services, policy-makers concerned with improving health, scientic researchers seeking to understand health, and also to phar- maceutical and other commercial organisations seeking to identify markets. There is a long tradition of maintaining health information systems. In most countries, the registration of births and deaths is required by law, and in the majority, the cause of death is also recorded (Fig. 5.5). There are numerous challenges in ensuring such data are useful, espe- cially for making comparisons across time and place. First, a system of standard terminologies is needed, such as the World Health Organization International Classication of diseases, which provides a list of diagnos- tic codes attempting to cover every diagnostic entity. Secondly, these terms must be understood to refer to the same, or at least similar dis- eases in different places. Thirdly, access to diagnostic skill and facilities is required, fourthly standard protocols for assigning clinical diagnoses to ICD-10 codes are needed and fthly, robust quality control processes are needed to maintain some level of data completeness and accuracy. Many countries employ similar systems for hospitalisations, either to allow recovery of healthcare utilisation costs, or to manage and plan ser- vices. Similar data are, however, rarely collected for community-based healthcare. Nor are detailed data on health-care process generally included in national data systems. Consequently, there has been considerable interest in using data from information technology systems used to deliver care – such as electronic patient records, drug-dispensing databases, radiological software, and clinical laboratory information systems. Data from such systems are, of course, much less structured than those obtained from vital registrations. Moreover, the completeness of such data depends greatly on local patterns of healthcare utilisation as well as how clinicians and others use IT systems within different settings. As such, deriving useful unbiased information from such data is a con- siderable challenge. Much of the discipline of health informatics is concerned with address- ing this challenge. One approach has been to develop comprehensive standard classication systems such as SNOMED-CT ‘a standardised, multilingual vocabulary of terms relating to the care of the individual’ which has been designed for electronic health-care records. An alterna- tive has been to use statistical methods such as natural language pro- cessing to automatically derive information from free text (such as culling diagnoses from radiological reports), or to employ ‘machine learning’, in which software algorithms are applied to data in order to derive useful insights. Such approaches are suited to large, messy data where the costs of systematisation would be prohibitive. It is likely that such inno- vations will over the coming years provide useful information to com- plement that obtained from more traditional health information systems. Cause of death Approximate interval between onset and death I Disease or condition directly leading to death* INTERNATIONAL FORM OF MEDICAL CERTIFICATE OF CAUSE OF DEATH due to (or as a consequence of) due to (or as a consequence of) due to (or as a consequence of) (a) (b) (c) (d) I21.9 E78.0 J47 *This does not mean the mode of dying, e.g. heart failure, respiratory failure. It means the disease, injury, or complication that caused death. Antecedent causes Morbid conditions, if any, giving rise to the above cause, stating the underlying condition last II Other significant conditions contributing to the death, but not related to the disease or condition causing it Fig. 5.5 Completed death certicate. International Classication of Diseases 10 (ICD-10) codes are appended in red. Based on World Health Organization, ICD-10, vol. 2. Geneva: WHO; 1990. Form retrieved from https://commons.m.wikimedia.org/wiki/File:International_form_of_medical_certicate_of_cause_of_death.png.
- 121. Further information 95 5 Management of epidemics An epidemic, as dened by the World Health Organization, occurs when ‘in a community or region [the] cases of an illness, specic health-related behaviour, or other health-related events [are] clearly in excess of normal expectancy’. Epidemics that are small-scale or conned to a small geo- graphic area are informally referred to as ‘outbreaks’. Epidemics are regularly caused where preventative measures break down; examples include breaches of food safety procedures in restau- rants resulting in outbreaks of enteropathogenic E. coli infection, failure to adequately maintain cooling towers causing Legionella infections and falls in vaccination coverage resulting in measles epidemics. Epidemics can also arise from novel infectious agents such as the SARS-CoV-1, MERS, SARS-CoV-2 and H1N1 viruses, for which new preventative measures require to be developed. Where epidemics from novel agents are not controlled locally, but instead spread beyond inter- national borders, these are termed pandemics, of which SARS-CoV-2 and H1N1 are examples. To detect epidemics early, public health agencies undertake surveil- lance. Surveillance involves the collection and review of cases that have been identied via statutory notications, or health information systems (such as microbiology reporting systems). For some infections such as E. coli and Legionella, one challenge for public health agencies is to distinguish epidemics from ‘sporadic’ cases at an early stage. This is done using human judgement, for example, if a large number of cases of E. coli occur in individuals who ate a specic food, although this task is sometimes supported using computer algorithms. Epidemics require an incident management team, some of whose members have legal powers to impose measures to control infection. The team establish a formal case denition for conrmed, probable and possible cases (based on epidemiological features as well as clinical and/ or microbiological ndings), interview individuals with whom cases have had signicant contact (termed contact tracing), test potential sources of infections (e.g. foodstuffs or industrial cooling towers), and implement control measures. The latter might include requiring infected individuals to isolate for a time period (e.g. until they are asymptomatic or until they test negative depending on the infectious agent), and/or ordering tem- porary closure of businesses thought to be sources of infection (e.g. a restaurant with poor food hygiene practices). Epidemic curves are crucial to the monitoring and management of epidemics. Figure 5.6 shows a notional epidemic curve for an epidemic caused by a single source, which is eliminated after 31 days. However, they are also used in more complex epidemics where there is per- son-to-person spread. In the latter, epidemic curves are used to esti- mate key statistics such as the basic reproduction number (R0) in the population, as well as to make projections about future infections. Where the source of an epidemic is not apparent, comparative epidemiological methods can be used to identify the likely source, for example, a case– control design may identify a higher than expected consumption of a given food – for example uncooked legumes – among cases compared to controls prompting testing of foods, an education campaign and/or product recalls. The principles for managing pandemics are similar to those for man- aging epidemics but operate on a national or international scale. The universality of pandemics, however, means that they pose special prob- lems. First, they pose risks to the society-wide infrastructure needed to deal with diseases, including, but not limited to health-care facilities. Secondly, pandemics, unlike local and regional epidemics are rare, so agencies have little direct experience with their management. For this reason, most settings develop pandemic plans and undertake regu- lar table-top simulations to test and improve their preparedness. The COVID-19 pandemic, caused by SARS-CoV-2, is a key example and is discussed in detail in Chapter 13 Further information Kindig D, Stoddart G. What is population health? Am J Publ Health 2003;93: 380–383. UK Faculty of Public Health. What is public health? http://www.fph.org.uk/what_ is_public_health Burden of disease GBD Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 2019; 2020(396): 1204–1222. GBD Risk Factors Collaborators. Global burden of 87 risk factors in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 2019; 2020(396):1223–1249. GBD Viewpoint Collaborators. Five insights from the Global Burden of Disease Study 2019. Lancet 2019; 2020(396):1135–1159. Screening Gov.UK. Population screening programmes. https://www.gov.uk/topic/population- screening-programmes Detailed information on 11 NHS population screening programmes. Immunisation Gov.UK. Immunisation against infectious disease. https://www.gov.uk/ government/collections/immunisation-against-infectious-disease-the-green- book The Green Book has the latest information on vaccines and vaccination procedures, for vaccine-preventable infectious diseases in the UK. Epidemiology Burgess S, Davey Smith G, Davies NM, et al. Guidelines for performing Mendelian randomization investigations. Wellcome Open Res 2020;4:186. STROBE-MR Steering Group: STROBE-MR: Guidelines for strengthening the reporting of Mendelian randomization studies. PeerJ https://peerj.com/ preprints/27857/ Days New cases 1 0 5 10 15 6 11 16 21 26 31 26 41 Fig. 5.6 Epidemic curve for a notional outbreak within a single ongoing source. Red line indicates time point where source of infection was removed (e.g. closure of a restaurant).
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- 123. Multiple Choice Questions 5.1.Which of the following are examples of large-scale screening programmes across all of the UK in 2021? A. Cervical cancer national screening programme in women B. Prostate cancer national screening programme in men C. Diabetic eye screening programme in both men and women D. Newborn hearing screening programme E. Abdominal aortic aneurysm screening programme in both men and women Answer: A, C and D. Prostate cancer screening has not proven to be cost-effective and thus is not approved by the UK National Screening Committee. An abdominal aortic aneurysm screening programme operates only in men 65 years of age or over but not in women. 5.2. Which of the following statements describe the current newborn blood spot screening programme in the UK? A. Ideally, blood spots should be collected on day 14 B. Babies who missed the screen can be tested up to 1 month of age C. Blood spots are screened for sickle-cell disease D. Blood spots are screened for cystic brosis E. Blood spots are screened for congenital hypothyroidism Answer: C, D and E. Ideally, blood spots should be collected on day 5. Babies who missed the screen can be tested up to 1 year of age. Newborn blood spot screens for: sickle-cell disease, cystic brosis, congenital hypothyroid- ism and inherited metabolic diseases (PKU, MCADD, MSUD, IVA, GA1 and HCU – see Fig. 5.2).
- 124. Principles of infectiousdisease 6 JAT Sandoe DH Dockrell Agents causing infection 98 Normal microbial ora 100 Host–pathogen interactions 101 Investigation of infection 102 Direct detection of pathogens 103 Culture 104 Indirect detection of pathogens 105 Antimicrobial susceptibility testing 106 Epidemiology of infection 106 Infection prevention and control 108 Health care-associated infection 109 Outbreaks of infection 109 Immunisation 111 Antimicrobial stewardship 112 Treatment of infectious diseases 113 Principles of antimicrobial therapy 113 Antibacterial agents 116 Antimycobacterial agents 121 Antifungal agents 121 Antiviral agents 122 Antiparasitic agents 124
- 125. 98 PRINCIPLESOF INFECTIOUS DISEASE ‘Infection’ in its strict sense describes the situation where microorganisms or other infectious agents become established in the host organism’s cells or tissues, replicate, induce a host response, and result in pathologic changes in tissues. If a microorganism survives and replicates on an epithe- lial surface without causing pathological change the host is said to be ‘colo- nised’ by that organism. If a microorganism survives and lies dormant after invading host cells or tissues, infection is said to be ‘latent’. When a micro- organism, or the host response to it, is sufcient to cause illness or harm, then the process is said to have caused infection, which may manifest by symptoms or signs. In milder cases there can be asymptomatic infection that may be identied by detection of a pathogen or the host response to the pathogen. Most pathogens (agents that can cause infection) are microorganisms but some are multicellular organisms. The manifestations of disease may aid pathogen dissemination (e.g. diarrhoea or coughing). The term ‘infection’ is often used interchangeably with ‘infectious dis- ease’ but not all infections are ‘infectious’, i.e. transmissible from person to person, and not all infections result in symptomatic disease. Infectious diseases caused by pathogens that are transmitted between hosts can also be called ‘communicable diseases’, whereas infection caused by organisms that are already colonising the host are described as ‘endog- enous’. The distinction is blurred in some situations, including health care-associated infections such as meticillin-resistant Staphylococcus aureus (MRSA) or Clostridioides (formerly Clostridium) difcile infection (CDI), in which colonisation precedes infection but the colonising bac- teria may have been recently transmitted between patients. The chain of infection (Fig. 6.1) describes elements for communicable disease transmission. Despite dramatic advances in hygiene, immunisation and antimicrobial therapy, infections still cause a massive burden of disease worldwide. Key challenges remain in tackling infection in resource-poor countries. Microorganisms are continually mutating and evolving; the emergence of new infectious agents (e.g. SARS-CoV-2, see Ch. 13) and antimi- crobial-resistant microorganisms is therefore inevitable. This chapter describes the biological and epidemiological principles of infectious dis- eases and the general approach to their prevention, diagnosis and treat- ment. Specic infectious diseases are described in Chapters 13–15 and many of the organ-based chapters. Agents causing infection The concept of an infectious agent was established by Robert Koch in the 19th century (Box 6.1). Although fullment of ‘Koch’s postulates’ became the standard for conrming the cause of an infection, many infectious agents do not full Koch’s postulates (e.g. uncultivable organ- isms and the causes of endogenous infections), and the postulates are now of mainly historical interest. The groups of infectious agents that are now recognised are described in the following sections. A B C Fig. 6.1 The chain of infection can be linear (A) and cyclical (B and C). Campylobacter enteritis) require a portal of exit from respiratory virus infection) require a mode of exit from the infected person, a mode of transmission (e.g. contaminated respiratory droplets or transmission via the surface of an susceptible human host and a mode of transmission back to the insect vector. Many infections involve a combination of these modes of transmission (e.g. Lyme disease, which has both an animal host and an insect vector) or several different modes of transmission. 6.1 Denition of an infectious agent – Koch’s postulates 1. The same organism must be present in every case of the disease. 2. The organism must be isolated from the diseased host and grown in pure culture. 3. The isolate must cause the disease, when inoculated into a healthy, susceptible animal. 4. The organism must be re-isolated from the inoculated, diseased animal.
- 126. Agents causing infection 99 6 Viruses Viruses are incapable of independent replication. Instead, they subvert host cellular processes to ensure synthesis of their nucleic acids and proteins. Viruses’ genetic material (the genome) consists of single- or double-stranded DNA or RNA. Retroviruses transcribe their RNA into DNA in the host cell by reverse transcription. An antigenically unique pro- tein coat (capsid) encloses the genome, and together these form the nucleocapsid. In many viruses, the nucleocapsid is packaged within a lipid envelope. Enveloped viruses are less able to survive in the envi- ronment and are spread by respiratory, sexual or blood-borne routes, including arthropod-based transmission. Non-enveloped viruses survive better in the environment and are predominantly transmitted by faecal– oral or, less often, respiratory routes. A generic virus life cycle is shown in Figure 6.2. A virus that infects a bacterium is a bacteriophage (phage). Prokaryotes: bacteria (including mycobacteria and actinomycetes) Prokaryotic cells can synthesise their own proteins and nucleic acids, and are able to reproduce autonomously, although they lack a nucleus. The bacterial cell membrane is bounded by a peptidoglycan cell wall, which is thick (20–80nm) in Gram-positive organisms and thin (5–10nm) in Gram- negative ones. The Gram-negative cell wall is surrounded by an outer mem- brane containing lipopolysaccharide. Genetic information is contained within a chromosome but bacteria may also contain rings of extra-chromosomal DNA, known as plasmids, which can be transferred between organisms, without cells having to divide. Bacteria may be embedded in a polysaccha- ride capsule, and motile bacteria are equipped with agella. Although many prokaryotes are capable of independent existence, some (e.g. Chlamydia tra- chomatis, Coxiella burnetii) are obligate intracellular organisms. Bacteria that can grow in articial culture media are classied and identied using a range of characteristics (Box 6.2); examples are shown in Figures 6.3 and 6.4 Eukaryotes: fungi, protozoa and helminths Eukaryotic cells contain membrane-bound organelles, including nuclei, mitochondria and Golgi apparatus. Pathogenic eukaryotes are unicellular (e.g. yeasts, protozoa) or complex multicellular organisms (e.g. nema- todes, trematodes and cestodes). Host cell 2 Penetration Receptor-mediated endocytosis or, in some enveloped viruses, membrane fusion (shown here) 3 Uncoating Nucleic acid is liberated from the phagosome (if endocytosed) and/or capsid by complex enzymatic and/or receptor-mediated processes Interaction between host receptor molecule and virus ligand (determines host-specificity of the virus) Adsorption 1 Lipid envelope Capsid Nucleic acid Virus Assembly 5 Assembly of virus components is mediated by host and/or viral enzymes Release 6 Complete virus particles are released by budding of host cell membrane (shown here) or disintegration of host cell 4 Synthesis Nucleic acid and protein synthesis is mediated by host and/or viral enzymes. This takes place in nucleus or cytoplasm, depending on the specific virus Fig. 6.2 A generic virus life cycle. Life cycle components common to most viruses are host cell attachment and penetration, virus uncoating, nucleic acid and protein synthesis, virus assembly and release. Virus release is achieved either by budding, as illustrated, or by lysis of the cell membrane. Life cycles vary between viruses. 6.2 How bacteria are identied Gram stain reaction (see Fig. 6.3) Gram-positive (thick peptidoglycan layer), Gram-negative (thin peptidoglycan) or unstainable Microscopic morphology Cocci (round cells) or bacilli (elongated cells) Presence or absence of capsule Cell association Association in clusters, chains or pairs Colonial characteristics Colony size, shape or colour Effect on culture media (e.g. β-haemolysis of blood agar in haemolytic streptococci; see Fig. 6.4) Atmospheric requirements Strictly aerobic (requires O2 ), strictly anaerobic (requires absence of O2 ), facultatively aerobic (grows with or without O2 ) or micro-aerophilic (requires reduced O2 ) Biochemical reactions Expression of enzymes (oxidase, catalase, coagulase) Ability to ferment or hydrolyse various biochemical substrates Motility Motile or non-motile Antibiotic susceptibility Identies organisms with invariable susceptibility (e.g. to optochin in Streptococcus pneumoniae or metronidazole in obligate anaerobes) Matrix-assisted laser desorption/ionisation time-of-ight mass spectrometry (MALDI-TOF-MS) A rapid technique that identies bacteria and some fungi from their specic molecular composition Sequencing bacterial 16S ribosomal RNA gene A highly specic test for identication of organisms in pure culture and in samples from normally sterile sites Whole-genome sequencing Although not yet in routine use, whole-genome sequencing (WGS) offers the potential to provide rapid and simultaneous identication, sensitivity testing and typing of organisms from pure culture and/or directly from clinical samples.As such,WGS is likely to replace many of the technologies described above over the next few years
- 127. 100 PRINCIPLESOF INFECTIOUS DISEASE Gram-positive bacilli Colony morphology, growth characteristics (e.g. growth in anaerobic atmosphere), Gram stain appearance, MALDI-TOF-MS identification Colony morphology, growth characteristics, oxidase reaction, sugar fermentation/MALDI-TOF-MS identification Colony morphology, growth characteristics, lactose fermentation, oxidase reaction, MALDI-TOF-MS identification Colony morphology (e.g. haemolysis), Gram stain appearance, agglutination reactions, coagulase test, catalase Examples Actinomycetes Arcanobacterium haemo- lyticum Bacillus spp. Corynebacterium diphtheriae Lactobacillus spp. Listeria monocytogenes Nocardia spp. Clostridium spp. or Examples Neisseria meningitidis Neisseria gonorrhoeae Moraxella catarrhalis Examples Escherichia coli Klebsiella pneumoniae Proteus spp. Enterobacter spp. Serratia spp. Salmonella spp. Shigella spp. Yersinia spp. Vibrio spp. Pseudomonas aeruginosa Gram-positive cocci–clusters Examples Staphylococcus aureus Coagulase-negative staphylococci Gram-negative cocci Gram stain Gram-negative bacilli Gram-positive cocci Gram-positive cocci–chains Examples Oral streptococci Streptococcus pneumoniae (often pairs) -haemolytic strepto- cocci Enterococci (short chains) Fig. 6.3 Flow chart for bacterial identication, including Gram lm appearances on light microscopy (×100). (MALDI-TOF-MS = matrix-assisted laser desorption/ ionisation time-of-ight mass spectroscopy). B A Fig. 6.4 β-haemolytic streptococci (A) and α-haemolytic streptococci (B) spread on each half of a blood agar plate (backlit). This image is half life-size. × 0.5. ß-haemolysis renders the agar transparent around the colonies (A) and α-haemolysis imparts a green tinge to the agar (B). Fungi exist as either moulds (lamentous fungi) or yeasts. Dimorphic fungi exist in either form, depending on environmental conditions (see Fig. 13.62). The fungal plasma membrane differs from the human cell membrane in that it contains the sterol, ergosterol. Fungi have a cell wall made up of polysaccharides, chitin and mannoproteins. In most fungi, the main structural component of the cell wall is β-1,3-D-glucan, a polysaccharide. These differences from mammalian cells are important because they offer useful therapeutic targets. Protozoa and helminths are often referred to as parasites. Many par- asites have complex multistage life cycles, which involve animal and/or plant hosts in addition to humans. Prions Although prions are transmissible and have some of the characteristics of infectious agents, they are not microorganisms, and are discussed on page 1181. Normal microbial ora The human body is colonised by large numbers of microorganisms (collec- tively termed the human microbiota). Colonising bacteria, also referred to as the ‘normal bacterial ora’, are able to survive and replicate on epithelial
- 128. Host–pathogen interactions 101 6 surfaces, e.g. skin and mucosal surfaces. The gastrointestinal tract and the mouth are the two most heavily colonised sites in the body and they have distinct microbiota, in both composition and function. Knowledge of non-sterile body sites and their normal bacterial ora is required to inform microbiological sampling strategies and interpret culture results (Fig. 6.5). The microbiota is the total burden of microorganisms, their genes and their environmental interactions, and is now recognised to have a profound inuence on human health and disease. Maintenance of the normal ora is benecial to normal immune function. Other functions include: lower gas- trointestinal tract bacteria synthesise and excrete vitamins (e.g. vitamins K and B12 ); colonisation with normal ora confers ‘colonisation resistance’ to infection with pathogenic organisms by altering the local environment (e.g. lowering pH), producing antibacterial agents (e.g. bacteriocins (small anti- microbial peptides/proteins), fatty acids and metabolic waste products), and inducing host antibodies that cross-react with pathogenic organisms. Conversely, some body sites are either sterile or contain very low num- bers of colonising bacteria. For example, the submucosal tissues, blood stream, peritoneal and pleural cavities are maintained as sterile by physi- cal separation from the external environment; and the lower airways and bladder, sites that were formerly believed to be sterile but are now known to support limited microbiota, are protected from excessive contamina- tion by the mucociliary escalator and urethral sphincter respectively, as well as local immune responses. Members of the normal ora can cause (endogenous) infection by ‘translocation’ from their normal habitat to other body sites or by exces- sive growth at the ‘normal’ site (overgrowth). Overgrowth is exemplied by dental caries and ‘blind loop’ syndrome (p. 821). Translocation results from spread along a surface or penetration through a colonised surface, e.g. urinary tract infection caused by perineal/enteric ora, and surgical site infections, particularly of prosthetic materials, caused by skin ora such as staphylococci. Normal ora also contribute to disease by cross-infection; organisms colonising one individual can cause disease when transferred to another, more susceptible, individual. The importance of limiting antimicrobial-induced perturbations of microbiota is increasingly recognised. ‘Probiotics’ are proprietary microbes or mixtures of microbes administered with the aim of restor- ing a benecial prole of gastrointestinal normal ora. Faecal microora transplantation (FMT) has the same aim, by giving gastrointestinal micro- biota from healthy people (ltered extract of faeces) to a patient. Although the clinical effectiveness of probiotics remains a subject of debate, FMT has proven benet in recurrent C. difcile infection. Host–pathogen interactions A ‘pathogen’ is a microorganism that can cause infection. The manifes- tations of infection, including a pathogen’s ability to cause severe disease in a previously healthy host, are affected by its ‘virulence’. Virulence is determined by the number and type of disease-causing proteins and other factors that it can produce (‘virulence factors’). Primary pathogens cause disease in a proportion of individuals to whom they are exposed, regardless of the host’s immunological status. Opportunistic pathogens cause disease only in individuals whose host defences are compromised, e.g. by an intravascular catheter, or when the immune system is compromised, by genetic suscepti- bility or immunosuppressive therapy. Pharynx Haemophilus spp. Moraxella catarrhalis Neisseria spp. (including N. meningitidis) Staph. aureus Strep. pneumoniae Strep. pyogenes (group A) Oral streptococci (α-haemolytic) Oral cavity Oral streptococci (α-haemolytic) Anaerobic Gram-positive bacilli (including Actinomyces spp.) Anaerobic Gram-negative bacilli Prevotella spp. Fusobacterium spp. Candida spp. Small bowel Distally, progressively increasing numbers of large bowel bacteria Candida spp. Large bowel Enterobacterales Escherichia coli Klebsiella spp. Enterobacter spp. Proteus spp. Enterococci E. faecalis E. faecium Streptococcus anginosus group Strep. anginosus Strep. intermedius Strep. constellatus Anaerobic Gram-positive bacilli Clostridium spp. Anaerobic Gram-negative bacilli Bacteroides spp. Prevotella spp. Candida spp. Scalp As for skin Nares Staph. aureus Coagulase-negative staphylococci Skin Coagulase-negative staphylococci Staph. aureus Corynebacterium spp. Propionibacterium spp. Malassezia spp. Hands Resident: as for skin Transient: skin flora (including meticillin-resistant and other Staph. aureus), bowel flora (including Clostridioides difficile, Candida spp. and Enterobacterales) Vagina Lactobacillus spp. Staph. aureus Candida spp. Enterobacterales Strep. agalactiae (group B) Perineum As for skin As for large bowel Fig. 6.5 Human non-sterile sites and normal ora in health.
- 129. 102 PRINCIPLESOF INFECTIOUS DISEASE Determinants of virulence For a primary pathogen to cause infection in a healthy host it must compete with colonising ora to reach target host cells. It can do this in various ways, including sequestration of nutrients, adapting metab- olism to exploit metabolites not used by commensal ora, production of bacteriocins, and using motility to ‘swim’ to the site of infection. Many microorganisms, including viruses, use ‘adhesins’ to initiate their attachment to host cells. Some pathogens can invade through tis- sues. Many bacteria and fungi multiply after initial adhesion to a host surface to form ‘biolms’. These are complex three-dimensional struc- tures surrounded by a matrix of host and bacterial products, which afford protection to the colony and limit the effectiveness of antimicro- bials. Biolm-related infections on man-made medical devices such as vascular catheters or grafts can be particularly difcult to treat. Pathogens may produce toxins, microbial molecules that cause adverse effects on host cells, either at the site of infection, or remotely following carriage through the blood stream. Endotoxin is the lipid component of Gram-negative bacterial outer membrane lipopoly- saccharide. It is released when bacterial cells are damaged and has generalised inflammatory effects. Exotoxins are proteins released by living bacteria, which often have specific effects on target organs (Box 6.3). Intracellular pathogens, including viruses, bacteria (e.g. Salmonella spp., Listeria monocytogenes and Mycobacterium tuberculosis), para- sites (e.g. Leishmania spp.) and fungi (e.g. Histoplasma capsulatum), are able to survive in intracellular environments, including after phagocytosis by macrophages. Pathogenic bacteria express different genes, depend- ing on environmental stress (pH, iron starvation, O2 starvation etc.) and anatomical location. Genetic diversity enhances the pathogenic capacity of bacteria. Some virulence factor genes are found on plasmids or in phages and are exchanged between different strains or species. The ability to acquire genes from the gene pool of all strains of the species increases diver- sity and the potential for pathogenicity. Viruses exploit their rapid repro- duction and potential to exchange nucleic acid with other strains of the virus to enhance diversity. Once a new strain acquires sufcient virulence genes, including those enhancing infectivity, it may become an epidemic or pandemic strain, resulting in regional or global transmission, respec- tively. This phenomenon accounts for inuenza and COVID-19 pandem- ics (see Box 6.10 and Ch. 13). The host response Innate and adaptive immune and inammatory responses, which humans use to control the normal ora and respond to pathogens, are reviewed in Chapter 4 Pathogenesis of infectious disease The severity of an infection is determined by the virulence of the pathogen and the host response. Whilst an intact host response protects against infection or reduces its severity, an excessive response can be damaging. Both the host immune response and pathogen-produced factors can contribute to tissue injury and systemic manifestations of infection (see ‘Sepsis’, p. 198). The contribution of the immune response to disease manifestations is exemplied by the immune reconstitution inammatory syndrome (IRIS), which can be seen in human immunodeciency virus (HIV) infection, post-transplantation neutropenia or tuberculosis (which causes suppression of T-cell function): there is a paradoxical worsening of the clinical condition as the immune dysfunction is corrected, caused by an exuberant but dysregulated inammatory response. Clinical manifestations of infection The clinical manifestations of infection can be localised to the site of infection or generalised. Examples of local manifestations include the inammation of cellulitis, facial pain of sinusitis or neck stiffness of men- ingitis (Ch. 13). Generalised manifestations include sweats, chills (feeling very cold, even with extra clothes/blankets), rigors, fevers, anorexia, leth- argy and generalised aches, and many of these result from the immune response to infection. While the presence of infection may be clinically clear in some settings, often it is not. Identifying the responsible patho- gen in patients with infection is usually not possible on clinical grounds, neither is prediction of pathogen susceptibility and resistance to antimi- crobial agents. Hence there is a need to carefully investigate suspected infections to optimise, or avoid unnecessary, antimicrobial therapy. Rigors are a clinical symptom (or sign if they are witnessed) characterised by feeling very cold (‘chills’) and uncontrollable shivering, usually followed by fever and sweating. Rigors occur when the thermoregulatory centre attempts to correct a core temperature to a higher level by stimulating skeletal muscle activity and shaking. Thermoregulation can be altered during infection, causing both hyper- thermia (fever) and hypothermia. Fever is mediated mainly by ‘pyrogenic cytokines’ (e.g. interleukins IL-1 and IL-6, and tumour necrosis factor (TNF)), which are released in response to various stimuli. including acti- vation of pattern recognition receptors (PRRs) by microbial products (e.g. lipopolysaccharide) and factors released by injured cells (Ch. 4). This induces prostaglandin E2 production, which binds to specic receptors in the preoptic nucleus of the hypothalamus (thermoregulatory centre), causing the core temperature to rise. Investigation of infection The aims of investigating a patient with suspected infection are: to con- rm the presence of infection; identify the specic pathogen(s); and, where appropriate, identify its susceptibility to specic antimicrobial agents in order to optimise therapy. Pathogens may be detected directly (e.g. by culturing a normally sterile body site) or their presence may be inferred by identifying the host response to the organism (‘indirect detection’, Box 6.4), e.g. C-reactive protein or procalcitonin as part of the acute phase response (p. 68), although these are activated to varying extents by other inammatory stimuli. Careful sampling increases the likelihood of diagnosis (Box 6.5). Culture results must be interpreted in the context of the normal ora at the sampled site (see Fig. 6.5). The extent to which a microbiological test result supports or excludes a particular diagnosis depends on its statistical performance (e.g. sensitivity, specicity, positive and negative predictive value). Sensitivity and specicity vary according to the type of test, sampling and processing techniques, and time between infection and testing. Positive and negative predictive values depend on the prevalence of the condition in the test population. The com- plexity of test interpretation is illustrated in Figure 6.8 below, which shows the ‘windows of opportunity’ afforded by various testing methods. Given this complexity, coordinated thought and action ensures appropriate test application and timing; effective communication between clinicians and the microbiologists facilitates optimal results and interpretation. 6.3 Exotoxin-mediated bacterial diseases Disease Organism Antibiotic-associated diarrhoea/ pseudomembranous colitis Clostridioides difcile Botulism Clostridium botulinum Cholera Vibrio cholerae Diphtheria Corynebacterium diphtheriae Haemolytic uraemic syndrome Enterohaemorrhagic Escherichia coli (E. coli O157 and other strains) Necrotising pneumonia Staphylococcus aureus Tetanus Clostridium tetani Toxic shock syndrome Staph. aureus Streptococcus pyogenes
- 130. Investigation of infection 103 6 Detection of whole organisms Whole organisms are detected by examination of biological uids or tis- sue using a microscope. Bright eld microscopy (in which the test sample is interposed between the light source and the objective lens) uses stains to enhance visual contrast between the organism and its background. Examples include Gram staining of bacteria and Ziehl–Neelsen or auramine staining of acid- and alcohol-fast bacilli (AAFB) in tubercu- losis (the latter requires an ultraviolet light source). In histopatholog- ical examination of tissue samples, stains are used to demonstrate not only the presence of microorganisms but also features of dis- ease pathology. Dark eld microscopy (in which light is scattered to make organisms appear bright on a dark background) is used, for example, to exam- ine genital chancre uid in suspected syphilis. Electron microscopy may be used to examine stool and vesicle uid to detect enteric and herpesviruses, respectively, but its use has largely been supplanted by nucleic acid detection (see below). Flow cytometry can be used to analyse liquid samples (e.g. urine) for the presence of particles based on properties such as size, imped- ance and light scatter. This technique can detect bacteria but may misidentify other particles as bacteria too. Detection of components of organisms Components of microorganisms detected for diagnostic purposes include nucleic acids, cell wall molecules, toxins and other antigens. Commonly used examples include SARS-CoV-2 antigen in respiratory secretions, Legionella pneumophila serogroup 1 antigen in urine and cryptococcal polysaccharide antigen in cerebrospinal uid (CSF). Most antigen detec- tion methods are based on in vitro binding of specic antigen/antibody and are therefore described with serological tests below. Other methods may be used, such as tissue culture cytotoxicity assay for C. difcile toxin. In toxin-mediated disease, detection of toxin may be of greater relevance than identication of the organism itself (e.g. stool C. difcile toxin). Nucleic acid amplication tests In a nucleic acid amplication test (NAAT), specic sequences of micro- bial DNA or RNA are identied using a nucleic acid primer that is ampli- ed exponentially by enzymes to generate multiple copies of a target nucleotide sequence. The most commonly used NAAT is the polymerase chain reaction (PCR; see Fig. 3.11). Reverse transcription PCR (RT-PCR) is used to detect RNA from RNA viruses. The use of uorescent labels in the reaction enables ‘real-time’ detection of amplied DNA; quanti- cation is based on the principle that the time taken to reach the detec- tion threshold is proportional to the initial number of copies of the target nucleic acid sequence. In ‘broad range’ (bacterial) PCR the primers are targeted to parts of the gene that encode 16S ribosomal RNA (rRNA) that have shared DNA sequences across most bacteria. Between these shared DNA sequences, the 16S rRNA gene varies between species; so, using PCR, nucleotide sequencing of the product and comparison of the DNA sequence information with large databases, bacterial detection and species identication can be achieved. In multiplex PCR, multiple primer pairs are used to enable detection of several different organisms in a single reaction. Determination of nucleotide sequences in a target gene(s) can be used to assign microorganisms to specic strains, which may be relevant to treatment and/or prognosis (e.g. in hepatitis C infection). Genes that are relevant to virulence (such as toxin genes) or antimicrobial resistance can also be detected; for example, the mecA gene can be used to screen for MRSA. NAATs are the most sensitive direct detection methods and are also relatively rapid. They are used widely in virology, where the possibility of false-positive results from colonising or contaminating organisms is 6.4 Tests used to diagnose infection Non-specic markers of inammation/infection e.g. White cell count in blood sample (WCC), plasma C-reactive protein (CRP), procalcitonin (PCT)*, serum lactate, cell counts in urine or cerebrospinal uid (CSF), CSF protein and glucose Direct detection of organisms or organism components Microscopy Detection of organism components (e.g. antigen, toxin) Nucleic acid amplication tests (e.g. polymerase chain reaction) Culture of organisms ± Antimicrobial susceptibility testing Tests of the host’s specic immune response Antibody detection Interferon-gamma release assays (IGRA) *Although PCT is used increasingly in clinical practice, further evidence is required to establish its precise role in distinguishing bacterial infections from other causes of inammation. 6.5 How to provide samples for microbiological sampling Communicate with the laboratory Discuss samples that require processing urgently or that may contain hazardous or unusual pathogens with laboratory staff before collection Communication is key to optimising microbiological diagnosis. If there is doubt about any aspect of sampling, it is far better to discuss it with laboratory staff beforehand than to risk diagnostic delay by inappropriate sampling or sample handling Take samples based on a clinical diagnosis Sampling in the absence of clinical evidence of infection is rarely appropriate (e.g. collecting urine, or sputum for culture) Use the correct container Certain tests (e.g. nucleic acid and antigen detection tests) require proprietary sample collection equipment Follow sample collection procedures Failure to follow sample collection instructions precisely can result in false- positive (e.g. contamination of blood culture samples) or false-negative (e.g. collection of insufcient blood for culture) results Label sample and request form correctly Label sample containers and request forms according to local policies, with demographic identiers, specimen type and time/date collected Include clinical details on request forms Identify samples carrying a high risk of infection (e.g. blood liable to contain a blood-borne virus) with a hazard label Use appropriate packaging Close sample containers tightly and package securely (usually in sealed plastic bags) Attach request forms to samples but not in the same compartment (to avoid contamination, should leakage occur) Manage storage and transport Transport samples to the microbiology laboratory quickly Consider pre-transport storage, conditions (e.g. refrigeration, incubation, storage at room temperature) vary with sample type Notify the receiving laboratory prior to arrival of unusual or urgent samples, to ensure timely processing Direct detection of pathogens Some direct detection methods provide rapid results and enable detec- tion of organisms that cannot be grown easily on articial culture media, such as Chlamydia spp.; they can also provide information on antimicro- bial susceptibility, e.g. M. tuberculosis.
- 131. 104 PRINCIPLESOF INFECTIOUS DISEASE remote, and are applied to blood, respiratory samples, stool and urine. In bacteriology, PCR is used to examine CSF, blood, tissue and genital samples, and multiplex PCR is being developed for use in faeces. PCR is particularly helpful for microorganisms that cannot be readily cultured, e.g. Tropheryma whipplei, and is being used increasingly in mycology and parasitology. Culture Microorganisms may be both detected and further characterised by cul- ture from clinical samples (e.g. tissue, swabs and body uids). Ex vivo culture (tissue or cell culture) was widely used in the isolation of viruses but has been largely supplanted by NAATs. In vitro culture (in articial culture media) of bacteria and fungi is used to conrm the presence of pathogens, allow identication, test antimicrobial susceptibility and subtype the organism for epidemio- logical purposes. Culture has its limitations: results are not immediate, even for organ- isms that are easy to grow, and negative cultures rarely exclude infection. Organisms such as M. tuberculosis are slow-growing, typically taking at least 2 weeks, even in rapid-culture systems. Certain organisms, such as Mycobacterium leprae and Tropheryma whipplei, cannot be cultivated on articial media, and others (e.g. Chlamydia spp. and viruses) grow only in culture systems, which are slow and labour-intensive. Blood culture The terms ‘bacteraemia’ and ‘fungaemia’ describe the presence of bac- teria and fungi in the blood without implication of clinical signicance, while the term ‘blood stream infection’ means bacteraemia or fungae- mia are present together with symptoms or signs infection; this is dis- cussed on p. 270. Bacteraemia/fungaemia is identied by inoculating a liquid culture medium with freshly drawn blood, which is then incubated in a system that monitors it constantly for growth of microorganisms (e.g. by detecting products of microbial respiration using uorescence; Fig. 6.6). If growth is detected, organisms are identied and sensitivity testing is performed. Traditionally, identication has been achieved by Gram stain appearance and biochemical reactions. However, matrix- assisted laser desorption/ionisation time-of-ight mass spectroscopy (MALDI-TOF-MS; see Box 6.2) is being used increasingly to identify organisms. MALDI-TOF-MS produces a prole of proteins of different sizes from the target microorganism and uses databases of such Department of Microbiology 1 Patient sampling Contamination minimised by aseptic technique. Maximise sensitivity by sampling correct volume 2 Sample handling Follow local instructions for safety, labelling, and numbers of samples and bottles required 3 Specimen transport Transport samples to laboratory as quickly as possible. Follow manufacturer’s instructions for the blood culture system used if temporary storage is required 4 Incubation Incubate at 35–37°C for 5–7 days. Microbial growth is usually detected by constant automatic monitoring of CO2. If no growth, specimen is negative and discarded 5 Growth detection Time to positivity (TTP) is usually 12–24 hrs in significant bacteraemia, but may be shorter in overwhelming sepsis or longer with fastidious organisms (e.g. Brucella spp.) 6 Preliminary results* A Gram film of the blood culture medium is examined and results are communicated immediately to the clinician to guide antibiotic therapy 7 Incubation A small amount of the medium is incubated on a range of culture media. Preliminary susceptibility testing may be carried out 8 Culture results* Preliminary susceptibility results are communicated to the clinician 9 Definitive results Further overnight incubation is often required for definitive identification of organisms (by biochemical testing) and additional susceptibility testing; identification by MALDI-TOF-MS (Fig. 6.7) is more rapid Overnight incubation required Urgent communication required 10 Reporting A final summary is released when all testing is complete. For clinical care, communication of interim results (Gram film, preliminary identification and susceptibility) is usually more important than the final report. Effective clinical–laboratory communication is vital Fig. 6.6 An overview of the processing of blood cultures. *In laboratories equipped with MALDI-TOF-MS (see Fig. 6.7), rapid denitive organism identication may be achieved at stage 6 and/or stage 8.
- 132. Investigation of infection 105 6 proles to identify the organism (Fig. 6.7). It is rapid and accurate. Taking multiple blood samples for culture at different times allows differ- entiation of transient (one positive sample) and persistent (majority are positive) bacteraemia. This can be clinically important in identifying the source of infection. Indirect detection of pathogens Tests may be used to detect the host’s immune (antibody) response to a specic microorganism, and can enable the diagnosis of infection with organisms that are difcult to detect by other methods or are no longer present in the host. The term ‘serology’ describes tests carried out on serum and includes both antigen (direct) and antibody (indirect) detection. Antigen detection tests used on other uids (e.g. CSF and respiratory secretions) are also described in this section, as they largely share the same methodology as serological tests. Antibody detection Organism-specic antibody detection is applied mainly to blood (Fig. 6.8). Results are typically expressed as titres: that is, the reciprocal of the highest dilution of the serum at which antibody is detectable (e.g. detection at serum dilution of 1:64 gives a titre of 64). ‘Seroconversion’ is dened as either a change from negative to positive detection or a fourfold rise in titre between acute and convalescent serum samples. An acute sample is usually taken during the rst week of disease and the convalescent sample 2–4 weeks later. Earlier diagnosis can be achieved by detection of immunoglobulin M (IgM) antibodies, which are produced early in infection. A limitation of these tests is that antibody production requires a fully functional host immune system, so there may be false-negative results in immunocompromised patients. Also, other than in chronic infections and with IgM detection, antibody tests usually provide a retrospective diagnosis. False-positive results can occur when there is cross-reactivity of the test reagents with other molecules or when patients have been given blood products containing other people’s anti- bodies. Serological testing methods are described below. Enzyme-linked immunosorbent assay The principles of the enzyme-linked immunosorbent assay (ELISA, EIA) are illustrated in Figure 6.9. These assays rely on linking an antibody with an enzyme that generates a colour change on exposure to a chromoge- nic substrate. Various congurations allow detection of antigens or spe- cic subclasses of immunoglobulin (e.g. IgG, IgM, IgA). ELISA may also be adapted to detect PCR products, using immobilised oligonucleotide hybridisation probes and various detection systems. Immunoblot (Western blot) Microbial proteins are separated according to molecular weight by poly- acrylamide gel electrophoresis (PAGE) and transferred (blotted) on to a nitrocellulose membrane, which is incubated with patient serum. Binding of specic antibody is detected with an enzyme–anti-immunoglobulin conjugate similar to that used in ELISA, and specicity is conrmed by its location on the membrane. Immunoblotting is a highly specic test, which may be used to conrm the results of less specic tests such as ELISA (e.g. in Lyme disease). Immunouorescence assays Indirect immunouorescence assays (IFAs) detect antibodies by incubat- ing a serum sample with immobilised antigen (e.g. virus-infected cells on a glass slide); any virus-specic antibody present in the serum binds to antigen and is then detected by uorescence microscopy using a u- orescent-labelled anti-human immunoglobulin (‘secondary’ antibody). This method can also detect organisms in clinical samples (usually tissue or centrifuged cells) using a specic antibody in place of immobilised antigen to achieve capture. Complement xation test (CFT) In a CFT, patient serum is heat-treated to inactivate complement and mixed with test antigen. Any specic antibody in the serum will com- plex with the antigen. Complement is then added to the reaction. If antigen–antibody complexes are present, the complement will be ‘xed’ (consumed). Sheep erythrocytes, coated with an anti-erythrocyte anti- body, are added. The degree of erythrocyte lysis reects the remaining complement and is inversely proportional to the quantity of the specic antigen–antibody complex present. Agglutination tests When antigens are present on the surface of particles (e.g. cells, latex particles or microorganisms) and cross-linked with antibodies, visible clumping (or ‘agglutination’) occurs. Lighter m/z Mass spectrum Detector Flight tube Laser Sample plate Voltage grid Intensity Heavier Separation region (electric field-free) Fig. 6.7 The workings of matrix-assisted laser desorption/ionisation time- of-ight mass spectrometry (MALDI-TOF MS). Adapted from Sobin K, Hameer D, Ruparel T. Digital genotyping using molecular afnity and mass spectrometry. Nature Rev Genet 2003; 4:1001–1008. Acute sample Nucleic acid (NA) detection Antigen (Ag) detection IgM NA Ag IgG Limit of detection Antibody detection: IgM Antibody detection: IgG (seroconversion) Antibody detection: IgG (fourfold rise in titre) Convalescent sample Windows of diagnostic opportunity Serum levels Fig. 6.8 Detection of antigen, nucleic acid and antibody in infectious disease. The acute sample is usually taken during the rst week of illness, and the convalescent sample 2–4 weeks later. Detection limits and duration of detectability vary between tests and diseases, although in most diseases immunoglobulin M (IgM) is detectable within the rst 1–2 weeks.
- 133. 106 PRINCIPLESOF INFECTIOUS DISEASE In direct agglutination, patient serum is added to a suspension of organisms that express the test antigen. The Widal agglutination test uses a suspension of Salmonella typhi and S. paratyphi ‘A’ and ‘B’, treated to retain only ‘O’ and ‘H’ antigens. These antigens are kept to detect corresponding antibodies in serum from a patient sus- pected of having typhoid fever. In indirect (passive) agglutination, specic antigen is attached to the surface of carrier particles, which agglutinate when incubated with patient samples that contain specic antibodies. In reverse passive agglutination (an antigen detection test), the car- rier particle is coated with antibody rather than antigen. Immunodiffusion Immunodiffusion involves antibodies and antigen migrating through gels and forming insoluble complexes where they meet. The complexes are seen on staining as ‘precipitin bands’. Immunodiffusion is used in the diagnosis of dimorphic fungi and some forms of aspergillosis. Lateral ow immunochromatography Lateral ow (LF) immunochromatography is mainly used to detect anti- gens, and often in uids other then blood (e.g. respiratory secretions, urine). The system consists of a porous test strip (e.g. a nitrocellulose mem- brane), at one end of which there is target-specic antibody, complexed with coloured microparticles. Further specic antibody is immobilised in a transverse narrow line some distance along the strip. Test material is added to the antibody–particle complexes, which then migrate along the strip by capillary action. If these are complexed with antigen, they will be immobilised by the specic antibody and visualised as a transverse line across the strip. If the test is negative, the antibody–particle complexes will bind to a line of immobilised anti-immunoglobulin antibody placed further along the strip, which acts as a negative control. Immunochromatographic tests are rapid and relatively cheap to perform, and are appropriate for point-of-care testing, e.g. in HIV-1, COVID-19 and malaria. Antibody-independent specic immunological tests Interferon-gamma release assays (IGRA) are used to diagnose latent tuberculosis infection. The principle behind IGRA is illustrated in Fig. 17.42. IGRA cannot distinguish between latent and active tubercu- losis infection and is therefore appropriate for use only in regions where the background incidence of tuberculosis is low. Antimicrobial susceptibility testing If growth of microorganisms in culture is inhibited by the addition of an antimicrobial agent, the organism is considered to be susceptible to that antimicrobial. Bacteriostatic agents cause reversible inhibition of replication and bactericidal agents cause cell death; the terms fungistatic/ fungicidal are equivalent for antifungal agents, and virustatic/virucidal for antiviral agents. The lowest concentration of the antimicrobial agent at which growth is inhibited is the minimum inhibitory concentration (MIC), and the lowest concentration that causes cell death is the minimum bac- tericidal concentration (MBC). If the MIC is less than or equal to a prede- termined breakpoint threshold, the organism is considered susceptible, and if the MIC is greater than the breakpoint, it is resistant. Breakpoints are determined for antimicrobial agents using a combination of pharma- cokinetic and clinical data. The relationship between in vitro antimicrobial susceptibility and clinical response is complex, as response also depends on severity of illness, site of infection, pharmacokinetics, immune status, comorbidities and antibiotic dosing. Thus, although treating a patient according to the results of susceptibility testing increases the likelihood of recovery, it does not guarantee therapeutic success. Susceptibility testing is often carried out by disc diffusion (Fig. 6.10). Antibiotic-impregnated lter paper discs are placed on agar plates con- taining bacteria; antibiotic diffuses into the agar, resulting in a concen- tration gradient centred on the disc. Bacteria are unable to grow where the antibiotic concentration exceeds the MIC, which may therefore be inferred from the size of the zone of inhibition. The MIC is commonly measured in diagnostic laboratories using ‘diffusion strips’. Epidemiology of infection The communicability of many infections means that, once a clini- cian has diagnosed an infectious disease, potential exposure of other patients must also be considered. Measures to control spread may be required at a patient level (e.g. separation from other patients (‘isola- tion’)), at an organisation or institutional levels (e.g. in a nursing home (Ch. 5) or hospital) at a national level, or, in the case of a pandemic, at an international level. The approach will be specic to the microorganism involved (Chs. 11–13) but the principles are outlined below. Geographical and temporal patterns of infection Endemic disease Endemic disease has a constant presence within a given geographical area or population. The infectious agent may have a reservoir, vector or intermediate host that is geographically restricted, or may itself have restrictive environmental requirements (e.g. temperature range, humid- ity). The population affected may be geographically isolated or the dis- ease may be limited to unvaccinated populations. Factors that alter geographical restriction include: expansion of an animal reservoir (e.g. Lyme disease from reforestation) vector escape (e.g. airport malaria) Antibody capture ELISA Patient Ab Ig subclass-specific Ab Ab specific to Ag from the disease-causing organism Specific Ag Chromogenic substrate Antibody–enzyme conjugate Competitive antibody detection ELISA Double antibody sandwich ELISA (for antigen detection) Antibody detection ELISA A B C D Fig. 6.9 Antibody (Ab) and antigen (Ag) detection by enzyme-linked immunosorbent assay (ELISA). antibody–enzyme conjugate and chromogenic substrate. In A, the conjugate Ab is specic for human immunoglobulin. In B–D, it is specic for Ag from the disease-causing organism.
- 134. Epidemiology of infection 107 6 extension of host range (e.g. schistosomiasis from dam construction) importation of foods human migration (e.g. carbapenemase-producing Klebsiella pneumoniae) public health service breakdown (e.g. diphtheria in unvaccinated areas) climate change (e.g. dengue virus and Rift Valley fever). Emerging and re-emerging disease An emerging infectious disease is one that has newly appeared in a pop- ulation, or has been known for some time but is increasing in incidence or geographical range. If the disease was previously known and thought to have been controlled or eradicated, it is considered to be re-emerging. Many emerging diseases are caused by organisms that infect animals and have undergone adaptations that enable them to infect humans. This is exemplied by HIV-1, which originated in higher primates in Africa, and SARS-CoV-2, from bats potentially via intermediate hosts. The geo- graphical pattern of some recent emerging and re-emerging infections is shown in Figure 6.11 Reservoirs of infection The US Centers for Disease Control (CDC) dene a reservoir of infec- tion as any person, other living organism, environment or combination of these in which the infectious agent lives and replicates and on which the infectious agent is dependent for its survival. The infectious agent is transmitted from this reservoir to a susceptible host. Human reservoirs Both colonised and infected individuals can act as human reservoirs, and infected human reservoirs may be asymptomatic. The organism must be long-lasting in at least a proportion of those affected, to facilitate onward transmission. Infections in which humans act as reservoirs include tuber- culosis, MRSA, HIV and COVID-19. For some infections (e.g. measles) humans are the only known reservoir. Animal reservoirs The World Health Organization (WHO) denes a zoonosis as ‘a disease or infection that is naturally transmissible from vertebrate animals to Zone of inhibition Zone of inhibition 1 2 A B C D E F A B C D E F 3 4 5 Fig. 6.10 Antimicrobial susceptibility testing by disc diffusion (panels 1–4) and minimum inhibitory concentration (MIC, panel 5). 1 The test organism is spread over the surface of an agar plate. 2 Antimicrobial- impregnated discs (A–F) are placed on the surface and the plate is incubated (e.g. overnight). 3–4 After incubation, zones of growth inhibition may be seen. The organism is considered susceptible if the diameter of the zone of inhibition exceeds a predetermined threshold. 5 In a ‘diffusion strip’ test, the strip is impregnated with antimicrobial at a concentration gradient that decreases steadily from top to bottom.The system is designed so that the MIC value is the point at which the ellipse cuts a scale on the strip (arrow). (4) Kindly supplied by Charlotte Symes. CPE Ebola virus disease Cholera Cholera Cholera Cryptococcus gattii Cryptococcus gattii Zika virus Zika virus Cyclospora Chikungunya virus Chikungunya virus XDR-TB MERS-Co-V Anthrax MDR-TB Fig. 6.11 Geographical locations of some infectious disease outbreaks, with examples of emerging and re-emerging diseases. (CPE = carbapenemase-producing Enterobacterales; MDR-TB = multidrug-resistant tuberculosis; MERS-Co-V = Middle East respiratory syndrome coronavirus; XDR-TB = extensively drug-resistant tuberculosis)
- 135. 108 PRINCIPLESOF INFECTIOUS DISEASE humans’. Infected animals may be asymptomatic. Zoonotic agents may be transmitted via any of the routes described below. Primary infection with zoonoses may be transmitted onward between humans, causing secondary disease (e.g. Q fever, brucellosis, Ebola virus disease). Environmental reservoirs Some pathogens are acquired from an environmental source (e.g. Pseudomonas aeruginosa from hospital water supplies). However, some of these are maintained in human or animal reservoirs, with the environ- ment acting only as a conduit for infection. Transmission of infection Communicable diseases may be transmitted by one or more of the fol- lowing routes: Respiratory route: airborne/droplet spread (see p. 293). Faecal–oral route: ingestion of material originating from faeces. Sexually transmitted infections: direct contact between mucous membranes. Blood-borne infections: direct inoculation of blood. Direct contact: very few organisms are capable of causing infec- tion by direct contact with intact skin. Most infection by this route requires contact with damaged skin (e.g. surgical wound). Via a vector or fomite: the vector/fomite bridges the gap between the infected host or reservoir and the uninfected host. Vectors are animate, and include mosquitoes in malaria and dengue virus infec- tion and humans in MRSA. Fomites are inanimate objects such as door handles, water taps and ultrasound probes, which are particu- larly associated with health care-associated infection (HCAI). The basic reproduction number (R0 ) is a measure of the propensity for a communicable disease to spread between people; it is the aver- age number of people one person with an infection is likely to pass on infection to. R0 is calculated by mathematical models that take into account infection rates, the period of infectivity (known or esti- mated), opportunities for transmission and susceptibility to infection. R0 assumes everyone is susceptible, whereas ‘effective R’ (Re ) takes into account the development of herd immunity within the population (e.g. from infection or vaccination) and therefore varies with time. R0 and Re are calculated for whole populations, so will hide local variations in transmission. The likelihood of infection following transmission of a pathogen depends on the virulence of the organism and the susceptibility of the host. The incubation period is the time between exposure and devel- opment of symptoms, and the period of infectivity is the period after exposure during which the patient is infectious to others. Knowledge of incubation periods and periods of infectivity is important in controlling the spread of disease, although for many diseases these estimates are imprecise (Boxes 6.6 and 6.7). Deliberate release Deliberate release of pathogens with the intention of causing disease is known as biological warfare or bioterrorism. Deliberate release inci- dents have included a 750-person outbreak of Salmonella typhimurium caused by contamination of salads in 1984 (Oregon, USA) and 22 cases of anthrax (ve fatal) from the mailing of nely powdered (weaponised) anthrax spores in 2001 (New Jersey, USA). Diseases with high potential for deliberate release include anthrax, plague, tularaemia, smallpox and botulism (through toxin release). Infection prevention and control Infection prevention and control (IPC) describes the measures applied to populations with the aim of breaking the chain of infection (see Fig. 6.1). 6.6 Incubation periods of important infections1 Infection Incubation period Short incubation periods Anthrax, cutaneous2 Anthrax, inhalational2 Bacillary dysentery4 Cholera2 Dengue haemorrhagic fever5 Diphtheria5 Gonorrhoea6 Inuenza4 Meningococcaemia2 Norovirus SARS2 Scarlet fever4 9hrs to 2 weeks 2 days3 1–6 days 2hrs to 5 days 3–14 days 1–10 days 2–10 days 1–3 days 2–10 days 1–3 days 2–7 days3 2–4 days Intermediate incubation periods Amoebiasis5 Brucellosis6 Chickenpox4 COVID-19 (SARS-CoV-2) Lassa fever2 Malaria² Measles4 Mumps4 Poliomyelitis5 Psittacosis6 Rubella4 Typhoid4 Whooping cough4 1–4 weeks 5–30 days 11–20 days 5–6 days2 3–21 days 10–15 days 6–19 days 15–24 days 3–35 days 1–4 weeks 15–20 days 5–31 days 5–21 days Long incubation periods Hepatitis A4 Hepatitis B6 Leishmaniasis, cutaneous5 Leishmaniasis, visceral5 Leprosy (Hansen’s disease)2 Rabies6 Trypanosoma brucei gambiense infection5 Tuberculosis4 3–7 weeks 6 weeks to 6 months Weeks to months Months to years 5–20 years 3–12 weeks3 Months to years 1–12 months 1 Incubation periods are approximate and may differ from local or national guidance. 2 World Health Organization. 3 Longer incubation periods have been reported. 4 Richardson M, et al. Paediatr Infect Dis J 2001; 20:380–88. 5 Centers for Disease Control, USA. 6 Public Health England. (SARS = severe acute respiratory syndrome) 6.7 Periods of infectivity in common childhood infectious diseases Disease Infectious period Chickenpox1 From 4 days before until 5 days after appearance of the rash (transmission before 48hrs prior to the onset of rash is rare)4 Measles2 From 4 days before onset to 4 days after onset of the rash Mumps3 From 2–3 days before to 5 days after disease onset5 Rubella3 From 10 days before until 15 days after the onset of the rash, but most infectious during prodromal illness4 Scarlet fever1 Unknown6 Whooping cough1 Unknown6,7 1 From Richardson M, Elliman D, Maguire H, et al. Pediatr Infect Dis J 2001; 20:380–388. 2 Centers for Disease Control, USA; cdc.gov/measles/hcp/. 3 Bennett JE, Dolin R, Blaser MJ. Mandell, Douglas and Bennett’s Principles and practice of infectious diseases, 8th edn. Philadelphia: Elsevier; 2015. 4–6 Exclude from contact with non-immune and immunocompromised people for 5 days from 4 onset of rash 5 onset of parotitis, or 6 start of antibiotic treatment. 7 Exclude for 3 weeks if untreated. Durations are approximate and vary between information sources, and these recommendations may differ from local or national guidance.
- 136. Infection prevention andcontrol 109 6 Health care-associated infection The risk of developing infection following admission to a health-care facility (health care-associated infection, HCAI) in the developed world is about 10%. Many nosocomial bacterial infections are caused by organisms that are resistant to numerous antibiotics (multi-resistant bacteria), including MRSA, extended-spectrum β-lactamases (ESBLs) and carbapenemase-producing Enterobacterales (CPE), and glycopep- tide-resistant enterococci (GRE). Other infections of particular concern in hospitals include C. difcile and norovirus. Some examples are shown in Figure 6.12 IPC measures are described in Box 6.8. The most important is maintenance of good hand hygiene (Fig. 6.13). Hand decontamination (e.g. using alcohol gel or washing) is mandatory before and after every patient contact. Decontamination with alcohol gel is usually adequate but hand-washing (with hot water, liquid soap and complete drying) is required after any procedure that involves more than casual physical contact, or if hands are visibly soiled. In situations where the prevalence of C. difcile is high (e.g. a local outbreak), alcohol gel decontamina- tion between patient contacts is inadequate as it does not kill C. difcile spores, and hands must be washed. Some infections necessitate additional measures to prevent cross-in- fection (Box 6.9) and sometimes these are combined, e.g. both droplet and contact precautions in the case of SARS-CoV-2. To minimise risk of infection, invasive procedures must be performed using strict aseptic technique. Outbreaks of infection Descriptive terms for infectious disease outbreaks are dened in Box 6.10. Conrmation of an infectious disease outbreak usually requires evidence from ‘typing’ that the causal organisms have identical Temporary central venous catheter infection Staphylococcus aureus (incl. MRSA) Coagulase-negative staphylococci Coliforms Candida Prosthetic joint infection Coagulase-negative staphylococci Staphylococcus aureus Streptococci Coliforms Cutibacterium (formerly Propionibacterium) acnes Staphylococcus aureus -haemolytic streptococci Coliforms Anaerobes Cuffed/tunnelled central venous catheter infection Coagulase-negative staphylococci Staphylococcus aureus (incl. MRSA) Coliforms Candida Pseudomonas spp. Enterococcus spp. External ventricular drain and Coagulase-negative staphylococci Staphylococcus aureus Diphtheroids Pseudomonas aeruginosa Peritoneal dialysis-related peritoniti Staphylococcus aureus Coagulase-negative staphylococci Coliforms Pseudomonas spp. Breast implant infection Staphylococcus aureus Coagulase-negative staphylococci Fig. 6.12 Commonly encountered health care-associated infections (HCAIs) and the factors that predispose to them. 6.8 Measures used in infection prevention and control (IPC) Organisational measures Handling, storage and disposal of clinical waste Containment and safe removal of spilled blood and body uids Cleanliness of environment and medical equipment Specialised ventilation (e.g. laminar ow, air ltration, controlled pressure gradients) Sterilisation and disinfection of instruments and equipment Food hygiene Laundry management Health-care staff interventions Education Hand hygiene, including hand-washing (see Fig. 6.13) Sharps management and disposal Use of personal protective equipment (PPE, e.g. masks, sterile and non-sterile gloves, gowns and aprons) Screening health workers for disease (e.g. tuberculosis, hepatitis B virus, MRSA) Immunisation and post-exposure prophylaxis Clinical practice Antibiotic stewardship Aseptic technique Perioperative antimicrobial prophylaxis Screening patients for colonisation or infection (e.g. MRSA, GRE, CPE) Response to infections Surveillance to detect alert organism (see text) outbreaks and antimicrobial resistance Antibiotic chemoprophylaxis in infectious disease contacts, if indicated (see Box 6.19) Isolation (see Box 6.9) Reservoir control Vector control Population measures See Box 6.12 and p. 293 (CPE = carbapenemase-producing Enterobacterales; GRE = glycopeptide-resistant enterococci; MRSA = meticillin-resistant Staphylococcus aureus)
- 137. 110 PRINCIPLESOF INFECTIOUS DISEASE Wash hands when visibly soiled! Decontaminate hands before and after each patient contact! Duration of the entire procedure: 40–60 sec. 1 2 3 Wet hands with water using elbow-operated or non- touch taps (if available) Apply enough soap to cover all hand surfaces Rub hands palm to palm 4 5 6 Right palm over left dorsum with interlaced fingers and vice versa Palm to palm with fingers interlaced Backs of fingers to opposing palms with fingers interlaced 7 8 9 Rotational rubbing of left thumb clasped in right palm and vice versa Rotational rubbing, backwards and forwards with clasped fingers of right hand in left palm and vice versa Rinse hands with water 10 11 12 Dry thoroughly with a single-use towel If hand-operated taps have been used, use towel to turn off tap ...and your hands are clean Fig. 6.13 Hand-washing. Good hand hygiene, whether with soap/water or alcohol handrub, includes areas that are often missed, such as ngertips, web spaces, palmar creases and the backs of hands. Adapted from the ‘How to Handwash’ URL: who.int/gpsc/5may/How_To_Handwash_Poster.pdf © World Health Organization 2009. All rights reserved. 6.9 Types of isolation precaution1 Airborne transmission Contact transmission Droplet transmission Precautions Negative pressure room with air exhausted externally or ltered N95 masks or personal respirators for staff Avoid using non-immune staff Private room preferred (otherwise, inter-patient spacing ≥1m) Gloves and gown for staff in contact with patient or contaminated areas Private room preferred (otherwise, inter-patient spacing ≥1m) Surgical masks for staff in close contact with patient Examples of infections managed with these precautions Measles Tuberculosis, pulmonary or laryngeal, suspected Enteroviral infections in young children (diapered or incontinent) Norovirus Clostridioides difcile infection Multidrug-resistant organisms (e.g. MRSA, ESBL, GRE, VRSA, penicillin-resistant Streptococcus pneumoniae)2 Parainuenza in infants and young children Rotavirus RSV in infants, children and immunocompromised Viral conjunctivitis, acute Diphtheria, pharyngeal Haemophilus inuenzae type b infection Herpes simplex infection, disseminated or severe Inuenza Meningococcal infection Mumps Mycoplasma pneumoniae Parvovirus (erythrovirus) B19 (erythema infectiosum, fth disease) Pertussis Plague, pneumonic Rubella Streptococcus pyogenes (group A), pharyngeal Infections managed with multiple precautions 3 ➤ SARS-CoV-2,4 adenovirus pneumonia ➤ SARS, viral haemorrhagic fever ➤ 1 Recommendations based on 2007 CDC guideline for isolation precautions, revised in July 2019. May differ from local or national recommendations. 2 Subject to local risk assessment. 3 Or in any immunocompromised patient until possibility of disseminated infection excluded. 4 SARS-CoV-2 and other respiratory viruses are managed with airborne precautions in certain circumstances (see p. 293). (ESBL = extended-spectrum β-lactamase; GRE = glycopeptide-resistant enterococci; MRSA = meticillin-resistant Staphylococcus aureus; RSV = respiratory syncytial virus; SARS = severe acute respiratory syndrome; VRSA = vancomycin-resistant Staphylococcus aureus; VZV = varicella zoster virus) phenotypic and/or genotypic characteristics. When an outbreak of infection is suspected, a case denition is agreed. The number of cases that meet the case denition is then assessed by case-nding, using methods ranging from administration of questionnaires to national reporting systems. Case-nding usually includes microbiological test- ing, at least in the early stages of an outbreak. Temporal changes in cases are noted in order to plot an outbreak curve, and demographic details are collected to identify possible sources of infection. A case– control study, in which recent activities (potential exposures) of affected ‘cases’ are compared to those of unaffected ‘controls’, may be under- taken to establish the outbreak source, and measures are taken to manage the outbreak and control its spread. Good communication between relevant personnel during and after the outbreak is important to inform practice in future outbreaks. Surveillance ensures that disease outbreaks are either prevented or identied early. In hospitals, staff are made aware of the isolation of ‘alert organisms’, which have the propensity to cause outbreaks, and ‘alert conditions’, which are likely to be caused by such organisms. Analogous ➤ ➤ ➤
- 138. Infection prevention andcontrol 111 6 6.10 Terminology in outbreaks of infection Term Denition Classication of related cases of infectious disease* Cluster An aggregation of cases of a disease that are closely grouped in time and place, and may or may not exceed the expected number Epidemic The occurrence of more cases of disease than expected in a given area or among a specic group of people over a particular period of time Outbreak Synonymous with epidemic. Alternatively, a localised, as opposed to generalised, epidemic Pandemic An epidemic occurring over a very wide area (several countries or continents) and usually affecting a large proportion of the population Classication of affected patients (cases) Index case The rst case identied in an outbreak Primary cases Cases acquired from a specic source of infection Secondary cases Cases acquired from primary cases Types of outbreak Common source outbreak Exposure to a common source of infection (e.g. water- cooling tower, medical staff member shedding MRSA). New primary cases will arise until the source is no longer present Point source outbreak Exposure to a single source of infection at a specic point in time (e.g. contaminated food at a party). Primary cases will develop disease synchronously Person-to- person spread Outbreak with both primary and secondary cases. May complicate point source or common source outbreak *Adapted from cdc.gov. (MRSA = meticillin-resistant Staphylococcus aureus) systems are used nationally; many countries publish lists of organisms and diseases, which, if detected (or suspected), must be reported to public health authorities. Reasons why a disease might be reportable are shown in Box 6.11 A pandemic is the most extensive form of outbreak, in which the dis- ease spreads over a wide area and may affect a large proportion of the population. The most recent pandemic was the COVID-19 pandemic of 2019 onwards. The measures that may be put in place in an attempt to control a pandemic are shown in Box 6.12 Immunisation Immunisation may be passive or active. Passive immunisation is achieved by administering antibodies targeting a specic pathogen. Antibodies are obtained from blood, so confer some of the infection risks associated with blood products. The protection afforded by passive immunisation is immediate but of short duration (a few weeks or months); it is used to prevent or attenuate infection before or after exposure (Box 6.13). Vaccination Active immunisation is achieved by vaccination with whole organisms, organism components or nucleic acids (DNA/RNA) (Box 6.14). Types of vaccine Whole-cell vaccines consist of live or inactivated (killed) microorganisms. Component vaccines contain only extracted or synthesised components of microorganisms (e.g. polysaccharides or proteins). Live vaccines con- tain organisms with attenuated (reduced) virulence, which cause only 6.11 Reasons for including an infectious disease on a regional/ national list of reportable diseases* Reason for inclusion Examples Endemic/local disease with the potential to spread and/or cause outbreaks Inuenza, Salmonella, tuberculosis Imported disease with the propensity to spread and/or cause outbreaks Typhoid, cholera (depending on local epidemiology) Evidence of a possible breakdown in health protection/public health functions Legionella, Cryptosporidium Evidence of a possible breakdown in food safety practices Botulism, verotoxigenic Escherichia coli Evidence of a possible failure of a vaccination programme Measles, poliomyelitis, pertussis Disease with the potential to be a novel or increasing threat to human health COVID-19, MERS-CoV, multi- resistant bacteria Evidence of expansion of the range of a reservoir/vector Lyme disease, rabies, West Nile encephalitis Evidence of possible deliberate release Anthrax, tularaemia, plague, smallpox, botulism *Given the different geographical ranges of individual diseases and wide national variations in public health services, vaccination programmes and availability of resources, reporting regulations vary between regions, states and countries. Many diseases are reportable for more than one reason. (MERS-CoV = Middle East respiratory syndrome) 6.12 Pandemic response* International travel restrictions National entry screening (e.g. testing for fever or pathogen) and quarantining new arrivals from areas with high infection rates Isolation of disease contacts Social isolation Shielding (strict separation of the vulnerable) Social distancing (maintaining physical separation between people and restricting public gatherings) Encouraging home working Restricting commuting and work-related travel to ‘key workers’ (workers required to maintain a functioning society) Home education Curfews Closure or reduction in public transport Requirement for PPE use in public areas (e.g. face coverings, eye protection) Litigation and imposition of legal sanctions to enforce the above responses *Pandemic control measures vary widely by jurisdiction and depend on the stage and extent of the outbreak and political considerations such as the acceptability of restriction of personal freedoms and the economic consequences of the interventions. See also p. 293. mild symptoms but induce T-lymphocyte and humoral responses and are therefore more immunogenic than inactivated whole-cell vaccines. The use of live vaccines in immunocompromised individuals is not gener- ally recommended, but they may be used by specialists following a risk/ benet assessment. Component vaccines consisting only of polysaccharides, such as the pneumococcal polysaccharide vaccine (PPV), are poor activators of T lymphocytes and produce a short-lived antibody response without long-lasting memory. Conjugation of polysaccharide to a protein, as in the Haemophilus inuenzae type B (Hib) vaccine and the protein con- jugate pneumococcal vaccine (PCV), activates T lymphocytes, which results in a sustained response and immunological memory. Toxoids are bacterial toxins that have been modied to reduce toxicity but maintain antigenicity. Vaccine response can be improved by co-administration with mildly pro-inammatory adjuvants, such as aluminium hydroxide.
- 139. 112 PRINCIPLESOF INFECTIOUS DISEASE Another approach is to use viral vectors in which an unrelated and mod- ied virus expresses the antigen of interest. These vectors include pox viruses (e.g. modied vaccinia virus Ankara or canary pox virus), adenovi- rus or adeno-associated viruses. The vector may replicate or be non-repli- cating. These vaccines work on the same basis as DNA vaccines and are safe and stable. Pre-existing immunity can inuence efcacy but use of rare human or related animal strains or a strategy of priming with a non-vi- ral DNA vaccine can help overcome this (‘prime-boost’ strategy). Nucleic acid vaccines are administered intramuscularly or intradermally while viral vector vaccines can be given by these routes but also intranasally or orally. The rst viral vector vaccine to receive clinical approval was for dengue virus, while to date DNA vaccines have only been used in veterinary set- tings. However, both strategies are employed in studies investigating a range of approaches against Ebola virus and pandemic infections. For COVID-19, vaccines in use or development include viral vectored, RNA, DNA, live attenuated, inactivated (killed) virus, subunit and virus-like particle (lacking genetic material) vaccines. The rst types to be used widely were mRNA and adenovirus vector RNA vaccines (see Box 13.38). Use of vaccines Vaccination may be applied to entire populations or to subpopulations at specic risk through travel, occupation or other activities. In ring vac- cination, the population immediately surrounding a case or outbreak of infectious disease is vaccinated to curtail further spread. This strategy has been used for Ebola in West Africa. Vaccination is aimed mainly at preventing infectious disease. However, vaccination against human pap- illomavirus (HPV) was introduced to prevent cervical and other cancers that complicate HPV infection. Vaccination guidelines for individuals are shown in Box 6.15 Vaccination becomes successful for a population once the number of susceptible hosts falls below the level required to sustain continued transmission of the target organism, i.e. when Re is less than 1 ( herd immunity’). Naturally acquired smallpox was declared to have been erad- icated worldwide in 1980 through mass vaccination. In 1988, the WHO resolved to eradicate poliomyelitis by vaccination; the number of cases of wild polio virus infection worldwide has since fallen from approximately 350000 per annum to 176 in 2019. Recommended vaccination sched- ules, including catch-up schedules for people who join vaccination pro- grammes late, vary between countries. Antimicrobial stewardship Antimicrobial stewardship (AMS) refers to the systems and processes applied to a population to optimise the use of antimicrobial agents. The populations referred to here may be a nation, region, hospital, or a unit within a health-care organisation (e.g. ward or clinic). AMS aims to improve patient outcomes and reduce antimicrobial resistance (AMR). IPC and AMS complement each other (Fig. 6.14). Elements of AMS include treatment guidelines, antimicrobial formularies and ward rounds by infection specialists. 6.13 Indications for post-exposure prophylaxis with immunoglobulins Human normal immunoglobulin (pooled immunoglobulin) Hepatitis A (unvaccinated contacts*) Measles (exposed child with heart or lung disease) Human specic immunoglobulin Hepatitis B (sexual partners, inoculation injuries, infants born to infected mothers) Tetanus (high-risk wounds or incomplete or unknown immunisation status) Rabies Chickenpox (immunosuppressed children and adults, pregnant women) *Active immunisation is preferred if contact is with a patient who is within 1 week of onset of jaundice. 6.14 Vaccines in current clinical use Live attenuated vaccines Measles, mumps, rubella (MMR) Oral poliomyelitis (OPV, not used in UK) Rotavirus Tuberculosis (bacille Calmette–Guérin, BCG) Typhoid (oral typhoid vaccine) Varicella zoster virus Inactivated (killed) whole-cell vaccines Cholera Hepatitis A Inuenza Poliomyelitis (inactivated polio virus, IPV) Rabies Component vaccines Anthrax (adsorbed extracted antigens) COVID-19 Diphtheria (adsorbed toxoid) Hepatitis B (adsorbed recombinant hepatitis B surface antigen, HBsAg) Haemophilus inuenzae type B (conjugated capsular polysaccharide) Human papillomavirus (recombinant capsid proteins) Meningococcal, quadrivalent A, C, Y, W135 (conjugated capsular polysaccharide) Meningococcal, serogroup C (conjugated capsular polysaccharide) Pertussis (adsorbed extracted antigens) Pneumococcal conjugate (PCV; conjugated capsular polysaccharide, 13 serotypes) Pneumococcal polysaccharide (PPV; puried capsular polysaccharide, 23 serotypes) Tetanus (adsorbed toxoid) Typhoid (puried Vi capsular polysaccharide) Viral vector vaccines Dengue virus (containing Yellow fever 17D vaccine strain with dengue virus genes) Ebola virus (vesicular stomatitis virus expressing Ebola virus glycoproteins) COVID-19 Nucleic acid vaccines COVID-19 (RNA vaccines) Ebola virus (DNA in clinical trials) Recent and emerging vaccine approaches include nucleic acid (DNA or RNA)-based vaccines, in which the vaccine nucleic acid encodes the micro- bial component of interest; when the vaccine enters the vaccinee’s cells they are induced to express viral antigens. They have several advantages over component vaccines: antigen is expressed for a period of time and with the modications that the host cell would normally produce; antigen is presented by both major histocompatibility class I and II and induces broad B- and T-lymphocyte responses; vaccines are stable and cost-effective; production can be at large scale. DNA and RNA vaccines can be admin- istered directly or may be added with other components to aid cell entry, e.g. liposomses for DNA vaccines or lipid nanoparticles for RNA vaccines. Long-term persistence and chromosomal integration with the potential for mutagenesis remain theoretical concerns for DNA vaccines. 6.15 Guidelines for vaccination against infectious disease The principal contraindication to inactivated vaccines is an anaphylactic reaction to a previous dose or a vaccine component Live vaccines should not be given during an acute infection, to pregnant women or to the immunosuppressed, unless the immunosuppression is mild and the benets outweigh the risks If two live vaccines are required, they should be given either simultaneously in opposite arms or 4 weeks apart Live vaccines should not be given for 3 months after an injection of human normal immunoglobulin (HNI) HNI should not be given for 2 weeks after a live vaccine Hay fever, asthma, eczema, sickle-cell disease, topical glucocorticoid therapy, antibiotic therapy, prematurity and chronic heart and lung diseases, including tuberculosis, are not contraindications to vaccination
- 140. Treatment of infectiousdiseases 113 6 Treatment of infectious diseases Key components of treating infection are: prompt initiation of antimicrobial therapy in severe infections, e.g. sepsis, meningitis optimising antimicrobial therapy while minimising selection for anti- microbial resistance and the impact on the normal microbial ora addressing predisposing factors, e.g. glycaemic control in diabetes mellitus; viral load control in HIV-1 infection achieving source control, e.g. removal of an infected medical device, pus or necrotic tissue managing complications, e.g. sepsis and acute kidney injury. For communicable disease, treatment must also take into account contacts of the infected patient, and may include IPC interventions such as isolation, antimicrobial prophylaxis, vaccination and contact tracing. Principles of antimicrobial therapy In some situations (e.g. pneumonia, meningitis, sepsis) it is important to start appropriate antimicrobial therapy promptly, whereas in others prior conrmation of the diagnosis and pathogen is preferred. The principles underlying the choice of antimicrobial agent(s) are discussed below. The WHO ‘World Antibiotic Awareness Week’ campaign is a yearly event aimed at highlighting the importance of prudent antimicrobial prescribing (see ‘Further information’). Antimicrobial action and spectrum Antimicrobial agents may kill or inhibit microorganisms by targeting essential and non-essential cellular processes, respectively. The range, or spectrum, of microorganisms that is killed or inhibited by a particu- lar antimicrobial agent needs consideration when selecting therapy. Mechanisms of action of the major classes of antibacterial agent are listed in Box 6.16 and appropriate agents for some common infecting organisms are shown in Box 6.17. In severe infections and/or immu- nocompromised patients, it is customary to use bactericidal agents in preference to bacteriostatic agents. Empiric versus targeted therapy Empiric antimicrobial therapy is selected to treat a suspected infection (e.g. meningitis) before the microbiological cause is known. Targeted or ‘directed’ therapy can be prescribed when the pathogen(s) is known. Empirical antimicrobial regimens need to have activity against the range of pathogens potentially causing the infection; because broad-spec- trum agents affect a wide range of bacteria they select for antimicrobial resistance. ‘Start Smart – Then Focus’ (Fig. 6.15) describes the prin- ciple of converting from empiric therapy to narrow-spectrum targeted therapy. Optimum empiric therapy depends on the site of infection, patient characteristics and local antimicrobial resistance patterns. National or local guidelines should inform antimicrobial prescribing decisions. Combination therapy It is sometimes appropriate to combine antimicrobial agents: when there is a need to increase clinical effectiveness (e.g. biolm infections) when no single agent’s spectrum covers all potential pathogens (e.g. polymicrobial infection) when there is a need to reduce development of antimicrobial resist- ance in the target pathogen, as the organism would need to develop resistance to multiple agents simultaneously (e.g. antituberculous chemotherapy and antiretroviral therapy (ART) for HIV. Antimicrobial resistance Microorganisms have evolved in the presence of naturally occur- ring antibiotics and have therefore developed resistance mechanisms to all classes of antimicrobial agent (antibiotics and their derivatives) (Fig. 6.16). Intrinsic resistance is an innate property of a microorganism, whereas acquired resistance arises by spontaneous mutation or hori- zontal transfer of genetic material from another organism, usually via a plasmid. Plasmids can be easily transferred between bacteria (especially Enterobacterales) and often encode resistance to multiple antibiotics. Penicillin-binding proteins (PBP) are enzymes involved in bacterial cell wall synthesis. The mecA gene encodes a PBP, which has a low afn- ity for penicillins and therefore confers resistance to β-lactam antibiotics in staphylococci. Extended-spectrum β-lactamases (ESBLs) are bacte- rial-produced enzymes that break down β-lactam antibiotics, and are frequently encoded on plasmids in Enterobacterales. Plasmid-encoded carbapenemases have been detected in strains of Klebsiella pneumo- niae (e.g. New Delhi metallo-β-lactamase 1, NDM-1). Strains of MRSA have been described that also have reduced susceptibility to glycopep- tides through the development of a relatively impermeable cell wall. Antimicrobial stewardship Infection prevention and control Effective antimicrobial stewardship reduces health care-associated infections Effective infection prevention and control reduces the need for antimicrobials Fig. 6.14 The relationship between infection prevention and control (IPC) and antimicrobial stewardship (AMS). 6.16 Target and mechanism of action of common antibacterial agents Aminoglycosides, chloramphenicol, macrolides, lincosamides, oxazolidinones Inhibition of bacterial protein synthesis by binding to subunits of bacterial ribosomes Tetracyclines Inhibition of protein synthesis by preventing transfer RNA binding to ribosomes ß-lactams Inhibition of cell wall peptidoglycan synthesis by competitive inhibition of transpeptidases (‘penicillin-binding proteins’) Cyclic lipopeptide (daptomycin) Insertion of lipophilic tail into plasma membrane causing depolarisation and cell death Fluoroquinolones Inhibition of DNA replication by binding to DNA topoisomerases (DNA gyrase and topoisomerase IV), preventing supercoiling and uncoiling of DNA Glycopeptides Inhibition of cell wall peptidoglycan synthesis by forming complexes with D-alanine residues on peptidoglycan precursors Nitroimidazoles The reduced form of the drug causes strand breaks in DNA Rifamycins Inhibition of RNA synthesis by inhibiting DNA-dependent RNA polymerase Sulphonamides and trimethoprim Inhibition of folate synthesis by dihydropteroate synthase (sulphonamides) and dihydrofolate reductase (trimethoprim) inhibition
- 141. 114 PRINCIPLESOF INFECTIOUS DISEASE 6.17 Antimicrobial options for common infecting bacteria Organism Antimicrobial options* Gram-positive organisms Enterococcus faecalis Ampicillin, vancomycin/teicoplanin Enterococcus faecium Vancomycin/teicoplanin, linezolid Glycopeptide-resistant enterococci Linezolid, tigecycline, daptomycin MRSA Clindamycin, vancomycin, rifampicin (never used as monotherapy), linezolid, daptomycin, tetracyclines, tigecycline, co-trimoxazole Staphylococus aureus Flucloxacillin, clindamycin Streptococcus pyogenes Penicillin, clindamycin, vancomycin Streptococcus pneumoniae Penicillin, cephalosporins, levooxacin, vancomycin Gram-negative organisms E. coli, ‘coliforms’ (enteric Gram-negative bacilli) Amoxicillin, trimethoprim, cefuroxime, ciprooxacin, co-amoxiclav Enterobacter spp., Citrobacter spp. Ciprooxacin, meropenem, ertapenem, aminoglycosides ESBL-producing Enterobacterales Ciprooxacin, meropenem, ertapenem (if sensitive), temocillin, aminoglycosides Carbapenemase-producing Enterobacterales Ciprooxacin, aminoglycosides, tigecycline, colistin Haemophilus inuenzae Amoxicillin, co-amoxiclav, macrolides, cefuroxime, cefotaxime, ciprooxacin Legionella pneumophila Azithromycin, levooxacin, doxycycline Neisseria gonorrhoeae Ceftriaxone/cexime, spectinomycin Neisseria meningitidis Penicillin, cefotaxime/ceftriaxone, chloramphenicol Pseudomonas aeruginosa Ciprooxacin, piperacillin–tazobactam, aztreonam, meropenem, aminoglycosides, ceftazidime/ cefepime Salmonella typhi Ceftriaxone, azithromycin (uncomplicated typhoid), chloramphenicol (resistance common) Strict anaerobes Bacteroides spp. Metronidazole, clindamycin, co-amoxiclav, piperacillin–tazobactam, meropenem Clostridioides difcile Metronidazole, vancomycin (oral), daxomicin Clostridium spp. Penicillin, metronidazole, clindamycin Fusobacterium spp. Penicillin, metronidazole, clindamycin Other organisms Chlamydia trachomatis Azithromycin, doxycycline Treponema pallidum Penicillin, doxycycline *Antibiotic selection depends on multiple factors, including local susceptibility patterns, which vary enormously between geographical areas. There are many appropriate alternatives to those listed. (ESBL= extended-spectrum β-lactamase; MRSA = meticillin-resistant Staphylococcus aureus) 1 Empiric therapy Based on: Predicted susceptibility of likely pathogens Local antimicrobial policies 2 Targeted therapy Based on: Predicted susceptibility of infecting organism(s) Local antimicrobial policies 3 Susceptibility-guided therapy Based on: Susceptibility testing results Antimicrobial susceptibility results Clinical diagnosis Information available: Organ system involved Endogenous or exogenous infection Likely pathogens Infecting organism(s) Likely antimicrobial susceptibility Level of knowledge of infecting organism(s) Antimicrobial spectrum of agent(s) used Antimicrobial susceptibility of infecting organism(s) Laboratory investigations: microbiological diagnosis Fig. 6.15 Stages in the selection and renement of antimicrobial therapy: ‘Start Smart – Then Focus’.
- 142. Treatment of infectiousdiseases 115 6 Factors promoting antimicrobial resistance include the inappropriate use of antibiotics (e.g. to treat viral infections), inadequate dosage or unnecessarily prolonged treatment, and use of antimicrobials as growth promoters in agriculture. However, any antimicrobial use exerts a selec- tion pressure that favours the development of resistance. Combination antimicrobial therapy may reduce the emergence of resistance in the target pathogen but not in the normal ora that it also affects. Despite use of combination therapy for M. tuberculosis, multi-resistant tubercu- losis (MDR-TB) and extremely drug-resistant tuberculosis (XDR-TB) have been reported worldwide and are increasing in incidence (see p. 524). The term ‘post-antibiotic era’ was coined to describe a future in which widespread antimicrobial resistance will render antimicrobials useless. At present there is a gradual but inexorable progression of resistance globally, necessitating the use of more expensive antimicrobials or older antimicrobials with signicant toxicity. Duration of therapy Treatment duration reects the severity of infection and accessibility of the infected site to antimicrobial agents. For most infections, there is limited evidence available to support a specic duration of treatment (Box 6.18). Depending on the indication, initial intravenous therapy can often be switched to oral as soon as the patient is apyrexial and improv- ing. In the absence of specic guidance, antimicrobial therapy should be stopped when there is no longer any clinical evidence of infection. Pharmacokinetics and pharmacodynamics Pharmacokinetics of antimicrobial agents is the study of how antibiotics are absorbed, distributed and excreted from the body. Septic patients often have poor gastrointestinal absorption, so the preferred initial route of therapy is intravenous. Knowledge of anticipated antimicrobial drug concentrations at sites of infection is critical. For example, achieving a ‘therapeutic’ blood level of gentamicin is of little practical use in treating meningitis, as CSF penetration of the drug is poor. Knowledge of routes of antimicrobial elimination is also critical; for instance, urinary tract infec- tion is ideally treated with a drug that is excreted unchanged in the urine. Pharmacodynamics describes the complex relationship between anti- microbialconcentrationsandmicrobialkillinginthebody.Formanyagents, antimicrobial effect can be categorised as ‘concentration-dependent’ or ‘time-dependent’. The concentration of antimicrobial achieved after a single dose is illustrated in Figure 6.17. The maximum concentration achieved is Cmax and the measure of overall exposure is the area under the curve (AUC). The efcacy of antimicrobial agents whose killing is con- centration-dependent (e.g. aminoglycosides) increases with the amount by which Cmax exceeds the minimum inhibitory concentration (Cmax :MIC ratio). For this reason, it has become customary to administer amino- glycosides (e.g. gentamicin) infrequently at high doses (e.g. 7mg/kg) rather than frequently at low doses. This has the added advantage of minimising toxicity by reducing the likelihood of drug accumulation. Conversely, the β-lactam antibiotics and vancomycin exhibit time-de- pendent killing, and their efcacy depends on Cmax exceeding the MIC for a certain time (which is different for each class of agent). This is reected in the dosing interval of benzylpenicillin, which is usually given every 4 hours in severe infection (e.g. meningococcal meningitis), and may be administered by continuous infusion. For other antimicrobial agents, the pharmacodynamic relationships are more complex and often less well understood. With some agents, bacterial inhibition persists after anti- microbial exposure (post-antibiotic and post-antibiotic sub-MIC effects). Therapeutic drug monitoring Therapeutic drug monitoring is used to conrm that levels of antimicro- bial agents with a low therapeutic index (e.g. aminoglycosides) are not Impermeability/reduced permeability Carbapenem resistance in Pseudomonas spp. Aminoglycoside resistance in anaerobes (uptake requires O2-dependent transport mechanism) Antimicrobial target Antimicrobial agent Active efflux of antimicrobial agent Tetracycline resistance in Gram-positive and Gram-negative bacteria Fluconazole resistance in Candida spp. Target modification β-lactam resistance in MRSA – altered penicillin-binding protein Glycopeptide resistance in enterococci – altered peptidoglycan amino acid sequence Rifampicin resistance in M. tuberculosis – RNA polymerase mutation Ciprofloxacin resistance in Enterobacterales – DNA gyrase mutation Linezolid resistance in staphylococci and enterococci – 23S rRNA methylation Enzymatic degradation of agent β-lactam resistance in many organisms (penicillinase in Staph. aureus; ESBLs, ampC and NDM-1 in Enterobacteriales) Chloramphenicol resistance in staphylococci (CAT) Fig. 6.16 Examples of mechanisms of antimicrobial resistance. (CAT = chloramphenicol acetyltransferase; ESBLs = extended-spectrum β-lactamases; MRSA = meticillin-resistant Staph. aureus; NDM-1 = New Delhi metallo-β-lactamase 1).
- 143. 116 PRINCIPLESOF INFECTIOUS DISEASE 6.18 Duration of antimicrobial therapy for some common infections* Infection Duration of therapy Viral infections Herpes simplex encephalitis 2–3 weeks Bacterial infections Gonorrhoea Single dose Infective endocarditis (streptococcal, native valve) 4 weeks ± gentamicin for rst 2 weeks Infective endocarditis (prosthetic valve) 6 weeks Osteomyelitis 6 weeks Pneumonia (community-acquired, severe) 7–10 days (no organism identied), 14–21 days (Staphylococcus aureus or Legionella spp.) Septic arthritis 2–4 weeks Urinary tract infection (male) 1–2 weeks depending on severity Urinary tract infection, upper tract, uncomplicated (female) 7 days Urinary tract infection, lower (female) 3 days Mycobacterial infections Tuberculosis (meningeal) 12 months Tuberculosis (pulmonary) 6 months Fungal infections Invasive pulmonary aspergillosis Until clinical/radiological resolution and reversal of predisposition Candidaemia (acute disseminated) 2 weeks after last positive blood culture and resolution of signs and symptoms *All recommendations are indicative. Actual duration takes into account predisposing factors, specic organisms and antimicrobial susceptibility, source control, current guidelines and clinical response. Time after dose Time above MIC Peak concentration (Cmax) Minimum inhibitory concentration (MIC) Area under the curve (AUC) Concentration Fig. 6.17 Antimicrobial pharmacodynamics. The curve represents drug concentrations after a single dose of an antimicrobial agent. Factors that determine microbial killing are Cmax :MIC ratio (concentration-dependent killing), time above MIC (time-dependent killing) and AUC:MIC ratio. excessive, and that levels of agents with marked pharmacokinetic var- iability (e.g. vancomycin) are adequate. Specic recommendations for monitoring depend on individual clinical circumstances; for instance, different pre- and post-dose levels of gentamicin are recommended, 6.19 Recommendations for antimicrobial prophylaxis in adults* Infection risk Recommended antimicrobial Bacterial Diphtheria (prevention of secondary cases) Erythromycin Gas gangrene (after high amputation or major trauma) Penicillin or metronidazole Lower gastrointestinal tract surgery Cefuroxime + metronidazole, gentamicin + metronidazole, or co- amoxiclav (single dose only) Meningococcal disease (prevention of secondary cases) Rifampicin or ciprooxacin Rheumatic fever (prevention of recurrence) Phenoxymethylpenicillin or sulfadiazine Tuberculosis (prevention of secondary cases) Isoniazid ± rifampicin Whooping cough (prevention of secondary cases) Erythromycin Viral HIV, occupational exposure (sharps injury) Combination tenofovir/emtricitabine and raltegravir. Modied if index case’s virus known to be resistant Inuenza A (prevention of secondary cases in adults with chronic respiratory, cardiovascular or renal disease, immunosuppression or diabetes mellitus) Oseltamivir Fungal Aspergillosis (in high-risk haematology patients) Posaconazole (voriconazole or itraconazole alternatives if intolerant) Pneumocystis pneumonia (prevention in HIV and other immunosuppressed states) Co-trimoxazole, pentamidine or dapsone Protozoal Malaria (prevention of travel- associated disease) Specic antimalarials depend on travel itinerary. Specialist guidance should be consulted *These are based on current UK practice. Recommendations may vary locally or nationally. Antimicrobial prophylaxis for infective endocarditis during dental procedures is not currently recommended in the UK. depending on whether it is being used in traditional divided doses, once daily or for synergy in infective endocarditis (p. 462). Antimicrobial prophylaxis Antimicrobial prophylaxis is the use of antimicrobial agents to prevent infec- tion. Primary prophylaxis is used to reduce the risk of infection following certain medical procedures (e.g. colonic resection or prosthetic hip inser- tion), following exposure to a specic pathogen (e.g. Bordetella pertussis) or in specic situations such as post-splenectomy (Box 6.19). Antimicrobial prophylaxis should be chosen to have minimal adverse effects and based on robust evidence. In the case of exposure, it may be combined with pas- sive immunisation (see Box 6.13). Secondary prophylaxis is used in patients who have been treated successfully for an infection but remain predisposed to it. It is used in haemato-oncology patients in the context of fungal infec- tion and in HIV-positive individuals with an opportunistic infection until a dened level of immune reconstitution is achieved. Antibacterial agents For details of antibacterial usage in pregnancy and old age, see Boxes 6.20 and 6.21.
- 144. Treatment of infectiousdiseases 117 6 infectious mononucleosis may develop a rash if given aminopenicillins; this does not imply lasting allergy. The relationship between allergy to penicillin and allergy to cephalosporins depends on the specic cephalo- sporin used. Avoidance of cephalosporins, however, is recommended in patients who have IgE-mediated penicillin allergy (p. 80). Cross-reactivity between penicillin and carbapenems is rare (approximately 1% by skin testing) and carbapenems may be administered if there are no suitable alternatives and appropriate resuscitation facilities are available. Gastrointestinal upset and diarrhoea are common, and a mild reversible hepatitis is recognised with many β-lactams. More severe forms of hep- atitis can be observed with ucloxacillin and co-amoxiclav. Leucopenia, thrombocytopenia, coagulation deciencies, interstitial nephritis and potentiation of aminoglycoside-mediated kidney damage are also rec- ognised. Seizures and encephalopathy have been reported, particularly with high doses in the presence of renal insufciency. Thrombophlebitis occurs in up to 5% of patients receiving parenteral β-lactams. Drug interactions Synergism occurs in combination with aminoglycosides in vitro. Ampicillin decreases the biological effect of oral contraceptives and the whole class is signicantly affected by concurrent administration of probenecid, pro- ducing a 2–4-fold increase in the peak serum concentration. Penicillins Natural penicillins are primarily effective against Gram-positive organ- isms (except staphylococci, most of which produce a penicillinase) and anaerobic organisms. Streptococcus pyogenes has remained sensitive to natural penicillins worldwide. According to the European Antimicrobial Resistance Surveillance Network (EARS-Net), the prevalence of non-sus- ceptibility to penicillin in Streptococcus pneumoniae in Europe in 2018 varied widely from 0.1% (Belgium) to 40% (Romania). Penicillinase-resistant penicillins are the mainstay of treatment for infections with Staph. aureus, other than MRSA. However, EARS-Net data from 2018 indicate that MRSA rates in Europe vary widely from 0% (Iceland) to 43% (Romania). Aminopenicillins have the same spectrum of activity as the natural pen- icillins, with additional Gram-negative cover against Enterobacterales. Amoxicillin has better oral absorption than ampicillin. Unfortunately, resistance to these agents is widespread (Escherichia coli Europe-wide in 2018, range 35.3%–67.6%), so they are no longer appropriate for empiric use in Gram-negative infections. In many organisms, resistance is due to β-lactamase production, which can be overcome by the addi- tion of β-lactamase inhibitors (clavulanic acid or sulbactam). Carboxypenicillins (e.g. ticarcillin) and ureidopenicillins (e.g. piperacil- lin) are particularly active against Gram-negative organisms, especially Pseudomonas spp., which are resistant to the aminopenicillins. ß-lactamase inhibitors may be added to extend their spectrum of activity (e.g. piperacillin– tazobactam). Temocillin is derived from ticarcillin; it has good activity against Enterobacterales, including those that produce ESBL enzymes, but poor activity against P. aeruginosa and Gram-positive bacteria. 6.21 Problems with antimicrobial therapy in old age Clostridioides difcile infection: all antibiotics predispose to some extent, but second- and third-generation cephalosporins, co-amoxiclav and clindamycin especially so. Hypersensitivity reactions: rise in incidence due to increased previous exposure. Renal impairment: may be signicant in old age, despite creatinine levels being within the reference range. Nephrotoxicity: more likely, e.g. aminoglycosides. Accumulation of β-lactam antibiotics: may result in myoclonus, seizures or coma. Reduced gastric acid production: gastric pH is higher, which causes increased penicillin absorption. Reduced hepatic metabolism: results in a higher risk of isoniazid-related hepatotoxicity. Quinolones: associated with delirium and may increase the risk of seizures. ß-lactam antibiotics These antibiotics have a β-lactam ring structure and exert a bactericidal action by inhibiting PBPs and cell wall synthesis. They are classied in Box 6.22 Pharmacokinetics Good drug levels are achieved in lung, kidney, bone, muscle and liver, and in pleural, synovial, pericardial and peritoneal uids. CSF levels are low, except when meninges are inamed. ‘Inoculum effect’: the activity of ß-lactams is reduced in the pres- ence of a high organism burden, although the clinical relevance of this effect is a subject of debate. Generally safe in pregnancy (except imipenem/cilastatin). Adverse effects Immediate (IgE-mediated) allergic reactions are rare but life-threaten- ing. Approximately 90% of patients who report a penicillin allergy do not have a true IgE-mediated allergy, highlighting the importance of careful allergy histories and documentation of reactions. Other reactions, such as rashes, fever and haematological effects (e.g. low white cell count), usually follow more prolonged therapy (more than 2 weeks). Patients with 6.22 ß-lactam antibiotics Penicillins Natural penicillins: benzylpenicillin, phenoxymethylpenicillin Penicillinase-resistant penicillins: methicillin*, ucloxacillin, nafcillin, oxacillin Aminopenicillins: ampicillin, amoxicillin Carboxy- and ureido-penicillins: ticarcillin, piperacillin, temocillin Cephalosporins See Box 6.23 Monobactams Aztreonam Carbapenems Imipenem, meropenem, ertapenem, doripenem *Not used for treatment. 6.20 Antimicrobial agents in pregnancy1 Contraindicated Chloramphenicol:neonatal‘grey baby’ syndrome – collapse,hypotension and cyanosis Fluconazole: teratogenic in high doses Quinolones: arthropathy in animal studies Sulphonamides: neonatal haemolysis and methaemoglobinaemia Tetracyclines, glycylcyclines: skeletal abnormalities in animals in rst trimester; fetal dental discoloration and maternal hepatotoxicity with large parenteral doses in second or third trimesters Trimethoprim: teratogenic in rst trimester Macrolides2 : major malformations in rst trimester and genital malformations any trimester Relatively contraindicated Aminoglycosides: potential damage to fetal auditory and vestibular nerves in second and third trimesters Metronidazole: avoidance of high dosages is recommended3 Not known to be harmful; use only when necessary Aciclovir Penicillins and cephalosporins Clindamycin Glycopeptides Linezolid Meropenem 1 Data extracted from Joint Formulary Committee. British National Formulary (online). London: BMJ Group and Pharmaceutical Press; (medicinescomplete.com) [accessed 16 March 2013]. 2 Fan H, Gilbert R, O’Callaghan F, Li L. Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: population based cohort study. BMJ 2020; 368:m331. 3 Theoretical risk of teratogenicity, not supported by available clinical evidence.
- 145. 118 PRINCIPLESOF INFECTIOUS DISEASE Cephalosporins and cephamycins Cephalosporins are broad-spectrum agents. Unfortunately, their use is associated with C. difcile infection. With the exception of ceftobiprole, the group has no activity against enterococci. Only the cephamycins have anti-anaerobic activity. All cephalosporins are inactivated by ESBL. Cephalosporins are arranged in ‘generations’ (Box 6.23). First-generation compounds have excellent activity against Gram- positive organisms and some activity against Gram-negatives. Second-generation drugs retain Gram-positive activity but have extended Gram-negative activity. Cephamycins (e.g. cefoxitin), included in this group, are active against anaerobic Gram- negative bacilli. Third-generation agents have improved anti-Gram-negative cover- age. For some (e.g. ceftazidime), this is extended to include Pseudomonas spp. Cefotaxime and ceftriaxone have excellent Gram-negative activity and retain good activity against Strep. pneu- moniae and β-haemolytic streptococci. Ceftriaxone is administered once daily and is therefore a suitable agent for outpatient intraven- ous (parenteral) antimicrobial therapy (OPAT). Fourth-generation agents, e.g. cefepime, have a broad spectrum of activity, including streptococci and some Gram-negatives, including P. aeruginosa Fifth-generation agents, such as ceftobiprole and ceftaroline, have an enhanced spectrum of Gram-positive activity that includes MRSA, and also have activity against Gram-negative bacteria; some, such as ceftobiprole, are active against P. aeruginosa Cederocol is a novel siderophore cephalosporin, which is also active in the presence of ESBLs and carbapenamases. The spectrum of cephalosporins has also been enhanced by add- ing β-lactamase inhibitors, e.g. ceftazidime/avibactam and ceftolazone/ tazobactam. Monobactams Aztreonam is the only available monobactam. It is active against Gram- negative bacteria, except ESBL-producing organisms, but inactive against Gram-positive organisms or anaerobes. It is a parenteral-only agent and may be used safely in most penicillin-allergic patients other than those with an allergy to ceftazidime, which shares a common side chain. Carbapenems These intravenous agents have the broadest antibiotic activity of the β-lactam antibiotics, covering most clinically signicant bacteria, includ- ing anaerobes (e.g. imipenem, meropenem, ertapenem). Carbapenems are also being combined with β-lactamase inhibitors in response to emergence of carbapenemase enzymes that inactivate this class (e.g. meropenem-vaborbactam). Macrolide and lincosamide antibiotics Macrolides (e.g. erythromycin, clarithromycin and azithromycin) and lin- cosamides (e.g. clindamycin) are bacteriostatic agents. Both classes bind to the same component of the ribosome, so they are not admin- istered together. Macrolides are used for Legionella, Mycoplasma, Chlamydia and Bordetella infections. Azithromycin is employed for sin- gle-dose/short-course therapy for genitourinary Chlamydia/Mycoplasma spp. infections. Clindamycin is used primarily for skin, soft tissue, bone and joint infections. Pharmacokinetics Macrolides Variable bioavailability (intravenous and oral preparations available). Frequency of administration: erythromycin is administered 4 times daily, clarithromycin twice daily, azithromycin once daily. High protein binding. Excellent intracellular accumulation. Lincosamides (e.g. clindamycin) Good oral bioavailability. Food has no effect on absorption. Good bone/joint penetration; limited CSF penetration. Adverse effects Gastrointestinal upset, especially in young adults (erythromycin 30%). Cholestatic jaundice with erythromycin estolate. Prolongation of QT interval can cause torsades de pointes (p. 418). Clindamycin predisposes to CDI. Aminoglycosides and spectinomycin Aminoglycosides are effective mainly in Gram-negative infections and are therefore commonly used in regimens for intra-abdominal infection. Some aminoglycosides, e.g. amikacin, are important components of therapy for MDR-TB. Because they act synergistically with β-lactam anti- biotics they are used in combinations to treat biolm infections, including infective endocarditis and orthopaedic implant infections. They cause very little local irritation at injection sites and negligible allergic responses. Oto- and nephrotoxicity must be avoided by monitoring of renal function and drug levels and by use of short treatment regimens. Aminoglycosides are not subject to an inoculum effect and they all exhibit a post-antibiotic effect. Resistance is mediated mainly through inactivation by aminogly- coside-modifying enzymes (AMEs). Plazomicin is a novel aminoglycoside that is not yet inactivated by AMEs. Pharmacokinetics Negligible oral absorption. Hydrophilic, so excellent penetration to extracellular uid in body cavities and serosal uids, but poor penetration into adipose tissue. Very poor intracellular penetration (except hair cells in cochlea and renal cortical cells). Negligible CSF and corneal penetration. Peak plasma levels 30 minutes after infusion. Exhibit a post-antibiotic effect. Monitoring of therapeutic levels required. Gentamicin dosing Gentamicin should be dosed according to actual body weight or ideal body weight if obese. Except in certain forms of endocarditis, pregnancy, severe burns, end-stage renal disease and paediatric patients, gentamicin can be administered at 7mg/kg body weight. The appropriate dose interval 6.23 Cephalosporins First generation Cefalexin, cefradine (oral) Cefazolin (IV) Second generation Cefuroxime (oral/IV) Cefaclor (oral) Cefoxitin (IV) Third generation Cexime (oral) Cefotaxime (IV) Ceftriaxone (IV) Ceftazidime (IV) Fourth generation Cefepime (IV) Fifth generation (also referred to as ‘next generation’) Ceftobiprole (IV) Ceftaroline (IV) (IV = intravenous)
- 146. Treatment of infectiousdiseases 119 6 depends on drug clearance and is determined by reference to the Hartford nomogram (Fig. 6.18). In most other situations, gentamicin is usually administered twice or 3 times daily at 3–5mg/kg/day with target pre- and post-dose levels of <1mg/L and 5–10mg/L. In streptococcal and enterococcal endocarditis, gentamicin is used with a cell wall active agent (usually a β-lactam), to provide synergy. Lower doses and target levels are used in this situation. For all aminoglycoside dosing local guidance should be consulted. Adverse effects Renal toxicity (usually reversible) accentuated by other nephrotoxic agents. Cochlear toxicity (permanent) more likely in older people and those with a predisposing mitochondrial gene mutation. Neuromuscular blockade after rapid intravenous infusion (poten- tiated by calcium channel blockers, myasthenia gravis and hypomagnesaemia). Spectinomycin Chemically similar to the aminoglycosides and given intramuscularly, spectinomycin was developed to treat strains of Neisseria gonor- rhoeae resistant to β-lactam antibiotics. Unfortunately, resistance to spectinomycin is very common. Its only indication is the treatment of gonococcal urethritis in pregnancy or in patients allergic to β-lactam antibiotics. Quinolones and uoroquinolones These are effective and generally well-tolerated bactericidal agents. The quinolones have purely anti-Gram-negative activity, whereas the uoroquinolones are broad-spectrum agents (Box 6.24). Ciprooxacin has anti-pseudomonal activity but resistance emerges rapidly. In 2018, European surveillance showed that resistance to uoroquinolones in E. coli ranged between 8.4% (Finland) and 42.4% (Cyprus). Quinolones and uoroquinolones are used for a variety of infections, including pyelone- phritis, osteomyelitis and less common problems like MDR-TB. Pharmacokinetics Well absorbed after oral administration but delayed by food, ant- acids, ferrous sulphate and multivitamins. Wide volume of distribution; tissue concentrations twice those in serum. Good intracellular penetration, concentrating in phagocytes. Adverse effects Gastrointestinal side-effects in 1%–5%. Rare skin reactions (phototoxicity). Tendinitis and Achilles tendon rupture, especially in older people. Central nervous system effects (delirium, tremor, dizziness and occasional seizures in 5%–12%), especially in older people. Reduces clearance of xanthines and theophyllines, potentially inducing insomnia and increased seizure potential. Prolongation of QT interval on ECG, cardiac arrhythmias. Ciprooxacin use is associated with acquisition of MRSA and strains of C. difcile Glycopeptides Glycopeptides (vancomycin and teicoplanin) are effective against Gram- positive organisms only, and are used mainly against staphylococci (including MRSA) and enterococci. Some staphylococci and enterococci are resistant, and glycopeptide use should be restricted to limit the emer- gence of resistance. Glycopeptides are not absorbed after oral adminis- tration but vancomycin is used orally to treat CDI. Dalbavancin and telavancin are semisynthetic derivatives of glyco- peptide (lipoglycopeptides). Dalbavancin is used primarily for skin and skin structure infections. Telavancin has a dual mechanism of action, inhibiting both cell wall synthesis and membrane polarisation; it is reserved for hospital-acquired pneumonia when other agents cannot be used. Pharmacokinetics Vancomycin is administered by slow intravenous infusion. It has good tissue distribution and a short half-life, and enters the CSF only in the presence of inammation. Therapeutic drug monitoring is rec- ommended, to maintain pre-dose levels of >10mg/L (15–20mg/L in serious staphylococcal infections). Teicoplanin is administered intravenously or intramuscularly. Its long half-life allows once-daily dosing Telavancin and dalbavancin are administered intravenously. Telavancin has a long half-life that allows once-daily dosing; dalba- vancin has a very long half-life, allowing once-weekly dosing. Dose every 48 hours Dose every 36 hours Dose every 24 hours Hours since administration Concentration in plasma (µg/mL) 2 6 7 8 9 10 11 12 13 14 4 6 8 10 12 14 Fig. 6.18 Dosing of aminoglycosides using the Hartford nomogram. The nomogram is used to determine the dose interval for 7mg/kg doses of gentamicin or tobramycin, using measurements of drug levels in plasma 6–14 hours after a single dose. 6.24 Quinolones and uoroquinolones Agent Route of administration Typical antimicrobial spectrum Quinolones Nalidixic acid Oral Enteric Gram-negative bacilli (not Pseudomonas aeruginosa) Fluoroquinolones Ciprooxacin Noroxacin Ooxacin IV/oral Oral IV/oral/topical Enteric Gram-negative bacilli, P. aeruginosa, Haemophilus spp., ‘atypical’ respiratory pathogens* Levooxacin (L-isomer of ooxacin) IV/oral Haemophilus spp., Streptococcus pneumoniae, ‘atypical’ respiratory pathogens* Moxioxacin Oral Strep pneumoniae. Staphylococcus aureus, ‘atypical’ respiratory pathogens,* mycobacteria and anaerobes *‘Atypical’ pathogens include Mycoplasma pneumoniae and Legionella spp. Fluoroquinolones have variable activity against Mycobacterium tuberculosis and other mycobacteria. }
- 147. 120 PRINCIPLESOF INFECTIOUS DISEASE Adverse effects Rapid infusion of vancomycin can cause histamine release (‘red man’ syndrome), although this is rare with modern preparations. Vancomycin and teicoplanin are associated with nephrotoxicity and ototoxicity. Vancomycin and teicoplanin can cause DRESS (drug reaction with eosinophilia and systemic symptoms, see Box 27.35). Lipopeptides Daptomycin is a cyclic lipopeptide with bactericidal activity against Gram- positive organisms only, including MRSA and glycopeptide-resistant enterococci. It is not absorbed orally, and is used intravenously to treat Gram-positive infections, such as soft tissue infections and Staph. aureus infective endocarditis. Daptomycin is inactivated by pulmonary surfactant and is not effective for pneumonia. Treatment can be associated with increased levels of creatine kinase and eosinophilic pneumonitis. Polymyxins Colistin is a polymyxin antibiotic that binds and disrupts the outer cell mem- brane of Gram-negative bacteria, including P. aeruginosa and Acinetobacter baumannii. Its use has increased with the emergence and spread of mul- ti-resistant Gram-negative bacteria, including CPEs. It can be administered by oral, intravenous and nebulised routes. Signicant adverse effects include neurotoxicity, including encephalopathy, and nephrotoxicity. Folate antagonists These are bacteriostatic antibacterials. A combination of a sulphona- mide and either trimethoprim or pyrimethamine is most commonly used, which interferes with two consecutive steps in the folate metabolic path- way. Available combinations include trimethoprim/sulfamethoxazole (co- trimoxazole) and pyrimethamine with either sulfadoxine (used to treat malaria) or sulfadiazine (used in toxoplasmosis). Co-trimoxazole is the rst-line drug for Pneumocystis jirovecii infection, the second-line drug for treatment and prevention of B. pertussis infection, and is also used for a variety of other infections, including Staph. aureus. Dapsone is used to treat leprosy (Hansen’s disease) and to prevent toxoplasmosis and pneu- mocystis when patients are intolerant of other medications. Folinic acid should be given to prevent myelosuppression if these drugs are used long-term or unavoidably in early pregnancy. Pharmacokinetics Well absorbed orally. Sulphonamides are hydrophilic, distributing well to the extracellular uid. Trimethoprim is lipophilic with high tissue concentrations. Adverse effects Trimethoprim is generally well tolerated, with few adverse effects. Sulphonamides and dapsone may cause haemolysis in glucose-6-phosphate dehydrogenase deciency. Sulphonamides and dapsone cause skin and mucocutaneous reactions, including Stevens–Johnson syndrome and ‘dapsone syndrome’ (rash, fever and lymphadenopathy). Dapsone causes methaemoglobinaemia and peripheral neuropathy. Tetracyclines and glycylcyclines Tetracyclines Of this mainly bacteriostatic class, the newer drugs doxycycline and minocycline show better absorption and distribution than older ones. Resistance is common in streptococci and Gram-negative bacteria. Tetracyclines are indicated for infections caused by Mycoplasma spp., Chlamydia spp., Rickettsia spp., Coxiella spp., Bartonella spp., Borrelia spp., Helicobacter pylori, Treponema pallidum and atypical mycobac- teria. Tetracyclines can also be used for malaria prevention. Pharmacokinetics Best oral absorption is in the fasting state (doxycycline is 100% absorbed unless gastric pH rises) and absorption is inhibited by cati- ons, e.g. calcium or iron, which should not be administered at the same time. Adverse effects All tetracyclines except doxycycline are contraindicated in renal failure. Dizziness with minocycline. Binding to metallic ions in bones and teeth causes discoloration (avoid in children and pregnancy) and enamel hypoplasia. Oesophagitis/oesophageal ulcers with doxycycline. Phototoxic skin reactions. Glycylcyclines (tigecycline) Chemical modication of tetracycline has produced tigecycline, a broad-spectrum, parenteral-only antibiotic with activity against resist- ant Gram-positive and Gram-negative pathogens, such as MRSA and ESBL (but excluding Pseudomonas spp.). Re-analysis of trial data has shown that there was excess mortality following tigecycline treatment as opposed to comparator antibiotics, so tigecycline should be used only when there has been adequate assessment of risk versus benet. Nitroimidazoles Nitroimidazoles (e.g. metronidazole) are highly active against strictly anaerobic bacteria, especially Bacteroides fragilis, C. difcile and Clostridium spp. Both metronidazole and tinidazole have signicant anti- protozoal activity against amoebae and Giardia lamblia. Nitroimidazoles are almost completely absorbed after oral administration (60% after rec- tal administration) and well distributed, especially to brain and CSF. They can be used in pregnancy after a risk assessment. Adverse effects include: metallic taste (dose-dependent), severe vom- iting if taken with alcohol (‘Antabuse effect’) and peripheral neuropathy with prolonged use. Phenicols (chloramphenicol) Chloramphenicol use is best reserved for severe and life-threatening infections when other antibiotics are either unavailable or impractical, due to toxicity. It is bacteriostatic to most organisms and has a very broad spectrum of activity against aerobic and anaerobic organisms. It competes with macrolides and lincosamides for ribosomal binding sites, so should not be used in combination with these agents. Signicant adverse effects are ‘grey baby’ syndrome in infants (cyanosis and circu- latory collapse due to inability to conjugate drug and excrete the active form in urine); reversible dose-dependent bone marrow depression in adults receiving high cumulative doses; and severe aplastic anaemia in 1 in 25000–40000 exposures (unrelated to dose, duration of therapy or route of administration). Oxazolidinones Linezolid and tedizolid are examples and have good activity against Gram-positive organisms. They are primarily used in infection caused by resistant Gram-positive bacteria, including MRSA and GRE, but also for resistant Mycobacterium tuberculosis. Administration can be intra- venous or oral. Common linezolid adverse effects include mild gastroin- testinal upset and tongue discoloration. Myelodysplasia and peripheral and optic neuropathy can occur with prolonged use. Linezolid has mon- oamine oxidase inhibitor (MAOI) activity, and co-administration with other MAOIs or serotonin re-uptake inhibitors should be avoided, as this may precipitate a ‘serotonin syndrome’.
- 148. Treatment of infectiousdiseases 121 6 Other antibacterial agents Fusidic acid This antibiotic, active against Gram-positive bacteria, is available in intra- venous, oral or topical formulations. It is lipid-soluble and distributes well to tissues. Its antibacterial activity is, however, unpredictable. Fusidic acid is used in combination, typically with antistaphylococcal penicillins, or for MRSA with clindamycin or rifampicin. It interacts with coumarin derivatives and oral contraceptives. Nitrofurantoin This drug has very rapid renal elimination and is active against aerobic Gram-negative and Gram-positive bacteria, including enterococci. It is used only for treatment of lower urinary tract infection, being generally safe in pregnancy and childhood. With prolonged treatment, however, it can cause eosinophilic lung inltrates, fever, pulmonary brosis, periph- eral neuropathy, hepatitis and haemolytic anaemia so its use must be carefully balanced against risks. Fidaxomicin Fidaxomicin is an RNA synthesis inhibitor, and was introduced for the treatment of CDI in 2012. The registration trial found daxomicin was non-inferior to oral vancomycin in non-severe CDI and was associated with a lower recurrence rate. Its effectiveness for severe CDI has not been assessed in trials. Fosfomycin Fosfomycin acts by inhibiting cell wall synthesis. It has activity against Gram-negative and Gram-positive bacteria and can demonstrate in vitro synergy against MRSA when combined with other antimicrobials. It is used for treatment of urinary tract infections but can be employed in other situations against multi-resistant bacteria. Lefamulin Lefamulin is a pleuromutilin antibiotic that inhibits the 50S ribosome and inhibits protein synthesis. It has recently been licensed for use in com- munity-acquired pneumonia and is available orally and intravenously. It should not be used in pregnancy and prolongs the QT interval. Antimycobacterial agents Isoniazid Isoniazid is bactericidal for replicating bacteria and bacteriostatic for non-replicating bacteria. It is activated by mycobacterial catalase-perox- idase (KatG) and inhibits the InhA gene product, a reductase involved in mycolic acid synthesis. Mutations in KatG or InhA result in isoniazid resist- ance, which was reported in 15% of cases of M. tuberculosis infection glob- ally in 2013. Isoniazid is well absorbed orally and metabolised by acetylation in the liver. The major side-effects are hepatitis, neuropathy (ameliorated by co-administration of pyridoxine) and hypersensitivity reactions. Rifampicin Rifampicin inhibits DNA-dependent RNA polymerase and is bacteri- cidal against replicating bacteria. It is also active in necrotic foci, where mycobacteria have low levels of replication, and is therefore important in sterilisation and sputum conversion. Resistance most often involves the β-subunit of RNA polymerase and most often occurs with isoniazid-re- sistant MDR-TB. Rifampicin is well absorbed orally. It is metabolised by the liver via the microsomal cytochrome P450 system and is one of the most potent inducers of multiple P450 isoenzymes, so is subject to extensive drug–drug interactions. Common side-effects include hepati- tis, inuenza-like symptoms and hypersensitivity reactions. Orange dis- coloration of urine and body secretions is expected. Pyrazinamide The mechanism of action of pyrazinamide is incompletely dened but includes inhibition of fatty acid synthase and ribosomal trans-translation, a quality control system for mRNA and protein synthesis. Pyrazinamide is often bacteriostatic but can be bactericidal and is active against semi- dormant bacteria in a low-pH environment. Primary resistance is rare but MDR-TB strains are frequently pyrazinamide-resistant and intrinsic resistance is a feature of Mycobacterium bovis strains. Pyrazinamide is well absorbed orally and metabolised by the liver. Side-effects include nausea, hepatitis, asymptomatic elevation of uric acid and myalgia. Ethambutol Ethambutol is a bacteriostatic agent. It inhibits arabinosyl transferase, which is involved in the synthesis of arabinogalactan, a component of the mycobacterial cell wall. Resistance is usually seen when resistance to other antimycobacterial agents is also present, e.g. in MDR-TB strains. It is orally absorbed but, in contrast to the rst-line agents described above, it achieves poor CSF penetration and is renally excreted. The major side-effect is optic neuritis with loss of red–green colour discrimi- nation and impaired visual acuity. Streptomycin Streptomycin is an aminoglycoside whose mechanism of action and side-effects are similar to those of other aminoglycosides. It is adminis- tered intramuscularly. Other antituberculous agents Second-line agents used in MDR or XDR strains (p. 524) include amino- glycosides (amikacin, capreomycin or kanamycin) and uoroquinolones (moxioxacin or levooxacin), discussed above. Other established sec- ond-line agents administered orally are cycloserine (which causes neuro- logical side-effects); ethionamide or prothionamide (which are not active with InhA-gene-mediated resistance but have reasonable CSF penetration; their side-effect prole includes gastrointestinal disturbance, hepatotoxicity and neurotoxicity); and paraminosalicylic acid (which causes rashes and gastrointestinal upset). Linezolid may also be used and has good CSF pen- etration, while meropenem with co-amoxiclav is occasionally chosen. New drugs developed for XDR-TB include delamanid and bedaquiline (which targets the ATP synthase); their adverse effects include QT prolongation and cardiac arrhythmias. Their co-administration with other agents with a similar side-effect prole (e.g. uoroquinolones) therefore requires careful risk assessment. Pretomanid is used in combinations with bedaquiline for drug-resistant strains and improves the bactericidal activity of combination therapy which may enable shorter durations. Its side-effects include nerve damage, headaches, gastrointestinal upset, abnormal liver function tests, low glucose and skin rash. Clofazimine Clofazimine is used against M. leprae and resistant strains of M. tubercu- losis. Its mode of action may involve induction of oxidative stress and it is weakly bactericidal. Oral absorption is variable and it is excreted in the bile. Side-effects include gastrointestinal upset, dry eyes and skin, and skin pigmentation, especially in those with pigmented skin. Antifungal agents See Box 6.25. Azole antifungals The azoles (imidazoles and triazoles) inhibit synthesis of ergosterol, a constituent of the fungal cell membrane. Side-effects vary but include gastrointestinal upset, hepatitis and rash. Azoles are inhibitors of cytochrome P450 enzymes, so tend to increase exposure to cytochrome P450-metabolised drugs. Imidazoles Miconazole, econazole, clotrimazole and ketoconazole are relatively toxic and therefore administered topically. Clotrimazole is used exten- sively to treat supercial fungal infections. Triazoles are used for systemic treatment because they are less toxic.
- 149. 122 PRINCIPLESOF INFECTIOUS DISEASE Polyenes Amphotericin B (AmB) deoxycholate causes cell death by binding to ergosterol and damaging the fungal cytoplasmic membrane. Its use in resource-rich countries has been largely supplanted by less toxic agents. Its long half-life enables once-daily administration. CSF penetration is poor. Adverse effects include immediate anaphylaxis, other infusion-related reactions and nephrotoxicity. Nephrotoxicity may be sufcient to require dialysis and occurs in most patients who are adequately dosed. It may be ameliorated by concomitant infusion of normal saline. Irreversible nephrotoxicity occurs with large cumulative doses of AmB. Nystatin has a similar spectrum of antifungal activity to AmB. Its toxicity limits it to topical use, e.g. in oral and vaginal candidiasis. Lipid formulations of amphotericin B Lipid formulations of AmB have been developed to reduce AmB toxicity and have replaced AmB deoxycholate in many regions. They consist of AmB encapsulated in liposomes (liposomal AmB, L-AmB) or complexed with phospholipids (AmB lipid complex, ABLC). The drug becomes active on dissociating from its lipid component. Adverse effects are similar to, but considerably less frequent than, those with AmB deoxycholate, and efcacy is similar. Lipid formulations of AmB are used in invasive fungal disease, as empirical therapy in patients with neutropenic fever and also in visceral leishmaniasis. Other antifungal agents Flucytosine Flucytosine (5-uorocytosine) has particular activity against yeasts. When it is used as monotherapy, acquired resistance develops rapidly, so it should be given in combination with another antifungal agent. Adverse effects include myelosuppression, gastrointestinal upset and hepatitis. Griseofulvin Griseofulvin has been largely superseded by terbinane and itraconazole for treatment of dermatophyte infections, except in children, for whom these agents remain largely unlicensed. It is deposited in keratin precur- sor cells, which become resistant to fungal invasion. Terbinane Terbinane distributes with high concentration to sebum and skin, with a half-life of more than 1 week. It is used topically for dermatophyte skin infections and orally for onychomycosis. The major adverse reaction is hepatic toxicity (approximately 1:50000 cases). Terbinane is not recom- mended for breastfeeding mothers. Antiviral agents Most viral infections in immunocompetent individuals resolve without intervention. Antiviral therapy is available for a limited number of infec- tions only (Box 6.26). Antiretroviral agents These agents, used predominantly against HIV, are discussed on page 366. Anti-herpesvirus agents Aciclovir, valaciclovir, penciclovir and famciclovir These antivirals are acyclic analogues of guanosine, which inhibit viral DNA polymerase after being phosphorylated by virus-derived thymi- dine kinase (TK). Aciclovir is poorly absorbed after oral dosing; better levels are achieved intravenously or by use of the prodrug valaciclovir. Famciclovir is the prodrug of penciclovir. Resistance is mediated by viral TK or polymerase mutations. 6.25 Antifungal agents Agent Usual route(s) of administration Clinically relevant antifungal spectrum Imidazoles Miconazole Econazole Clotrimazole Topical Candida spp., dermatophytes Ketoconazole Topical, oral Malassezia spp., dermatophytes, agents of eumycetoma Triazoles Fluconazole Oral, IV Yeasts (Candida and Cryptococcus spp.) Itraconazole Oral, IV Yeasts, dermatophytes, dimorphic fungi (p. 342), Aspergillus spp. Voriconazole Oral, IV Yeasts and most lamentous fungi (excluding mucoraceous moulds) Posaconazole Oral, IV Yeasts and many lamentous fungi (including most mucoraceous moulds) Isavuconazole Oral, IV Yeasts and many lamentous fungi (variable activity against mucoraceous moulds) Echinocandins Anidulafungin Caspofungin Micafungin IV only Candida spp., Aspergillus spp. (no activity against Cryptococcus spp. or mucoraceous moulds) Polyenes Amphotericin B IV Yeasts and most dimorphic and lamentous fungi (including mucoraceous moulds) Nystatin Topical Others 5-uorocytosine Oral, IV Yeasts Griseofulvin Oral Dermatophytes Terbinane Topical, oral Dermatophytes (IV = intravenous) } } Triazoles Fluconazole is effective against yeasts (Candida and Cryptococcus spp.) and has a long half-life (approximately 30 hours) and an excellent safety prole. The drug is highly water-soluble and distributes widely to all body sites and tissues, including CSF. Itraconazole is lipophilic and distributes extensively, including to toenails and ngernails. Its CSF penetration is poor. Because oral absorption of itraconazole is erratic, therapeutic drug monitoring is required. Voriconazole is well absorbed orally but varia- bility in levels requires therapeutic drug monitoring. It is used mainly in aspergillosis. Side-effects include photosensitivity, hepatitis and transient retinal toxicity. Posaconazole and isavuconazole are broad-spectrum azoles, with activity against Candida spp., Aspergillus spp. and some mucoraceous moulds. Isavuconazole is non-inferior to voriconazole in the management of invasive aspergillosis and may be considered as an alternative when voriconazole cannot be used. Echinocandins The echinocandins inhibit β-1,3-glucan synthesis in the fungal cell wall. They have few signicant adverse effects. Caspofungin, anidulafungin and micafungin are used to treat systemic candidosis, and caspofungin is also used in aspergillosis.
- 150. Treatment of infectiousdiseases 123 6 6.26 Antiviral agents Drug Route(s) of administration Indications Signicant side-effects Antiretroviral therapy (ART, p. 366) Oral HIV infection (including AIDS) CNS symptoms, anaemia, lipodystrophy Anti-herpesvirus agents Aciclovir Topical/oral/IV Herpes zoster Chickenpox (esp. in immunosuppressed) Herpes simplex infections: encephalitis (IV only), genital tract, oral, ophthalmic Signicant side-effects rare Hepatitis, renal impairment and neurotoxicity reported rarely Valaciclovir Oral Herpes zoster, herpes simplex As for aciclovir Famciclovir Oral Herpes zoster, herpes simplex (genital) As for aciclovir Penciclovir Topical Labial herpes simplex Local irritation Ganciclovir IV Treatment and prevention of CMV infection in immunosuppressed Gastrointestinal symptoms, liver dysfunction, neurotoxicity, myelosuppression, renal impairment, fever, rash, phlebitis at infusion sites Potential teratogenicity Valganciclovir Oral Treatment and prevention of CMV infection in immunosuppressed As for ganciclovir but neutropenia is predominant Cidofovir IV/topical HIV-associated CMV infections and occasionally other viruses (see text) Renal impairment, neutropenia Foscarnet IV CMV and aciclovir-resistant HSV and VZV infections in immunosuppressed Gastrointestinal symptoms, renal impairment, electrolyte disturbances, genital ulceration, neurotoxicity Anti-inuenza agents Zanamivir Inhalation Inuenza A and B Allergic reactions (very rare) Oseltamivir Oral Inuenza A and B Gastrointestinal side-effects, rash, hepatitis (very rare) Peramivir IV, IM Amantadine, rimantadine Oral Inuenza A (but see text) CNS symptoms, nausea Agents used in other virus infections* Ribavirin Oral/IV/ inhalation Lassa fever (IV) RSV infection in infants (inhalation) Haemolytic anaemia, cough, dyspnoea, bronchospasm and ocular irritation (when given by inhalation) Remdesivir IV COVID-19 (experimental, not recommended for clinical use at the time of writing) Signicant side-effects rare *Antiviral agents used in viral hepatitis are discussed on pages 884–890. (AIDS = acquired immunodeciency syndrome; CMV = cytomegalovirus; CNS = central nervous system; HIV = human immunodeciency virus; HSV = herpes simplex virus; IM = intramuscular; IV = intravenous; RSV = respiratory syncytial virus; VZV = varicella zoster virus) } Ganciclovir Chemical modication of the aciclovir molecule allows preferential phospho- rylation by protein kinases of cytomegalovirus (CMV) and other β-herpes- viruses (e.g. human herpesvirus (HHV) 6/7) and hence greater inhibition of the DNA polymerase, but at the expense of increased toxicity. Ganciclovir is administered intravenously or as a prodrug (valganciclovir) orally. Cidofovir Cidofovir inhibits viral DNA polymerases with potent activity against CMV, including most ganciclovir-resistant CMV. It also has activity against aciclo- vir-resistant herpes simplex virus (HSV) and varicella zoster virus (VZV), HHV6 and occasionally adenovirus, poxvirus, papillomavirus or polyoma virus, and may be used to treat these infections in immunocompromised hosts. Foscarnet This analogue of inorganic pyrophosphate acts as a non-competitive inhibitor of HSV, VZV, HHV6/7 or CMV DNA polymerase. It does not require signicant intracellular phosphorylation and so may be effective when HSV or CMV resistance is due to altered drug phosphorylation. It has variable CSF penetration. Letermovir Letermovir is a CMV DNA terminase inhibitor that plays a role in cleavage of viral DNA for packaging into mature virions. It is available in oral and intravenous formulations. It is well tolerated and is approved for proph- ylaxis of CMV in allogeneic haematopoeitic stem cell transplant recipi- ents. Gastrointestinal disturbance and drug–drug interactions occur and resistance may develop. Anti-inuenza agents Zanamivir and oseltamivir These agents inhibit inuenza A and B neuraminidase, which is required for release of virus from infected cells (see Fig. 6.2). They are used in the treatment and prophylaxis of inuenza. Administration within 48 hours of disease onset reduces the duration of symptoms by approximately 1–1½ days. In the UK, their use is limited mainly to adults with chronic respiratory or renal disease, signicant car- diovascular disease, immunosuppression or diabetes mellitus, dur- ing known outbreaks. Peramivir has been developed as a distinct chemical structure, which means that it retains activity against some oseltamivir- and zanamivir-resistant strains. It has poor oral bioavail- ability and has been developed as an intravenous or intramuscular formulation for treatment of severe cases of inuenza, e.g. in intensive care units. It is now approved for use in adults in a number of coun- tries. An intravenous formulation of zanamivir is also in development for critically ill patients. Laninamivir is approved as an intranasal for- mulation in Japan.
- 151. 124 PRINCIPLESOF INFECTIOUS DISEASE Other anti-inuenza agents Amantidine and rimantadine inhibit viral M2 protein ion channel function, which is required for uncoating (see Fig. 6.2). Resistance is widespread, and these are only used to treat oseltamivir-resistant inuenza A in patients unable to take zanamivir (e.g. ventilated patients) and when the strain is susceptible to these agents. Baloxavir marboxil inhibits a com- ponent of viral RNA synthesis. It is licensed for uncomplicated inuenza but is likely to be reserved for neuraminidase-resistant strains. Faviparvir is an oral or intravenous RNA-dependent RNA polymerase that may also play a role against resistant strains of inuenza but also other RNA viruses and has been studied against SARS-CoV-2. Other agents used to treat viruses Antiviral agents used to treat hepatitis B and C virus are discussed on pages 886 and 889, and those used against HIV-1 are described on page 366. Remdesivir Remdesivir is an intravenous RNA-dependent RNA polymerase inhibitor that has a broad antiviral spectrum in vitro and has decreased the time to recovery following SARS-Cov-2 infection. So far it has not demonstrated efcacy against other viruses clinically. Initial studies have not shown signi- cant effects on SARS-CoV-2 viral replication, suggesting it may need to be used early in the course of infection before peak viral replication. The main side-effects include abnormal liver function tests and infusion reactions. Ribavirin Ribavirin is a guanosine analogue that inhibits nucleic acid synthesis in a variety of viruses. It is used in particular in the treatment of hepatitis C virus but also against certain viral haemorrhagic fevers, e.g. Lassa fever, although it has not been useful against Ebola virus. Antiparasitic agents Antimalarial agents Artemisinin (qinghaosu) derivatives Artemisinin originates from a herb (sweet wormwood, Artemisia annua), which was used in Chinese medicine to treat fever. Its derivatives, artemether and artesunate, were developed for use in malaria in the 1970s. Their mechanism of action is unknown. They are used in the treatment, but not prophylaxis, of malaria, usually in combination with other antimalarials, and are effective against strains of Plasmodium spp. that are resistant to other antimalarials. Artemether is lipid-soluble and may be administered via the intramuscular and oral routes. Artesunate is water-soluble and is administered intravenously or orally. Serious adverse effects are uncommon. Current advice for malaria in pregnancy is that the artemisinin derivatives should be used to treat uncomplicated fal- ciparum malaria in the second and third trimesters, but should not be prescribed in the rst trimester until more information becomes available. Atovaquone Atovaquone inhibits mitochondrial function. It is an oral agent, used for treatment and prophylaxis of malaria, in combination with proguanil (see below), without which it is ineffective. It is also employed in the treatment of mild cases of Pneumocystis jirovecii pneumonia, or as prophylaxis, where there is intolerance to co-trimoxazole. Signicant adverse effects are uncommon. Folate synthesis inhibitors (proguanil, pyrimethamine–sulfadoxine) Proguanil inhibits dihydrofolate reductase and is used for malaria prophy- laxis. Pyrimethamine–sulfadoxine may be used in the treatment of malaria. Quinoline-containing compounds Chloroquine and quinine are believed to act by intraparasitic inhibition of haem polymerisation, resulting in toxic build-up of intracellular haem. The mechanisms of action of other agents in this group (quinidine, amodiaquine, meoquine, primaquine, etc.) may differ. They are employed in the treatment and prophylaxis of malaria. Primaquine is used for radical cure of malaria due to Plasmodium vivax and P. ovale (destruction of liver hypnozoites). Chloroquine may also be given for extraintestinal amoebiasis. Chloroquine can cause signicant pruritus. If used in long-term, high- dose regimens, it causes an irreversible retinopathy. Overdosage leads to life-threatening cardiotoxicity. The side-effect prole of meoquine includes neuropsychiatric effects ranging from mood change, nightmares and agitation to hallucinations and psychosis. Quinine may cause hypo- glycaemia and cardiotoxicity, especially when administered parenterally. Primaquine causes haemolysis in people with glucose-6-phosphate dehydrogenase deciency, which should be excluded before therapy. Chloroquine is considered safe in pregnancy but meoquine should be avoided in the rst trimester. Chloroquine (and its metabolite hydroxychloroquine) exhibits in vitro activity against the virus SARS-CoV-2 but has not demonstrated clinical efcacy. Lumefantrine Lumefantrine is used in combination with artemether to treat uncom- plicated falciparum malaria, including chloroquine-resistant strains. Its mechanism of action is unknown. Signicant adverse effects are uncommon. Drugs used in trypanosomiasis The antiparasitic agents used to treat human African trypanosomiasis (HAT) and American trypanosomiasis (Chagas’ disease) (benznidazole, eornithine, fexinidazole, melarsoprol, nifurtimox, pentamidine and suramin) are discussed in detail on pages 324 and 325. In addition to its use in HAT, pentamidine is used in leishmaniasis (p. 327) and in severe Pneumocystis jirovecii pneumonia, if co-trimoxazole cannot be tolerated or is ineffective. It is administered via intravenous or intramuscular routes. It is a relatively toxic drug, commonly causing rash, renal impairment, profound hypotension (especially on rapid infusion), electrolyte disturbances, blood dyscrasias and hypoglycaemia. Other antiprotozoal agents Pentavalent antimonials Sodium stibogluconate and meglumine antimoniate inhibit protozoal glycolysis by phosphofructokinase inhibition. They are used parenter- ally (intravenous or intramuscular) to treat leishmaniasis. Adverse effects include arthralgia, myalgias, raised hepatic transaminases, pancreatitis and electrocardiogram changes. Severe cardiotoxicity leading to death is not uncommon. Diloxanide furoate This oral agent is used to eliminate luminal cysts following treatment of intestinal amoebiasis, or in asymptomatic cyst excreters. The drug is absorbed slowly (enabling luminal persistence) and has no effect in hepatic amoebiasis. It is a relatively non-toxic drug, the most signicant adverse effect being atulence. Iodoquinol (di-iodohydroxyquinoline) Iodoquinol is a quinoline derivative with activity against Entamoeba his- tolytica cysts and trophozoites. It is used orally to treat asymptomatic cyst excreters or, in association with another amoebicide (e.g. metroni- dazole), to treat extraintestinal amoebiasis. Long-term use of this drug is not recommended, as neurological adverse effects include optic neuritis and peripheral neuropathy. Nitazoxanide Nitazoxanide is an inhibitor of pyruvate–ferredoxin oxidoreductase- dependent anaerobic energy metabolism in protozoa. It is a broad-spec- trum agent, active against various nematodes, tapeworms, ukes and
- 152. Further information 125 6 intestinal protozoa. Nitazoxanide also has activity against some anaero- bic bacteria and viruses. It is administered orally in giardiasis and crypto- sporidiosis. Adverse effects are usually mild and involve the gastrointestinal tract (e.g. nausea, diarrhoea and abdominal pain). Paromomycin Paromomycin is an aminoglycoside that is used to treat visceral leish- maniasis and intestinal amoebiasis. It is not signicantly absorbed when administered orally, and is therefore given orally for intestinal amoebiasis and by intramuscular injection for leishmaniasis. It showed early prom- ise in the treatment of HIV-associated cryptosporidiosis but subsequent trials have demonstrated that this effect is marginal at best. Drugs used against helminths Benzimidazoles (albendazole, mebendazole) These agents act by inhibiting both helminth glucose uptake, causing depletion of glycogen stores, and fumarate reductase. Albendazole is used for hookworm, ascariasis, threadworm, Strongyloides infec- tion, trichinellosis, Taenia solium (cysticercosis) and hydatid disease. Mebendazole is used for hookworm, ascariasis, threadworm and whip- worm. The drugs are administered orally. Absorption is relatively poor but is increased by a fatty meal. Signicant adverse effects are uncommon. Bithionol Bithionol is used to treat uke infections with Fasciola hepatica. It is well absorbed orally. Adverse effects are mild (e.g. nausea, vomiting, diar- rhoea, rashes) but relatively common (approximately 30%). Diethylcarbamazine Diethylcarbamazine (DEC) is an oral agent used to treat lariasis and loi- asis. Treatment of lariasis is often followed by fever, headache, nausea, vomiting, arthralgia and prostration. This is caused by the host response to dying microlariae, rather than the drug, and may be reduced by pre-treatment with glucocorticoids. Ivermectin Ivermectin binds to helminth nerve and muscle cell ion channels, causing increased membrane permeability. It is an oral agent, used in Strongyloides infection, lariasis and onchocerciasis. Signicant side- effects are uncommon. Niclosamide Niclosamide inhibits oxidative phosphorylation, causing paralysis of helminths. It is an oral agent, used in Taenia saginata and intestinal T. solium infection. Systemic absorption is minimal and it has few signi- cant side-effects. Piperazine Piperazine inhibits neurotransmitter function, causing helminth mus- cle paralysis. It is an oral agent, used in ascariasis and threadworm (Enterobius vermicularis) infection. Signicant adverse effects are uncom- mon but include neuropsychological reactions such as vertigo, delirium and convulsions. Praziquantel Praziquantel increases membrane permeability to Ca2+ , causing violent contraction of worm muscle. It is the drug of choice for schistosomi- asis and is also used in T. saginata, T. solium (cysticercosis) and uke infections (Clonorchis, Paragonimus) and in echinococcosis. It is admin- istered orally and is well absorbed. Adverse effects are usually mild and transient, and include nausea and abdominal pain. Pyrantel pamoate This agent causes spastic paralysis of helminth muscle through a suxamethonium-like action. It is used orally in ascariasis and thread- worm infection. Systemic absorption is poor and adverse effects are uncommon. Thiabendazole Thiabendazole inhibits fumarate reductase, which is required for energy production in helminths. It is used orally in Strongyloides infection and topically to treat cutaneous larva migrans. Signicant adverse effects are uncommon. Further information Websites cdc.gov. Centers for Disease Control and Prevention, Atlanta, USA. Provides information on all aspects of communicable disease, including prophylaxis against malaria. gov.uk/government/collections/immunisation-against-infectious-disease-the- green-book. UK Department of Health recommendations for immunisation. ecdc.europa.eu. European Centre for Disease Prevention and Control. Includes data on prevalence of antibiotic resistance in Europe. gov.uk/government/organisations/public-health-england. Public Health England. Provides information on infectious diseases relating mainly to England, including community infection control. idsociety.org. Infectious Diseases Society of America. Publishes up-to-date, evidence-based guidelines. who.int. World Health Organization. Provides up-to-date information on global aspects of infectious disease, including outbreak updates. Also has information on the ‘World Antibiotic Awareness Week’ campaign.
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- 154. Multiple Choice Questions 6.1.A 19-year-old student who had not received any childhood vaccines through parental choice attends a music festival. Nine days later she develops an illness consisting of conjunctivitis and malaise with some intraoral lesions, followed by a generalised maculopapular rash. With respect to the most likely causative organism, which of the following statements is false? A. The basic reproduction number (R0 ) for this pathogen is one of the highest encountered for an infectious disease B. R0 gives an estimate of how many infections are likely to arise from an infected individual and is dependent on vaccine uptake and previous infections C. R0 for this infection is higher than that for SARS-CoV-2 and Ebola D. Since R0 for this infection is high the proportion of the population who need to be immunised to prevent spread of infection is high E. Re gives an estimate of how many infections are likely to arise from an infected individual taking into account vaccine uptake in the population Answer: B. The case describes a measles infection. R0 is an estimate of the num- ber of cases that can be expected to be acquired from a single primary case when all individuals in the population are susceptible to infection, and is high for measles (usually cited as 12–18). R0 is dependent on the inherent transmissibility of the organism and assumes susceptibility of the population. R0 is affected by the social habits and interactions of a population at the time it is calculated, and therefore the Ro for a disease transmitted by close contact will be higher if calculated in a densely pop- ulated area than a sparsely populated area. Because measles has a high R0 the number of people in the population who need to be vaccinated to control measles is high. Re gives a more accurate assessment of the number of infections that can be expected to arise within a population than R0 because it takes into account the number of susceptible indi- viduals within the population (i.e. vaccinated individuals and those who have acquired immunity through natural infection) as well as changes in behaviour (e.g. the introduction of social distancing, use of personal protective equipment etc.). Re therefore varies with time and population behaviour. 6.2. A 23-year-old woman with cystic brosis and a history of multiple infectious exacerbations is admitted to hospital with increasing breathlessness. A chest X-ray reveals patchy inltrates throughout the right lower lung on a background of bronchial dilatation in both lungs. Sputum culture yields profuse growth of an oxidase-positive Gram-negative bacillus. The patient has a history of rash with piperacillin-tazobactam but has tolerated cephalosporins without previous problems. Which of the following would be a suitable agent to treat the most likely causative organism? A. Cefaclor B. Cefazolin C. Ceftriaxone D. Ceftazidime E. Cephalexin Answer: D. The patient has a history of cystic brosis with multiple infectious exac- erbations. Although an oxidase-positive Gram-negative bacillus could describe several organisms, the most likely one in a setting of cystic brosis with multiple infective exacerbations is P. aeruginosa. As the patient has tolerated cephalosporins previously with no problems, it is reasonable to treat her with an anti-pseudomonal cephalosporin despite her history of rash with another beta-lactam antibiotic (piperacillin- tazobactam). Ceftazidime is the only anti-pseudomonal cephalosporin on this list. The only other third-generation cephalosporin that has good Gram-negative coverage on the list is ceftriaxone, but it lacks activity against P. aeruginosa 6.3. A 58-year-old man with diabetes mellitus is hospitalised with an acute myocardial infarction. He develops cardiac failure and acute kidney injury (AKI) and spends a period of time in the cardiac intensive care unit. He subsequently develops a fever and his blood cultures are positive for a yeast, which is identied as Candida krusei. An antifungal agent is selected on the basis of likely susceptibility and patient comorbidities. The mechanism of action of this antifungal is: A. Accumulation of toxic 14α-methylated sterols B. DNA topoisomerase inhibition C. Ergosterol synthesis inhibition in the cell membrane D. Impairment of DNA synthesis due to inhibition of thymidylate synthase E. Inhibition of β-1,3-glucan synthesis in the cell wall Answer: E. The candidaemia is likely to be related to a central venous catheter infection and Candida krusei is resistant to antifungal azoles. The best initial therapy is therefore an echinocandin such as caspofungin, which acts by inhibiting fungal β-1,3-glucan synthase. It would not be appro- priate to treat this patient with an amphotericin B preparation because of his AKI and the potential for nephrotoxicity. Antifungal azoles act by inhibiting ergosterol synthesis resulting in toxic accumulation of 14α- methylated sterols. Flucytosine (5-uorocytosine) inhibits DNA synthesis by its actions on thymidylate synthase. Inhibition of bacterial DNA topo- isomerases is the mechanism of action of uoroquinolones, but not of any antifungals. 6.4. A 26-year-old man who grew up on a farm in rural Argentina is investigated for chronic abdominal pain and weight loss. He is found on investigation to have infection with Taenia saginata and treatment is recommended. Guidelines suggest you should prescribe praziquantel but your pharmacy is not able to obtain any supplies of this drug. What would be a suitable alternative agent to use to treat this infection? A. Bithionol B. Diethycarbazamine C. Niclosamide D. Piperazine E. Thiabendazole Answer: C. Infections with intestinal tapeworms such as T. saginata are often asymptomatic but can occasionally give rise to symptoms, as in this case. The preferred treatment for Taenia infections is praziquantel but niclosamide or nitazoxanide are alternatives. The other agents listed are used for other helminth infections.
- 155. S Clive M Stares 7 Clinicalexamination of the cancer patient 128 Clinical examination of the patient on cancer treatment 129 The 10 hallmarks of cancer 130 1. Genome instability and mutation 130 2. Resisting cell death 130 3. Sustaining proliferative signalling 131 4. Evading growth suppressors 131 5. Enabling replicative immortality 131 6. Inducing angiogenesis 132 7.Activating invasion and metastasis 132 8. Deregulating cellular energetics 133 9.Tumour-promoting inammation 133 10. Evading immune destruction 133 Environmental and genetic determinants of cancer 133 Investigations 133 Determining the extent of disease (staging) 133 Establishing the type of cancer 135 Assessing tness 137 Multidisciplinary teams 138 Acute oncology 138 Acute presentation of new cancer 138 Oncological emergencies 139 Other acute presentations in oncology 142 Symptoms from locally advanced cancer or metastatic sites 143 Treatment-related toxicities 145 Therapeutics in oncology 145 Surgical treatment 145 Radiotherapy 145 Systemic anti-cancer therapy 146 Evaluation of treatment 148 Late toxicity of therapy 148 Cancer clinical trials 148 Specic cancers 149 Breast cancer 149 Ovarian cancer 150 Endometrial cancer 150 Cervical cancer 150 Head and neck tumours 151 Survivorship 151 Oncology
- 156. 128 OncOlOgy Clinicalexamination of the cancer patient Observation Breast asymmetry, lump Lymph nodes (see p. 923) Cervical Supraclavicular Axillary Inguinal Face Conjunctival pallor Icterus Horner syndrome Cushingoid features Cardiovascular Superior vena cava obstruction (SVCO) (see Box 7.15) Atrial fibrillation Pericardial effusion (see Ch. 16) Hypo-/hypertension Abdomen (see p. 783) Surgical scars Umbilical nodule Mass in epigastrium Visible peristalsis Abdominal distension Ascites Hepatomegaly Splenomegaly Renal mass Pelvic or adnexal mass Cachexia Dehydration Asymmetry/lumps Hands Clubbing Signs of smoking Pallor Periphery Calf tenderness, venous thrombosis Rash, skin changes (see also p. 1065) Skin tethering above the nipple Finger clubbing in lung cancer SVCO in a patient with a mediastinal mass Skeletal survey Focal bone tenderness (pelvis, spine, long bones) Wrist tenderness (hypertrophic pulmonary osteoarthropathy) Neurological Ascites (ovarian carcinoma) 6 5 7 8 9 10 3 4 2 1 6 7 Respiratory Stridor Consolidation Pleural effusion (see p. 481) 4 8 9 10 1 5 3 2 Focal neurological signs Sensory deficit Spinal cord compression Memory deficit Personality change
- 157. ciia examiatio ofthe patiet o aer treatmet 129 7 Clinical examination of the patient on cancer treatment Peripheral neuropathy – cisplatin, oxaliplatin, taxanes, gemcitabine, brentuximab, immunotherapy Encephalopathy – ifosfamide, cisplatin, immunotherapy Nervous system Hearing loss – cisplatin Posterior reversible encephalopathy syndrome (PRES) – VEGF inhibitors, rituximab, immunotherapy Eye Uveitis – immunotherapy, BRAF inhibitors, cytarabine, erlotinib Cataracts – anti-oestrogen Lens – steroids Heart Cardiomyopathy – HER2 inhibitors, anthracyclines, radiotherapy Myocarditis – immunotherapy, cisplatin Myocardial ischaemia – 5-FU/ capecitabine, bevacizumab, radiotherapy Arrhythmia/QTc prolongation – cytotoxic, TKIs Kidneys Nephritis – immunotherapy Nephrotic syndrome – VEGF inhibitors Haemorrhagic cystitis – ifosfamide Nephrotoxicity – cisplatin GI tract Nausea and vomiting – all treatment Diarrhoea – all treatment Colitis – ipilimumab, 5-FU/capecitabine, taxanes, radiotherapy Paralytic ileus – vinca alkaloids Bowel perforation – bevacizumab Strictures – radiotherapy Haematological Neutropenia – cytotoxics, CDK4/6 inhibitors, PARP inhibitors Bleeding – cytotoxics, VEGF inhibitors Anaemia – cytotoxics, radiotherapy Hands and feet Palmar plantar erythrodysesthesia – 5-FU, capecitabine, VEGF inhibitors Paronychia – EGFR inhibitors Colour key Finger tip cracks – EGFR inhibitors Vascular Venous/arterial thrombo-embolism – platinum agents, taxanes, TKIs Phlebitis – fluorouracil, epirubicin, cisplatin, gemcitabine Hair Constitutional all Fatigue – all treatment Fever – all treatment Alopecia – cytotoxic Cytotoxic chemotherapy Hormone therapy Targeted therapy Immunotherapy Radiotherapy Supportive Trichomegaly – EGFR inhibitors Loss of pigmentation – pazopanib Skin Dry skin – all Maculopapular rashes – TKIs Acneiform rashes – EGFR inhibitors DRESS syndrome – immunotherapy Telangiectasia – radiotherapy Tattoo point marks – radiotherapy Mouth Dysgeusia – all treatment Xerostomia – all treatment Stomatitis – 5-FU, methotrexate, cyclophosphamide, radiotherapy Osteonecrosis of jaw – VEGF inhibitors, bisphosphonates Lungs Pneumonitis – immunotherapy, taxanes, bleomycin, gemcitabine, TKIs, radiotherapy Fibrosis – bleomycin, gemcitabine, methotrexate, cyclophosphamide, radiotherapy Non-cardiogenic pulmonary oedema – gemcitabine, methotrexate Liver Hepatitis – cisplatin, vinblastine, rituximab, immunotherapy Pseudocirrhosis – gemcitabine Steatosis – oxaliplatin, irinotecan,tamoxifen Sinusoidal obstructive syndrome – cyclophosphamide, oxaliplatin, vincristine Endocrine Hypothyroidism – VEGF inhibitors, immunotherapy, radio-iodine Hypophysitis – immunotherapy Adrenalitis – immunotherapy Addison’s – steroids (withdrawal) Diabetes – immunotherapy, steroids Rheumatological Arthralgia – taxanes, anti-oestrogens, mTOR inhibitors Myalgia – taxanes, anti-oestrogens Bone pain – G–CSF 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 (CDK = cyclin-dependent kinase; EGFR = epidermal growth factor receptor; G–CSF = granulocyte–colony stimulating factor; PARP = poly-ADP ribose polymerase; TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor) (Acneiform rashes) From Potthoff K, Hofheinz R, Hassel JC, et al. Interdisciplinary management of EGFR- inhibitor-induced skin reactions: a German expert opinion. Ann Oncol 2011; 22(3):524–535. (Colitis) From Som A, Mandaliya R, Alsaadi D, et al. Immune checkpoint inhibitor- induced colitis: A comprehensive review. World J Clin Cases 2019; 7(4):405–418.
- 158. 130 OncOlOgy Cancerrepresents a signicant global health, social and economic burden. In 2018 there were 17 million new cases of cancer worldwide and 9.6 million cancer deaths, making it the second leading cause of death. By 2030, it is projected that there will be 26 million new cancer cases and 17 million cancer deaths per year. The developing world is disproportionately affected by cancer and in 2018 approximately 70% of cancer deaths occurred in low- and middle-income countries. These deaths happen in countries with limited or no access to investigations or treatment and with low per capita expenditure on health care. The most common solid organ malignancies arise in the lung, breast and gastrointestinal tract (Fig. 7.1), but the most common form world- wide is skin cancer. Cigarette smoking accounts for more than 20% of all global cancer deaths, 80% of lung cancer cases in men and 50% of lung cancer cases in women worldwide, which could be prevented by smoking cessation. Diet and alcohol contribute to a further 30% of cancers, including those of the stomach, colon, oesophagus, breast and liver. Lifestyle modication could reduce these if steps were taken to avoid animal fat and red meat, reduce alcohol, increase bre, fresh fruit and vegetable intake, avoid obesity and increase physical activity. Infections account for a further 15% of cancers (25% of cancers in low- and middle-income countries), including those of the cervix, stomach, liver, nasopharynx, anus and bladder, and some of these could be pre- vented by infection control and vaccination. The 10 hallmarks of cancer The formation and growth of cancer is a multistep process, during which normal cells are transformed into malignant cells. Ten key characteristics that underlie these steps, collectively referred to as the ‘Hallmarks of Cancer’, have been described. 1. Genome instability and mutation Random genomic aberrations occur continuously throughout all cells of the body. This may include somatic point mutations, insertions, deletions and chromosome structural changes (i.e. copy number changes, chro- mosomal translocations). Epigenomic aberrations, such as DNA meth- ylation and histone modication, may also occur. Rarely, aberrations will confer a selective survival advantage on single cells, ‘driving’ overgrowth and dominance in local tissue environments. Multistep carcinogenesis results from successive clonal expansions of pre-malignant cells, each expansion being triggered by acquisition of a random driver aberration. Under normal circumstances, genome maintenance systems and DNA repair mechanisms are so effective that almost all spontaneous genomic aberrations are repaired, or damaged cells are forced into senescence or apoptosis. In cancer cells, though, the accumulation of mutations can be accelerated by compromising these maintenance mechanisms. In turn, this leads to the accumulation of driver genomic aberrations which lead to cancer growth and progression. Genomic sequencing technology demonstrates that the pattern of aberrations vary dramatically between cancer types. However, defects in genome maintenance mechanisms leading to genome instability are common ndings across all cancers. This enabling characteristic may lead to the acquisition of other hallmarks. 2. Resisting cell death There are three principal mechanisms through which cell death occurs in healthy tissues: apoptosis, autophagy and necrosis. Apoptosis This is programmed cell death. It is frequently found at markedly reduced rates in cancers, particularly those of high grade or those resistant to treatment. The cellular apoptotic system has regulatory elements that sense intrinsic and extrinsic pro-apoptotic signals. This initiates a cas- cade of proteolysis and cell disassembly with nuclear fragmentation, chromosomal condensation and shrinking of the cell with loss of inter- cellular contact, followed by cellular fragmentation and the formation of apoptotic bodies that are phagocytosed by neighbouring cells. The most important regulator of apoptosis is the TP53 tumour suppressor gene, often described as the ‘guardian of the genome’ as it is able to induce apoptosis in response to sufcient levels of genomic damage. The larg- est initiator of apoptosis via TP53 is cellular injury, particularly that due to DNA damage from cytotoxic chemotherapy, oxidative damage and ultraviolet (UV) radiation. Disruption of p53 protein function as a result of mutations in the TP53 gene are found in over half of cancers. Autophagy This is a catabolic process during which cellular constituents are degraded by lysosomal machinery within the cell. It is an important phys- iological mechanism; it usually occurs at low levels in cells but can be induced in response to environmental stresses, particularly radiotherapy and cytotoxic chemotherapy, which induce elevated levels of autophagy that are cytoprotective for malignant cells, thus impeding rather than per- petuating the killing actions of these stress situations. Severely stressed cancer cells have been shown to shrink via autophagy to a state of reversible dormancy. Necrosis This is the premature death of cells and is characterised by the release of cellular contents into the local tissue microenvironment, in marked con- trast to apoptosis, where cells are disassembled in a step-by-step fash- ion and the resulting cellular fragments are phagocytosed. Necrotic cell Fig. 7.1 The most commonly diagnosed cancers in the UK. (CNS = central nervous system; NHL = non-Hodgkin lymphoma) Statistics from Cancer Research UK website (http://info.cancerresearchuk.org) Breast Prostate Lung Bowel Melanoma NHL Kidney Head and neck CNS Pancreas Bladder Leukaemia Uterus Oesophagus Cancer of unknown primary Ovary Stomach Liver Myeloma Thyroid Other 0 5 10 15 20 25 30 35 40 45 50 55 60 Number of new cases (thousands) Male Female
- 159. The 10 hamarksof aer 131 7 death results in the recruitment of inammatory immune cells, promotion of angiogenesis and release of stimulatory factors that increase cellular proliferation and tissue invasion, thereby enhancing rather than inhibiting carcinogenesis. 3. Sustaining proliferative signalling The ‘cell cycle’ is tightly controlled at different stages. Normal cells grow and divide in response to external signals, typically growth factors. These are able to bind to cell surface-bound receptors that activate an intra- cellular tyrosine kinase-mediated signalling cascade, ultimately leading to changes in gene expression that promote cellular proliferation and growth. The cell cycle The cell cycle is composed of four ordered, strictly regulated phases referred to as G1 (gap 1), S (DNA synthesis), G2 (gap 2) and M (mitosis) (Fig. 7.2). Normal cells grown in culture will stop proliferating and enter a quiescent state called G0 once they become conuent or are deprived of serum or growth factors. The rst gap phase (G1 ) prior to the initiation of DNA synthesis represents the period of commitment that separates M and S phases as cells prepare for DNA duplication. Cells in G0 and G1 are receptive to growth signals, but once they have passed a restric- tion point, they are committed to enter DNA synthesis (S phase). Cells demonstrate arrest at different points in G1 in response to different inhib- itory growth signals. Mitogenic signals promote progression through G1 to S phase, utilising phosphorylation of the retinoblastoma gene product (pRB, p. 40). Following DNA synthesis, there is a second gap phase (G2 ) prior to mitosis (M), allowing cells to repair errors that have occurred during DNA replication and thus preventing propagation of these errors to daughter cells. Although the duration of individual phases may vary, depending on cell and tissue type, most adult cells are in a G0 state at any one time. Stimulation of the cell cycle Many cancer cells produce growth factors, which drive their own prolifer- ation by a positive feedback mechanism known as autocrine stimulation. Examples include transforming growth factor-alpha (TGF-α) and platelet- derived growth factor (PDGF). Other cancer cells express growth factor receptors at increased levels due to gene amplication or express abnor- mal receptors that are permanently activated. This results in abnormal cell growth in response to physiological growth factor stimulation or even in the absence of growth factor stimulation (ligand-independent signalling). The epidermal growth factor receptor (EGFR) is often over-expressed in lung and gastrointestinal tumours and the human epidermal growth fac- tor receptor 2 (HER2)/neu receptor is frequently over-expressed in breast cancer. Both receptors activate the Ras–Raf–mitogen activated protein (MAP) kinase pathway, causing cell proliferation. 4. Evading growth suppressors The cell cycle is orchestrated by a number of molecular mechanisms, most importantly by cyclins and cyclin-dependent kinases (CDKs). Cyclins bind to CDKs and are regulated by both activating and inacti- vating phosphorylation, with two main checkpoints at G1 /S and G2 /M transition. The genes that inhibit progression play an important part in tumour prevention and are referred to as tumour suppressor genes (e.g. TP53, TP21, TP16 genes). The products of these genes deactivate the cyclin–CDK complexes and are thus able to halt the cell cycle. The com- plexity of cell cycle control is susceptible to dysregulation, and mutations within inhibitory proteins are common in cancer. 5. Enabling replicative immortality Normal cells have a limited number of divisions before they are unable to divide further (senescence) or before they die (crisis). These limits are controlled by telomeric DNA sequences, which protect and stabilise chromosomal ends. During replication, telomeres shorten progressively as small fragments of telomeric DNA are lost with successive cycles of replication. This shortening process represents a mitotic clock and even- tually prevents the cell from dividing further. Telomerase, a specialised polymerase enzyme, adds nucleotides to telomeres, allowing continued cell division and thus preventing premature arrest of cellular replication. The telomerase enzyme is almost absent in normal cells but is expressed at signicant levels in the majority of human cancers. Fig. 7.2 The cell cycle and sites of action of chemotherapeutic agents. (CDK = cyclin-dependent kinase; RB = retinoblastoma gene) DNA replication checkpoint for: Damaged DNA RB blocks TP53 CDKs blocked Restriction point (regulated by growth factors) G1 Quiescent G1 Cell growth G0 Cyclin D CDK4, 6 Cell growth Cyclin E CDK2 G S M Cyclin A CDK2 Cyclin B CDK 2 1 Terminal differentiation Apoptosis Mitosis Prophase telophase Nuclear and cellular division Terminal differentiation Apoptosis G2 checkpoint for: DNA damage DNA replication incomplete Further growth or DNA repair
- 160. 132 OncOlOgy 6.Inducing angiogenesis All cells and body tissues require sustenance in the form of nutrients and oxygen, as well as an ability to evacuate metabolic waste products and carbon dioxide. Tumours require a functional vascular network to ensure continued growth and are unable to grow beyond 1mm3 without stimulating the development of a vascular supply through angiogenesis (Figs. 7.3 and 7.4). Angiogenesis is dependent on the production of angiogenic growth factors, of which vascular endothelial growth factor (VEGF) and plate- let-derived growth factor (PDGF) are the best characterised. During tumour progression, an angiogenic switch is activated and remains on, causing normally quiescent vasculature to develop new vessels continu- ally to help sustain expanding tumour growth. Angiogenesis is governed by a balance of pro-angiogenic stimuli and angiogenesis inhibitors, such as thrombospondin (TSP)-1, which binds to transmembrane receptors on endothelial cells and evokes suppressive signals. A number of cells can contribute to the maintenance of a functional tumour vasculature and therefore sustain angiogenesis. These include pericytes and a variety of bone marrow-derived cells such as macrophages, neutrophils, mast cells and myeloid progenitors. 7. Activating invasion and metastasis The ability to invade neighbouring tissue determines whether a tumour is benign or malignant. Clinically, the presence of metastases often determines whether a cancer can be cured. The invasion-metastatic cascade is a complex multistep process. The initiation of this process is enabled by epithelial-mesenchymal transition (EMT). Cancer cells in a tumour lose normal cell–cell adhesion through the down-regulation or, occasionally, mutational inactivation of E-cadherin, a calcium-dependent cell–cell adhesion glycoprotein. After breaking through the basement membrane, cancer cells enter the blood stream (intravasation). These cir- culating tumour cells (CTCs) then exit the blood stream into distant tissues (extravasation) to form small nodules of cancer cells (micrometastases). Fig. 7.3 Oncogenesis. The multistep origin of cancer, showing events implicated in cancer initiation, progression, invasion and metastasis. Basal lamina First mutation Inherited or acquired gain of oncogene Loss of tumour suppressor gene Normal epithelium Blood vessel Connective tissue Lymphatic First mutation Initial proliferation Clonal expansion Further mutation Further mutation; subset selected for rapid growth Localised Further mutation Blood spread Lymphatic spread Ectopic growth factor production and autostimulation Failed apoptosis (e.g. TP53 mutation) Local invasion through basal lamina Angiogenesis to support tumour growth (see Fig. 7.4) Breakdown of connective tissue via tumour production of e.g. collagenase tissue metalloproteinases Loss of cell adhesion molecules e.g. E-cadherin invasion or metastasis Inhibition Loss of inhibition Viable tumour cell Apoptotic tumour cell Angiogenic factors VEGF VEGF receptor Tissue factor αvβ3 integrin Plasminogen Coagulation factor Coagulation Fibrinogen Fibrin Cell adhesion Urokinase Urokinase receptor Proteolysis Plasmin A B C Fig. 7.4 Angiogenesis, invasion and metastasis. beyond 1mm3 the release of angiogenic factors by the tumour cells and loss of inhibition of the matrix allow cells to extravasate into the blood stream and metastasise to distant sites. (VEGF = vascular endothelial growth factor) Following mesenchymal–epithelial transition these micrometastatic lesions develop into macroscopic tumours (colonisation) (see Fig. 7.3). Cross-talk between cancer cells and cells of the surrounding stro- mal tissue is involved in the acquired capability for invasive growth and metastasis. Mesenchymal stem cells in tumour stroma have been found
- 161. Ivestiatios 133 7 tosecrete CCL5, a protein chemokine that helps recruit leucocytes into inammatory sites. With the help of particular T-cell-derived cytokines (interleukin (IL)-2 and interferon-gamma (IFN-γ)), CCL5 induces pro- liferation and activation of natural killer cells and then acts reciprocally on cancer cells to stimulate invasive behaviour. Macrophages at the tumour periphery can foster local invasion by supplying matrix-degrading enzymes such as metalloproteinases and cysteine cathepsin proteases. 8. Deregulating cellular energetics Under aerobic conditions, oxidative phosphorylation functions as the main metabolic pathway for energy production; cells process glucose, rst to pyruvate via glycolysis and thereafter to carbon dioxide in the mitochondria. While under anaerobic conditions, glycolysis is favoured to produce adenosine triphosphate (ATP). Cancer cells can reprogram their glucose metabolism to limit energy production to glycolysis, even in the presence of oxygen. This has been termed ‘aerobic glycolysis’. Up-regulation of glucose transporters, such as GLUT1, is the main mechanism through which aerobic glycolysis is achieved. This reprogramming of energy metabolism appears paradoxical, as overall energy production from glycolysis is signicantly lower (18-fold) than that from oxidative phosphorylation. One explanation may be that the increased production of glycolytic intermediates can be fed into var- ious biosynthetic pathways, including those that generate the nucleo- sides and amino acids, necessary for the production of new cells. 9. Tumour-promoting inammation Almost all tumours show inltration with immune cells on pathological inves- tigation and historically this nding was thought to represent an attempt of the immune system to eradicate the cancer. It is now clear that tumour- associated inammatory responses contribute to several hallmark capabili- ties and promote tumour formation and cancer progression. Immune cells may promote invasive behaviour, and bioactive molecules such as cytokines, growth factors and pro-angiogenic factors may be released into the tumour microenvironment. In particular, the release of reactive oxygen species, which are actively mutagenic, will accelerate the genetic evolution of surrounding cancer cells, enhancing growth and contributing to cancer progression. 10. Evading immune destruction Cancer cells continuously shed antigens into the circulatory system, prompting an immune response that includes cytotoxic T-cell, natural killer cell and macrophage production. The immune system is thought to provide continuous surveillance, with resultant elimination of cells that undergo malignant transformation. However, if not all cancer cells are eliminated there may be a period of equilibrium where tumour growth is controlled by the immune system and cancer cells may enter a dormant state, sometimes for many years. Alternatively, cancer cells may escape immune control and grow into clinically apparent tumours. Several fac- tors may contribute to immune escape, including reduced immune rec- ognition, increased resistance or survival and the development of an immunosuppressive tumour microenvironment. Immune checkpoints are increasingly recognised as key factors in the immune escape of tumours. These pathways are crucial for regulating the immune response to normal cells by down-regulating the immune system and promoting self-tolerance by suppressing T-cell immune activity. However, some cancers co-opt these protective mechanisms by stimulating immune checkpoint molecular targets such as the pro- grammed cell death ligand (PD-L1), a protein that helps stop immune cells from attacking other cells in the body (see Fig. 7.12). Environmental and genetic determinants of cancer The majority of cancers do not have a single cause but rather are the result of a complex interaction between genetic factors and exposure to environmental carcinogens. These are often tumour type-specic but some general principles do apply. Environmental factors Environmental triggers for cancer have mainly been identied through epidemiological studies that examine patterns of distribution of cancers in patients in whom parameters such as age, sex, presence of other illnesses, social class, geography and diet differ. Sometimes, these give strong pointers to the molecular or cellular causes of the disease, such as the association between aatoxin production within contaminated food supplies and hepatocellular carcinomas. For most solid cancers, however, there is evidence of a multifactorial pathogenesis, even when there is a principal environmental cause (Box 7.1). Smoking is now established beyond all doubt as a major cause of lung cancer, but there are additional predisposing factors since not all smok- ers develop cancer. Similarly, most carcinomas of the cervix are related to infection with human papillomavirus (HPV subtypes 16 and 18). For carcinomas of the bowel and breast, there is strong evidence of an envi- ronmental component. For example, the risk of breast cancer in women of Far Eastern origin remains relatively low when they rst migrate to a country with a Western lifestyle, but rises in subsequent generations to approach that of the resident population of the host country. The precise environmental factors that cause this change are unclear but may include diet (higher intake of saturated fat and/or dairy products), reproductive patterns (later onset of rst pregnancy) and lifestyle (increased use of articial light and shift in diurnal rhythm). Genetic factors A number of inherited cancer syndromes are recognised and account for 5%–10% of all cancers (Box 7.2). Their molecular basis is discussed in Chapter 3, but in general they result from inherited mutations in driver genes that regulate cell growth, cell death and apoptosis. Although carri- ers of these gene mutations have a greatly elevated risk of cancer, none has 100% penetrance and additional modulating factors, both genetic and environmental, are likely to be operative. Exploration of a possible genetic contribution is a key part of cancer management. It may inform anti-cancer therapy decisions in people with cancer. Patients and their family members may also benet from screening investigations to detect cancer early, or preventative treatments such as prophylactic mastec- tomy in women who carry a BRCA1 or BRCA2 mutation. Investigations When a patient is suspected of having cancer, a full history should be taken. Attention should be paid to potential risk factors such as smoking and occupational exposures, any family history of cancer and elucidating potential complications of the disease. A thorough clinical examination is essential to identify both the primary cancer site and possible sites of metastases, and to discover any other conditions that may have a bear- ing on the management plan. In order to plan the most appropriate investigations and management, information is needed on: the extent of disease the type of cancer the patient’s tness. Determining the extent of disease (staging) The extent of disease, such as how large a tumour is and if it has spread, is determined by the process of staging. It entails clinical examination, imaging (e.g. CT, MRI, PET), specialised investigations (e.g. colonoscopy, endoscopy, laparoscopy, mediastinoscopy) and, in some cases, surgery. The outcome is recorded using a standard staging classication that
- 162. 134 OncOlOgy 7.1Environmental factors that predispose to cancer Environmental aetiology Processes Diseases Occupational exposure (see ‘Radiation’ below) Dye and rubber manufacturing (aromatic amines) Bladder cancer Asbestos mining, construction work, shipbuilding (asbestos) Lung cancer and mesothelioma Vinyl chloride (PVC) manufacturing Liver angiosarcoma Petroleum industry (benzene) Acute leukaemia Chemicals Cytotoxic chemotherapy (e.g. melphalan, cyclophosphamide) Acute myeloid leukaemia Cigarette smoking Exposure to carcinogens from inhaled smoke Lung, throat, oesophagus and bladder cancer Viral infection Epstein–Barr virus Human papillomavirus Hepatitis B and C viruses Burkitt lymphoma and nasopharyngeal cancer Cervical cancer, anal cancer, oropharyngeal cancer Hepatocellular carcinoma Bacterial infection Helicobacter pylori Gastric MALT lymphomas, gastric cancer Parasitic infection Liver uke (Opisthorchis sinensis) Schistosoma haematobium Cholangiocarcinoma Squamous cell bladder cancer Dietary factors Low-roughage/high-fat content diet High nitrosamine intake Aatoxin from contamination of Aspergillus avus Colonic cancer Gastric cancer Hepatocellular cancer Obesity Reduced physical activity, increased insulin Increased oestrogen Colon cancer Breast and endometrial cancer Radiation UV exposure Basal cell carcinoma Melanoma Non-melanocytic skin cancer Nuclear fallout following explosion (e.g. Hiroshima, Chernobyl) Leukaemia Solid tumours, e.g. thyroid Diagnostic exposure (e.g. CT) Cholangiocarcinoma following Thorotrast usage Occupational exposure (e.g. beryllium and strontium mining) Lung cancer Therapeutic radiotherapy Medullary thyroid cancer Sarcoma Inammatory diseases Ulcerative colitis Colon cancer Hormonal Use of diethylstilbestrol Oestrogens Vaginal cancer Endometrial cancer Breast cancer (CT = computed tomography; MALT = mucosa-associated lymphoid tissue; UV = ultraviolet) allows comparisons to be made between different groups of patients. One of the most commonly used systems is the T (tumour), N (regional lymph nodes), M (metastatic sites) approach of the International Union against Cancer (UICC, see Box 7.3). For most cancers staging will dene patients into having: early, localised disease, which can be cured with surgery or other localised therapy (e.g. radiotherapy or ablative therapies) locally advanced disease, which can often be cured with a com- bination of surgery and/or systemic anti-cancer therapy and radiotherapy metastatic disease, where the cancer has spread to distant sites, which can only rarely be cured with systemic anti-cancer therapy, radiotherapy and/or surgery. Imaging plays a critical role in the diagnosis and staging of cancer. It is also used to determine the response to treatment. The imaging modality employed depends primarily on the site of the disease and likely patterns of spread. Computed tomography Computed tomography (CT) is a key investigation in cancer patients and is particularly useful in imaging the thorax and abdomen (Fig. 7.5). With modern scanners it is possible to visualise the large bowel if it is prepared (CT colonography), allowing accurate detection of colorectal cancers and adenomas ≥10mm. Ultrasound Ultrasound is useful in characterising lesions within the liver, kidney, pan- creas and reproductive organs. It may be used for guiding biopsies of tumours in the breast and liver. Endoscopic ultrasound is helpful in stag- ing upper gastrointestinal and pancreatic cancers, involving a special endoscope with an ultrasound and biopsy probe attached. Magnetic resonance imaging Magnetic resonance imaging (MRI) has a high resolution and is the pre- ferred technique for brain, bone and pelvic imaging. It is widely employed for the staging of rectal, cervical and prostate cancers. Positron emission tomography Positron emission tomography (PET) visualises metabolic activity of tumour cells and is often used in combination with CT (PET–CT) to eval- uate the extent of the disease, particularly in the assessment of potential distant metastases when a radical treatment approach is being consid- ered. Not all tumour types are ‘PET-avid’ and the metabolic activity of
- 163. Ivestiatios 135 7 7.2Inherited cancer predisposition syndromes Syndrome Malignancies Inheritance Gene Ataxia telangiectasia Leukaemia, lymphoma, ovarian, gastric, brain, colon AR AT Bloom syndrome Leukaemia, tongue, oesophageal, colonic, Wilms' tumour AR BLM Breast/ovarian Breast, ovarian, colonic, prostatic, pancreatic AD BRCA1, BRCA2 Cowden syndrome Breast, thyroid, gastrointestinal tract, pancreatic AD PTEN Familial adenomatous polyposis Colonic, upper gastrointestinal tract AD APC, MUTYH Familial atypical multiple mole melanoma (FAMMM) Melanoma, pancreas AD CDKN2A (TP16) Fanconi anaemia Leukaemia, oesophageal, skin, hepatoma AR FACA, FACC, FACD Gorlin syndrome Basal cell skin, brain AD PTCH Hereditary diffuse gastric cancer Diffuse gastric cancer AD E-cadherin Hereditary non-polyposis colon cancer (HNPCC) Colonic, endometrial, ovarian, pancreatic, gastric AD MSH2, MLH1, MSH6, PMS1, PMS2 Li–Fraumeni syndrome Sarcoma, breast, osteosarcoma, leukaemia, glioma, adrenocortical AD TP53 Multiple endocrine neoplasia (MEN) 1 Pancreatic islet cell, pituitary adenoma, parathyroid adenoma and hyperplasia AD MEN1 MEN 2 Medullary thyroid, phaeochromocytoma, parathyroid hyperplasia AD RET Neurobromatosis 1 Neurobrosarcoma, phaeochromocytoma, optic glioma AD NF1 Neurobromatosis 2 Vestibular schwannoma AD NF2 Papillary renal cell cancer syndrome Renal cell cancer AD MET Peutz–Jegher syndrome Colonic, ileal, breast, ovarian AD STK11 Prostate cancer Prostate AD HPC1 Retinoblastoma Retinoblastoma, osteosarcoma AD RB1 von Hippel–Lindau syndrome Haemangioblastoma of retina and CNS, renal cell, phaeochromocytoma AD VHL Wilms’ tumour Nephroblastoma, neuroblastoma, hepatoblastoma, rhabdomyosarcoma AD WT1 Xeroderma pigmentosum Skin, leukaemia, melanoma AR XPA, XPC, XPD (ERCC2), XPF (AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system) small but malignant lymph nodes may not be detected, limiting the sen- sitivity of PET-CT. Biochemical markers Many cancers produce substances called tumour markers, some of which may assist in diagnosis, response evaluation and detection of relapse. Unfortunately, most tumour markers are neither sufciently sen- sitive nor sufciently specic to be used in isolation for diagnosis and need to be interpreted in the context of other clinical features. Some can be used for antibody-directed therapy or imaging, where they have a greater role in diagnosis. Tumour markers in routine use are outlined in Box 7.4 Establishing the type of cancer In most cases a biopsy is required in order to establish the tumour type. Biopsies can be taken at endoscopy, laparoscopy, surgery or by ultra- sound- or CT- guided biopsy with the help of interventional radiology. At times a diagnosis can be obtained by examination of cells (cytology) from uid (e.g. pleural or peritoneal), from a smear (e.g. cervical) or by doing ne needle aspiration of a palpable or visible lump (Box 7.5). 7.3 TNM classication Extent of primary tumour* TX T0 T1 T2 T3 T4 Not assessed No tumour Increase in primary tumour size or depth of invasion Increased involvement of nodes* NX N0 N1 N2/3 Not assessed No nodal involvement Increases in involvement Presence of metastases MX Not assessed M0 Not present M1 Present *Exact criteria for size and region of nodal involvement have been dened for each anatomical site.
- 164. 136 OncOlOgy Fig.7.5 Computed tomography (CT) images. after cytotoxic chemotherapy showing a partial radiological response to treatment. These remain stable 9 years later. A B P P 7.4 Commonly used serum tumour markers Name Natural occurrence Tumours Alpha-fetoprotein (AFP) Glycoprotein found in yolk sac and fetal liver tissue. Transient elevation in liver diseases. Has a role in screening during pregnancy for the detection of neural tube defects and Down syndrome Ovarian non-seminomatous germ cell tumours (80%), testicular teratoma (80%), hepatocellular cancer (50%) Beta-2-microglobulin A human leucocyte antigen (HLA) common fragment present on surface of lymphocytes, macrophages and some epithelial cells. Can be elevated in autoimmune disease and renal glomerular disease Non-Hodgkin lymphoma, myeloma Calcitonin 32-amino-acid peptide from C cells of thyroid. Used to screen for MEN 2 Medullary cell carcinoma of thyroid Cancer antigen 125 (CA-125) Differentiation antigen of coelomic epithelium (Müller’s duct). Raised in any cause of ascites, pleural effusion or heart failure. Can be raised in inammatory conditions Ovarian epithelial cancer (75%), gastrointestinal cancer (10%), lung cancer (5%) and breast cancer (5%) CA-19.9 A mucin found in epithelium of fetal stomach, intestine and pancreas. It is eliminated exclusively via bile and so any degree of cholestasis can cause levels to rise Pancreatic cancer (80%), mucinous tumour of the ovary (65%), gastric cancer (30%), colon cancer (30%) Carcinoembryonic antigen (CEA) Glycoprotein found in intestinal mucosa during embryonic and fetal life. Elevated in smokers, cirrhosis, chronic hepatitis, ulcerative colitis, pneumonia Colorectal cancer, particularly with liver metastasis, gastric cancer, breast cancer, lung cancer, mucinous cancer of the ovary Human chorionic gonadotrophin (hCG) Glycoprotein hormone, 14kD α subunit and 24kD β subunit from placental syncytiotrophoblasts. Used for disease monitoring in hydatidiform mole and as the basis of a pregnancy test Choriocarcinoma (100%), hydatidiform moles (97%), ovarian non-seminomatous germ cell tumours (50%–80%), seminoma (15%) Placental alkaline phosphatase (PLAP) Isoenzyme of alkaline phosphatase Seminoma (40%), ovarian dysgerminoma (50%) Prostate-specic antigen (PSA) Glycoprotein member of human kallikrein gene family. PSA is a serine protease that liquees semen in excretory ducts of prostate. Can be elevated in benign prostatic hypertrophy and prostatitis Prostate cancer (95%) Thyroglobulin Matrix protein for thyroid hormone synthesis in normal thyroid follicles Papillary and follicular thyroid cancer (MEN = multiple endocrine neoplasia) Histopathology Histopathological analysis of tumour tissue is pivotal in identifying the type of cancer and provides information that may direct subsequent management. The results of histopathological analysis are most informa- tive when combined with knowledge of the clinical picture; biopsy results should therefore be reviewed and discussed within the context of a multi- disciplinary team meeting. Light microscopy Examination of tumour samples by light microscopy remains the core method of cancer diagnosis and, in cases where the primary site is unclear, may give clues to the origin of the tumour: Signet-ring cells favour a gastric primary. Presence of melanin favours melanoma.
- 165. Ivestiatios 137 7 Mucin is common in gut/lung/breast/endometrial and ovarian cancers. Psammoma bodies are a feature of ovarian cancer (mucin +) and thyroid cancer (mucin ). Immunohistochemistry Immunohistochemical (IHC) staining for tumour markers can provide useful diagnostic information and may help with treatment decisions. Commonly used examples of IHC in clinical practice include: Oestrogen (ER) and progesterone (PR) receptor positivity indicate that the cancer may be sensitive to hormonal manipulation. Alpha-fetoprotein (AFP) and human chorionic gonadotrophin (hCG) favour germ-cell tumours. Prostate-specic antigen (PSA) favours prostate cancer. Cytokeratins and epithelial membrane antigen (EMA) favour epithelial carcinomas. HER2 receptor positivity in breast or gastric cancers indicate that the tumour may respond to HER2 inhibitor targeted therapy. T-cell receptor and cluster designation (CD) antigen expression aid in the diagnosis and classication of lymphomas. Molecular pathology Molecular proling of individual tumours is used to better understand their clinical behaviour and to stratify treatment options. Treatment selec- tion is increasingly tailored to specic ‘druggable’ molecular pathways which include: EGFR mutations – predict response to EGFR inhibitor targeted therapy in lung cancer RAS mutations – predict resistance to EGFR inhibitor targeted therapy in colon cancer ALK fusion oncogene rearrangement – predict response to ALK inhibitor targeted therapy in lung cancer microsatellite instability – predict response to checkpoint inhibitor immunotherapy in several cancer types Cytogenetic analysis Some tumours demonstrate typical chromosomal changes that help in diagnosis. The utilisation of uorescent in situ hybridisation (FISH) tech- niques can be useful in Ewing's sarcoma and peripheral neuro-ectodermal tumours where there is a translocation between chromosome 11 and 22: t(11;22)(q24;q12). In some cases, gene amplication can be detected via FISH (e.g. determining over-expression of HER2/neu). Assessing tness When making decisions about investigations and management in patients with cancer it is important to consider an individual’s general condition and comorbidities. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) scale is used to formally assess a patient’s t- ness (Box 7.6). Outcomes for patients with PS 3–4 are worse in almost all malignancies than for those with PS 0–2, and this has a strong inu- ence on the approach to treatment in the individual patient. Additionally, outcomes are typically worse for patients with a low albumin and raised inammatory markers (i.e. white blood cell count, C-reactive protein). Comorbidities also frequently inuence treatment options. For example, hepatic or renal dysfunction means some systemic therapies cannot be used or can only be given in lower doses. In some patients poor tness or comorbidities may preclude any anti-cancer therapy options, in which case comprehensive diagnostic and staging investigations add little clini- cal value and may not be in the best interests of the patient. Although the incidence of cancer increases with patient age, the approach to investigation and management is similar at all ages (Box7.7). However, assessing tness in this group of patients can be difcult, with 7.5 How to perform a ne needle aspiration (FNA) of a tumour/ lesion Ensure the patient is in a comfortable position with the lesion accessible to the operator. Identify the tumour, conrm that it is easily palpable and make sure there are no nearby critical structures. If tumour is not palpable or concern about nearby critical structures then perform FNA under ultrasound guidance. Clean the skin over the lesion. Inject local anaesthetic (if required) into the skin over the lesion. Label glass slide(s) and have ready near to the patient. Immobilise the lesion between thumb and forenger of one hand. Introduce needle (usually with syringe attached) into lesion with the other hand. When the needle tip is at the edge of the lesion, apply negative pressure by pulling on the syringe and continue to enter the lesion. Make multiple rapid passes through the lesion, varying the angles if necessary. Stop sampling if blood is seen in the syringe hub as blood reduces the quality of the sample. Release the negative pressure while the needle is still in the lesion. Withdraw the needle and expel the cellular material from the needle onto the labelled glass slide(s) for pathological evaluation. 7.6 Eastern Cooperative Oncology Group (ECOG) performance status scale 0 Fully active, able to carry on all usual activities without restriction and without the aid of analgesics 1 Restricted in strenuous activity but ambulatory and able to carry out light work or pursue a sedentary occupation.This group also contains patients who are fully active, as in grade 0, but only with the aid of analgesics 2 Ambulatory and capable of all self-care but unable to work. Up and about more than 50% of waking hours 3 Capable of only limited self-care, conned to bed or chair more than 50% of waking hours 4 Completely disabled, unable to carry out any self-care and conned totally to bed or chair 7.7 Cancer in old age Incidence: around 50% of cancers occur in the 15% of the population aged over 65 years. Screening: women over 65 in the UK are not invited to breast cancer screening but can request it. Uptake is low despite increasing incidence with age. Presentation: may be later for some cancers. When symptoms are non- specic, patients (and their doctors) may initially attribute them to age alone. Life expectancy: an 80-year-old woman can expect to live 8 years, so cancer may still shorten life and an active approach remains appropriate. Prognosis: histology, stage at presentation and observation for a brief period are better guides to outcome than age. Rate of progression: malignancy may have a more indolent course. This is poorly understood but may be due to reduced effectiveness of angiogenesis with age, inhibiting the development of metastases. Response to treatment: equivalent to that in younger people – well documented for a range of cancers and for surgery, radiotherapy, cytotoxic chemotherapy and hormonal therapy. Toxicity of treatment: may be greater due to subclinically reduced baseline hepatic, renal and bone marrow function and reduced baseline energy. Treatment selection: chronological age is of minor importance compared to comorbid illness and patient choice. Although older patients can be treated effectively and safely, aggressive intervention is not appropriate for all. Symptom control may be all that is possible or desired by the patient.
- 166. 138 OncOlOgy increasingcomorbidity and declining physiological reserve in particular placing patients at increased risk of treatment toxicity. Geriatric assess- ment tools to assess patient tness and toxicity risks have been developed. Multidisciplinary teams The multidisciplinary team (MDT) is well established in oncology and meets on a regular basis to discuss patient progress and provide a forum for patient-centred, interdisciplinary communication to coor- dinate care and decision-making. It is a platform on which individual clinicians can discuss complex cases or situations and draw on the collective experience of the team membership to decide on the best approach for an individual patient. This can be particularly important when discussing patients with a rare condition or in an unusual situation. As a minimum, most MDTs include a radiologist, pathologist, specialist physician, specialist surgeon, radiation oncologist, medical oncologist, nurse specialist, auditor and scheduler. Additional staff may be relevant to different MDTs, e.g. dermatologists in skin cancer MDTs, dieticians in upper gastrointestinal cancer MDTs, stoma nurses in colorectal can- cer MDTs, palliative care doctors in pancreatic cancer or cancer of unknown primary (CUP) MDTs. Specic roles of the MDT are outlined in Box 7.8 Acute oncology Cancer centres are usually based in cities and have busy radiother- apy and systemic anti-cancer therapy units containing specialist equipment and teams of highly trained physicians, surgeons, nurses, pharmacists, radiographers, physicists and support workers amongst others. Most patients with cancer undergo investigations, assess- ments and treatment as outpatients. However, patients may present acutely to any specialty in any hospital with a new cancer, cancer-re- lated symptoms, emergency complications of cancer or with treat- ment-related toxicities. Acute presentation of new cancer Despite cancer screening initiatives, most patients still present with symp- tomatic disease. They may have symptoms related to the local effect of a primary tumour or metastatic deposit, such as nding a lump, dyspha- gia or persistent pain. These are sometimes called ‘red ag’ symptoms of cancer (Box 7.9). Patients may present with constitutional symptoms such as unexplained weight loss, fatigue or fevers. Paraneoplastic syn- dromes due to the production of biologically active hormones by the tumour, or as the result of an immune response to the tumour, may also be the presenting symptom of new cancer (Box 7.10). The pattern of symptoms, detailed clinical history and examination will most often direct the initial investigations and early referral to the appropriate specialist multidisciplinary team. Cancer of unknown primary (CUP) When a patient is found to have advanced or metastatic cancer but history, examination and imaging is unable to dene a primary cancer site, an assessment of patient tness, disease extent, comorbidities and patient wishes should be made. Selected investigations should be car- ried out (Box7.11). However, a primary cancer site does not need to be ‘hunted down’ in all patients and investigations should be limited to those that will help management. Specialist investigations (e.g. endos- copies) are only indicated when there is radiological suspicion or if there are localising symptoms. In some cases, such as those with clinical suspicion of germ cell tumours, high-grade lymphoma or small cell cancer, or those present- ing with oncological emergencies, urgent referral directly to oncology or haematology is essential to allow rapid initiation of anti-cancer therapy, sometimes before investigations are completed (Fig. 7.6). If patients are t to undergo investigations and t enough to be consid- ered for treatment then a core biopsy of the most accessible metastatic 7.8 Specic roles of the cancer multidisciplinary team (MDT) Agreeing on cancer type and nal stage. Deciding on the appropriate primary treatment modality (most commonly surgery but the use of neoadjuvant systemic anti-cancer therapy and/or radiotherapy before surgery is increasing). Arranging review by the appropriate team to coordinate management. Planning surveillance strategies. Diagnosing cancer recurrence or metastases. Ensuring the appropriate transition from treatment with curative intent to that of palliation. Promoting recruitment into clinical trials. Agreeing on operational policies to deliver high-quality care to patients. Planning and reviewing audit data to ensure delivery of quality care to patients. Identifying late effects of cancer treatments. 7.9 Red ag symptoms of malignancy Symptom Typical site or possible tumour Lump Breast, lymph node (any site), testicle Skin abnormality Melanoma, basal cell carcinoma Bleeding Stomach, colon, lung, endometrium, bladder, kidney Dysphagia, odynophagia Oesophagus, bronchus, gastric, head and neck Change in bowel habit Colon, rectum, ovary Cough, hoarseness, stridor Lung, head and neck, thyroid Bone pain or fracture Bone (primary sarcoma, secondary metastasis from breast, prostate, bronchus, thyroid, kidney) Abdominal swelling (ascites) Ovary, stomach, pancreas Unexplained weight loss, anorexia Lung, gastrointestinal tract, CUP Unexplained fatigue Any (CUP = cancer of unknown primary) 7.10 Paraneoplastic syndromes Feature Common cancer site associations Lambert–Eaton myasthenic syndrome Small cell lung cancer Subacute cerebellar degeneration Small cell lung cancer, ovarian cancer Encephalomyelitis Small cell lung cancer Retinopathy Non-small cell lung cancer Dermatomyositis/polymyositis Gastric, lung cancer Acanthosis nigricans Gastric, oesophageal cancer Vitiligo Melanoma Pruritus Lymphoma, leukaemia, central nervous system tumours Pemphigus Lymphoma, Kaposi’s sarcoma, thymic Dermatitis herpetiformis Enteropathy-associated T-cell lymphoma (EATL)
- 167. Aute ooo 139 7 Metastatic malignant disease of undened primary origin (MUO) Patients who present as emergencies to hospital with symptomatic new metastatic cancer often have a short prognosis. Features associated with poor prognosis, irrespective of subsequent diagnosis, include: poor performance status (PS 3–4), requirement for hospital admission, bulky or multi-organ metastatic disease, signicant comorbidity, raised LDH, raised inammatory markers and low albumin. Further investigations, including biopsy, may not be warranted and honest conversations about palliative care and end-of-life planning are often preferable. Appropriate analgesia, palliative radiotherapy (for bleeding or pain) and interventional/ surgical palliation can all help improve symptoms. Oncological emergencies Oncological emergencies are a group of potentially life-threatening con- ditions that occur as a direct result of cancer or its treatment. Positive outcomes depend upon prompt recognition and implementation of appropriate management. Malignant spinal cord compression Malignant spinal cord compression complicates 5% of cancers and is most common in myeloma, prostate, breast and lung cancers that most frequently involve bone. Malignant spinal cord compression often results from posterior extension of a vertebral body mass but intrathecal spinal cord metastases can cause similar signs and symptoms. The thoracic region is most commonly affected (Fig. 7.7). Clinical features The earliest sign is back pain, often rapidly worsening or in a ‘band’, most marked on coughing and lying at. Subsequently, sensory changes develop in dermatomes below the level of compression, and motor weakness distal to the block occurs. Finally, sphincter distur- bance, causing urinary retention and bowel incontinence, is observed. 7.11 Initial diagnostic tests in patients presenting with carcinoma of unknown primary Detailed medical history and examination, including breast, nodal areas, skin, genital, rectal and pelvic regions Full blood count, urea and electrolytes, renal function, liver function tests, albumin, calcium, urinalysis, lactate dehydrogenase, CRP Myeloma screen (if lytic bone lesions) CT scan of chest, abdomen and pelvis CT neck if thyroid lump or neck nodes Histological examination by biopsy, with immunohistochemistry and/or molecular pathology if required Upper or lower gastrointestinal endoscopy if gastrointestinal symptoms Mammography and/or breast MRI for women with axillary nodes or adenocarcinoma Breast MRI for women with adenocarcinoma limited to axillary nodes Testicular ultrasound (if midline disease in young man or clinical features suggest germ cell tumour) Naso-endoscopy for squamous neck nodes PET scan for single-site disease or squamous neck nodes with no primary on endoscopic evaluation Tumour markers: prostate-specic antigen (PSA) in men with bone lesions, cancer antigen 125 (CA-125) in women with peritoneal malignancy or ascites, α-fetoprotein (AFP) in liver-limited disease, α-fetoprotein (AFP) and human chorionic gonadotrophin (hCG) in midline disease in young men (CRP = C-reactive protein; CT = computed tomography; MRI = magnetic resonance imaging; PET = positron emission tomography) Fig. 7.6 Young male patient presenting with a bulky midline tumour and elevated hCG and AFP suggestive of a non-seminomatous testicular cancer. P lesion is usually the quickest way of obtaining tissue for pathological eval- uation of cancer type. Review of tumour morphology, immunohistochem- istry and molecular pathology will usually be sufcient to plan appropriate treatment. Patients with clinico-pathological features suggestive of a particular cancer should be identied early and referred promptly to the appropriate multidisciplinary/oncology team for consideration of further investigations and treatment. Where the primary site remains unclear fol- lowing comprehensive investigations, a patient is said to have a cancer of unknown primary (CUP). Whilst it is crucial to identify patients with highly treatable CUPs (Box 7.12), some of whom can live for years (see Fig. 7.5), or even be cured by treatment, most CUPs are poorly differentiated cancers or adenocarcinomas with liver and/or multi-site metastases. These cancers often behave aggressively so early discussion with oncology, within the context of a specialist MDT, is essential to streamline investi- gations and assess tness for anti-cancer treatment. Whilst responses to generic systemic anti-cancer treatment are modest, gene expression tests or molecular tumour proling are increasingly providing greater information about likely tissue of origin or possible treatment targets which may ultimately lead to improved understanding of CUP and better outcomes. 7.12 Cancer of unknown primary – favourable clinicopathological features Clinicopathological features Management Women with serous papillary adenocarcinoma of the peritoneal cavity Treat like ovarian cancer Women with isolated adenocarcinoma of axillary lymph nodes Treat like breast cancer Men with poorly differentiated carcinoma with midline distribution Treat like germ cell cancer Poorly differentiated neuro-endocrine carcinoma of unknown origin Treat like small cell cancer Well-differentiated neuro-endocrine tumour (NET) Treat with somatostatin analogues or as per NETs of known primary sites Squamous cell carcinoma of non- supraclavicular cervical lymph nodes Treat like head and neck squamous cell cancer Adenocarcinoma with a colorectal-IHC prole (CK20+ , CK7 , CDX2+ ) Treat like colon cancer Men with blastic bone metastases or elevated prostate-specic antigen (adenocarcinoma) Treat like prostate cancer Isolated inguinal adenopathy squamous carcinoma Treat like anogenital squamous cancer Patients with one small, potentially resectable tumour Assess for surgical resection
- 168. 140 OncOlOgy Involvementof the lumbar spine may cause conus medullaris or cauda equina compression (Box 7.13). Physical examination ndings consist- ent with an upper motor neuron lesion, but lower motor neuron nd- ings, may predominate early on or in cases of nerve root or cauda equina compression. Management Malignant spinal cord compression is a medical emergency and should be treated with analgesia and high-dose glucocorticoid therapy (Box 7.14). Neurosurgical intervention produces superior outcomes and survival compared to radiotherapy alone, and should be considered rst for all patients. It is the preferred treatment if there is a single site of disease, low volume metastatic disease, if a biopsy is required to make a diagnosis or if it is a treatable cancer (e.g. lymphoma, breast cancer). Radiotherapy is used for the remaining patients and selected tumour types when the cancer is likely to be radiosensitive. The prognosis varies considerably, depending on tumour type, but the degree of neurological dysfunction at presentation is the strongest predictor of outcome, irre- spective of the underlying diagnosis. Mobility can be preserved in more Fig. 7.7 MRI images of patient presenting with back pain and lower limb neurological disturbance. arising from thoracic vertebra compressing spinal cord. B A 7.13 Comparison of features of neurological decit Clinical feature Spinal cord Conus medullaris Cauda equina Weakness Symmetrical and profound Symmetrical and variable Asymmetrical, may be mild Reexes Increased (or absent) knee and ankle reexes with extensor plantar reex Increased knee reex, decreased ankle reex, extensor plantar reex Decreased knee and ankle reexes with exor plantar reex Sensory loss Symmetrical, sensory level Symmetrical, saddle distribution Asymmetrical, radicular pattern Sphincters Late loss Early loss Often spared Progression Rapid Variable Variable 7.14 Management of suspected spinal cord compression Conrm diagnosis with urgent MRI scan of whole spine Administer high-dose glucocorticoids: Dexamethasone 16mg IV or oral stat Dexamethasone 8mg twice daily orally Ensure adequate analgesia Refer for surgical decompression or urgent radiotherapy (IV = intravenous; MRI – magnetic resonance imaging)
- 169. Aute ooo 141 7 than 80% of patients who are ambulatory at presentation, but neurologi- cal function is seldom regained in patients with established decits such as paraplegia. Superior vena cava obstruction Superior vena cava obstruction (SVCO) is a common complication of cancer that can occur through extrinsic compression or intravascu- lar blockage. The most common causes of extrinsic compression are lung cancer, lymphoma and metastatic tumours (Fig. 7.8). Patients with cancer can also develop SVCO due to intravascular blockage in asso- ciation with a central catheter or thromboembolism secondary to the tumour. Clinical features The classical presentation is with breathlessness, oedema of the arms and face, distended neck and arm veins and dusky skin coloration over the chest, arms and face. Collateral vessels may develop over a period of weeks and the ow of blood in the collaterals helps to conrm the diag- nosis. Headache secondary to cerebral oedema arising from the back- ow pressure may also occur and tends to be aggravated by bending forwards, stooping or lying down. The severity of symptoms is related to the rate of obstruction and the development of a venous collateral circu- lation. Accordingly, symptoms may develop rapidly or gradually. Clinical features are summarised in Box 7.15 Investigations and management The investigation of choice is a CT scan of the thorax to conrm the diag- nosis and distinguish between extra- and intravascular causes. A biopsy should be obtained when the tumour type is unknown because tumour type has a major inuence on treatment. CT of the head may be indicated if cerebral oedema is suspected. Tumours that are exquisitely sensitive to cytotoxic chemotherapy, such as germ cell tumours and lymphoma, can be treated with cytotoxic chemotherapy alone. For most other patients with symptomatic SVCO, SVC stenting provides the best outcomes although mediastinal radiotherapy may also be considered. Where possible, these measures should be followed by treatment of the primary tumour, as long-term outcome is strongly dependent on the prognosis of the underlying cancer. Neutropenic fever Neutropenia is a common complication of malignancy. It is usually sec- ondary to cytotoxic chemotherapy but may occur with radiotherapy, if large amounts of bone marrow are irradiated, and some targeted therapy agents; it may also be a component of pancytopenia due to malignant inltration of the bone marrow. After cytotoxic chemotherapy neutropenic fever is most commonly dened as a single oral temperature of ≥38.3°C or a temperature of ≥38°C sustained for over 1hour in a patient with a neutrophil count of <0.5 × 109 /L (or <1.0 × 109 /L if the nadir is anticipated to drop to <0.5 × 109 /L in the next 48hours). The risk of sepsis is greater with profound neutropenia (neutrophil count <0.1 × 109 /L), prolonged neu- tropenia (<0.5 neutrophils for ≥7 days) or a rapid rate of decline in neu- trophils as well as the presence of other risk factors, such as intravenous cannulae or urinary catheters. Neutropenic fever is an emergency in can- cer patients as, if left untreated, it can result in sepsis with a high mortality rate. Clinical features The typical presentation is with high fever, and affected patients may feel non-specically unwell. If patients have been taking paracetamol or steroids then fever or symptoms may be masked. Examination is usually unhelpful in dening a primary source of the infection. Hypotension is an adverse prognostic feature and may progress to systemic circulatory shutdown and organ failure. Investigations and management An infection screen should be performed, including blood cultures (both peripheral and from central lines), urine culture, chest X-ray and swabs for culture (throat, central line, wound). High-dose intravenous antibiotics should be commenced (ideally within 1hour of admission) for all febrile patients on systemic anti-cancer therapy, without awaiting test results. The standard approach is to commence empirical broad-spectrum anti- biotics according to local hospital policies agreed with microbiologists and based on local antibiotic resistance patterns. Depending on the patient’s MASCC risk index score (Box 7.16) and likely organisms this Fig. 7.8 Computed tomography (CT) image of extrinsic compression of the superior vena cava by a small cell lung cancer (arrow) performed as part of investigations for an acute presentation of cancer. 7.15 Common symptoms and physical ndings in superior vena cava obstruction* Symptoms Dyspnoea (63%) Facial swelling and head fullness (50%) Cough (24%) Arm swelling (18%) Chest pain (15%) Dysphagia (9%) Physical ndings Venous distension of neck (66%) Venous distension of chest wall (54%) Elevated, non-pulsatile jugular venous pulse (66%) Facial oedema (46%) Cyanosis (20%) Plethora of face (19%) Oedema of arms (14%) *Percentage of patients affected. 7.16 MASCC* risk index score for neutropenic fever Characteristic Score Burden of current illness No or mild symptoms (normal function) 5 Moderate symptoms (uncomfortable or inuences daily activities) 3 Severe symptoms (signicant discomfort or limits daily activities) 0 No hypotension (systolic BP > 90mmHg) 5 No chronic obstructive pulmonary disease 4 Solid tumour or lymphoma with no previous fungal infection 4 No dehydration requiring parenteral uids 3 Outpatient at onset of fever 3 Age <60 years 2 Score ≥21 = low risk febrile neutropenia Score <21 = high risk febrile neutropenia *Multinational Association of Supportive Care in Cancer.
- 170. 142 OncOlOgy maybe either monotherapy (e.g. piperacillin–tazobactam or meropenem) or combination therapy (e.g. with the addition of gentamicin if high risk on MASCC score, metronidazole if anaerobic infection is suspected, or vancomycin/teicoplanin where Gram-positive infection is suspected). Antibiotics should be adjusted according to culture results, although these are often negative. If there is no clinical improvement after 36–48hours antibiotics should be reviewed with microbiological advice, and antifungal cover should be considered (e.g. uconazole or liposomal amphotericin B). Granulocyte–colony-stimulating factor (G–CSF) can be used to hasten neutrophil recovery in some patients with febrile neutro- penia, in line with local guidelines. Other supportive therapy, including intravenous uids, oxygen, inotrope therapy, ventilation or haemoltra- tion, may be required. Hypercalcaemia of malignancy Hypercalcaemia is the most common metabolic disorder in patients with cancer and has a prevalence of up to 20% in cancer patients. The inci- dence is highest in myeloma and breast cancer (approximately 40%), intermediate in non-small cell lung cancer, and uncommon in colon, prostate and small cell lung carcinomas. It is most commonly due to over-production of PTHrP (80%), which binds to the PTH receptor and elevates serum calcium by stimulating osteoclastic bone resorption and increasing renal tubular reabsorption of calcium. Direct invasion of bone by metastases accounts for around 20% of cases while other mecha- nisms, such as ectopic PTH secretion, are rare. Clinical features The symptoms of hypercalcaemia are often non-specic and may mimic those of the underlying malignancy. They include drowsiness, delirium, nausea and vomiting, constipation, polyuria, polydipsia and dehydration. Investigations and management The diagnosis is made by measuring serum total calcium and adjust- ing for albumin. It is especially important to correct for albumin in can- cer because hypoalbuminaemia is common and total calcium values under-estimate the level of ionised calcium. The principles of manage- ment are outlined in Box 7.17 Patients should initially be treated with intravenous 0.9% saline to improve renal function and increase urinary calcium excretion. This alone often results in clinical improvement. Concurrently, intravenous bisphosphonates should be given to inhibit bone resorption. Calcitonin acts rapidly to increase calcium excretion and to reduce bone resorp- tion, and can be combined with uid and bisphosphonate therapy for the rst 24–48hours in patients with life-threatening hypercalcaemia. Bisphosphonates will usually reduce the serum calcium levels to nor- mal within 5 days, but, if not, treatment can be repeated. The dura- tion of action is up to 4 weeks and repeated therapy can be given at 3–4-weekly intervals in the outpatient department. Hypercalcaemia is frequently a sign of tumour progression and the patient requires fur- ther investigation to establish disease status and review the anti-cancer treatment strategy. Immune-related adverse events Immunotherapy has revolutionised the treatment of many cancers (see ‘Immunotherapy’ below). Checkpoint inhibitor immunotherapy, in particular, is now widely used in the treatment of many different cancers. Side-effects of checkpoint inhibitor immunotherapy agents occur when the immune system is stimulated to attack healthy cells and tissues in the body. These immune-related adverse events (IRAEs) are increasingly being recognized as oncological emergencies. Clinical features Almost any body system may be affected, but inammation of the colon, endocrine organs (thyroid, adrenal and pituitary glands) lungs, liver, skin and nervous system are most frequently seen (see p. 129). IRAEs may occur at any point in a patient’s treatment, or even after they have stopped receiving the checkpoint inhibitor immunotherapy agent. Investigations and management Investigation and management of IRAEs requires a multidiscipli- nary approach including oncologists and relevant system specialists. Specialist investigations may be required depending on the body system affected. The focus of treatment is on dampening the immune response, often using high-dose steroids. Additional immunosuppressant therapies are sometimes required. In the case of endocrine organ inammation, replacement of decient hormones is also important. In patients who experience severe IRAEs, checkpoint inhibitor immunotherapy treatment will usually be permanently discontinued. In other cases, and in patients with endocrine IRAEs who commence replacement hormone therapy, it may be possible to reintroduce checkpoint inhibitor immunotherapy treatment. Tumour lysis syndrome The acute destruction of a large number of cells can be associated with metabolic sequelae and is called tumour lysis syndrome. It is usually related to bulky, chemosensitive disease, including lymphoma, leukae- mia and germ cell tumours. More rarely, it can occur spontaneously. Clinical features Cellular destruction results in the release of potassium, phosphate, nucleic acids and purines that can cause transient hypocalcaemia, hyperphosphataemia, hyperuricaemia and hyperkalaemia. This can lead to acute impairment of renal function and the precipitation of uric acid crystals in the renal tubular system. These can manifest with symptoms associated with multiple underlying electrolyte abnormalities, including fatigue, nausea, vomiting, cardiac arrhythmia, heart failure, syncope, tetany, seizures and sudden death. Investigations and management Serum biochemistry should be monitored regularly for 48–72 hours after treatment in patients at risk. Elevated serum potassium may be the earliest biochemical marker but pre-treatment serum lactate dehydrogenase (LDH) correlates with tumour bulk and may indicate increased risk. Good hydration and urine output should be maintained throughout treatment administration. Prophylaxis with allopurinol should be considered and recombinant urate oxidase (rasburicase) can be used to reduce uric acid levels when other treatments fail. Adequate hydration is vital, as it has a dilution effect on the extracel- lular uid, improving electrolyte imbalance, and increases circulating volume, improving ltration in the kidneys. In high-risk patients, hydra- tion and rasburicase should be commenced 24hours before the start of treatment. If normal treatment methods fail to correct the problems, haemodialysis should be considered at an early stage to prevent pro- gression to irreversibility. Other acute presentations in oncology Venous thromboembolism Venous thromboembolism (VTE) is the second leading cause of death amongst patients with cancer. Malignancy is a strong risk factor for 7.17 Medical management of severe hypercalcaemia IV 0.9% saline 2–4L/day Zoledronic acid 4mg IV or pamidronate 60–90mg IV For patients with severe, symptomatic hypercalcaemia that is refractory to zoledronic acid, denosumab (initial dose 60mg SC, with repeat dosing based on response) is an alternative option (IV = intravenous; SC = subcutaneous)
- 171. Aute ooo 143 7 VTE and may be the rst presenting feature of an underlying cancer. Several mechanisms lead to a prothrombotic state in cancer. This includes the ability of cancer cells to produce procoagulant/brinolytic substances and inammatory cytokines and the physical interaction between tumour cells and blood (monocytes, neutrophils, platelets) or endothelial cells. Anti-cancer therapy (i.e. surgery, cytotoxic chemo- therapy, hormone therapy and radiotherapy) and any in-dwelling access devices (i.e. central venous catheters) further increase the risk. As in patients without cancer, the management of cancer-associated VTE primarily involves anticoagulation therapy. However, the choice of therapy must take into account bleeding risk and possible interactions with anti-cancer therapies and their side-effects, such as thrombocy- topenia. In patients with metastatic cancer, anticoagulation therapy will often be lifelong. Ectopic hormone production Some cancers are associated with metabolic abnormalities due to ectopic production of hormones by tumour cells, including insulin, ACTH, vasopressin (antidiuretic hormone, ADH), broblast growth fac- tor (FGF)-23, erythropoietin and parathyroid hormone-related protein (PTHrP). This can result in a wide variety of presentations, as summa- rised in Box 7.18 Neurological paraneoplastic syndromes These form a group of conditions associated with cancer that are thought to be due to an immunological response to the tumour that results in damage to the nervous system or muscle (see Box 7.10). The cancers most commonly implicated are those of the lung, pan- creas, breast, prostate, ovary and lymphoma. Many are associated with specic detectable immune biomarkers such as antibodies to pre-synaptic calcium channels (Lambert–Eaton syndrome), anti-Hu antibodies (encephalomyelitis) and anti-Yo or anti-Tr antibodies (cere- bellar degeneration). However, these are not always specic and neg- ative results do not exclude the diagnosis. The management of these syndromes is multidisciplinary and includes treatment of the underly- ing cancer itself and treatment of the syndrome primarily with immu- nosuppressive agents. Cutaneous manifestations of cancer Cancers can present with skin manifestations that are not due to metas- tases (see Box 7.10). The clinical features and management of these skin conditions are discussed in Chapter 27 Symptoms from locally advanced cancer or metastatic sites Metastatic disease is the major cause of death in cancer patients and the principal cause of morbidity. For the majority of patients with metastatic disease the goal of treatment is to control cancer, maintain quality of life, treat symptoms and prolong life (i.e. ‘palliative treatment’). Patients of PS 3–4 (Box 7.6) or with low albumin plus high inammatory markers often have a limited prognosis irrespective of anti-cancer treatments. Systemic anti-cancer therapies have resulted in improved survival for many can- cers so that some patients live a good quality life for many years with metastatic cancer. Treatment of a solitary metastasis or highly treatable cancers (e.g. germ cell) can be curative. Brain metastases Brain metastases occur in 10%–30% of adults and 6%–10% of chil- dren with cancer and are an increasingly important cause of morbidity. Cancers of lung, breast, melanoma and gastrointestinal tract most com- monly metastasise to the brain. Most involve the brain parenchyma but can also affect the meninges, cranial nerves, the blood vessels and other intracranial structures. In cases of solitary metastasis to the brain, the use of surgery followed by adjuvant radiotherapy, or alternatively stereotactic radiotherapy, has been shown to increase survival in patients whose dis- ease is otherwise controlled. Outcomes for patients with more advanced brain metastases depends on the primary cancer, extent of extracranial disease and what systemic treatment options are available. For patients with advanced untreatable cancer and multiple brain metastases, prog- nosis is often short. Glucocorticoids can improve symptoms, particularly where there is evidence of peri-lesional oedema. In treatable cancers whole brain radiotherapy can allow steroid dose to be reduced whilst systemic therapy is used to treat the remaining cancer. With improved systemic therapies, including targeted therapies and immunotherapy, some patients are now living for several years with brain metastases. Clinical features Presentation is with headaches and nausea (40%–50%), focal neuro- logical dysfunction (20%–40%), cognitive dysfunction (35%), seizures (10%–20%) and papilloedema (<10%). Investigations and management The diagnosis can be conrmed by CT or contrast-enhanced MRI. Treatment options include high-dose glucocorticoids for tumour-associated oedema (dexamethasone 4–12mg daily depending on amount of oedema), anticonvulsants for seizures, whole-brain radiotherapy and systemic anti-cancer therapy. Surgery may be considered for single sites of disease and can be curative; stereotactic radiotherapy may also be considered for solitary site involvement or where surgery is more difcult or not possible. Lung metastases Lung metastases are common in breast cancer, colon cancer, renal can- cer, sarcoma and tumours of the head and neck. The presentation is usu- ally with a lesion on chest X-ray or CT. Solitary lesions require investigation, as single metastases can be difcult to distinguish from a primary lung tumour. Patients with two or more pulmonary nodules can be assumed to have metastases. The approach to treatment depends on the extent of disease in the lung and elsewhere. For solitary lesions, surgery should be considered, with a generous wedge resection, or radiofrequency abla- tion if available. Radiotherapy and systemic anti-cancer therapies can be used, dependent on the underlying primary cancer diagnosis (Fig. 7.9). Liver metastases Metastatic cancer in the liver can represent the sole or life-limiting com- ponent of disease for many with colorectal cancer, ocular melanoma, 7.18 Ectopic hormone production by tumours Hormone Consequence Tumours ACTH Cushing’s syndrome SCLC Erythropoietin Polycythaemia Kidney, HCC, cerebellar haemangioblastoma, uterine broids FGF-23 Hypophosphataemic osteomalacia Mesenchymal tumours PTHrP Hypercalcaemia NSCLC (squamous cell), breast, kidney Vasopressin (ADH) Hyponatraemia SCLC (ACTH = adrenocorticotrophic hormone; ADH = antidiuretic hormone; FGF = broblast growth factor; HCC = hepatocellular carcinoma; NSCLC = non-small cell lung cancer; PTHrP = parathyroid hormone-related protein; SCLC = small cell lung cancer)
- 172. 144 OncOlOgy neuro-endocrinetumours (NETs) and, less commonly, other tumour types. The most common clinical presentations are with right upper quadrant pain due to stretching of the liver capsule, jaundice, deranged liver function tests or an abnormality detected on imaging. In selected cases, resection of the metastasis can be contemplated. In colorectal cancer, successful resection of metastases improves 5-year survival from 3% to 30%–40%. Other techniques, such as chemoembolisation, radio- frequency ablation or microwave ablation, can also be used, provided the number and size of metastases remain small. If these are not feasible, symptoms may respond to systemic anti-cancer therapy (Fig. 7.5). Bone metastases Bone is the third most common organ involved by metastasis, after lung and liver. Bone metastases are a major clinical problem in patients with myeloma and breast or prostate cancers, but other tumours that commonly metastasise to bone include those of the kidney and thyroid. Bone metastases are increasingly seen in other tumour types that do not classically target bone, due to effective anti-cancer treatments prolong- ing survival of patients with many cancers. Accordingly, effective man- agement of bony metastases has become a focus in the treatment of patients with many incurable cancers. Clinical features The main presentations are with pain, pathological fractures, spinal cord compression (see above) and hypercalcaemia. Pain tends to be progressive and worst at night, and may be partially relieved by activ- ity, but subsequently becomes more constant in nature and is exacer- bated by movement. Most pathological fractures occur in metastatic breast cancer (53%); other tumour types associated with fracture include the kidney (11%), lung (8%), thyroid (5%), lymphoma (5%) and prostate (3%). Investigations and management The most sensitive way of detecting bone metastases is by isotope bone scan. This can have false-positive results in healing bone, particularly as a are response following treatment and false-negative results occur in multiple myeloma due to suppression of osteoblast activity. Plain X-ray lms or MRI scans are therefore preferred for any sites of bone pain, as lytic lesions may not be detected by a bone scan. In patients with a single lesion, it is especially important to perform a biopsy to obtain a tissue diagnosis, since primary bone tumours may look very similar to metastases on X-ray. The main goals of management are: pain relief preservation and restoration of function skeletal stabilisation local tumour control (e.g. relief of tumour impingement on normal structure). Surgical intervention may be warranted where there is evidence of skeletal instability (e.g. anterior or posterior spinal column fracture) or an impending fracture (e.g. a large lytic lesion on a weight-bearing bone with more than 50% cortical involvement). Intravenous bisphosphonates (pamidronate, zoledronic acid or denosumab) are widely used for bone metastases and are effective at improving pain and in reducing further skeletal related events, such as fractures and hypercalcaemia. In certain types of cancer, such as breast and prostate, hormonal therapy may be effective. Radiotherapy, in the form of external beam therapy or systemic radionuclides (strontium treatment), can also help pain. In some settings (e.g. breast carcinoma), systemic anti-cancer therapy may be used in the management of bony metastases. Malignant pleural effusion This is a common complication of cancer and 40% of all pleural effusions are due to malignancy. The most common causes are lung and breast cancers, and the presence of an effusion indicates incurable disease. The presentation may be with dyspnoea, cough or chest discomfort, which can be dull or pleuritic in nature. Diagnosis and management of pleural effusion is discussed on page 494. Investigations and management Pleural aspirate is the key investigation and may show the presence of malignant cells. Malignant effusions are commonly blood-stained and are exudates with a raised uid to serum LDH ratio (>0.6) and a raised uid to serum protein ratio (>0.5). Treatment should focus on palliation of symptoms and be tailored to the patient's physical condition, treatment options and prognosis. Aspiration alone may be an appropriate treat- ment in frail patients with a limited life expectancy. Those who present with malignant pleural effusion as the initial manifestation of breast can- cer, small cell lung cancer, germ cell tumours or lymphoma should have the uid aspirated and should be given systemic anti-cancer therapy to try to treat disease in the pleural space. Treatment options for patients with recurrent pleural effusions include pleurodesis, implanted drainage catheters, pleurectomy and pleuroperitoneal shunt. Other common symptoms Other symptoms that commonly arise from metastatic cancer are: gastrointestinal obstruction, malignant abdominal ascites, hydronephro- sis and cancer cachexia. Fig. 7.9 A B R
- 173. Therapeutis i ooo 145 7 Treatment-related toxicities Whilst most anti-cancer therapies cause some side-effects, most of these can be managed with supportive medicines at home. Some patients will develop severe toxicities and an acute assessment will be needed. Examination of the patient on anti-cancer treatment (p. 128) should consider the type of anti-cancer treatment, duration since the last treatment and other concurrent toxicities. Patients on anti-cancer therapy can deteriorate quickly and prompt assessment and manage- ment is required. There may be specic management protocols to help manage treatment-related toxicities and advice should be sought from the patient’s cancer centre or acute oncology team. Therapeutics in oncology Anti-cancer therapy may be used with either curative or palliative intent, and this distinction inuences the approach to management of individual patients. The goal of treatment should be recorded in the medical notes. Curative therapy is given with the aim of achieving complete remis- sion. Surgery to remove all macroscopic disease is most frequently the primary curative intervention. However, in some circumstances radiotherapy, systemic anti-cancer therapy or a combination of these may be used with curative, or radical, intent. Adjuvant therapy is additional therapy given after the primary curative intervention to lower the risk of disease recurrence. Radiotherapy and/or systemic anti-cancer therapy may be given after surgery with the intention of eradicating any micrometastatic disease that remains. Neoadjuvant therapy is additional therapy given prior to the primary curative intervention. Systemic anti-cancer therapy may be admin- istered prior to planned surgery. The principal aim is to lower the risk of disease recurrence. Any reduction in the volume of disease, or ‘downstaging’, may also allow less extensive surgery, increase the likelihood of successful debulking and improve subsequent surgical morbidity. Direct evaluation of the surgical specimen allows assessment of the effectiveness of neoadjuvant therapies, guiding subsequent management and lending this approach to translational research. Palliative therapy is primarily used to treat patients with metastatic disease, or where curative treatment is not possible. The goal is to control cancer, with the aim of improving or maintaining quality of life, treating and preventing symptoms and improving survival. The choice of therapy depends on the clinical situation and a careful evaluation of the risks and benets of the intervention. Surgical treatment Surgery has a pivotal role in the management of cancer. It is the main curative management of most solid cancers. In early localised cases of colorectal, breast and lung cancer, cure rates are high with surgery. There is evidence that outcome is related to surgical expertise, and most multi- disciplinary teams include surgeons experienced in the management of a particular cancer. There are some cancers for which surgery is one of two or more options for primary management, and the role of the MDT is to recommend appropriate treatment for an individual patient. Examples include prostate and transitional cell carcinoma of the bladder, in which radiotherapy and surgery may be equally effective. Specialised surgical, or interventional radiology techniques may also be employed with cura- tive intent. Radiofrequency ablation, microwave ablation or cryotherapy may be used to treat small renal cell carcinomas or hepatocellular carci- nomas. Surgery has less of a role in lymphoma, high-grade neuro-endo- crine tumours or small cell cancer, where systemic anti-cancer therapy is the main treatment used. Surgical procedures are often the quickest and most effective way of palliating symptoms in patients with metastatic disease. Examples include the treatment of faecal incontinence with a defunctioning colostomy; xation of pathological fractures; decompression of spinal cord compression; and the treatment of fungating skin lesions by ‘toilet’ sur- gery. Debulking cytoreductive surgery may improve survival in some can- cers, including renal cell carcinoma and ovarian cancer. In very selected cases, such as patients with oligometastatic disease, resection of metas- tases may improve survival and reduce the need for other therapies. Radiotherapy Radiotherapy (radiation therapy) involves treating the cancer with ionis- ing radiation such as X-rays, gamma rays, electrons or charged atoms. Ionising radiation kills cancer cells by two mechanisms; directly damag- ing cancer DNA or indirectly by triggering the formation of very reactive molecules (free radicals) that also damage cancer DNA. Two main types of radiation therapy exist: external beam radiotherapy, and brachytherapy (internal radiotherapy). External beam radiotherapy is most commonly delivered by a linear accelerator, which produces elec- tron or photon beams. As normal tissues can also be damaged by radio- therapy, treatments are planned to ensure maximum exposure of the tumour and minimal exposure of surrounding normal tissues. Improved localisation of the target volume, or tumour, can be achieved by the use of surgical clips at the site of resection and fusion of radiotherapy- planning CT scans with diagnostic MRI or PET-CT scans. Treatment- planning software controls the size and shape of the beam. Intensity modulated radiotherapy (which allows for more homogeneous dose distribution), and volumetric radiotherapy (in which the shape of the radi- ation beam is designed to closely t the tumour), have largely replaced conventional methods that use a limited number of square or rectangular beams. Stereotactic radiotherapy is a highly targeted method to deliver focused radiation beams from many different angles which converge on the tumour to deliver high doses precisely. Proton therapy uses a cyclotron to produce beams of high-energy protons, which deposit their radiation dose by a means that allows further sparing of normal tissues. Brachytherapy, or internal radiation therapy, involves the direct appli- cation of a radioactive source onto or into a tumour. This allows the deliv- ery of a high, localised dose of radiation. Brachytherapy is a common treatment for cancers of the prostate, uterus and cervix. Most commonly, an applicator device is used to deliver a radioactive source to the tumour for a set time, typically 10–20minutes. In other cases, such as in prostate cancer, small radioactive seeds may be permanently placed, releasing radiation slowly over several months. Radioactive liquid treatments, such as 223 radium for bone metastases from prostate cancer or 131 iodine for thyroid cancers are other examples of internal radiation therapy. Biological differences between normal and tumour tissues are exploited to obtain therapeutic benet. Fundamental to this is fractiona- tion, which entails delivering the radiation as a number of small doses on a daily basis. This allows normal cells to recover from radiation damage but recovery occurs to a lesser degree in malignant cells. Fractionation regimens vary depending on the tumour being treated, the total radia- tion dose to be delivered and the intent of treatment. Curative, or rad- ical treatments typically deliver a higher overall dose in 20–35 fractions over 4–7 weeks. For palliative treatments a smaller dose given over 1–10 fractions is usually adequate. Malignant tissues vary widely in their sen- sitivity to radiotherapy. Germ cell tumours and lymphomas are extremely radiosensitive, and relatively low doses are adequate for cure. However, most other cancers require higher doses. Normal tissue also varies in its radiosensitivity, with the central nervous system, small bowel and lung being among the most sensitive. The side-effects of radiotherapy depend on the site being treated, the tissue’s radiosensitivity and the dose delivered. For example, skin reac- tions are common with high-dose radical head and neck cancer treat- ments, or proctitis and cystitis with treatment to the bladder or prostate. These acute reactions typically settle within a few weeks after treatment. Late effects of radiotherapy develop more than 6 weeks after treatment and occur in 5%–10% of patients. Examples include brachial nerve damage and subcutaneous brosis after breast cancer treatment. There
- 174. 146 OncOlOgy Fig.7.10 Commonly used cytotoxic chemotherapy agents and their mechanisms of action. Precursors Purine biosynthesis DNA Proteins Antimetabolites Alkylating agents Alkaloids Topoisomerase inhibitors Antitumour antibiotics Enzymes Microtubules RNA (transfer, messenger, ribosomal) Precursors Ribonucleotides Deoxyribonucleotides Pyrimidine biosynthesis Antifolates Fluoropyrimidines Mitotic inhibitors Microtubule aggregators Nucleoside analogues Platinum agents Nitrogen mustards Topoisomerase I inhibitors Topoisomerase II inhibitors Anthracyclines Bleomycin Actinomycin D 1. Intercalate with DNA and inhibit the progression of topoisomerase I 2. Induce DNA strand breaks by oxidative damage 3. Bind to DNA to prevent transcription Antifolates Fluoropyrimidines Nucleoside analogues Nitrogen mustards Platinum agents Topoisomerase I/II inhibitors Mitotic inhibitors Microtubule aggregators Others – acting on DNA Mechanism of action Examples 1. Anthracyclines: epirubicin, doxorubicin 2. Bleomycin 3. Actinomycin D Inhibit dihydrofolate reductase and so purine and pyrimidine synthesis Inhibit thymidylate synthase and so pyrimidine synthesis Incorporated into DNA during synthesis, leading to irreparable errors Form covalent cross-links between DNA molecules by adding an alkyl group to DNA Form inter-/ intra-strand cross-links between DNA molecules, not by adding an alkyl group, so considered alkylating-like agents Prevent re-ligation of DNA strands by topoisomerase I/II Bind tubulin, blocking microtubule formation Stabilise the microtubule polymer preventing its disassembly Methotrexate 5-Fluorouracil, capecitabine Gemcitabine, fludarabine Cyclophosphamide, ifosfamide Cisplatin, carboplatin, oxaliplatin Etoposide (II); topotecan, irinotecan (I) Vinca alkaloids: vincristine, vinblastine, vinorelbine Taxanes: paclitaxel, docetaxel is also a risk of inducing new cancer after radiotherapy, which varies depending on the site treated and on whether the patient has had other treatment such as cytotoxic chemotherapy. Systemic anti-cancer therapy Systemic anti-cancer therapy (SACT) is a collective term to describe the growing number of differing drug therapies used to treat cancer. These drugs reach throughout the body to treat cancer cells wherever they may be. Increasingly, treatment is tailored to a patient’s particular cancer and its molecular prole, allowing more personalised therapy. Cytotoxic chemotherapy Cytotoxic chemotherapy drugs work by interfering with the processes involved in cell division. They are sub-classied by their mode of action (Fig. 7.10). Cytotoxic chemotherapies have their greatest activity in prolif- erating cells and this provides the rationale for their use in the treatment
- 175. Therapeutis i ooo 147 7 of cancer. However, they are not specic for cancer cells and the side- effects of treatment are largely a result of their antiproliferative actions in normal tissues such as the bone marrow, skin and gut (p. 129). Other organs, such as the heart, kidney and peripheral nervous system, may also be affected by some cytotoxic drugs. The choice of cytotoxic chemotherapy agent, or combination of treatments, is determined by the cancer type. The dosing schedule is determined by the choice of treatments and recovery of normal tissues, usually the bone marrow. For most common cytotoxic chemotherapy regimens the treatment is administered in cycles. A course of treatment may constitute a pre-dened number of cycles, or may continue inde- nitely until evidence of disease progression or until limiting side-effects. Supportive therapy is used to enable patients to tolerate therapy and achieve benet. Nausea and vomiting are common, but with modern antiemetics, regimens such as the combination of dexamethasone and highly selective 5-hydroxytryptamine (5-HT3 , serotonin) receptor antago- nists such as ondansetron, most patients now receive cytotoxic chemo- therapy without any signicant problems. Myelosuppression is common to almost all cytotoxics and this not only limits the dose of drug but also can cause life-threatening complications. The risk of neutropenia can be reduced with the use of specic growth factors that accelerate the repopulation of myeloid precursor cells. The most commonly employed is G–CSF, which is widely used in conjunction with cytotoxic chemother- apy regimens that induce a high rate of neutropenia. Hormone therapy Hormones are important cell-signalling molecules and, in some cancers, may be key drivers of tumour growth. Blocking hormonal signalling path- ways in these cancers may be a very effective treatment strategy. Approximately 80% of breast tumours are positive for expression of the oestrogen receptor (ER). Assessment of ER status is now standard in the diagnostic workup of breast cancer. Drugs that reduce oestrogen levels or block the effects of oestrogen on the receptor are widely used in the management of ER-positive breast cancer. Adjuvant hormone ther- apy may reduce the risk of relapse and death at least as much as cyto- toxic chemotherapy and in advanced cases can induce stable disease and remissions that may last months to years, with acceptable toxicity. Hormonal manipulation may be effective in other cancers. In prostate cancer, hormonal therapy (e.g. luteinising hormone releasing hormone (LHRH) analogues such as goserelin and/or anti-androgens such as bicalutamide) aimed at reducing androgen levels can provide good long- term control of advanced disease. The side-effects of hormone therapies are linked to their hormonal targets. Targeted therapies Advances in knowledge about the molecular basis of cancer have resulted in the development of treatments to target specic genes and proteins that are involved in the growth and survival of cancer cells (Fig. 7.11). These signalling pathways may have broad importance to a range of cancer types or be specic to certain cancers. They may not be important in all tumours of the same cancer type, requiring specic molecular testing to predict whether the patient may benet. Targeted therapies are broadly divided into two groups: monoclonal antibodies (-mab) and small molecule inhibitors (-ib). The -mab family are typically utilised for targets that are overexpressed on the outside of the cancer cell. The -ib family typically target processes within the cell, such as the cytoplasmic tyrosine kinase, and are designed to be small enough to enter the cell. A wide range of targeted therapies are now used routinely in onco- logical practice. Some of these are described below. The side effects of targeted therapies are determined by the molecular pathway being targeted (p. 129). Epidermal growth factor receptor (EGFR) is an important transmem- brane signalling protein. Mutations in the EGFR gene lead to overexpres- sion of the EGFR protein or constitutive activation of the cell-signalling Fig. 7.11 Examples of targeted anti-cancer therapies and their actions in relation to the Hallmarks of Cancer. (For abbreviations see text.) Deregulating cellular energetics: aerobic glycolysis inhibitors Resisting cell death: BCL-2 inhibitors Genome instability and mutation: PARP inhibitors Tumour- promoting inflammation: selective anti- inflammatory agents Enabling replicative immortality: telomerase inhibitors Avoiding immune destruction: checkpoint inhibitors as immunotherapy Evading growth suppressors: CDK4/6 inhibitors Sustaining proliferative signalling: EGFR, HER2 and BRAF inhibitors Inducing angiogenesis: VEGF inhibitors Activating invasion and metastases: HGF/c-MET inhibitors pathway, leading to uncontrolled cell division, in several cancer types. Approximately 15% of lung adenocarcinomas have activating mutations of EGFR, which may be targeted with drugs such as getinib, erlotinib or osimertinib. The latter of these agents has been designed to overcome a particular mutation (i.e. T790M) responsible for 50% of resistance to older EGFR inhibitors. In colorectal cancer drugs such as cetuximab and panitumumab are active in patients where molecular testing does not detect resistance inferred by mutations in the RAS/RAF family of genes. Vascular endothelial growth factor receptor (VEGFR) inhibitors such as sunitinib, pazopanib and cabozantinib have been a pillar of renal cell carcinoma treatment for over a decade. Activation of members of the VEGFR family play an important role in tumour angiogenesis. VEGFR small molecule inhibitors are commonly used in the management of hepatocellular carcinoma and thyroid cancer. Bevacizumab, a monoclo- nal antibody therapy targeted at VEGF-A, is active in a number of can- cers, including ovarian, colorectal and breast. HER2 is a member of the epidermal growth factor receptor family. Amplication or over-expression of HER2 is found in breast, gastric, pan- creatic, lung and some uterine cancers. Approximately 20% of breast cancers are HER2-positive, where it is associated with increased risk of recurrence and poor prognosis. Several agents have been developed to target HER2, including trastuzumab and pertuzumab. The agent tras- tuzumab emtansine is an antibody-drug conjugate consisting of trastu- zumab covalently linked to the cytotoxic chemotherapy agent emtansine which is delivered specically to the HER2-positive breast cancer cell. Immunotherapy The term immunotherapy encompasses a range of anti-cancer thera- pies that work by harnessing the immune system to attack cancer cells. Cytokines, such as interferon alpha and interleukin-2, have been used with some success in melanoma and renal cell carcinoma. However, in recent years the development of other immunotherapy treatments has revolutionized the management of several cancer types. Immune checkpoints are key regulators of the immune system which work to prevent the immune response from attacking normal healthy cells. Cancers may co-opt this mechanism to evade immune destruction. Targeted therapies that inhibit these checkpoint molecules (CTLA4, PD-1) or their ligands (PD-L1) (Fig. 7.12) are now licensed in
- 176. 148 OncOlOgy themanagement of many cancers, including melanoma, renal cell car- cinoma, lung, bladder, head and neck, and, more broadly, any cancers demonstrating microsatellite instability. Checkpoint inhibitor immunother- apies may be used alone, or in combination with other checkpoint inhibi- tor immunotherapies, targeted therapies or cytotoxic chemotherapy. Adoptive cell therapy, also known as cellular immunotherapy, is increas- ingly being used, particularly in haematological malignancies. Immune cells isolated from either the patient’s tumour or bloodstream may be acti- vated and expanded, before being infused back into the patient to attack cancer cells (i.e. tumour inltrating lymphocyte (TIL) therapy). The immune cells may also be genetically modied to improve the likelihood that they identify the cancer cells (i.e. engineered T-cell (TCR) therapy, chimeric antigen receptor T-cell (CAR-T) therapy). Cancer treatment vaccines are also in development. These aim to boost the immune system’s ability to recognise and destroy antigens using a number of different techniques. Immunotherapy treatment is likely to become more prevalent in the future for many types of cancers and indications. In patients with advanced or metastatic disease a key observation has been the poten- tial for durable treatment responses. For example, average survival for patients with metastatic melanoma has improved from 6–8 months in the pre-immunotherapy era to over 5 years with the use of combination anti- CTLA4 and anti-PD-1 checkpoint inhibitors in clinical trials. However, many patients do not respond and others are affected by potentially life-threatening immune-related adverse events (see above). Evaluation of treatment In advanced or metastatic cancer the evaluation of treatment is an ongoing process and includes assessments of treatment response, tox- icity and quality of life. Clinical evaluation alongside radiological imaging or biochemical monitoring are commonly used to determine whether a treatment is being effective. Uniform criteria have been established to measure these, including the response evaluation criteria in solid tumours (RECIST, Box 7.19) and common toxicity criteria (e.g. common terminology criteria for adverse events (CTCAE)). This allows clinicians to inform patients accurately about the prognosis, effectiveness and toxicity of systemic anti-cancer therapy and empowers patients to take an active role in treatment decisions. Late toxicity of therapy The late toxicities of treatment for cancer are particularly important for patients where multimodality therapy is given with curative intent, where the patient is young and as more patients are living longer. This can cause considerable morbidity: for example, radiotherapy can retard bone and cartilage growth, impair intellect and cognitive function, and cause dysfunction of the hypothalamus, pituitary and thyroid glands. Late consequences of cytotoxic chemotherapy include heart failure due to cardiotoxicity, pulmonary brosis, nephrotoxicity and neurotoxicity. Premature gonadal failure can result from cytotoxic chemotherapy or radiotherapy and leave a patient subfertile. Patients should be made aware of this before treatment is initiated, as it may be possible to store sperm for male patients before treatment starts; this should always be offered, if practical. Egg storage or embryo banking after in vitro fertil- isation may be an option for young women. Sterility develops at higher radiotherapy doses but erectile dysfunction is seen in patients receiving high radiotherapy doses to the pelvis, as in prostate cancer. Additional social or psychological support may be required to address these issues. Infertility and pubertal delay are potential late effects of therapy in chil- dren, especially boys. Second malignancies may be induced by cancer treatment and occur at greatest frequency following chemoradiation. Secondary acute leukaemia (mostly AML) can occur 1–2 years after treatment with topoisomerase II inhibitors, or 2–5 years after treatment with alkylating agents. The most common second malignancy within a radiation eld is osteosarcoma but others include soft tissue sarcoma and leukaemia. Cancer clinical trials Cancer clinical trials are embedded within routine practice in oncol- ogy. Close collaboration with laboratory scientists, active recruitment of cancer patients into clinical trials and robust translational research have led to many new cancer treatments, personalised therapies and a transformation of cancer management over the last 20 years. As many Fig. 7.12 activation and tumour cell death. (PD-1 = programmed cell death protein 1; PD-L1 = programmed cell death ligand 1) A T cell T-cell inhibited T-cell activated T-cell receptor Antigen T-cell receptor Antigen Tumour cell PD-L1 PD-1 B T cell Tumour cell death PD-L1 PD-1 Anti-PD-1 Anti-PD-L1 T-cell proliferation T-cell effector function 7.19 Response evaluation criteria in solid tumours (RECIST) Response Criteria Complete response (CR) Disappearance of all target lesions Partial response (PR) At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD Progressive disease (PD) At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started and at least 5mm increase or the appearance of one or more new lesions Stable disease (SD) Neither sufcient shrinkage to qualify for PR nor sufcient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started
- 177. Speifi aers 149 7 anti-cancer drugs are expected to have toxicities, which may ultimately limit the deliverable dose, clinical trials in cancer differ from trials of other medicines. Phase I cancer clinical trials take treatments of interest from labor- atory studies and test them in patients with advanced cancer for whom no other standard anti-cancer treatment exists. Phase I trials assess the safety of a treatment and identify an optimal dose and dosing schedule. Initial doses are very low and each sequential cohort of patients receives a higher dose. Doses are escalated in controlled cohorts of 1–6 patients, according to toxicities, pharma- cokinetics and pharmacodynamics, until the maximum tolerated dose is reached. Phase II cancer clinical trials treat patients with specic cancers of interest with the trial drug, using the dose established in phase I trials. Phase II trials may be randomised or non-randomised but will recruit enough patients to further assess the safety of the treatment and whether it results in enough anti-cancer activity in a specic cancer to develop the drug further by way of phase III trials. Phase III cancer trials are large, multi-centre randomised controlled trials to compare the new treatment of interest with the current established therapy for this indication. Cancer response, toxicity, quality of life and survival data will usually be assessed. Phase III trials may also compare current standard treatment with a different treatment, either looking for improved outcome or improved quality of life with non-inferior outcome. If a treatment is deemed to be safe and effective it will be licensed for clinical use. Phase IV trials involve the continuing safety surveillance of a treat- ment after it receives a licence for clinical use. This can be particu- larly useful to detect any rare or long-term adverse effects in a much larger population and longer time period than was possible during Phase I–III trials. Specic cancers As cancer management becomes more complex and personalised, and incorporates multi-modality treatment approaches, oncology teams are increasingly subspecialised and work as part of tumour-specic multidis- ciplinary teams. The diagnosis and management of specic cancers are discussed in more detail elsewhere in the book (Box 7.20). Here we dis- cuss the pathogenesis, clinical features, investigation and management of some common tumours that are not covered elsewhere. Breast cancer Globally, the incidence of breast cancer is second only to that of lung cancer, and the disease represents the leading cause of cancer-re- lated deaths among women. Invasive ductal carcinoma with or with- out ductal carcinoma in situ (DCIS) is the most common histology, accounting for 70%, whilst invasive lobular carcinoma accounts for most of the remaining cases. DCIS constitutes 20% of breast cancers detected by mammography screening. It is multifocal in one-third of women and has a high risk of becoming invasive (10% at 5years fol- lowing excision only). Pure DCIS does not cause lymph node metas- tases, although these are found in 2% of cases where nodes are examined, owing to undetected invasive cancer. Lobular carcinoma in situ (LCIS) is a predisposing risk factor for developing cancer in either breast (7% at 10 years). The survival for breast cancer by stage is outlined in Box 7.21 Pathogenesis Both genetic and hormonal factors play a role: about 5%–10% of breast cancers are hereditary and occur in patients with mutations of BRCA1, BRCA2, AT or TP53 genes. Prolonged oestrogen exposure associated with early menarche, late menopause and use of hormone replacement therapy (HRT) has been associated with an increased risk. Other risk factors include obesity, alcohol intake, nulliparity and late rst pregnancy. There is no denite evidence linking use of the contraceptive pill to breast cancer. Clinical features Breast cancer usually presents as a result of mammographic screen- ing or as a palpable mass with nipple discharge in 10% and pain in 7% of patients. Less common presentations include inammatory carcinoma with diffuse induration of the skin of the breast, and this confers an adverse prognosis. Around 40% of patients will have axil- lary nodal disease, with likelihood correlating with increasing size of the primary tumour. Distant metastases are infrequently present at diagnosis and the most common sites of spread are bone (70%), lung (60%), liver (55%), pleura (40%), adrenals (35%), skin (30%) and brain (10%–20%). Investigations Following clinical examination, patients should undergo imaging with mam- mography or ultrasound evaluation, and a biopsy using ne needle aspi- ration for cytology or core biopsy for histology. Histological assessment should be carried out to assess tumour type and to determine oestrogen and progesterone receptor (ER/PR) status and HER2 status. If distant spread is suspected, CT of the thorax and abdomen and an isotope bone scan are required. Molecular subtyping is being used to classify tumours into four major subtypes: luminal A, luminal B, HER2 type and basal-like 7.20 Specic cancers covered in other chapters Bladder cancer p. 607 Colorectal cancer p. 826 Familial cancer syndromes p. 55 Gastric cancer p. 817 Hepatocellular carcinoma p. 901 Leukaemia p. 963 Lung cancer p. 528 Lymphoma p. 971 Mesothelioma p. 546 Myeloma p. 976 Oesophageal cancer p. 809 Pancreatic cancer p. 855 Prostate cancer p. 610 Renal cancer p. 606 Seminoma p. 611 Skin cancer p. 1082 Teratoma p. 611 Thyroid cancer p. 665 7.21 Five-year survival rates for breast cancer by stage Tumour stage Stage denition 5-year survival (%) I Tumour <2cm, no lymph nodes 98 II Tumour 2–5cm and/or mobile axillary lymph nodes 90 III Chest wall or skin xation and/or xed axillary lymph nodes 72 IV Metastasis 26
- 178. 150 OncOlOgy (oftencalled ‘triple negative’, as these tumours are ER-, PR- and HER2- negative). This may allow more targeted selection of therapies in future. Management Surgery is the mainstay of curative treatment. This can range from a lumpectomy, where only the tumour is removed, to mastectomy, where the whole breast is removed. Breast-conserving surgery is as effective as mastectomy if complete excision with negative margins can be achieved. Lymph node sampling is performed at the time of surgery. There is signicant evidence to support the use of additional therapies to reduce the risk of breast cancer recurrence. Adjuvant radiotherapy is given to reduce the risk of local recurrence. In those patients considered at high risk of recurrence (i.e. tumour of >1cm, ER-negative disease or the presence of involved axillary lymph nodes) cytotoxic chemotherapy may be offered. In patients with HER2-positive breast cancer adjuvant trastu- zumab, a humanised monoclonal antibody to HER2, may be used along- side standard cytotoxic chemotherapy. These treatments are increasingly being used in the neoadjuvant setting, with the aim of achieving a complete pathological response when the cancer is resected, often with a more organ-preserving surgical procedure. In patients with ER-positive tumours adjuvant hormonal therapy may gain additional disease-free and overall survival benets. Patients at low risk of recurrence (i.e. small, ER-positive disease) may require only adjuvant hormonal therapy. In post-menopausal women adjuvant bisphosphonate therapy may also be used. The treatment of metastatic breast cancer is complex. Radiotherapy may be used to palliate painful bone metastases. SACT decisions are made with consideration of ER status, HER2 status, the distribution of metastatic disease and previous neo/adjuvant treatment, alongside assessments of performance status (PS) and comorbidities. For exam- ple, in a post-menopausal patient with ER-positive, HER2-negative bone-only metastatic disease who is PS 0, hormonal therapy (i.e. an aromatase inhibitor) in combination with a CDK4/6 targeted therapy (i.e. palbociclib, abemaciclib or ribociclib) may be used as rst-line treatment. In a similar patient with additional symptomatic liver metas- tases, cytotoxic chemotherapy may be more appropriate. Ovarian cancer Ovarian cancer is the most common gynaecological tumour in Western countries. Most ovarian cancers are epithelial in origin (90%), and up to 7% of women with ovarian cancer have a positive family history. Patients often present late in ovarian cancer with vague abdominal dis- comfort, low back pain, bloating, altered bowel habit and weight loss. Occasionally, peritoneal deposits are palpable as an omental ‘cake’ and nodules in the umbilicus (Sister Mary Joseph nodules). Pathogenesis Genetic and environmental factors play a role. The risk of ovarian cancer is increased in patients with BRCA1 or BRCA2 mutations, and Lynch type II families (a subtype of hereditary non-polyposis colon cancer, HNPCC) can have ovarian, endometrial, colorectal and gastric tumours due to mutations of mismatch repair enzymes. Advanced age, nulliparity, ovarian stimulation and European descent all increase the risk of ovarian cancer, while suppressed ovulation appears to protect, so pregnancy, prolonged breastfeeding and the contraceptive pill have all been shown to reduce the risk of ovarian cancer. Investigations Initial workup for patients with suspected ovarian cancer includes imaging in the form of ultrasound and CT. Serum levels of the tumour marker CA-125 are often measured. Surgery plays a key role in the diagnosis, staging and treatment of ovarian cancer, and in early cases, palpation of viscera, perito- neal washings and biopsies are generally performed to dene disease extent. Management In early disease, surgery followed by adjuvant cytotoxic chemotherapy with carboplatin, or carboplatin plus paclitaxel, is the treatment of choice. Surgery should include removal of the tumour along with total abdom- inal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Even in advanced disease, surgery is undertaken to maximally debulk the tumour and is followed by cytotoxic chemotherapy, typically using carbo- platin and paclitaxel. Bevacizumab, a targeted therapy against VEGFR, is indicated for patients with high-grade tumours that are suboptimally debulked or those with a more aggressive biological pattern. Subsequent treatment decisions are made with consideration of response to rst-line cytotoxic chemotherapy and germline BRCA mutation status. Options include further platinum/paclitaxel combination, liposomal doxorubicin or targeted therapy against poly-ADP ribose polymerase (PARP, e.g. olapa- rib, niraparib or rucaparib). The serum tumour marker CA-125 and clinical examination may be used to monitor treatment response in ovarian cancer, with CT imaging for those with suspected progressive disease. Endometrial cancer Endometrial cancer accounts for 4% of all female malignancies, produc- ing a 1 in 73 lifetime risk. The majority of patients are post-menopausal, with a peak incidence at 50–60 years of age. Mortality from endome- trial cancer is currently falling. The most common presentation is with post-menopausal bleeding, which often results in detection of the dis- ease before distant spread has occurred. Pathogenesis Oestrogen plays an important role in the pathogenesis of endometrial cancer, and factors that increase the duration of oestrogen exposure, such as nulliparity, early menarche, late menopause and unopposed HRT, increase the risk. Endometrial cancer is 10 times more common in obese women and this is thought to be due to elevated levels of oestrogens. Investigations The diagnosis is conrmed by endometrial biopsy. Management Surgery is the treatment of choice and is used for staging. A hysterec- tomy and bilateral salpingo-oophorectomy are performed with peritoneal cytology and, in some cases, lymph node dissection. Where the tumour extends beyond the inner 50% of the myometrium or involves the cer- vix and local lymph nodes, or there is lymphovascular space invasion, adjuvant pelvic radiotherapy is recommended. Cytotoxic chemotherapy is used as adjuvant therapy, and hormonal therapy and cytotoxic chemo- therapy are used to palliate symptoms in recurrent disease. Cervical cancer Cervical cancer is the fourth most common cancer in women and the leading cause of death from gynaecological cancer worldwide. The incidence is decreasing in high-income industrialised countries but con- tinues to rise in low- and middle-income nations. The most common presentation in the UK is with an abnormal smear test, but with locally advanced disease the presentation is with vaginal bleeding, discomfort, discharge or symptoms attributable to involvement of adjacent struc- tures, such as bladder, or rectal or pelvic wall. Occasionally, patients present with distant metastases to bone and lung. Pathogenesis Almost all cases of cervical cancer are linked to high-risk human papil- lomaviruses (HPV), transmitted through sexual contact. This has under- pinned the introduction of programmes to immunise adolescents against HPV in an effort to prevent up to 90% of cervical cancer. Investigations Diagnosis is made by smear or cone biopsy. Further examination may require cystoscopy and exible sigmoidoscopy if there are symptoms ref- erable to the bladder, colon or rectum. In contrast to other gynaecological
- 179. Further iformatio 151 7 Management In general, the majority of patients with early or locally advanced disease are treated with curative intent. In localised disease where there is no involvement of the lymph nodes, long-term remission can be achieved in up to 90% of patients with surgery or radiotherapy. The choice of surgery versus radiotherapy often depends on patient preference, as surgical treatment can be mutilating with an adverse cosmetic outcome. Patients with lymph node involvement are treated with a combination of surgery and radiotherapy (often with a radiosensitising agent such as cisplatin or cetuximab), and this produces long-term remission in approximately 60%–70% of patients. Recurrent or metastatic tumours may be palli- ated with further surgery or radiotherapy to aid local control, or systemic cytotoxic chemotherapy or immunotherapy may be used. Second malig- nancies are common (3% per year) following successful treatment for pri- mary disease, and all patients should be encouraged to give up smoking and drinking alcohol to lower their risk. Survivorship Advances in cancer prevention, diagnosis and treatment mean that more people are surviving cancer. Cancer survival has doubled in the last 40years in the UK. There are an estimated 2 million people living with, or beyond, cancer in the UK today and 50% of those diagnosed with can- cer will survive their disease for 10 years or more. Cancer survivorship has at least two common meanings: completing treatment for cancer and having no signs of cancer after nishing treatment living with, through and beyond cancer, thus including people who receive curative treatment and people who receive intermittent anti-cancer treatment to control their cancer over a longer time. Many people feel that life is never the same after a cancer diagno- sis. There are often long-lasting physical, social and emotional conse- quences of both cancer and its treatment. These start at diagnosis and last through rst treatment (acute survivorship), continue through and beyond cancer treatments (extended survivorship) and can be long- lasting, even when risk of cancer recurrence is low (permanent survivor- ship). An increasing awareness of survivorship, the impact of a cancer diagnosis and its wide-ranging effects on patients has highlighted the need for holistic and patient-centred care, support and services through- out and after cancer treatment. Further information Books and journal articles Cassidy J, Bissett D, Spence RAJ, etal. Oxford handbook of oncology, 4th edn. Oxford: Oxford University Press; 2015. Hanahan D, Weinberg RA. The hallmarks of cancer: perspectives for cancer medicine. In: Kerr DJ, Haller DG, van de Velde CJH, Baumann M, eds. Oxford textbook of oncology, 3rd edn. Oxford: Oxford University Press; 2016. Oxford Medicine Online DOI: 10.1093/med/9780199656103.003.0001. Tobias J, Hochhauser D. Cancer and its management, 7th edn. Chichester: Wiley–Blackwell; 2014. Websites cancer.org American Cancer Society: clinical practice guidelines ctep.cancer.gov/reporting/ctc.html Common toxicity criteria info.cancerresearchuk.org/cancerstats/ Cancer statistics that can be sorted by type or geographical location 7.22 Common presenting features by location in head and neck cancer Hypopharynx Dysphagia Odynophagia Referred otalgia Enlarged lymph nodes Mouth and tongue Non-healing ulcers Ipsilateral otalgia Nasal cavity and sinuses Discharge (bloody) or obstruction Nasopharynx Nasal discharge or obstruction Conduction deafness Atypical facial pain Diplopia Hoarse voice Horner syndrome Oropharynx Dysphagia Pain Otalgia Salivary gland Painless swelling Facial nerve palsy malignancies, cervical cancer is a clinically staged disease, although MRI is often used to characterise the primary tumour. CT of the chest, abdo- men and pelvis is performed to look for metastases in the lungs, liver and lymph nodes, and to exclude hydronephrosis and hydroureter. Management This depends on the stage of disease. Pre-malignant disease can be treated with laser ablation or diathermy, whereas in microinvasive dis- ease a large loop excision of the transformation zone (LLETZ) or a simple hysterectomy is employed. Invasive but localised disease requires rad- ical surgery, while cytotoxic chemotherapy and radiotherapy, including brachytherapy, may be given as primary treatment, especially in patients with adverse prognostic features such as bulky or locally advanced dis- ease, or lymph node or parametrium invasion. In metastatic disease, platinum-based cytotoxic chemotherapy may be benecial in improving symptoms but does not increase survival signicantly. Head and neck tumours Head and neck cancers are typically squamous tumours that arise in the nasopharynx, hypopharynx and larynx. They are most common in older adult males but oropharyngeal cancers now occur with increasing frequency in a younger cohort of patients, including in women. The rising incidence of oropharyngeal cancers, especially in high-income countries, is thought to be secondary to HPV infection. Presentation depends on the location of the primary tumour and the extent of disease. For exam- ple, early laryngeal cancers may present with hoarseness, while more extensive local disease may present with pain due to invasion of local structures or with a lump in the neck. Patients who present late often have pulmonary symptoms, as this is the most common site of distant metastases (Box 7.22). Pathogenesis The tumours are strongly associated with a history of smoking and excess alcohol intake, but other recognised risk factors include Epstein– Barr virus for nasopharyngeal cancer and HPV infection for oropharyn- geal tumours. Investigations Careful inspection of the primary site is required as part of the staging process, and most patients will require endoscopic evaluation and exami- nation under anaesthesia. Tissue biopsies should be taken from the most accessible site. CT of the primary site and the thorax is the investigation of choice for visualising the tumour, while MRI may be useful in certain cases.
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- 181. Multiple Choice Questions 7.1.A 54-year-old woman presents to the emergency department with fevers and a sore throat. She has recently been diagnosed with left-sided breast cancer and associated axillary lymph node disease. Twelve days ago she received her rst cycle of neoadjuvant cytotoxic chemotherapy (5-uorouracil, epirubicin and cyclophosphamide). On clinical examination her temperature is 38.3°C, she appears dehydrated and there is evidence of oral candidiasis. An intravenous catheter is placed and bloods, including blood cultures, taken. What is the most appropriate next step in this patient’s care? A. Start oral uconazole B. Await blood test results to inform further management C. Start intravenous uids D. Perform a chest X-ray, collect a urine sample and throat swab to complete the infection screen E. Start high-dose broad-spectrum intravenous antibiotic therapy immediately Answer: E. The clinical features here are of fever in a patient at high risk of neu- tropenia. This is an oncological emergency. Patients are at risk of neu- tropenia at any point during their systemic anti-cancer therapy treatment cycle, with the highest risk typically 10–14 days after a treatment. In patients with potential neutropenic sepsis high-dose broad spectrum intravenous antibiotics should be commenced, ideally within 1hour of admission, without awaiting test results. In this patient uconazole (A) for oral candidiasis, intravenous uids (C) and further tests (D) are also appropriate, but should not delay the rst dose of antibiotic therapy. Test results may later inform changes to antimicrobial therapy and its duration. 7.2. A 61-year-old man recently diagnosed with colon cancer and associated liver and lung metastases is seen in the oncology clinic. He is keen to talk about treatment for his cancer. His ECOG performance status is 1 and he has no signicant comorbidities. He has some mild symptoms of abdominal discomfort and has lost 5kg in weight. His routine bloods demonstrate anaemia (Hb105g/L) and mild elevations in his liver enzymes. A biopsy of his tumour has shown a moderately differentiated adenocarcinoma which is KRAS/NRAS wildtype and BRAF mutant. What is the most appropriate treatment option for this patient? A. Cytotoxic chemotherapy (5-uorouracil, folinic acid and oxaliplatin) alone B. Surgery to all cancer sites C. Cytotoxic chemotherapy (5-uorouracil, folinic acid and oxaliplatin) with an EGFR inhibitor (cetuximab) D. Cytotoxic chemotherapy (5-uorouracil, folinic acid and oxaliplatin) with a BRAF inhibitor (dabrafenib) E. Refer to palliative care Answer: A. This man wishes to pursue anti-cancer therapy and, from the informa- tion provided, appears t to do so. In patients with metastatic disease systemic anti-cancer therapies are most often used, unless there is a need to palliate a specic symptom. Cytotoxic chemotherapy would be an appropriate option here. As the tumour is BRAF mutant he is unlikely to respond to an EGFR inhibitor such as cetuximab. BRAF inhibitors such as dabrafenib are not used in colon cancer regardless of the mutational status. 7.3. A 59-year-old woman is seen in the emergency department with a 2-day history of severe diarrhoea. She has had 10 loose stools today, the most recent of which have been bloody and associated with crampy abdominal pain. Her past medical history includes metastatic melanoma and she had her fourth cycle of ipilimumab and nivolumab therapy 20 days ago. At the time of her treatment she was constipated and the outpatient systemic anti-cancer therapy unit doctor prescribed her a macrogol laxative. She notes that the evening prior to the diarrhoea starting she had reheated some leftover rice for her supper. What is the most important likely diagnosis? A. Bacillus cereus-associated food poisoning B. Overow diarrhoea C. Laxative overuse D. Immunotherapy-related colitis E. Clostridioides difcile infection Answer: D. Immune-related adverse events should be considered in all patients who present acutely unwell following immunotherapy treatments for cancer. Although the other options are on the differential diagnosis list, severe IRAEs are oncological emergencies and prompt recognition and management are vital. This is a grade 3 colitis and should be treated with IV methylprednisolone in the rst instance. Investigations such as bloods, stool sample, radiological imaging and exible sigmoidoscopy or colonoscopy are also appropriate. 7.4. A 58-year-old man is seen in clinic with a diagnosis of metastatic lung cancer. He is coping well at home, where he lives alone. However, he has taken early retirement as a brick-layer as he feels unable to work due to increasing fatigue. He awakes early each morning and goes to the shops to collect his newspaper, but has taken to napping for an hour in the afternoon. What is this man’s ECOG performance status? A. 0 B. 1 C. 2 D. 3 E. 4 Answer: B. This man is ambulatory and capable of self-care, but unable to under- take strenuous activity. He is up for more than 50% of waking hours. Performance status is a key assessment tool in patients with cancer. 7.5. You have been asked to see a 70-year-old man on a medical ward. He was admitted 2 weeks ago following a fall. On admission he had abnormal liver function tests and an elevated CRP. He has been treated for a urinary tract infection. A CT scan has demonstrated multiple liver, lung and bone metastases, but no obvious primary cancer. The ward nurses tell you he remains mildly confused at times, sleeps for most of the day and does not wish to engage with physiotherapy. What is the most appropriate management for this man? A. Refer to the Hepatobiliary Pancreatic Cancer Multidisciplinary Team B. Ultrasound-guided liver biopsy C. Colonoscopy D. Palliative care E. Cytotoxic chemotherapy Answer: D.
- 182. This man hasa new diagnosis of metastatic cancer of undened pri- mary origin (MUO). His ECOG performance status (3), requirement for hospital admission, multi-organ metastatic disease, end-organ dys- function and raised inammatory markers are poor prognostic features. Further investigations may not be warranted and honest conversations about the likely diagnosis, palliative care and end-of-life care, taking into account the patient’s wishes are often preferable. 7.6. A 56-year-old woman is seen in oncology clinic following surgery to remove a localised clear cell renal cell carcinoma. She is eligible for a phase III clinical trial comparing adjuvant immunotherapy to the current clinical standard of observation. Patients will be randomised to receive either the immunotherapy treatment or a placebo every 4 weeks for 1 year. Neither the patient nor the investigator will know what treatment she is receiving. Which of the following statements regarding randomised controlled trials (RCTs) is true? A. Patients may choose which treatment they receive B. RCTs are always ‘double blinded’ C. RCTs are considered to be the ‘gold standard’ for determin- ing efcacy and safety in clinical research D. RCTs always have a control arm that uses placebo E. RCTs always equally divide patients between each treatment arm Answer: C. Phase III RCTs are often used to determine whether a treatment should be licensed for clinical use. Patients are randomised to each arm, sometimes with stratication to ensure equal allocation of patient sub- groups. RCTs may be double-blinded, as is the case here, single-blinded or ‘open-label’. The control arm should be the current clinical standard treatment. In this example a placebo is used in the place of observation only to ensure blinding and avoid potential bias of results. Patients may be divided in alternative ratios. This is sometimes the case when earlier studies suggest large differences between the investigational and current treatment.
- 183. Pain and palliativecare 8 LA Colvin M Fallon Clinical examination in pain and palliative care 154 Clinical evaluation and management in a patient with chronic pain or in the palliative care setting 155 Pain 156 Functional anatomy and physiology 156 Investigations 158 Principles of management 160 Interventions 162 Chronic pain syndromes 165 Palliative care 167 Presenting problems in palliative care 167 Death and dying 172
- 184. 154 PAINAND PALLIATIVE CARE Venous system SVC obstruction due to lung carcinoma Mouth Increased secretions due to dysphagia Extremities Neuropathic pain due to CRPS type I 1 Abdomen Abdominal swelling secondary to malignant ascites Lower limb Phantom limb pain (CRPS type II) following amputation Lungs Dyspnoea due to pleural effusion 3 4 5 2 Hand Muscle wasting and pain due to nerve compression 1 2 Spine Back pain due to bone metastases 3 4 5 6 6 7 9 9 8 7 8 Nervous system Drowsiness due to hypercalcaemia or brain metastases Insets (SVC obstruction, wasting in the hand, pleural effusion, ascites, amputation) From Forbes CD, Jackson WF. Color atlas and text of clinical medicine, 3rd edn. Edinburgh: Mosby; 2002. (CRPS = chronic regional pain syndrome; SVC = superior vena cava) Clinical examination in pain and palliative care
- 185. Clinical evaluation andmanagement in a patient with chronic pain or in the palliative care setting 155 8 VAS score Record severity of pain Take careful history, recording character and radiation of pain Assess pinprick, fine touch and heat/cold sensation Formulate management plan with patient and set goals Consider TENS and acupuncture Consider nerve block or ablation Consider psychological therapies and mindfulness Increase physical activity Conduct biopsychosocial assessment Conduct general examination Educate patient on nature of pain and promote self-management Consider yoga, pilates or tai chi Assess mood and screen for depression Check gait and whether using a walking aid Conduct neurological examination Optimise medication (TENS = transcutaneous electrical nerve stimulation) Clinical evaluation and management in a patient with chronic pain or in the palliative care setting
- 186. 156 PAINAND PALLIATIVE CARE Pain Pain is dened as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage’. It is one of the most common symptoms for which people seek health-care advice. Our understanding of the mechanisms of pain has evolved considerably from Hippocrates’ suggestion in 450 BC that pain arose as a result of an imbalance in vital uids. We now know that pain is a complex symptom that is inuenced and modied by many social, cultural and emotional factors, as illustrated in Figure 8.1. The sensation of acute pain that occurs in response to inammation or tissue damage plays an important role in protection from further injury. Chronic pain serves no useful function but results in signicant distress and suffering for the patient affected, as well as having a wider societal impact. Functional anatomy and physiology The functional anatomy of the somatosensory system is shown in Figures 28.3 and 28.6. Here, discussion will focus on the mechanisms and medi- ators that are involved in pain processing. Peripheral nerves Peripheral nerves contain several types of neuron. These can be classi- ed into two groups, depending on whether or not they are surrounded by a myelin sheath. Myelinated neurons have a fast conduction velocity and are responsible for transmission of various sensory signals, such as proprioception, light touch, heat and cold, and the detection of localised pains, such as pin-prick. Unmyelinated bres have a much slower con- duction velocity and are responsible for transmitting diffuse and poorly localised pain, as well as other sensations (Box 8.1). Sensory neurons (also known as primary afferent neurons) connect the spinal cord to the periphery and supply a dened territory or a der- matome, which can be used to identify the position of a nerve lesion (see Fig. 28.10). In healthy individuals, dermatomes have distinct bor- ders, but in pathological pain syndromes these may become blurred as the result of neuronal plasticity, which means that pain may be felt in an area adjacent to that supplied by a specic nerve root. Autonomic neu- rons also contain pain bres and are responsible for transmitting visceral sensations, such as colic. In general, visceral pain is diffuse and less well localised than pain transmitted by sensory neurons. Anatomical features of the afferent pain pathway are illustrated in Figure 8.2. Pain signals are transmitted from the periphery to the spinal cord by sensory neurons. These have the following components: A cell body, containing the nucleus, which is situated in the dorsal root ganglion close to the spinal cord. The cell body is essential for survival of the neuron, production of neurotransmitters and neuronal function. The nerve bre (axon) and peripheral nerve endings, which are located in the periphery and contain a range of receptors in the neuronal membrane. Specialised receptors in the periphery, consisting of bare nerve end- ings known as nociceptors or pain receptors, which are activated by various mediators. They are situated mainly in the epidermis. The central termination, which travels to the dorsal horn of the spinal cord to form the rst central synapse with neurons that transmit pain sensation to the brain. When a noxious stimulus is encountered, activation of nociceptors leads to generation of an action potential, which travels upwards to the dorsal root ganglion and also stimulates the release of neurotransmitters that have secondary effects on surrounding neurons. Spinal cord Sensory neurons, through their central termination, synapse with sec- ond-order neurons in the dorsal horn of the spinal cord. There is consid- erable modulation of pain messages at this site, both from local neurons within the spinal cord and from neurons that descend from the brain, as depicted in Figure 28.11. Several neurotransmitters are involved in pain processing at this level and these are summarised in Box 8.2. They include amino acids, such as glycine and γ-aminobutyric acid (GABA), which are inhibitory, and glutamate, which is excitatory; neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP); and endorphins. Whether or not they increase or decrease pain perception depends on the connectivity of the neurons on which they act. Illness and pain behaviour (underlying disease, impact on quality of life, fear avoidance) Social and cultural (socioeconomics, religion, family) Affect and emotional state (mood, self-efficacy) Cognition (catastrophising, acceptance) Sensory (genetic, anatomical, biomedical) Fig. 8.1 The biopsychosocial model of pain. The perception of pain as a symptom is dependent not only on sensory inputs but also on the individual’s cognitive reaction to the pain, their emotional state, their underlying disease and their social and cultural background. 8.1 Types of nerve bre Fibre type Diameter (µm) Conduction velocity (ms 1 ) Function Large myelinated Aα 12–20 70–120 Proprioception Motor to muscle bres Aβ 5–12 30–70 Light touch, pressure A 3–6 15–30 Motor to muscle spindles Small myelinated A 2–5 12–30 Well-localised pain Thermal sensation B <3 3–15 Pre-ganglionic autonomic Unmyelinated C 0.4–1.3 0.5–3 Diffuse pain Poorly localised thermal sensation Post-ganglionic autonomic
- 187. Pain 157 8 Centralprocessing of pain The signals transmitted by second-order neurons in the spinal cord are relayed to the sensory cortex by third-order neurons, which synapse with second-order neurons in the thalamus. At this site, perception of pain is inuenced by interactions between a range of structures in the brain, where sensory, cognitive and emotional aspects are integrated. This is termed the pain neuromatrix (see Fig. 8.2). Signals within the neuromatrix are multidirectional in nature, involving modulation of incoming messages by the cerebral cortex (top-down regulation), as well as a complex net- work of connections between other subcortical structures. Under normal conditions, there is a degree of descending inhibition from the brainstem that reduces input from peripheral stimuli. It is thought that chronic widespread pain (CWP) and opioid-induced hyperalgesia may result, at least in part, from abnormalities in central pro- cessing of pain signals. It has also been suggested that variations in the levels of descending inhibition between individuals may make some peo- ple more vulnerable than others to developing chronic pain. Over recent years, there has been increasing interest in the role that glial cells (see Fig. 28.1) play in pain processing. Both astrocytes and microglial cells can become activated in chronic pain states and release pro-inammatory cytokines, as well as altering re-uptake of excitatory neurotransmitters such as glutamate, which can inuence pain perception considerably. As our understanding of these processes improves, there is increasing potential to develop novel therapies targeted at these mediators, with some early clinical studies in neuropathic pain (pain related to nerve injury or disease, with characteristic neurobiological changes). Sensitisation Sensitisation is one of the key features of pain processing. It refers to the fact that both peripheral and central nervous systems adapt rapidly to the presence of pain, especially in response to tissue damage. This adaptive process is called neuronal plasticity. In some situations, neuronal plas- ticity can lead to prolonged changes in the pathways that are involved in detecting and processing nociceptive stimuli, resulting in chronic pain syndromes. The specic changes in key neurotransmitters and recep- tors differ between chronic pain states, with implications for the efcacy of treatments. For example, mu opioid receptors are down-regulated in neuropathic pain, potentially leading to limited opioid responsiveness. Peripheral sensitisation Peripheral sensitisation can occur in association with a variety of clin- ical conditions, including sepsis, cancer, inammatory disease, injury, Primary afferent neuron Second-order neuron First central synapse Spinothalamic tract Dorsal root ganglion Peripheral input Spinal cord Medulla Mid-brain Cell body C fibre Nociceptors: chemicals, changes in pH, cytokines Thalamus PAG RVM Synapse Hypothalamus Amygdala Emotional Cognitive Sensory Sensory Emotional Cerebral cortex Fig. 8.2 Ascending and descending pain pathways. Ascending pathways are shown in blue and descending in red. Pain signals are detected in the periphery by nociceptors, which are activated by chemicals, changes in pH and cytokines. The signal is transmitted by the primary afferent neuron to the spinal cord, where there is a synapse with a second-order neuron, which transmits the signal onwards to the thalamus. Thereafter, the pain signal is transmitted to the cerebral cortex. The intensity of pain signals is subject to extensive modulation at several levels within the nervous system. Cognitive inuences derived from the frontal lobe, coupled with sensory inuences from cortex and emotional inuences from the amygdyla, affect pain perception in the mid-brain around the periaqueductal grey matter (PAG) and the rostroventrolateral medulla (RVM) in the medulla. These structures form part of the descending modulatory systems, which, under normal circumstances, inhibit pain perception. In some chronic pain states, however, dysfunction of the descending pathways can occur, increasing pain.
- 188. 158 PAINAND PALLIATIVE CARE surgery and obesity. The nal common pathway by which sensitisation takes place in all of these conditions is inammation. Inammation is accompanied by increased capillary permeability and tissue oedema with the release of a diverse range of mediators, including bradykinin, hydrogen ions, prostaglandins and adenosine, which bind to receptors and ion channels on nociceptors of primary afferent neurons (Fig. 8.3). The signalling pathways activated by these mediators generate action potentials, which are transmitted by sensory neurons to the spinal cord. If these pain-provoking stimuli persist, the activation threshold of sensory neurons is reduced, resulting in an increased transmission of pain signals to the spinal cord. Central sensitisation Sensitisation may also take place at the level of the spinal cord in response to a sustained painful stimulus. It can occur acutely and rapidly, such as immediately after surgery, or may progress to chronic changes, such as chronic infection, cancer, repeated surgery or multiple trau- matic episodes. Glutamate, acting via the N-methyl-D-aspartate (NMDA) receptor complex, plays a key role in central sensitisation (Fig. 8.4). In response to a sustained peripheral painful stimulus, increased amounts of glutamate are released in the spinal cord, overcoming the inhibitory action of magnesium ions and resulting in activation of the NMDA recep- tor. This initiates a cascade of intracellular signalling events that lead to prolonged modications of somatosensory processing, with amplica- tion of pain responses within the spinal cord and continued neuronal ring, even after the noxious stimulus has stopped. This phenomenon is termed ‘after-discharge’. In neuropathic pain, prolonged activation of the NMDA pathway results in a decrease in the number of inhibitory interneu- rons, which further potentiates pain. Genetic determinants of pain perception There are marked ethnic and individual variations in how people respond to painful stimuli and studies in twins have estimated that the heritability of CWP ranges between 30% and 50%. In the general population, the individual variants in response to pain and perception of pain are most likely due to a complex interaction between genetic and environmental inuences. Few variants have been identied with robust evidence of association with CWP. Several rare syndromes have been described, however, in which insensitivity to pain or heightened pain responses occur as the result of a single gene disorder, as summarised in Box 8.3. Most are due to mutations affecting ion channels that play a key role in neurotransmission (see Fig. 8.3), but other causes include mutations in the NTKR1 gene, which encodes the receptor for nerve growth factor, and mutations in the PDRM12 transcription factor, which is involved in neuron development. Investigations Pain can be a presenting feature of a wide range of disorders and the rst step in evaluation of a patient with pain should be to perform what- ever investigations are required to dene the underlying cause of the pain, unless this is already known. However, with most chronic pain syndromes, such as bromyalgia, complex regional pain syndrome and CWP, investigations are negative and the diagnosis is made on the basis of clinical history and exclusion of other causes. Specic investigations that are useful in the assessment of selected patients with chronic pain are discussed below. 8.2 Neurotransmitters and receptors involved in pain processing in the spinal cord Neurotransmitter Receptor(s) Receptor type Comments* Amino acids Glutamate AMPA Ion channel Excitatory; permeable to cations: can be Ca2+ , Na+ or K+ , depending on subunit structure NMDA Ion channel Excitatory; blocked by Mg2+ in the resting state; block can be altered if membrane potential changes; permeable to Ca2+ , Na+ and K+ Kainate Ion channel Post synaptic – excitatory Gp I GPCR Pre-synaptic – inhibitory through GABA release; permeable to Na+ and K+ Gp II GPCR Activates a range of signalling pathways; long-term effects on synaptic excitability Gp III GPCR Probably inhibitory; can decrease cAMP production; pre-synaptic; decreases glutamate release Glycine GlyR Ion channel Mainly inhibitory; permeable to Cl ; blocked by caffeine GABA GABAA Ion channel Mainly inhibitory in spinal cord; permeable to Cl ; indirectly modulated by benzodiazepines (increased ion channel opening); not specically involved in nociception, generally depressant effect on spinal cord activity GABAB GPCR Predominantly inhibitory; activated by baclofen Neuropeptides Substance P Neurokinin receptors GPCR Mainly excitatory; increased in inammation, decreased in neuropathic pain Cholecystokinin CCKRs1–8 GPCR Excitatory; clinical trials of antagonists in progress Calcitonin gene-related peptide CALCRL GPCR Excitatory; slows degradation of substance P; implicated in migraine Opioids Dynorphin DOP GPCR Excitatory?; may be pro-nociceptive β-endorphin MOP GPCR Inhibitory Nociceptin NOP GPCR Inhibitory; also expressed by immune cells (AMPA = α-amino 3-hydroxy, 5-methyl, 4-isoxazole propionic acid; CALCRL = calcitonin receptor-like receptor; cAMP = cyclic adenosine monophosphate; CCKR = cholecystokinin receptor; DOP = delta opioid receptor; GABA = γ-aminobutyric acid; Gp = group; GPCR=G-protein-coupled receptor; MOP = mu opioid receptor; NMDA = N-methyl-D-aspartate; NOP = nociceptin/orphan receptor) *Excitatory = increased pain; inhibitory = reduced pain.
- 189. Pain 159 8 Magneticresonance imaging Magnetic resonance imaging (MRI) can be helpful in the assessment of an underlying cause in patients with focal pain that follows a nerve root or peripheral nerve distribution. Imaging is seldom helpful in individuals with CWP. Blood tests Blood tests are not generally helpful in the diagnosis of chronic pain, except in patients with peripheral neuropathy; in this case, a number of blood tests may be required to investigate the underlying causes of the neuropathy. Full details are provided in Box 28.85. Genetic testing may Stimulus ATP Temperature or low pH Osmosis Cold or limitants Cool Low pH Mechanical Bradykinin Prostanoids ATP NGF Transducer P2X TRPV1/2 TRPV4 TRPA1 TRPM8 ASIC Unknown BK1/2 EP P2Y NTRK1 Kv HCN2 Nav1.7 Sensitisation Stimulus Agonists [H+] Receptors Response Nav1.8 Nav1.9 B A C Fig. 8.3 channels that act as mediators of pain. They include sodium channels implicated in congenital pain syndromes; the purinergic 2X (P2X) and purinergic 2Y (P2Y) receptor for adenosine triphosphate (ATP); members of the transient receptor potential (TRP) superfamily of ion channel receptors, which detect changes in osmolality and temperature; acid-sensing ion channel (ASIC) receptors, which detect hydrogen ions; G-protein-coupled receptors, which detect bradykinin (BK), prostaglandins and ATP; sodium-potassium hyperpolarization-activated cyclic nucleotide-gated channels (HCN2), and voltage gated potassium channels (Kv) and the neurotrophic tyrosine kinase 1 (NTRK1) receptor, which + ] and high temperature (>42°C) amplies action potentials, which increase pain signals and cause peripheral sensitisation. (EP = E-prostanoid receptor) Adapted from Bennett DL, Woods CG. Painful and painless channelopathies. The Lancet Neurol 2014; 13:587–599; reproduced with permission from Elsevier. Glutamate Amino acids (and other neurotransmitters) Pain signal Amplified signal Kinase Dorsal root ganglia Neurotransmitter changes Glycine NR1 NR2 Mg2+ Regulation of pain response NMDA receptor Fig. 8.4 Mechanisms of central sensitisation. Post-synaptic activation of the N-methyl-D-aspartate (NMDA) receptor requires the amino acids glycine and glutamate, which bind to the NR1 and NR2 subunits, respectively; these amplify pain signals at the level of the spinal cord. In contrast, magnesium ions block receptor activation.
- 190. 160 PAINAND PALLIATIVE CARE be of value in patients with clinical features that point to an inherited disorder of pain processing (see Box 8.3). Quantitative sensory testing Quantitative sensory testing can be helpful in the detailed assessment of patients with chronic pain. A simple set of tools can be used in the clinical setting (Fig. 8.5). Lightly touching the skin with a brush, swab or cotton-wool ball can be used to test for abnormalities of ne touch. This may include allodynia, where a normally non-painful stimulus is perceived as painful. Assessing the patient’s response to a pin-prick can be used to test for abnormalities in mechanical hyperalgesia. Finally, touching the patient’s skin with warm and cool thermal rollers can be used to test for abnormalities of thermal sensation. An unaffected area of skin should be tested rst, to establish normal sensation, before testing the affected area. Nerve conduction studies Nerve conduction studies can be helpful in demonstrating and quanti- fying a denitive nerve lesion, either peripherally or centrally. They can be used to help differentiate between central and peripheral neuropathic pain. They do not, however, effectively examine small nerve bre function. Nerve blocks Performing a nerve block with inltration of a local anaesthetic such as 1% lidocaine can be used diagnostically, in assessing whether a pain syndrome is due to involvement of a specic nerve or nerve root. Where inammation and or swelling may be contributing to the underlying pain – for example, if there is compression of a nerve root – then a mixture of local anaesthetic and depot glucocorticoid may be helpful in alleviating pain. Nerve blockade can also be used to determine whether more radi- cal therapies, such as nerve ablation, might be helpful in controlling pain, particularly that related to cancer. Pain scoring systems Various questionnaires and other instruments have been devised to localise pain, rate its severity and assess its impact on quality of life. Some of the most widely used are listed in Box 8.4. The distribution of pain can be documented on a diagram of the body, on which the patient can mark the sites that are painful. Similarly, other methods have been developed with which to assess the severity of pain using verbal, numer- ical and behavioural rating scales. Visual scoring systems employing dif- ferent facial expressions may be of value in paediatric patients and those with cognitive impairment. Documenting changes in pain scores using questionnaires can be helpful in indicating to what extent drug treat- ments have been successful and can reduce the time taken to achieve pain control. Principles of management Effective management of chronic pain depends in part on the underlying cause but some general principles can be applied. In general terms, the treatment goals are to: educate the patient promote self-management optimise function enhance quality of life control pain. 8.3 Genetic regulators of pain perception Gene (protein) Mutation (inheritance) Protein function Phenotypes SCN9A (Na,1.7) LoF (AR) Ion channel Absent pain, hypohydrosis, anosmia SCN9A (Na,1.7) GoF (AD) Ion channel Erythromelalgia, paroxysmal pain, burning pain, autonomic dysfunction SCN11A (Na,1.9) GoF (AD) Ion channel Absent pain, hyperhydrosis, muscular weakness, gut dysmotility SCN10A (Na,1.8) GoF (AD) Ion channel Burning pain, autonomic dysfunction TRPA1 (TRPA1) GoF (AD) Ion channel Absent pain PDRM12 (PDRM12) LoF (AR) Transcription factor; neuron development Absent pain NTRK1 (high-afnity NGF receptor) LoF (AR) Tyrosine kinase; promotes neuron development Absent pain; anhydrosis, mental retardation, increased cancer risk (AD = autosomal dominant; AR = autosomal recessive; GoF = gain of function; LoF = loss of function; NGF = nerve growth factor) Cotton wool Neurology pin Allodynia Warm and cool thermal rollers Increased or decreased thermal sensation Hyperalgesia Fig. 8.5 Equipment for bedside sensory testing.
- 191. Pain 161 8 Clinicalhistory Biopsychosocial assessment A full biopsychosocial assessment should be performed in all patients with chronic pain. Although this is time-consuming, the time invested is likely to pay dividends in improving the long-term outcome for patients. A biopsychosocial assessment takes account of the underlying neurobi- ology of the condition in the context of wider inuences, including cogni- tion and beliefs, emotions, and social and cultural factors. For example, an individual with abdominal pain might respond differently if a close relative had recently died of gastric cancer than if a colleague had been off work with gastric upset. An accurate clinical history is important, taking note of the dura- tion of pain, any precipitating and relieving factors, its location and, if the pain is located at more than one site, which site is the one that impacts most on the patient’s quality of life. The characteris- tics of the pain should be documented, by assessing whether it is described as dull, sharp, aching or burning. Associated features, such as hypersensitivity to ne touch or temperature, numbness, paraesthesia, tingling and formication (the feeling of insects crawl- ing over the skin), should be noted. It is important to determine to what extent the pain is interfering with normal daily activities, such as work, leisure pursuits and sleep. The patient’s social circumstances and cultural background should be documented, including any car- ing responsibilities, employment status and social and family sup- port. The intensity of pain should also be recorded, preferably using a validated questionnaire (see Box 8.4). The patient’s mood should be assessed and, if evidence of low mood is detected, a suicide risk assessment should be considered (see Box 31.14). The past medi- cal and medication history should be recorded and specic enquiry made about substance misuse and any previous history of physical or mental abuse. This should be approached sympathetically, with infor- mation about how to access appropriate support if required. It is also useful to enquire specically about the patient’s beliefs as to what is causing their pain, as well as what their expectation of treatment is; unless these are addressed, management may be less effective. There are some patient populations in whom particular challenges arise, often related to differences in communication ability. Strategies that can be used to overcome these difculties are summarised in Box 8.5 Examination The patient’s general appearance should be noted, including ability to walk and use of a walking aid. In those with focal pain, neurological examination should be performed, focusing particularly on any areas of abnormal sensation, reexes and evidence of muscle wasting. A general examination should be carried out to determine whether there is any evidence of an underlying physical disorder that can account for the pain. In addition to the use of investigations to nd the underlying cause of pain, patients with persistent or chronic pain may benet from sensory testing or diagnostic nerve blocks to explore the underlying mechanisms and direct treatment. For example, a combined femoral and sciatic nerve block may be used in a patient with lower limb amputation to assess whether the pain is predominantly peripherally or centrally generated. If the pain is not improved by an effective nerve block, then peripherally directed therapies are unlikely to be effective. 8.4 Instruments used in the assessment of pain and its impact Instrument Comments Brief Pain Inventory Developed for use in cancer pain, validated and widely employed for chronic pain; based on 0–10 ratings of pain intensity and the impact of pain on a range of domains, including sleep, work and enjoyment of life Pain Detect, s-LANSS, DN-4 A number of screening questionnaires to aid diagnosis of neuropathic pain Pain Catastrophising Scale Developed to assess individual levels of catastrophising, encompassing three different domains: helplessness, rumination and magnication Tampa Scale of Kinesiophobia Measures how much an individual is fearful of movement Pain Self-efcacy Questionnaire Assesses individual beliefs about self-efcacy in the context of chronic pain, and how this impacts on function Visual analogue scale (VAS) Patient marks pain intensity on a horizontal line Localisation of pain Body chart, allowing the patient to indicate where pain is situated Beck Depression Inventory Assesses emotional function SF-36/EQ-5D Assesses health-related quality of life (DN-4 = Douleur Neuropathique questionnaire; EQ-5D = EuroQol 5-Domain questionnaire; SF-36 = Short Form 36; s-LANSS = self-completed Leeds Assessment of Neuropathic Signs and Symptoms) 8.5 Challenges in pain assessment in particular patient populations Patient population Challenges Solutions Paediatric Assessment needs to be appropriate to developmental stage Consider visual tools to aid pain assessment Older adults May have impaired cognitive function Cultural factors may reduce self-reporting of pain Risk of adverse effects of medication increased Consider formal assessment of cognitive function Consider non-verbal assessment Consider visual tools to assess pain Employ a number of tools assessing pain behaviours Cognitive impairment Reporting and expression of pain may change Increased sensitivity to central nervous system effects of analgesics Perform formal assessment of cognitive function Use non-verbal assessment: facial expressions, vocalisations, body movements, changes in social interactions Substance misuse Response to analgesics altered Increased tolerance Increased risk of addiction Substance misuse may affect reporting of pain Seek specialist support early Ensure prescribing is safe
- 192. 162 PAINAND PALLIATIVE CARE Interventions Probably the most effective mode of treatment for pain is to identify the underlying cause. Examples include the use of immunosuppressive med- ication in inammatory disease, chemotherapy, radiotherapy or hormone therapy in cancer, and antimicrobial therapy in patients with infection. There are many circumstances, however, in which the underlying cause of pain cannot be treated or the treatments available are incompletely effective. Under these circumstances, several management options are available. In all cases, a multidisciplinary approach is necessary that combines pharmacological management with supported self-manage- ment, and other specic interventions when appropriate. Supported self-management Self-management strategies are useful in the treatment of chronic pain. Self-management works best if the patient has some understanding of their chronic pain, and acceptance that it is unlikely to resolve completely. The aim is for patients to maximise their quality of life and function despite ongoing pain. Support for self-management can be delivered by health- care professionals, patients who suffer from the same condition or lay people, either on an individual basis, in a group setting or, increasingly, through web-based resources. There is a strong educational component to supported self-management, which seeks to generate an interaction between patient and tutor. The key aspects include: increasing activity levels, while understanding and practising pacing techniques (not overdoing things and cycling between over- and under-activity) using relaxation and mindfulness techniques as part of daily management using medication when appropriate having a plan to manage pain ares. All these are covered in formal pain management programmes (see ‘Psychological therapies’), where a structured approach is used, in a group-based setting, to address all these aspects with expert multidis- ciplinary input, that may include psychologists, occupational therapists, nurses, pharmacists and pain medicine specialists. For less complex cases, or to provide ongoing support, there are a number of useful online self-help resources (see ‘Further information’). Physical therapies There is strong evidence that exercise can help in the management of chronic pain. Several types of exercise have been successfully delivered in various ways, through physiotherapists, exercise classes or individual tuition. In choosing a form of exercise therapy, it is important to tailor the approach most likely to be acceptable to the individual patient. A successful exercise programme can help overcome ‘fear avoidance’, a well-recognised problem in chronic pain, where patients associate activ- ity with an increase in pain and therefore do progressively less activity, with resultant deconditioning. Because of this it is important to pace physical activity to ensure that patients do not cycle from over-activity, with a are in pain, to fatigue and deconditioning. This can be done by working with patients to establish their baseline level of activity and using an individually tailored, graded exercise programme (Box 8.6). This may include normal household activities, as well as targeted exercises and stretches. Manual therapy covers a variety of hands-on treatments, including manipulation, mobilisation and massage. Manual therapy can be provided by a range of therapists, including physiotherapists, osteo- paths and chiropractors. There is some evidence of short-term benet for manual therapy but limited evidence of long-term efcacy. Pharmacological therapies A range of analgesics can be used in the management of chronic pain but, for most of these, the evidence of long-term benet is limited, and there may be considerable risks associated with long-term use for some agents. If using analgesics as part of a holistic treatment plan (e.g. to manage short-term are-ups, or target neuropathic pain), in general, it is advisable to use a multimodal approach, choosing different drugs to target pain processing at multiple points (Box 8.7). By employing different classes of analgesic, it is possible to use lower doses of each, thereby improving the side-effect prole and reducing risk. There is considera- ble inter-individual variability in response to analgesics, even within the same class. There are many reasons for this, including genetic variations in the enzymes that metabolise drugs. For example, the CYP2D6 gene encodes for a liver enzyme, cytochrome P450 2D6, which metabolises a number of commonly used analgesics. Genetic variation in CYP2D6 can inuence circulating levels of many drugs, depending on whether someone is a rapid or poor metaboliser. This is particularly important if metabolites are active, as is the case with codeine and dihydrocodeine, which are metabolised to morphine. Genetic variations have also been described in the opioid receptors and downstream pathways that they affect, with good pre-clinical evidence that variations in mu opioid recep- tors alter analgesic response to different opioids. Because of this there is a good rationale to try different drugs, even ones from the same class, if there is an inadequate response or there are unacceptable side-effects with one agent. Whatever drug or combination of drugs is chosen, the key to suc- cessful pharmacological management is careful assessment and review, aiming for an acceptable balance between the benets of treatment in providing pain relief, maximising function, and improving quality of life and adverse effects. Specic drug treatments are described below. Non-opioid analgesics Paracetamol Paracetamol is widely used in the treatment of mild to moderate pain. Its mechanism of action is incompletely understood but it is known to be a weak inhibitor of the cyclo-oxygenase type 1 (COX-1) and cyclo- oxygenase type 2 (COX-2) enzymes, providing weak anti-inammatory properties. There is also some evidence that it activates inhibitory descending spinal pathways, via a serotonergic mechanism. Other postulated mechanisms include endocannabinoid re-uptake inhibi- tion, and inhibition of nitric oxide and tumour necrosis factor alpha. For migraine and tension-type headache it has moderate efcacy at a dose of 1000mg. It is used widely for musculoskeletal disorders and osteo- arthritis, with very little high-quality evidence that it is much better than placebo, even at doses of up to 4000mg per day. Acute liver failure is a well-recognised complication of paracetamol overdose but this risk may also be increased with long-term use, even within the recommended dose range. In view of this, it should be employed with caution in older patients and those weighing less than 50kg. Non-steroidal anti-inammatory drugs Non-steroidal anti-inammatory drugs (NSAIDs) are widely used in the treatment of inammatory pain and osteoarthritis. These drugs can be given systemically or locally and are discussed in more detail in Chapter 26. They are also useful in the management of pain in cancer patients, as discussed later in this chapter. Although widely prescribed, there is 8.6 Physical therapies for chronic pain Land-based Walking Gym work Exercise classes Yoga Pilates Tai-chi Water-based Hydrotherapy Swimming Exercise classes
- 193. Pain 163 8 limitedhigh-quality evidence of long-term efcacy in chronic pain, and concerns about risks of long-term use particularly around cardiovascular and renal effects. There is a clear need for further studies in this area. Topical analgesics Topical capsaicin cream (0.025 or 0.075%) has some efcacy for osteo- arthritis and may be used for neuropathic pain, although evidence of benet is limited. A single application (done by a trained health-care professional) of a high-dose 8% capsaicin patch can give around 12 weeks of pain relief for neuropathic pain and can be repeated there- after. Capsaicin is an agonist at the transient receptor potential vanilloid 1 (TRPV1) ion channel, found on some C bres. Capsaicin activates the channel, causing an initial sensation of heat, but an analgesic effect sub- sequently results due to desensitisation of the channel, with a reduction in intra-epidermal nerve bre density. Lidocaine 5% patches can also be helpful in focal neuropathic pain and should be applied for 12 hours out of 24 hours, with up to 4–6 weeks before maximum benet is seen. The mode of action is blockade of sodium channels in primary afferent neurons and nociceptors, which reduces peripheral input to the spinal cord. Anti-neuropathic agents Anti-neuropathic agents are also termed ‘adjuvant analgesics’. This term is used to cover a range of medicines that are employed in the treatment of neuropathic pain, and in certain patients with CWP. It should be noted that these medicines should only be used as part of a holistic management plan, including physical and psychological therapies, sometimes in com- bination with classical analgesics. Typically, these agents do not produce an immediate reduction in pain, but rather exert an analgesic effect over a longer timeframe through their effects on central processing of pain. They are of particular value when used in combination in the management of pain with a neuropathic component but require careful dose titration over a number of weeks, to reach a dose that balances efcacy with side-effects. While the response to individual agents is variable, it is often possible to nd an agent or combination of agents that works for most patients. In the majority of current recommendations, including those from the International Association for the Study of Pain, rst-line treatments include antidepressants such as serotonin noradrenaline reuptake inhibitors (mainly duloxetine) or tri-cyclic anti-depressants such as ami- triptyline and nortriptyline. Anti-epileptic agents such as gabapentin or pregabalin are also recommended for use as second-line treatments, although there is increasing concern around their abuse potential and association with an increase in drug deaths. Opioid analgesics Opioids have been used for centuries to reduce pain, and were origi- nally obtained from the resin of the opium poppy (Papaver somniferum). Over recent years, new synthetic opioids such as fentanyl, oxycodon and tramadol have been introduced. The pharmacological effects of opi- oids are mediated by binding to a number of opioid receptors which are G-protein-coupled receptors, as summarised in Box 8.8. When opioids bind to their receptors, several intracellular signalling pathways are acti- vated, increasing cyclic adenosine monophosphate (cAMP) levels and altering calcium and potassium permeability of neurons. Opioids are tra- ditionally divided into subclasses of weak opioids, such as codeine and dihydrocodeine, and strong opioids, such as morphine and oxycodone. While tramadol is a weak agonist at the mu opioid receptor, it is classi- ed as a strong opioid in some countries. Codeine and dihydrocodeine are metabolised in the liver to morphine by CYP2D6 at a rate that is genetically determined. Similarly, tramadol is metabolised by CYP2D6 to yield o-desmethyltramadol, which has greater afnity than tramadol for opioid receptors. Up to 10% of people are rapid metabolisers and this may be associated with differences in efcacy and adverse effects of these drugs between individuals (see Box 2.5). The dosages and char- acteristics of commonly prescribed opioids are shown in Box 8.9. There has been a large increase in the use of strong opioids for chronic pain over the last few decades, to the extent that it has been referred to as an ‘opioid epidemic’. A number of factors contribute to this, including a rising incidence of chronic pain with an ageing population, reluctance to use NSAIDs because of cardiovascular and gastrointestinal adverse effects, changes in patient expectation, societal attitudes and availa- bility of new formulations of opioids. There is very limited evidence of short- to medium-term benet for strong opioids in low back pain and osteoarthritis with more recent longer-term evidence nding no improve- ment in function, worse pain and increased side-effects in people on opioids compared to non-opioid analgesia. More good-quality studies of 8.7 Pharmacological management of chronic pain Drug or class of drug Mechanism of action Paracetamol Central inhibition of COX-1 and COX-2 enzymes Mechanisms of action incompletely understood Non-steroidal anti-inammatory drugs Inhibition of prostaglandin production Opioids Agonists at opioid receptors at multiple levels in the central nervous system Blockade of ascending pain pathways Ketamine Antagonist of NMDA receptors Reduction of central sensitisation Gabapentin and pregabalin Inhibition of glutamate release by primary afferent neurons at rst central synapse Decrease of excitatory neuronal activity Tricyclic antidepressants Inhibition of serotonin and noradrenaline (norepinephrine) re-uptake at synapses in the spinal cord, and also potential effects in the limbic system Inhibition of Na+ channels in neurons Serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (norepinephrine) re-uptake inhibitors Inhibition of serotonin and noradrenaline re-uptake at synapses in the spinal cord, and also potential effects in the limbic system Lidocaine patches Inhibition of Na+ in sensory neurons Capsaicin patch Activation of TRPV1 channels on subset of C bres, causing selective pharmacological denervation, with a decrease in intra-epidermal nerve bre density Nerve blocks with lidocaine and glucocorticoids Temporary denervation due to blockade of Na+ channels in sensory neurons Local anti-inammatory effect (COX = cyclo-oxygenase; NMDA = N-methyl-D-aspartate; OP = opioid; TRPV1 = transient receptor potential vanilloid 1)
- 194. 164 PAINAND PALLIATIVE CARE long-term use are needed. Additionally, there is increasing concern about potential harm from long-term use. This includes addiction, dependence, opioid-induced hyperalgesia, endocrine dysfunction, fracture risk (espe- cially in older people), overdose and cardiovascular events, with many of these adverse effects being dose-related. Doses of more than 50mg morphine equivalents per day may be detrimental, with an increased in harm at doses of >90mg morphine equivalents per day. National and international guidelines have changed to reect this, with most only rec- ommending short- to medium-term use of opioids in carefully selected patients, as part of a holistic management plan. Regular review is essen- tial to assess ongoing benet, and any opioid trial should have clear goals, and a plan for cessation if these are not reached. A suggested strategy for using strong opioids in chronic pain is shown in Box 8.10 Psychological therapies The aims of psychological therapy are to increase coping skills and improve quality of life when facing the challenges of living with chronic pain. There are a range of ways in which psychological therapies can be delivered, including individual one-to-one sessions, group sessions, multidisciplinary pain management programmes, or web-based or tele- phone-based programmes. There is good evidence for the use of a cognitive behavioural therapy (CBT)-based approach for chronic pain, delivered either individually or in a group. The overall aim is to reduce negative thoughts and beliefs, and develop positive coping strategies. The interaction between thoughts, behaviours and emotions is explored, and a problem-focused approach is used in therapy delivery. Relaxation techniques, such as biofeedback and mindfulness medi- tation, require a degree of stillness and withdrawal, with regular practice required for sustained benet (see ‘Further information’). Acceptance and commitment therapy (ACT) is based on CBT principles but also uses components of mindfulness to improve psychological exibility in the context of living with chronic pain. Stimulation therapies These range from minimally invasive procedures like acupuncture and transcutaneous electrical nerve stimulation (TENS) to more invasive techniques such as spinal cord stimulation. 8.8 Endogenous opioids and opioid receptors Endogenous ligand Receptor (IUPHAR) Alternative classication Potential sites Pharmacological effects Endomorphin 1 and 2 Met-enkephalin Dynorphin A Dynorphin B MOP Mu Brain, spinal cord, peripheral nerves, immune cells Analgesia, reduced gastrointestinal motility, respiratory depression, pruritus Leu-enkephalin Met-enkephalin β-endorphin DOP Delta Brain, spinal cord, peripheral nerves Analgesia, cardioprotection, thermoregulation Dynorphin A Dynorphin B β-endorphin KOP Kappa Brain (nucleus accumbens, neocortex, brainstem, cerebellum) Analgesia, neuroendocrine (hypothalamic–pituitary axis), diuresis, dysphoria Orphanin FQ (nociceptin) NOP Orphan Nucleus raphe magnus, spinal cord, afferent neurons Opioid tolerance, anxiety, depression, increased appetite It is thought that opioids used clinically act through the MOP. (IUPHAR = International Union of Basic and Clinical Pharmacology) 8.9 Commonly used opioids Opioid Typical starting dose Route Oral morphine equivalent Comments Morphine 10mg Oral 10mg Most widely used Codeine 30–60mg; max 240mg/24hr Oral 3–6mg Metabolised to morphine byCYP2D6 enzyme Dihydrocodeine 60mg; max 240mg/24hr Oral 6mg Metabolised to morphine byCYP2D6 enzyme Tramadol 100mg; max 400mg/24hr Oral 10mg Metabolised to o-desmethyl tramadol by CYP2D6 enzyme Oxycodone 6.6mg Oral 10mg More predictable bioavailability than morphine Buprenorphine 5µg/hr Transdermal 12mg/day Patch change usually every 7 days (frequency of change dependent on manufacturer and dose); advantages in impaired renal function Fentanyl 12µg/hr Transdermal 30mg/day Use with care in opioid-naïve patients; patch change usually every 72 hrs Tapentadol 50mg; max 600mg/24hr Oral 20mg Use with care in opioid-naïve patients Hydromorphone 2mg Oral 10mg Semi-synthetic; hepatic metabolism Morphine 3mg Subcutaneous, intramuscular, intravenous 10mg Mainly used for acute pain or palliative care
- 195. Pain 165 8 Acupuncture(Fig. 8.6) has been used successfully in Eastern med- icine for centuries. The mechanisms are incompletely understood, although endorphin release may explain, in part, the analgesic effect. Acupuncture is particularly effective in pain related to muscle spasm, with some evidence of short-term benet for patients with low back pain. Similar mechanisms probably apply to TENS, which is worth consider- ing in many types of chronic pain. Neuromodulation, using implanted electrodes in the epidural space (or, more recently, adjacent to periph- eral nerves), has been shown to be an effective option for neuropathic pain, including failed back surgery syndrome and chronic regional pain syndrome (see below). Specialist assessment and ongoing support is necessary, as there are many potential complications, including infection, malfunction and battery failure. The likelihood of success is increased when this technique is used within the context of multidisciplinary assessment and management. Complementary and alternative therapies Complementary techniques, such as herbal medicines, vitamins, homeopathy and reexology, have been used for the treatment of chronic pain but with little evidence of efcacy. It should be noted that herbal medications may interact with conventional drugs, causing adverse effects as the result of drug–drug interactions. St John’s wort (Hypericum perforatum) interacts with many drugs, including many antidepressants used in chronic pain, with increased serotonergic effects. Grapefruit may also increase the risk of serotonergic effects with some antidepressants. Ginkgo biloba may interact with paraceta- mol to increase bleeding time. Nerve blocks and nerve ablation The use of specialist nerve blocks and nerve ablation therapy can be considered for pain that is unresponsive to less invasive approaches. If these are being considered, they should form part of a multidis- ciplinary management plan, with the aim of restoring function and reducing pain. Local anaesthetic with or without depot glucocorticoid (non-particulate for neuraxial administration) can be effective in some circumstances. Examples include occipital nerve blocks for migraine or cervicogenic headache and trigger point injections for myofascial pain. If there is limited compression of a spinal nerve root, the nerve root injections into the epidural space may help settle symptoms and avoid the need for surgical intervention. Neurodestructive procedures can also be employed for intractable pain but are rarely used outside the palliative care setting. Chronic pain syndromes Chronic pain is a feature of several recognised syndromes, which are discussed in more detail below. Neuropathic pain Neuropathic pain is dened as ‘pain associated with a lesion or disease of the somatosensory nervous system’. Neuropathic pain may be acute, such as in sciatica, which occurs as the result of a prolapsed disc, but is most problematic when it becomes chronic. Neuropathic pain causes major morbidity; in a recent study, 17% of those affected rated their 8.10 Use of opioids in chronic pain: Always use as part of a holistic management plan Step Factors to take into account Comment 1. Assess suitability for opioids Type of pain Neuropathic pain and chronic widespread pain less likely to respond Likelihood of dependence Increased risk in those with history of alcohol and substance misuse Co-morbidity Avoid use in conditions where adverse effects more likely: Chronic obstructive pulmonary disease Chronic liver disease Chronic kidney disease 2. Discuss with patient Discuss potential benets Improvement in pain Improvement in function Discuss adverse effects Nausea Constipation Drowsiness Establish treatment goal Improvement in function 3. Plan treatment trial Set timescale Dene duration of treatment Agree frequency of review Agree on dose Aim for lowest effective dose Set upper dose limit Agree on stopping rules Consider stopping if: Treatment goal is not met There is no dose response Tolerance develops rapidly Fig. 8.6 Acupuncture.
- 196. 166 PAINAND PALLIATIVE CARE quality of life as ‘worse than death’. The clinical features of neuropathic pain are summarised in Box 8.11. The diagnosis is easily missed and so careful assessment is vital, in order to make the diagnosis in the rst place and then to direct management appropriately. An algorithm for the management of neuropathic pain is provided in Figure 8.7. It is important to recognise the negative impact of neuropathic pain on quality of life, which has been shown to be greater than with other types of chronic pain. As a result, appropriate support and multidisciplinary management should always be considered in addition to pharmacological therapies. Complex regional pain syndrome Complex regional pain syndrome (CRPS) is a type of neuropathic pain that affects one or more limbs. It was previously termed reex sympathetic dystro- phy (RSD), reecting the fact the disease is thought to be caused in part by an abnormality in the autonomic nervous system. It is a rare syndrome, occur- ring in about 20 per 100000 individuals, and is more common in females, typically presenting between the ages of 35 and 50. It is classied into type 1 CRPS, which may be precipitated by a traumatic event such as a fracture but is not associated with peripheral nerve damage, and type 2 CRPS, which is associated with a peripheral nerve lesion. The diagnosis is primarily clinical, with the current standard being based on the Budapest criteria, as outlined in Box 8.12. Other diagnostic tools, none of which provide a denitive diagno- sis, include thermography (temperature difference of >1°C), and electromy- ography (if myoclonus is a feature). Increased tracer uptake on radionuclide bone scan and bone marrow oedema on MRI scan may be observed in CRPS but the diagnosis is primarily clinical, as outlined in Box 8.12 Prompt diagnosis and early treatment with physiotherapy, and addi- tional approaches such as desensitisation, and graded motor imagery, may prevent progression of symptoms. Pharmacological management is similar to that for neuropathic pain. Specic approaches (with varia- ble quality evidence) that may be considered include bisphosphonates or calcitonin. Intravenous regional block with guanethidine is not rec- ommended, as there is limited evidence of benet, and an increased risk of adverse effects. If medical management is incompletely effective, consideration should be given to the appropriateness of a spinal cord stimulator, with reasonable evidence of efcacy. Phantom limb pain Phantom limb is a common complication of amputation, occurring in up to 70% of patients. It is a form of neuropathic pain but can 8.11 Clinical features of neuropathic pain Characteristic Symptom or clinical feature* Descriptive term Spontaneous pain No stimulus required to evoke pain Positive sensory disturbance Light touch painful Pressure painful Increased pain on pin-prick Cool and warm temperatures painful Dynamic allodynia Punctate allodynia Hyperalgesia Thermal allodynia Negative sensory disturbance Numbness Tingling Loss of temperature sensitivity Loss of sensation Paraesthesia Other features Feeling of insects crawling over skin Affected area feels abnormal Formication Dysaesthesia *Symptoms may cluster, with a predominance of either positive or negative symptoms, or a mixture of both, reecting differences in underlying mechanisms. Are there clinical features of neuropathic pain? (Box 8.11) Assess likelihood of neuropathic pain Tricyclic antidepressant Gabapentin or pregabalin SNRI First line (moderate to high evidence; strong recommendation) Probable Possible Definite Response? Continue Yes Capsaicin patch Lidocaine patch Tramadol Second line (moderate evidence; weak recommendation) No Yes Response? Continue Botulinum toxin Strong opioids Third line (moderate evidence; weak recommendation) No Yes Fig. 8.7 Algorithm for pharmacological management of neuropathic pain. (SNRI = serotonin noradrenaline (norepinephrine) re-uptake inhibitor) Adapted from SIGN 136 and NeuPSIG recommendations; reproduced from Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. The Lancet Neurol 2015; 14:162–173, with permission from Elsevier. be particularly distressing, as the pain is felt in the area where the absent limb was previously. Although usually presenting after limb amputation, reports of phantom pain in other body parts have been reported, such as phantom breast pain following mastectomy. It is very often associated with phantom sensations, which are described as non-painful sensations in the absent body part and pain in the stump. Diagnostic nerve blocks may be helpful in directing therapy, with use of anti-neuropathic medications as outlined in Box 8.7. If there is a denite neuroma at the stump site that is interfering with pros- thesis use, surgical review may be necessary. Management should use rehabilitation approaches with physical therapy. Additional approaches such as mirror visual feedback and desensitisation may also be considered. Chronic widespread pain Chronic widespread pain (CWP) is often associated with other features, such as fatigue and irritable bowel syndrome. Fibromyalgia is a subtype of CWP in which there are myofascial trigger points, and is often associ- ated with sleep disturbance. Clinical features and management of bro- myalgia are discussed in more detail in Chapter 26. Joint hypermobility syndrome Hypermobility can be associated with chronic musculoskeletal pain that often targets the joints and periarticular tissues. It is thought to be caused by abnormal stresses being placed on the joints and surrounding
- 197. Palliative care 167 8 soft tissues due to ligament laxity, although the mechanisms are poorly understood since many people with hypermobile joints do not suffer pain. It is described in more detail in Chapter 26 Palliative care Palliative care is the term used to describe the active total care of patients with incurable disease. It can be distinguished from end-of-life care, which refers to the care of patients with far advanced, rapidly pro- gressive disease that will soon prove fatal. The focus of palliative care is on symptom control alongside supportive care. While palliative care can and should be delivered at any stage of an incurable illness along- side optimal disease control, the focus of end-of-life care is on quality of life rather than prolongation of life or cure. Palliative care encompasses a distinct body of knowledge and skills that all good physicians must possess to allow them to care effectively for patients. Palliative care is seen traditionally as a means of managing distress and symptoms in patients with cancer, when metastatic disease has been diagnosed and death is seen as inevitable. However, prognosis in metastatic cancers has evolved signicantly with the emergence of improved anti-cancer treatments, hence the principle of delivering palliative and supportive care whenever a patient needs it, as opposed to a specic stage of dis- ease, is now even more important. There is also a growing recognition that the principles of palliative care and some of the interventions it uses are equally applicable in other conditions. Palliative care may be applied to any chronic disease state. Which elements are used will depend on the individual patient’s need. For conditions other than cancer, the challenge is recognising when patients have entered the terminal phase of their illness, as there are fewer clear markers and the course of the illness is much more variable. Different chronic disease states progress at different rates, allowing some general trajectories of illness or dying to be dened (Fig. 8.8). These tra- jectories are useful in decision-making for individual patients but also in the planning of services. The ‘rapid decline’ trajectory following a gradual decline, as occurs in cancer, is the best-recognised pattern of the need for palliative care, although a similar trajectory may be observed in other conditions, such as motor neuron disease. Many traditional hospice services are designed to meet the needs of people on this trajectory. Over recent years, improvements in management of malignant disease mean that some types of cancer may follow an erratic or intermittent decline trajectory. Many chronic diseases, such as advanced chronic obstructive pul- monary disease (COPD) and intractable congestive heart failure, carry as high a burden of symptoms as cancer, as well as psychological and family distress. The ‘palliative phase’ of these illnesses may be more dif- cult to identify because of periods of relative stability interspersed with acute episodes of severe illness. However, it is still possible to recognise those patients who may benet from a palliative approach to their care. The challenge is that symptom management needs to be delivered at the same time as treatment for acute exacerbations. This leads to dif- cult decisions as to the balance between symptom relief and aggressive management of the underlying disease. The starting point of need for palliative care in these conditions is the point at which consideration of comfort and individual values becomes important in decision-making, often alongside management of the underlying disease. The third major trajectory is categorised by years of poor function and frailty before a relatively short terminal period; it is exemplied by demen- tia but is also increasingly true for patients with many different chronic illnesses. As medical advances extend survival, this mode of dying is being experienced by increasing numbers of people. The main challenge lies in providing nursing care and ensuring that plans are agreed for the time when medical intervention is no longer benecial. In a situation where death is inevitable and foreseeable, palliative care aims to strike a balance between addressing the wishes, expectations and values of the patient with a realistic assessment of the benets of medical interventions. This often results in a greater focus on comfort, symptom control and support for patient and family, and may enable withdrawal of both futile and burdensome interventions. In cases of prognostic uncertainty, open, honest and gentle communication with the patient and family is important. The most common symptoms in palliative care are discussed in the next section. The central networks we have heard about above in relation to chronic pain also exist for all other symptoms. In addition there is an extra complexity in cancer as a result of the additional layer of biological complexity resulting from the factors released by the tumour such as pro-inammatory cytokines and the body’s response to these factors. Presenting problems in palliative care Pain Pain is a common problem in palliative care. It has been estimated that about two-thirds of patients with cancer experience moderate or severe pain, and a quarter have three or more different sites of pain. Many of 8.12 The Budapest criteria for diagnosis of complex regional pain syndrome (CRPS) Category Symptom or sign Sensory Allodynia to: Temperature Light touch Deep somatic pressure Movement Hyperalgesia to pin-prick Vasomotor Temperature asymmetry Skin colour change and/or asymmetry Sudomotor Oedema Sweating change and/or asymmetry Motor/trophic Reduced range of motion Motor dysfunction: Weakness Tremor Dystonia Trophic changes: Hair Nails Skin Type 1 CRPS: without evidence of major nerve damage; type 2 CRPS: evidence of major nerve damage. For a positive diagnosis, the patient should report at least one symptom in at least three out of the four categories, and at least one sign should be detected in two out of the four categories. Other causes that might explain the signs and symptoms should be excluded. High Death Cancer Organ failure Physical and cognitive frailty Function Low Time Fig. 8.8 Archetypal trajectories of dying. From Murray SA, Kendall M, Boyd K, et al. Illness trajectories and palliative care. BMJ 2005; 330:7498; reproduced with permission from the BMJ Publishing Group.
- 198. 168 PAINAND PALLIATIVE CARE these are of a mixed aetiology and about half of patients with cancer- associated pain have a neuropathic element. Clinical assessment The commonest barrier to assessment of pain is the development of idio- syncratic shortcuts in the belief that these are also easier for the patient. A common example is, ‘How is your pain?’ The patient will often give a reex response such as, ‘OK’, which might be documented by the clini- cian as 0, 1 or 2 out of 10. If the same patient were asked, ‘Have you had any pain in the last 24 hours, on a scale of 0–10, where 0 is none at all and 10 is the worst imaginable?’ the same patient might record a score as high as 8 or 9 out of 10. This emphasises the importance of using a validated question that screens for pain effectively. Improved control of cancer-associated pain has been demonstrated with use of the Edinburgh Pain Assessment and management Tool (EPAT). This involves administration of a simple screening question about worst pain on a scale of 0–10 in the last 24 hours, followed by questions to identify specic pain/s such as neuropathic or bone, in addition to distress. The identied pains are linked to management algorithms. Review of pain and opioid side-effects completes the loop (see ‘Further information’). Clinical features and suggested management strategies for common types of pain in cancer are shown in Box 8.13. The majority of patients with cancer-associated pain can be managed effectively using a step- wise approach, as outlined below. Management: pharmacological treatments Pharmacological treatments are the mainstay of management in can- cer-associated pain, however, they have to be underpinned by an appropriate assessment of pain and associated symptoms. In addition, non-pharmacological treatments and disease-modifying treatments run through each step of pain control. A stepwise approach is adopted, fol- lowing the principles of the World Health Organization (WHO) analgesic ladder (Fig. 8.9), in which analgesia that is appropriate for the degree of pain is prescribed rst. Patients with mild pain should be started on a non-opioid analgesic drug, such as paracetamol (maximum: 1g 4 times daily) or an NSAID (step 1). If the patient fails to respond adequately or has moderate pain, a weak opioid, such as codeine (60mg 4 times daily), should be added (step 2). This can be prescribed separately or in the form of the compound analgesic co-codamol. If pain relief is still not achieved or if the patient has severe pain, a strong opioid should be substituted for the weak opioid (step 3). If the pain is severe at the outset, strong opioids should be prescribed and increased or titrated according to the patient’s response. It is important not to move ‘sideways’ (change from one drug to another of equal potency), which is a common problem during step 2 of the analgesic ladder. In recent years there has been a tendency to use a low dose of a step 3 opioid rather than a traditional step 2 opioid such as codeine. It has now been demonstrated that it is safe, effective and has cost savings to miss out step 2 of the analgesic ladder. This is of great importance in low- and middle-income countries where step 2 drugs are usually much more expensive than morphine. Opioids Opioid analgesia plays a key role in patients with moderate to severe pain. Its successful use depends on appropriate assessment and a detailed explanation to the patient and carer about the benets and potential side-effects of therapy. Morphine is the most commonly pre- scribed strong opioid, although there are several alternatives, as outlined in Box 8.9 Oral morphine takes about 20 minutes to exert an effect and usu- ally provides pain relief for 4 hours. Most patients with continuous pain should be prescribed oral morphine every 4 hours initially, as this will provide continuous pain relief over the whole 24-hour period. Controlled- release morphine lasts for 12 or 24 hours, depending on the formulation, and if clinical circumstances dictate, a controlled-release formulation can be used to initiate and titrate morphine. The median effective morphine equivalent dose for cancer pain is about 200mg per 24 hours. In addition to the regular dose of morphine, an extra dose of imme- diate-release (IR) morphine should be prescribed ‘as required’ for the treatment of breakthrough pain that has not been controlled by the reg- ular prescription. As a rule of thumb, this additional dose should be one- sixth of the total 24-hour dose of opioid. The frequency of breakthrough 8.13 Common types of pain in cancer Type of pain Features Management options Bone pain Tender area over bone Possible pain on movement NSAIDs Bisphosphonates Radiotherapy Increased intracranial pressure Headache, worse in the morning, associated with vomiting and occasionally delirium Glucocorticoids Radiotherapy Opioid Abdominal colic Intermittent, severe, spasmodic, associated with nausea or vomiting Antispasmodics Hyoscine butylbromide Antiemetic and opioid may be required for intestinal obstruction Liver capsule pain Right upper quadrant abdominal pain, often associated with tender enlarged liver Responds poorly to opioids Glucocorticoids Neuropathic pain Spontaneous pain Light touch, pressure and temperature changes are painful; increased pain on pin-prick Numbness, tingling or loss of temperature sensation Skin feels abnormal Anticonvulsants: Gabapentin Pregabalin Antidepressants: Amitriptyline Duloxetine Ketamine Ischaemic pain Diffuse, severe, aching pain associated with evidence of poor perfusion Responds poorly to opioids NSAIDs Ketamine Incident pain Episodic pain usually related to movement Intermittent short-acting opioids Nerve block (NSAIDs = non-steroidal anti-inammatory drugs) Opioid for moderate to severe pain ± non-opioid ± adjuvant Opioid for mild to moderate pain ± non-opioid ± adjuvant Non-opioid ± adjuvant Pain persisting or increasing Pain persisting or increasing Freedom from cancer pain Pain Fig. 8.9 The WHO analgesic ladder. From WHO. Cancer pain relief, 2nd edn. Geneva: WHO; 1996.
- 199. Palliative care 169 8 doses should be dictated by their efcacy and any side-effects, rather than by a xed time interval. A patient may require breakthrough analge- sia as frequently as hourly if pain is severe, but this should lead to early review of the regular prescription. The patient or carer should note the timing of any breakthrough doses and the reason for them. These should be reviewed daily and the regular 4-hourly dose increased for the next 24 hours on the basis of: the frequency of and reasons for breakthrough analgesia the degree and acceptability of side-effects. The regular dose should be increased by adding the total of the break- through doses over the previous 24 hours, unless there are signicant problems with unacceptable side-effects. When the correct dose has been established, a continuous release (CR) preparation can be pre- scribed, usually twice daily. Breakthrough analgesia used for move- ment-related pain is generally not included in background opioid dose titration. Attempts to control movement-related pain with background opioid dose will usually lead to over-dosing and opioid-related side-ef- fects. This can be a risk in metastatic bone pain. Some patients may have concerns about using opioids and it is vital for these to be explored. Patients should be reassured that psycholog- ical dependence is rare when opioids are used for cancer pain, unless a pre-existing dependence problem exists. Recent survey data from the United States have suggested that opioid abuse may occur in up to 20% of cancer patients, but to-date, these data have not been replicated in other countries. In fact, the majority of the world’s population do not have any access to opioids for cancer pain relief. Good prescribing practice, clear communication and reassessment of benets and side-effects are all critical in achieving good cancer pain relief. Pharmacological tolerance is not usually a clinically relevant problem; however, physical depend- ence, which is physiological, as manifest by a physical withdrawal syn- drome, can occur if opioids are suddenly discontinued. Nearly all types of cancer pain respond to morphine to some degree but there is a spectrum of response, such that in some patients the dose of opioid required to control neuropathic pain and all elements of metastatic bone pain may be high and associated with unacceptable side-effects. In these situations, other methods of analgesia, both phar- macological and non-pharmacological, should be explored and consid- ered at an early stage. The most effective and appropriate route of morphine administration is oral but transdermal preparations of strong opioids (usually fentanyl) are useful in certain situations, such as in patients with dysphagia or those who are reluctant to take tablets on a regular basis. Diamorphine is a highly soluble strong opioid used for subcutaneous infusions, par- ticularly in the last few days of life, but is only available in certain coun- tries and morphine is now the most commonly prescribed parenteral opioid. Opioid-related adverse effects Adverse effects are a common problem with opioids, especially on initiat- ing treatment and on increasing the dose. The most common side-effects are nausea, drowsiness, constipation and dry mouth, as summarised in Box 8.14. Nausea and vomiting can occur initially but usually settle after a few days. Drowsiness is usually transient at opioid initiation and dose increase. If it is persistent, an alternative opioid and/or a non-opioid should be considered. In acute dosing, respiratory depression can occur but this is rare in patients on regular opioids or in those starting on small, regular doses with appropriate titration. Tolerance usually develops to nausea, vomiting and drowsiness but not to constipation or dry mouth. All patients should therefore be pre- scribed a laxative, unless suffering from diarrhoea, and have access to an antiemetic and good mouth care, along with rationalisation of any concomitant medication that might exacerbate drowsiness. Newer developments include the use of preparations in which opioids are com- bined with opioid antagonists, such as naloxone. The naloxone is poorly absorbed and does not antagonise the systemic analgesic effect but rather acts locally to block opioid receptors in the gut, thereby reduc- ing opioid-related constipation. Vivid dreams, visual hallucinations (often consisting of a sense of movement at the periphery of vision), delirium and myoclonus are typical of opioid-related toxicity and, if present, require urgent reassessment of the opioid dose. Biochemistry should also be checked to exclude renal impairment, dehydration, electrolyte disturbance or hypercalcaemia. Since opioid toxicity can occur at any dose, side-effects should be assessed regularly, but particularly after a dose increase. Pain should be reassessed to ensure that appropriate adjuvants are being used. Parenteral rehydration is often helpful to speed up excretion of active metabolites of morphine. The dose of opioid may need to be reduced or the opioid changed to a strong alternative. Different opioids have different side-effect proles in different peo- ple. If a patient develops side-effects, switching to an alternative strong opioid may be helpful. Options include oxycodone, transdermal fenta- nyl, hydromorphone and occasionally methadone, any of which may produce a better balance of benet against side-effects. Fentanyl has no renally excreted active metabolites and may be particularly useful in patients with renal failure. Buprenorphine is also particularly useful in signicant renal impairment. It is possible to switch between opioids but great care must be taken when doing so to make sure the dose is correct and to avoid prescribing too much or too little opioid. Adjuvant analgesics An adjuvant analgesic is a drug that has a primary indication other than pain but which provides analgesia in some painful conditions and may enhance the effect of the primary analgesic. Commonly used adjuvant analgesics in the palliative care setting are shown in Box 8.15. Some adjuvant analgesics may enhance the side-effect prole of the primary analgesic, and dose reductions of opioids may be required when an adjuvant analgesic is added. At each step of the WHO analgesic ladder, an adjuvant analgesic should be considered, the choice depending on the type of pain. Management: non-pharmacological treatments Neurodestructive interventions Neurodestructive techniques have an important role in the management of cancer pain, where life expectancy is limited. They should be used as part of an overall management plan and considered when the response to drug treatment has been inadequate. Intrathecal analgesia, delivered via either an external pump or a fully implanted device, is a good option, 8.14 Opioid side-effects Side-effect Management Constipation Regular laxative Opioid/naloxone oral combination, in resistant constipation Dry mouth Frequent sips of iced water, soft white parafn to lips, chlorhexidine mouthwashes twice daily, sugar-free gum, water or saliva sprays Nausea/vomiting Oral haloperidol 0.5–1mg at night, oral metoclopramide 10mg 3 times daily or oral domperidone 10mg 3 times daily If constant, haloperidol or levomepromazine may be given parenterally to break the nausea cycle Sedation Explanation is very important Symptoms usually settle in a few days Avoid other sedating medication where possible Ensure appropriate use of adjuvant analgesics that can have an opioid-sparing effect May require an alternative opioid
- 200. 170 PAINAND PALLIATIVE CARE particularly where life expectancy is more than 3 months. Coeliac plexus blocks can be helpful for visceral pain, such as in pancreatic cancer. Lateral cordotomy to disrupt the spinothalamic tracts (either open or per- cutaneous) may be considered for unilateral chest wall pain, such as may occur in mesothelioma, where life expectancy is limited. Radiotherapy Radiotherapy is the treatment of choice for pain from bone metastases (see Box 8.13) and can also be considered for metastatic involvement at other sites. All patients with pain secondary to bone metastases should be considered for palliative radiotherapy, which can usually be given in a single dose. Some patients experience a transient are of pain after radi- otherapy and this can be managed by 24–48 hours of dexamethasone (4–8mg once in the morning). Physiotherapy Physiotherapy has a key role in the multidisciplinary approach to a wide spectrum of cancer-related symptoms, including the prevention and management of pain, muscle spasm, reduced mobility, muscle wast- ing and lymphoedema. Rehabilitation in palliative care has expanded and now includes pre-habilitation, which involves the use of proactive focused exercise to maintain muscle mass during cancer chemotherapy and in other chronic conditions such as COPD. Psychological techniques As with chronic pain, there is increasing use of psychological techniques in cancer pain management, which train the patient to use coping strat- egies and behavioural techniques. Other issues related to the specic experience of a cancer diagnosis and cancer treatment may be complex, and individual therapy in addition to group-based approaches can be helpful. Stimulation therapies Acupuncture and TENS are low-risk stimulation therapies that may be useful in palliative care for management of pain and nausea. Both are particularly useful for secondary muscle spasm and TENS is increasingly used for bone pain. Complementary and alternative therapies Palliative care patients often seek symptom relief from both comple- mentary and alternative therapies. While the evidence base is poorly 8.15 Adjuvant analgesics in cancer pain Drug Example Indications Side-effects* NSAIDs Diclofenac Bone metastases, soft tissue inltration, liver pain, inammatory pain Gastric irritation and bleeding, uid retention, headache Caution in renal impairment Glucocorticoids Dexamethasone 8–16mg per day, titrated to lowest dose that controls pain Raised intracranial pressure, nerve compression, soft tissue inltration, liver pain Gastric irritation if used together with NSAID, uid retention, proximal muscle myopathy, delirium, Cushingoid appearance, candidiasis, hyperglycaemia Anticonvulsants Evidence strongest for: Duloxetine Gabapentin Pregabalin Neuropathic pain of any aetiology Mild sedation, tremor, delirium Exacerbation of opioid-related side-effects Tricyclic antidepressants Amitriptyline Nortriptyline (less sedative) Neuropathic pain of any aetiology Sedation, dizziness, delirium, dry mouth, constipation, urinary retention Avoid in cardiac disease Exacerbation of opioid-related side-effects NMDA receptor blockers Ketamine Severe neuropathic pain (only under specialist supervision) Delirium, anxiety, agitation, hypertension *In old age, all drugs can cause delirium. (NMDA = N-methyl-D-aspartate; NSAIDs = non-steroidal anti-inammatory drugs) developed, individual patients can gain signicant benets from the complementary therapies as outlined earlier in this chapter. It is critically important that patients are encouraged to discuss any alternative med- icines they are considering, given the potential interactions with other therapies. Breathlessness Breathlessness is one of the most common symptoms in palliative care and is distressing for both patients and carers. Patients with breathless- ness should be fully assessed to determine whether there is a reversible cause, such as a pleural effusion, heart failure or bronchospasm; if so, this should be managed in the normal way. If symptoms persist, addi- tional measures may be necessary. There are many potential causes of dyspnoea in cancer patients and in other chronic diseases; apart from direct involvement of the lungs, muscle loss secondary to cachexia, anx- iety and fear can all contribute. A cycle of panic and breathlessness, often associated with fear of dying, can be dominant. Exploration of precipitating factors is important and patient education about breath- lessness and effective breathing has been shown to be effective. Non- pharmacological approaches that include using a hand-held fan, pacing and following a tailored exercise programme can help. There is no evi- dence to suggest that oxygen therapy reduces the sensation of breath- lessness in advanced cancer any better than cool airow, and oxygen is indicated only if there is signicant hypoxia. Opioids, through both their central and their peripheral action, can palliate breathlessness. Both oral and parenteral opioids are effective and are now licensed for this indica- tion in Australia. A low dose should be used initially and titrated against symptoms, unless opioids are already being prescribed for pain, in which case the existing dose can be increased further. If anxiety is considered to be playing a signicant role, a quick-acting benzodiazepine, such as lorazepam (used sublingually for rapid absorption), may also be useful. Cough Persistent unproductive cough can be helped by opioids, which have an antitussive effect. Troublesome respiratory secretions can be treated with hyoscine hydrobromide (400–600µg every 4–8 hours), although dry mouth is a common adverse effect. As an alternative, glycopyrro- nium can be useful and is given by subcutaneous infusion (0.6–1.2mg in 24 hours). FCPS Single Best
- 201. Palliative care 171 8 Nausea and vomiting The presentation of nausea and vomiting differs depending on the under- lying cause, of which there are many. Large-volume vomiting with little nausea is common in intestinal obstruction, whereas constant nau- sea with little or no vomiting is often due to metabolic abnormalities or adverse effects of drugs. Vomiting related to raised intracranial pressure is worse in the morning. Different receptors are activated, depending on the cause or causes of the nausea (Fig. 8.10). For example, dopamine receptors in the chemotactic trigger zone in the fourth ventricle are stim- ulated by metabolic and drug causes of nausea, whereas gastric irritation stimulates histamine receptors in the vomiting centre via the vagus nerve. Reversible causes, such as hypercalcaemia and constipation, should be treated appropriately. Drug-induced causes should be considered and the offending drugs stopped if possible. As different classes of antiemetic drug act at different receptors, antiemetic therapy should be based on a careful assessment of the probable causes and a rational decision to use a particular class of drug (Box 8.16). The subcutaneous route is often required initially to overcome gastric stasis and poor absorption of oral medicines. Gastrointestinal obstruction Gastrointestinal obstruction is a frequent complication of intra-abdomi- nal cancer. Patients may have multiple levels of obstruction and symp- toms may vary greatly in nature and severity. Surgical mortality is high in patients with advanced disease and obstruction should normally be managed without surgery. The key to effective management is to address the presenting symptoms – colic, abdominal pain, nausea, vomiting, intestinal secretions – individually or in combination, using parenteral drugs that do not cause or worsen other symptoms. This can be prob- lematic when a specic treatment worsens another symptom. Cyclizine improves nausea and colic responds well to anticholinergic agents, such as hyoscine butylbromide, but both slow gut motility. Nausea will improve with metoclopramide, although this is usually contraindicated in the pres- ence of colic because of its prokinetic effect. There is some low-quality evidence that glucocorticoids (dexamethasone 8mg) can shorten the length of obstructive episodes. Somatostatin analogues, such as octre- otide, will reduce intestinal secretions and therefore large-volume vomits. Occasionally, a nasogastric tube is required to reduce gaseous or uid distension. Weight loss Patients with cancer lose weight for a variety of reasons, including reduced appetite or the effects of drug treatment, or as a consequence of low mood and anxiety. There is, however, a particularly challenging syn- drome associated with weight loss, which is known as cancer cachexia. This results from an alteration of metabolism caused by a complex inter- action of tumour-related factors and the body’s response to these fac- tors, resulting in muscle loss, along with anorexia. Treatment involves prescribing exercise to maintain muscle mass and strengthen muscles, ensuring that there is an adequate calorie intake and providing nutri- tional supplements. Anti-inammatory medication to attenuate systemic inammation is the subject of research and many patients self-medicate with sh oil. Glucocorticoids can temporarily boost appetite and general well-being but may cause false weight gain by promoting uid retention. Their benets need to be weighed against the risk of side-effects, and glucocorticoids should generally be used on a short-term basis only. Anxiety and depression Anxiety and depression are common in palliative care but the diagnosis may be difcult, since the physical symptoms of depression are similar to those of advanced cancer. It is therefore important to acknowledge that these symptoms are not inevitable in advanced cancer. Patients should still expect to look forward to things and to enjoy them, within the context of the situation. Simply asking the question ‘Do you think you are depressed?’ can be very useful in deciding with the patient whether antidepressants or psychological interventions may be of benet. In this regard, psycho-oncology has been evolving rapidly and there is now good evidence for the role of ‘talk therapy’ in palliative care, along with other appropriate management of anxiety and depression. If antidepres- sants are required, citalopram and mirtazapine are good choices since they are generally well tolerated in patients with advanced disease. Delirium and agitation Many patients become confused or agitated in the last days of life. It is important to identify and treat potentially reversible causes unless the patient is too close to death for this to be feasible. Early diagno- sis and effective management of delirium are extremely important. As in Higher centres Vestibular input Vomiting centre H1, ACh, 5-HT Chemotactic trigger zone D2, 5-HT Vagal afferents Metabolic toxins Chemoreceptors Mechanoreceptors Retroperistalsis Gastric pyloric contraction Abdominal and thoracic wall contraction Peripheral circulation Fig. 8.10 Mechanisms of nausea. (ACh = acetylcholine; D2 = dopamine; 5-HT = 5-hydroxytryptamine, serotonin; H1 = histamine) 8.16 Receptor site activity of antiemetic drugs Area Receptors Drugs Chemotactic trigger zone Dopamine2 5-HT Haloperidol Metoclopramide Vomiting centre Histamine1 Acetylcholine Cyclizine Levomepromazine Hyoscine Gut (gastric stasis) Metoclopramide Gut distension (vagal stimulation) Histamine1 Cyclizine Gut (chemoreceptors) 5-HT Levomepromazine (5-HT = 5-hydroxytryptamine, serotonin)
- 202. 172 PAINAND PALLIATIVE CARE other palliative situations, it may not be possible to identify and treat the underlying cause, and the focus of management should be to ensure that the patient is comfortable. It is important to distinguish between behavioural change due to pain and that due to delirium, as opioids will improve one and worsen the other. The management of delirium is detailed in Chapter 34. It is important, even in the care of the actively dying patient, to treat delirium with antipsychotic medicines, such as haloperidol, or olanzapine if under 70 years, rather than to regard it as distress or anxiety and use benzodiazepines only. Dehydration Deciding whether to give intravenous uids can be difcult when a patient is very unwell and the prognosis is uncertain. A patient with a major stroke, who is unable to swallow but is expected to survive the event, will develop renal impairment and thirst if not given uids and should be hydrated. On the other hand, when a patient has been deteri- orating and is clearly dying, parenteral hydration needs very careful con- sideration and it is very important to manage this on an individual basis. Patient comfort and avoidance of distress in the family are the primary aims. Where a patient and family are happy with meticulous oral hygiene and care to reduce the sensation of dryness in the mouth, this is usually more appropriate and effective at the end of life than parenteral hydra- tion, which by itself will not necessarily improve the sensation of dryness. In some patients, parenteral hydration will simply exacerbate pooling of secretions, causing noisy and distressing breathing. Each decision should be individual and discussed with the patient’s family. Death and dying Planning for dying There have been dramatic improvements in the medical treatment and care of patients with cancer and other illnesses over recent years but the inescapable fact remains that everyone will die at some time. Planning for death should be actively considered in patients with chronic dis- eases when the death is considered to be foreseeable or inevitable. Doctors rarely know exactly when a patient will die but are usually aware that an individual is about to die and that medical interventions are unlikely to extend life or improve its quality signicantly. Most people wish their doctors to be honest about this situation to allow them time to think ahead, make plans and address practical issues. A few do not wish to discuss future deterioration or death; if this is felt to be the case, avoidance of discussion should be respected. For doctors, it is helpful to understand an individual’s wishes and values about medical interventions at this time, as this can help guide decisions about inter- ventions. It is important to distinguish between interventions that will not provide clinical benet (a medical decision) and those that do not confer sufcient benet to be worthwhile (a decision that can only be reached with a patient’s involvement and consent). A common exam- ple of this would be decisions about not attempting cardiopulmonary resuscitation. In general, people wish for a dignied and peaceful death and most, but not all, prefer to die at home. Families also are grateful for the chance to prepare themselves for the death of a relative, by timely and gentle discussion with the doctor or other health professionals. Early discussion and effective planning improve the chances that an individual’s wishes will be achieved. There are two important caveats: rstly, wishes can and do change as the terminal situation evolves, and secondly, planning in general can only be done over time as patients form a relationship with professionals and evolve an understanding of the situation in which they nd themselves. Attempts to carry out and nalise advanced care planning at a single consultation, especially if a rst meeting, are usually unsatisfactory. Structures for assessment and planning around end-of-life care are for guidance only and the focus should evolve with the individual patient. Diagnosing dying When patients with cancer or other conditions become bed-bound, semi-comatose, unable to take tablets and only able to take sips of water, with no reversible cause, they are likely to be dying and many will have died within 2 days. Doctors are sometimes poor at recognising this and should be alert to the views of other members of the multidisciplinary team. A clear decision that the patient is dying should be agreed and recorded. Management of dying Once the conclusion has been reached that a patient is going to die in days to a few weeks, there is a signicant shift in management (Box 8.17). Symptom control, relief of distress and care for the family become the most important elements of care. Medication and investigation are justi- able only if they contribute to these ends. When patients can no longer drink because they are dying, intravenous uids are usually not neces- sary and may cause worsening of bronchial secretions; however, this is a decision that can be made only on an individual basis. Management should not be changed without discussion with the patient and/or family. Medicines should always be prescribed for the relief of symptoms. For example, morphine or diamorphine may be used to control pain, levo- mepromazine to control nausea, haloperidol to treat delirium, diazepam or midazolam to treat distress, and hyoscine hydrobromide to reduce respiratory secretions. Side-effects, such as drowsiness, may be accept- able if the principal aim of relieving distress is achieved. It is important to discuss and agree the aims of care with the patient’s family. Poor com- munication with families at this time is one of the most common reasons for family distress afterwards and for formal complaints. Ethical considerations The overwhelming force in caring for any patient must be to listen to that patient and family and take their wishes on board. Patients know 8.17 How to manage a patient who is dying Patient and family awareness Assess patient’s and family’s awareness of the situation Ensure patient, if able, and family understand plan of care Medical interventions Stop non-essential medications that do not contribute to symptom control Stop inappropriate investigations and interventions, including routine observations Resuscitation Complete Do Not Attempt Cardiopulmonary Resuscitation (DNACPR) form Deactivate implantable debrillator Symptom control Ensure availability of parenteral medication for symptom relief Support for family Make sure you have contact details for family, that you know when they want to be contacted and that they are aware of facilities available to them Religious and spiritual needs Make sure any particular wishes are identied and followed Ongoing assessment Family’s awareness of condition Management of symptoms Need for parenteral hydration Care after death Make sure family know what they have to do Notify other appropriate health professionals
- 203. Further information 173 8 when health-care professionals are just receiving the information, as opposed to receiving and understanding the information in the context of the patient, their illness and needs, their carers and the socioeco- nomic context. It is impossible to provide holistic care for a patient with- out this comprehension. Every patient is unique and it is important to avoid slipping into a tick-box mentality in addressing items that should be covered in patients with advanced, incurable disease. While the key to successful palliative care is effective interdisciplinary working, every patient needs to know who has overall responsibility for their care. Trust in the whole team will come through a solid lead working with a team who are appropriately informed and in sympathy with the patient’s situ- ation, each having a clear role. Families and other carers are often unprepared for the challenge of caring for a dying person. It can be an exhausting experience, both emotionally and physically, and without a critical number of carers battle fatigue can ensue, resulting in urgent admissions. With much discus- sion about advance directives, we should not lose sight of the reality of changing circumstances and wishes. Good anticipatory care means not just providing for new physical symptoms, but also planning for any time when care at home becomes no longer possible. Capacity and advance directives The wishes of the patient are paramount in Western societies, whereas in other cultures the views of the family are equally important. If a patient is unable to express their view because of communication or cognitive impairment, that person is said to lack ‘capacity’. In order to decide what the patient would have wished, as much information as possible should be gained about any previously expressed wishes, along with the views of relatives and other health professionals. An advance directive is a pre- viously recorded, written document of a patient’s wishes. It should carry the same weight in decision-making as a patient’s expressed wishes at that time, but may not be sufciently specic to be used in a particular clinical situation. The legal framework for decision-making varies in different countries. Euthanasia In the UK and Europe, between 3% and 6% of dying patients will ask a doctor to end their life. Many of these requests are transient; some are associated with poor control of physical symptoms or a depressive illness. All expressions of a wish to die are an opportunity to help the patient discuss and address unresolved issues and problems. Reversible causes, such as pain or depression, should be treated. Sometimes, patients may choose to discontinue life-prolonging treatments, such as diuretics or anticoagulation, following discussion and the provision of adequate alternative symptom control. However, there remain a small number of patients who have a sustained, competent wish to end their lives, despite good control of physical symptoms. Euthanasia is now permitted or legal under certain circumstances in some countries but remains illegal in many others; public, ethical and legal debate over this issue continues and is often inuenced by many complex non-palliative care issues. The European Association for Palliative Care does not see euthanasia or physician-assisted suicide as part of the role of palliative care physicians. The British Medical Association (BMA) has published results from its recent poll on assisted dying in the BMJ (8 October 2020). Respect for others’ freedom is reected in this poll as, even though 50% supported a change in the law to permit assisted dying, only 36% of those polled would be personally willing to prescribe lethal drugs. The results were similar for euthanasia, with 37% supporting a change in the law, but only 26% willing to participate in any way in the process of administering drugs with the intention of ending an eligible patient’s life. It can be inferred from the poll, that although some BMA members would support a legal framework, thereby respecting freedom of opinion and demonstrating a toleration of others’ views, the majority would not be prepared to be involved in assisted dying or in euthanasia themselves, even if legal (see ‘Further information’). Further information Journal articles Fallon M, Walker J, Colvin L, Rodriguez A, Murray G, Sharpe M, on behalf of the EPAT© Study Group. Does the institutionalisation of pain assessment using the EPAT package reduce pain in cancer unit inpatients more than usual care; a cluster randomised trial. J Clin Oncol 2018; 36(13):1284–1290. Finnerup NB, Attal N, Haroutounian S, etal. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015;14:162–173. A comprehensive, high-quality review of the current evidence for the pharmacological management of neuropathic pain . McDonald J, Lambert DG. Opioid receptors. Cont Edu Anaesth Crit Care Pain. 2005;5(1):22–25. https://bjaed.org/article/S1743-1816(17)30577-2/pdf. A concise review of opioid receptors. Websites bma.org.uk/advice-and-support/ethics/end-of-life/physician-assisted-dying- survey Survey on UK doctors’ views on assisted dying. breathworks-mindfulness.org.uk An online resource to support learning the use of mindfulness to deal with pain, illness or stress. cuh.org.uk/breathlessness Information and resources from Cambridge University Hospital on managing breathlessness. ed.ac.uk/cancer-centre/research/fallon-group/epat Edinburgh Pain Assessment Tool (EPAT) hospiceuk.org A resource from UK hospices. mdanderson.org Brief Pain Inventory (Short Form) questionnaire. nhmrc.gov.au Australia and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Acute pain management: scientic evidence, 3rd edn; 2010 . npcrc.org Short-form McGill Pain questionnaire. paintoolkit.org Pain toolkit self-help resource for managing pain. palliativecareguidelines.scot.nhs.uk Regularly reviewed, evidence-based clinical guidelines. palliativedrugs.com Practical information about drugs used in palliative care. rcplondon.ac.uk/guidelines-policy/complex-regional-pain-syndrome-adults Guidelines on CRPS, providing recommendations for diagnosis, treatment and referral in a variety of clinical settings (updated 2018). sign.ac.uk/assets/sign136.pdf SIGN guideline 136 – Management of chronic pain (updated Aug 2019). A comprehensive review of the evidence for assessment and management of chronic pain.
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- 205. Multiple Choice Questions 8.1.A 45-year-old woman consults her GP with gradually worsening low back pain that started over 2 years ago. There is no radiation, nor any red ags. She can’t take non-steroidal anti-inammatory drugs (NSAIDs) due to gastrointestinal upset. She takes co-codamol 30/500, at a dose of 8 tablets per day, with limited benet. She works as a cleaner in the local school and is a single parent, with three children ranging in age from 7 to 18. She has been off work for the last 6 months after a are-up that has not settled, and is worried about her job and her nances. Her mother lives nearby and is very supportive, helping out with child care and shopping. She saw a physiotherapist for one session, but didn’t go back as she felt the exercises were too hard and made the pain worse. She worries that if the pain gets worse she must be damaging her back, and she spends much of her time in bed or lying on the couch. What management approach should be used to increase her physical activity? A. Refer back to the physiotherapist for more effective exercises B. Prescribe stronger analgesics, such as morphine, to control the pain better, and thus allow her to do more. C. Assess what barriers there are to increasing her physical activity before agreeing on management D. Refer for further investigations, such as X-ray or magnetic resonance imaging (MRI), of her lumbar spine to exclude any sinister causes, such as malignancy, or to identify any surgical target E. Add in diazepam to help with muscle spasm and reduce her anxiety about the impact of the pain Answer: C. There is good evidence that increasing physical activity is an effective way to manage chronic pain, but it is acknowledged that there may be a number of barriers preventing people who live with chronic pain from doing this successfully. These can include fear avoidance, not pacing activities well, nancial problems or other commitments that prevent their ability to attend appointments or go to a leisure centre. Advice alone is not enough and personal preference/previous experience will impact on patient engagement. There is no one type of exercise that will work for everyone (see Box 8.6). Strong opioids are not recommended for long- term use in chronic pain, and combining these with other sedative drugs may be harmful. There is no good evidence that benzodiazepines are helpful in chronic low back pain. Continued investigation in the absence of specic concerns is not recommended. 8.2. A 27-year-old man was involved in a severe road trafc accident, and suffered multiple lower limb fractures requiring orthopaedic intervention and several surgeries. His pain control was challenging whilst he was an in-patient, and he was discharged on oramorph 10–20 mg as required for pain, prescribed up to 6 times daily, plus MST 40 mg 2 times daily and paracetamol 1 g 4 times daily. The plan was that he would be reviewed in the orthopaedic clinic, but he defaulted from attending. He lived alone, with no family nearby or supportive friends. He attended his GP complaining of severe, poorly controlled pain, nightmares, ashbacks to the accident and with very poor sleep and low mood, to the extent that he felt that life was not worth living. He was asking for an increase in his oramorph to help him cope, as he had tried taking a higher dose (40 mg) and felt it was effective, especially in improving sleep. What would be the rst step in your management plan? A. Increase his oramorph as a short-term solution in order to relieve distress and improve sleep B. Assess suicide risk and institute appropriate urgent support if required C. Refer back to the orthopaedic team for consideration of further investigations or surgery D. Add in anti-neuropathic agents, such as gabapentin, in case there is a neuropathic component to his pain E. Refer for assessment and management of possible post-traumatic stress disorder (PTSD) syndrome Answer: B. This is the most urgent action as he has a number of risk factors, including co-morbid mental health issues, high levels of distress, iso- lation, limited social support, being prescribed strong opioids and not using them according to prescribing advice. Suicide risk assessment should include risk factors, evidence of planning and means to carry it out, and protective factors. Further management depends on the degree and urgency of risk, ranging from urgent involvement of the duty mental health team to liaison with GP/other relevant health-care professionals and offering information on support available (local, telephone, online). Increasing oramorph with the aim of improving sleep and/or mood would not be appropriate or safe (see Box 8.10). Similarly, adding in gab- apentin may increase the risk of death, and further assessment of neuro- pathic features would be needed if being considered at a later date (see Fig. 8.7). Additionally, consideration should be given to using controlled dispensing arrangements to help improve safety (e.g. daily pick-up from the pharmacy). Further orthopaedic involvement and treatment of PTSD symptoms would be appropriate, but do not address the immediate problem. 8.3. John is a 73-year-old, retired joiner with a 3-month history of right-sided chest pain and cough. He has been receiving palliative radiotherapy for right-sided Pancoast’s tumour. He lives with his wife, and his family are not nearby. Timeline 1. John was reviewed during radiotherapy because of pain in his right shoulder and arm. He experiences constant severe background pain, rated as 9/10. He also experiences intermittent, excruciating shooting pain associated with pins and needles and a tight sensa- tion, rated as 10/10. 2. John is unable to sleep. He says he feels miserable and hopeless, and that he ‘doesn’t look forward to anything, each day is a chal- lenge’. He has also lost weight and has a poor appetite. 3. His medication is: Co-codamol (30/500 mg) 2 tablets 4 times a day Laxidol (laxative) 1 sachet daily 4. He was able to give a clear history that a codeine and paracetamol combination worked within 40 minutes, but lasted for just an hour, reducing background pain from 10/10 to 8/10. John has normal biochemistry. Which of the following did John’s doctor suggest? A. Stop co-codamol and start titration with a strong opioid to 5 mg of normal release morphine orally 6 times daily, with the same dose provided for breakthrough analgesia (1/6 of the total 24-hour dose). Advice with regard to continuing with the laxative and a metoclopramide made available in case of nausea. Arranged a review in 48 hours B. As in answer A, but also continue with co-codamol C. His doctor was concerned about commencing a strong opioid too soon, as John was not yet actively dying. So, he decided to try tramadol instead of co-codamol.
- 206. D. In viewof John’s mood and inability to sleep, analgesia should be left unchanged; however, night sedation and an antidepressant can be introduced E. The doctor knew it was important to control John’s pain as quickly as possible, therefore slow-release morphine 60 mg 2 times daily was commenced Answer: A. Pain affects, and is affected by, many other symptoms and aspects of daily living. Time spent on the initial detailed assessment of all aspects of the patient is key to successful management. For John, rapid proposed solutions to his myriad of problems would only lead to therapeutic chaos. The key decision is what is the greatest driver of the symptoms and how does this potentially interact with other symptoms and distress. Our patient had very severe pain with a strong neuropathic compo- nent, as would be expected from pressure on and/or invasion of the brachial plexus by the tumour. It is not surprising that he was not sleep- ing, because of this extremely severe pain, and felt thoroughly miserable and hopeless. His poor appetite and weight loss could be a result of the uncontrolled pain; however, it could also be the result of the cancer process via a cachexia mechanism. It is important to recognise that neu- ropathic pain is particularly associated with mood disturbances. When assessing complexities, it is important to ground decisions on information obtained directly from the patient. John was able to give a clear history that a codeine and paracetamol combination worked within 40 minutes but lasted for just an hour, and the clue here is that his pain was at least partially opioid responsive. It is critical not to move sideways on an analgesic ladder and if maximum dose of codeine is not effective, the patient should move to a strong opioid, such as morphine. The usual starting dose in this situation of normal renal function and such severe pain should be 5 mg of normal release morphine orally 6 times daily. If starting modied-release morphine, the dose is 10–15 mg 2 times daily. For breakthrough analgesia the dose is usually 1/6 of the total 24-hour dose, so 5 mg in this case. The patient should be advised that if break- through pain relief is required it will take 30 minutes to start having an effect. The patient should be instructed to take a careful note of duration onset and duration of effect of the regular dose, and frequency of onset and duration and effect of the breakthrough dose. 8.4. On review after 48 hours, John reported that his background pain reduced from 9/10 to 4/10 within 40 minutes of taking 5 mg of normal-release morphine. The improvement lasted for 2 hours, after which background pain returned to 9/10. A breakthrough dose of 5 mg immediate-release morphine then reduced background pain to 4/10 again and this lasted for another 2 hours. In total 5 regular doses and 6 breakthrough doses of 5 mg normal- release morphine were used in 24 hours. Crucially, there was no sedation, sleepiness or vivid dreams. Bowels were moving normally with the laxative prescribed and no nausea was present. The severe, intermittent, shooting pain was less frequent and reduced from 10/10 to 5/10. Sleep, appetite, mood and interactions with others were much improved. What did John’s doctor decide to do next? A. Switch to slow-release morphine, 15 mg 2 times daily and continue to encourage use of breakthrough analgesia with 5 mg normal release morphine as required B. As A, but also add in amitriptyline 10 mg at bedtime C. Continue on normal-release morphine 5 mg 6 times daily and increase breakthrough to 10 mg normal release morphine as required and review in 48 hours D. Switch to slow-release morphine, 30 mg 2 times daily and prescribe normal-release morphine 10 mg for breakthrough pain E. No changes to opioid regimen, but add dexamethasone for brachial plexus pressure, appetite and general wellbeing Answer: D. The strong history provided by John is of an opioid-responsive pain. It is clear that a dose of 10 mg 6 times daily would bring background pain from 9/10 to 4/10. At present there are no opioid-related side effects, therefore a switch to a sustained-release morphine of 30 mg 2 times daily is reasonable, instead of 10 mg normal-release 6 times daily. Breakthrough normal-release morphine should be increased to 10 mg and used as required. Ongoing review of common opioid side effects is crucial. On further review of pain relief, breakthrough opioid required, intermit- tent component of pain and other symptoms, such as mood, appetite and weight, may lead to further manipulation of John’s management at follow-up.
- 207. Acute medicine and criticalillness VR Tallentire MJ MacMahon Clinical examination in critical care 176 Monitoring 177 Acute medicine 178 The decision to admit to hospital 178 Ambulatory care 178 Presenting problems in acute medicine 178 Chest pain 179 Acute breathlessness 181 Anaphylaxis 183 Syncope/presyncope 184 Headache 186 Unilateral leg swelling 188 Acute abdomen 189 Identication and assessment of deterioration 191 Early warning scores and the role of the medical emergency team 191 Immediate assessment of the deteriorating patient 191 Selecting the appropriate location for ongoing management and anticipatory care planning 191 Common presentations of deterioration 191 Tachypnoea 193 Hypoxaemia 194 Tachycardia 195 Hypotension 195 Hypertension 197 Decreased conscious level 197 Decreased urine output/deteriorating renal function 198 Disorders causing critical illness 198 Sepsis and the systemic inammatory response 198 Acute respiratory distress syndrome 201 Acute circulatory failure (cardiogenic shock) 202 Cardiac arrest 202 Post cardiac arrest 205 Other causes of multi-organ failure 206 9 Critical care medicine 206 Decisions around intensive care admission 206 Stabilisation and institution of organ support 207 Respiratory support 207 Cardiovascular support 210 Renal support 212 Neurological support 212 Daily clinical management in intensive care 212 Clinical review 212 Infection surveillance 212 Sedation and analgesia 212 Delirium in intensive care 213 Weaning from respiratory support 213 Extubation 214 Tracheostomy 214 Nutrition 214 Other essential components of intensive care 214 Complications and outcomes of critical illness 214 Adverse neurological outcomes 215 Airway complications 215 Micro- and macrovascular complications 215 Other complications 216 The older patient 216 Withdrawal of active treatment and death in intensive care 216 Discharge from intensive care 217 Critical care scoring systems 218
- 208. 176 ACUTEMEDICINE AND CRITICAL ILLNESS Clinical examination in critical care Airway Is the airway patent? Is the end-tidal CO2 trace normal? Are there any signs of airway obstruction? A B Circulation Is the physiology normal (heart rate, blood pressure, peripheral temperature, lactate, urine output)? How much support is required (inotrope,vasopressor)? C D E Glucose What is the glucose level? Is insulin being administered? G G D Haematology What are the haemoglobin/ platelet levels? Are there any signs of bleeding? H Infection What is the temperature? Review recent infective markers and trend What antibiotics are being given and what is the duration of treatment? I Enteral/exposure Feeding regimen Stool frequency Abdominal tenderness/bowel sounds present? Disability Level of responsiveness Delirium screen Pupillary responses Doses of sedative drugs F Fluids, electrolytes and renal system What is the fluid balance? Urine volume and colour? Is there any oedema? Review the renal biochemistry and electrolyte levels Breathing Is the physiology normal (SpO2, respiratory rate, tidal volume)? What is the level of support? Are there any abnormal signs on chest examination? Review the ventilator settings, arterial blood gases and recent chest X-ray F E C B A
- 209. Monitoring 177 9 Basicprinciples Uses the different red and infrared absorption proles of oxyhaemoglobin and deoxyhaemoglobin to estimate arterial oxyhaemoglobin saturation (SaO2 ) Only pulsatile absorption is measured A poor trace correlates with poor perfusion Sources of error Carboxyhaemoglobin – absorption prole is the same as oxyhaemoglobin: falsely elevated SpO2 Methaemoglobinaemia – SpO2 will tend towards 85% Ambient light/poor application of probe/severe tricuspid regurgitation (pulsatile venous ow): falsely depressed SpO2 Reduced accuracy below 80% saturation Hyperbilirubinaemia does not affect SpO2 Monitoring Electrocardiography Heart rate, rhythm and QRS morphology Arterial line trace Size of the area under the curve is proportional to stroke volume Narrow peaks suggest low stroke volume as shown here Oxygen saturation Saturation of haemoglobin measured by plethysmography (SpO2). Gives an indication of adequacy of oxygenation, and the quality of tissue perfusion can also be inferred – a flat trace suggests poor peripheral perfusion Central venous pressure trace A non-specific guide to volume status and right ventricular function. Increased values in fluid overload and right ventricular failure Capnography Numerical value of end-tidal CO2 (ETCO2) is less than arterial PCO2 (PaCO2) by a variable amount. Shape of trace can signify airway displacement/obstruction, bronchospasm or a low cardiac output (as shown below) kPa mmHg Time (secs) 0 5 40 Normal Steep ‘upstroke’ in early expiration Bronchospasm Shallow ‘upstroke’ in early expiration Partial obstruction/displacement of airway device Decreasing cardiac output Decreasing size of ETCO2 waveform No ventilation (from any cause) Bedside physiological data commonly monitored in an intensive care unit setting. Pulse oximetry (SpO2 )
- 210. 178 ACUTEMEDICINE AND CRITICAL ILLNESS Hospital medicine is becoming ever-more specialised and people are living longer while accruing increasing numbers of chronic disease diag- noses. Rather than diminishing the role of the generalist, these factors paradoxically create a need for experts in the undifferentiated presenta- tion. In the UK such physicians are known as ‘general physicians’, while in the United States they are referred to as ‘hospitalists’. Acute illness can present in a large variety of ways, depending on the nature of the illness, the underlying health of the individual, and their cul- tural and religious background. The skills of prompt diagnosis formation and provision of appropriate treatment rely on the integration of infor- mation from all the available sources, along with careful consideration of underlying chronic health problems. Patients who deteriorate while in hospital make up a small but impor- tant cohort. If they are well managed, in-hospital cardiac arrest rates will be low. This can be achieved through the combined effects of prompt resuscitation and appropriate end-of-life decision-making. Early recog- nition of deterioration by ward teams and initial management by health- care professionals operating within a functioning rapid response system are the central tenets of any system designed to improve the outcomes of deteriorating ward patients. Intensive care medicine has developed into a prominent specialty, central to the safe functioning of a modern acute hospital. Scientic endeavour has resulted in a much better understanding of the molecu- lar pathophysiology of processes such as sepsis and acute respiratory distress syndrome, which account for much premature death worldwide. Acute medicine Acute medicine is the part of general medicine that is concerned with the immediate and early management of medical patients who require urgent care. As a specialty, it is closely aligned with emergency medicine and intensive care medicine, but is rmly rooted within general medicine. Acute physicians manage the adult medical take and lead the development of acute care pathways that aim to reduce variability, improve care and cut down hospital admissions. In order to achieve these aims, acute physicians must use their knowledge, combined with high-level clinical reasoning and decision-making skills, to minimise both diagnostic error and the risks of over-investigation. These concepts are explained more fully in Chapter 1 The decision to admit to hospital Every patient presenting to hospital should be assessed by a clinician who is able to determine whether or not admission is required. The requirement for admission is determined by many factors, including the severity of illness, the patient's physiological reserve, the need for urgent investigations, the nature of proposed treatments and the patient's social circumstances. In many cases, it is clear early in the assessment process that a patient requires admission. In such cases, a move into a med- ical receiving unit – often termed a medical admissions unit (MAU) or acute medical unit (AMU) – should be facilitated as soon as the initial assessment has been completed and urgent investigations and/or treat- ments have been instigated. In hospitals where such units do not exist, patients will need to be moved to a downstream ward once treatment has been commenced and they have been deemed sufciently stable. In suspected cases of airborne-transmissible infectious diseases, patients should be isolated initially and may require cohorting in specic areas of the hospital once diagnoses have been conrmed. Following the ini- tial assessment, it may be possible to discharge stable patients home with a plan for early follow-up (such as a rapid-access specialist clinic appointment). Ambulatory care In some hospitals, it is increasingly possible for patient care to be coordi- nated in an ambulatory setting, negating the need for a patient to remain in hospital overnight. In the context of acute medicine, ambulatory care can be employed for conditions that are perceived by either the patient or the referring practitioner as requiring prompt clinical assessment by a competent decision-maker with access to appropriate diagnostic resources. The patient may return on several occasions for investigation, observation, consultation or treatment. Some presentations, such as a unilateral swollen leg (p. 188), lend themselves to this type of manage- ment (Box 9.1). If indicated, a Doppler ultrasound can be arranged, and patients with conrmed deep vein thrombosis can be anticoagulated on an outpatient basis. Successful ambulatory care requires careful patient selection; while many patients may cherish the opportunity to sleep at home, others may nd frequent trips to hospital or clinic too difcult due to frailty, poor mobility or transport difculties. Presenting problems in acute medicine Thissectiondetailssomeofthemostcommonpresentationstoacutemed- icine. However, many people present to hospital with physical complaints that do not appear to be the symptoms of a medical condition, referred to as ‘medically unexplained’ or ‘functional’ symptoms (see Chs 23, 28 and 31). It is thought that such symptoms may account for up to half of all new visits to hospital in the UK. Rather than providing reassur- ance, a lack of understanding of the cause of the symptoms can result in more distress for patients. When the unexplained symptoms relate to the nervous system (such as limb weakness, numbness, shaking or black- outs), the term ‘functional neurological disorder’ is used (see p. 1152). Medically unexplained symptoms are more common in women, younger people, those who have previously suffered from depression or anxiety, recently bereaved people and those recovering from a recent physical 9.1 Groups of patients who are potentially suitable for ambulatory care Group Example(s) Quality and safety issues Diagnostic exclusion group Chest pain – possible myocardial infarction; breathlessness – possible pulmonary embolism Even when a specic condition has been excluded, there is still a need to explain the patient's symptoms through the diagnostic process Low-risk stratication group Non-variceal upper gastrointestinal bleed with low Blatchford score (Box 23.16); community- acquired pneumonia with low CURB-65 score (see Fig. 17.32) Appropriate treatment plans should be in place Specic procedure group Replacement of percutaneous endoscopic gastrostomy (PEG) tube; drainage of pleural effusion/ascites The key to implementation is how ambulatory care for this group of patients can be delivered when they present out of hours Outpatient group with supporting infrastructure Deep vein thrombosis (DVT); cellulitis These are distinct from the conditions listed above because the infrastructure required to manage them is quite different
- 211. Presenting problems inacute medicine 179 9 illness. For every acute medical presentation, there will be a cohort of patients for whom the diagnosis remains elusive. In such circumstances, consideration should be given to the potential harm of over-investiga- tion and the alternative approaches required to manage medically unex- plained symptoms. Further detail can be found on p. 1256. Chest pain Chest pain is a common symptom in patients presenting to hospital. The differential diagnosis is wide (Box 9.2), and a detailed history and thor- ough clinical examination are paramount to ensure that the subsequent investigative pathway is appropriate. Presentation Chest ‘pain’ is clearly a subjective phenomenon and may be described by patients in a variety of different ways. Whether the patient describes ‘pain’, ‘discomfort’ or ‘pressure’ in the chest, there are some key fea- tures that must be elicited from the history. Site and radiation Pain secondary to myocardial ischaemia is typically located in the centre of the chest. It may radiate to the neck, jaw and upper or even lower arms. Occasionally, it may be experienced only at the sites of radiation or in the back. The pain of myocarditis or pericarditis is characteristically felt retrosternally, to the left of the sternum, or in the left or right shoulder. The severe pain of aortic dissection is typically central with radiation through to the back. Central chest pain may also occur with tumours affecting the mediastinum, oesophageal disease (p. 806) or disease of the thoracic aorta (p. 342). Pain situated over the left anterior chest and radiating laterally is unlikely to be due to cardiac ischaemia and may have many causes, including pleural or lung disorders, musculoskeletal problems or anxiety. Rarely, sharp, left-sided chest pain that is suggestive of a mus- culoskeletal problem may be a feature of mitral valve prolapse (p. 455). Characteristics Pleurisy, a sharp or ‘catching’ chest pain aggravated by deep breathing or coughing, is indicative of respiratory pathology, particularly pulmonary infection or infarction. However, the pain associated with myocarditis or pericarditis is often also described as ‘sharp’ and may ‘catch’ dur- ing inspiration, coughing or lying at. It typically varies in intensity with movement and the phase of respiration. A malignant tumour invading the chest wall or ribs can cause gnawing, continuous local pain. The pain of myocardial ischaemia is typically dull, constricting, choking or ‘heavy’, and is usually described as squeezing, crushing, burning or ach- ing. Patients often emphasise that it is a discomfort rather than a pain. Angina occurs during (not after) exertion and is promptly relieved (in less than 5minutes) by rest. It may also be precipitated or exacerbated by emotion but tends to occur more readily during exertion, after a large meal or in a cold wind. In crescendo or unstable angina, similar pain may be precipitated by minimal exertion or at rest. The increase in venous return or preload induced by lying down may also be sufcient to provoke pain in vulnerable patients (decubitus angina). Patients with reversible airways obstruction, such as asthma, may also describe exertional chest tightness that is relieved by rest. This may be difcult to distinguish from myocardial ischaemia. Bronchospasm may be associated with wheeze, atopy and cough (p. 489). Musculoskeletal chest pain is variable in site and intensity but does not usually fall into any of the patterns described above. The pain may vary with posture or movement of the upper body, or be associated with a specic movement (bending, stretching, turning). Many minor soft tissue injuries are related to everyday activities, such as driving, manual work and sport. Onset The pain associated with myocardial infarction (MI) typically takes sev- eral minutes or even longer to develop to its maximal intensity; similarly, angina builds up gradually in proportion to the intensity of exertion. Pain that occurs after, rather than during, exertion is usually musculoskele- tal or psychological in origin. The pain of aortic dissection (severe and ‘tearing’), massive pulmonary embolism (PE) or pneumothorax is usually very sudden in onset. Other causes of chest pain tend to develop more gradually, over hours or even days. Associated features The pain of MI, massive PE or aortic dissection is often accompanied by autonomic disturbance, including sweating, nausea and vomiting. Some patients describe a feeling of impending death, referred to as ‘angor animi’. Breathlessness, due to pulmonary congestion arising from transient ischaemic left ventricular dysfunction, is often a prominent feature of myo- cardial ischaemia. Breathlessness may also accompany any of the res- piratory causes of chest pain and can be associated with cough, wheeze or other respiratory symptoms. Patients with myocarditis or pericarditis may describe a prodromal viral illness. Gastrointestinal disorders, such as gastro-oesophageal reux or peptic ulceration, may present with chest pain that is hard to distinguish from myocardial ischaemia; it may even be precipitated by exercise and be relieved by nitrates. However, it is usually possible to elicit a history relating chest pain to supine posture or eating, drinking or oesophageal reux. The pain of gastro-oesophageal reux often radiates to the interscapular region and dysphagia may be present. Severe chest pain arising after retching or vomiting, or following oesophageal instrumentation, should raise the possibility of oesophageal perforation. Anxiety-induced chest pain may be associated with breathlessness (without hypoxaemia), throat tightness, perioral tingling and other evi- dence of emotional distress. It is important to remember, however, that chest pain itself can be an extremely frightening experience, and so psy- chological and organic features often coexist. Anxiety may amplify the effects of organic disease and a confusing clinical picture may result. 9.2 Differential diagnosis of chest pain Central Cardiac Myocardial ischaemia (angina) Myocardial infarction Myocarditis Pericarditis Mitral valve prolapse syndrome Aortic Aortic dissection Aortic aneurysm Oesophageal Oesophagitis Oesophageal spasm Mallory–Weiss syndrome Oesophageal perforation (Boerhaave syndrome) Pulmonary embolus Mediastinal Malignancy Anxiety/emotion1 Peripheral Lungs/pleura Pulmonary infarct Pneumonia Pneumothorax Malignancy Tuberculosis Connective tissue disorders Musculoskeletal2 Osteoarthritis Rib fracture/injury Acute vertebral fracture Costochondritis (Tietze syndrome) Intercostal muscle injury Epidemic myalgia (Bornholm disease) Neurological Prolapsed intervertebral disc Herpes zoster 1 May also cause peripheral chest pain. 2 Can sometimes cause central chest pain.
- 212. 180 ACUTEMEDICINE AND CRITICAL ILLNESS A detailed and clear history is key to narrowing the differential diagno- sis of chest pain. Figure 9.1 shows how certain features of the history, particularly when combined, can tip the balance of evidence towards or away from ischaemic cardiac chest pain. Clinical assessment Cardiorespiratory examination may detect clinical signs that help guide ongoing investigation. Patients with a history compatible with myocardial ischaemia should have a 12-lead electrocardiogram (ECG) performed while clinical examination proceeds. Ongoing chest pain with clinical fea- tures of shock or pulmonary oedema, or ECG evidence of ventricular arrhythmia or complete heart block, should prompt urgent cardiology review and referral to a higher level of care. Chest pain that is accompanied by clinical evidence of increased intra- cardiac pressure (especially a raised jugular venous pressure) increases the likelihood of myocardial ischaemia or massive PE. The legs should be examined for clinical evidence of deep vein thrombosis. A large pneumothorax should be evident on clinical examination, with absent breath sounds and a hyper-resonant percussion note on the affected side. Other unilateral chest signs, such as bronchial breathing or crackles, are most likely to indicate a respiratory tract infection, and a chest X-ray should be expedited. Pericarditis may be accompanied by a pericardial friction rub. In aortic dissection, syncope or neurological decit may occur. Examination may reveal asymmetrical pulses, features of undiagnosed Marfan syndrome (p. 445) or a new early diastolic murmur representing aortic regurgitation. Any disease process involving the pleura may restrict rib movement and a pleural rub may be audible on the affected side. Local tenderness of the chest wall is likely to indicate musculoskeletal pain but can also be found in pulmonary infarction. Subdiaphragmatic inammatory pathology, such as a liver abscess, cholecystitis or ascending cholangitis, can mimic pneumonia by causing fever, pleuritic chest pain and a small sympathetic pleural effusion, usu- ally on the right. Likewise, acute pancreatitis can present with thoracic symptoms, and an amylase or lipase level should be requested where appropriate. It is imperative that the abdomen is examined routinely in all patients presenting with pleuritic chest pain. Initial investigations Chest X-ray, ECG and biomarkers (e.g. troponin, D-dimer) play a piv- otal role in the evaluation of chest pain. However, indiscriminate order- ing of such investigations may result in diagnostic confusion and over-investigation. The choice of investigation(s) is intimately linked to the history and examination ndings. A chest X-ray and 12-lead ECG should be performed in the vast majority of patients presenting to hospital with chest pain. Pregnancy is not a contraindication to chest X-ray, but par- ticular consideration should be given to whether the additional diagnostic information justies breast irradiation. The chest X-ray may conrm the suspected diagnosis, particularly in the case of pneumonia. Small pneumothoraces are easily missed, as are rib fractures or small metastatic deposits, and all should be considered individually during chest X-ray review. A widened mediastinum suggests acute aortic dissection but a normal chest X-ray does not exclude the diagnosis. Provided it has been more than 1hour since the onset of pain, chest X-ray in oesophageal rupture may reveal subcutaneous emphy- sema, pneumomediastinum or a pleural effusion. Patients with a history compatible with myocardial ischaemia require an urgent 12-lead ECG. Acute chest pain with ECG changes indicating a ST segment elevation myocardial infarction (STEMI) suggests that the patient is likely to benet from immediate reperfusion therapy. Specic information relating to cocaine or amphetamine use should be sought, particularly in younger patients. In the context of a compatible history, an ECG showing ischaemic changes that do not meet STEMI criteria should prompt regular repeat ECGs and treatment for non-ST segment elevation myocardial infarction (NSTEMI)/unstable angina. Measurement of serum troponin concentration on admission is often helpful in cases where there is diagnostic doubt, but a negative result should always prompt a repeat sample 6–12hours after maximal pain. Acute coronary syndrome may be diagnosed with condence in patients with a convinc- ing history of ischaemic pain (see Fig. 9.1) and either ECG evidence of ischaemia or an elevated serum troponin. If an elevated serum troponin is found in a patient who has an atypical history or is at low risk of ischae- mic heart disease, then alternative causes of raised troponin should be considered (Box 9.3). Further management of acute coronary syndromes is discussed on page 432. In the absence of convincing ECG evidence of myocardial ischaemia, other life-threatening causes of chest pain, such as aortic dissection, massive PE and oesophageal rupture, should be considered. Suspicion of aortic dissection (background of hypertension, trauma, pregnancy or previous aortic surgery) should prompt urgent thoracic computed tomography (CT) or transoesophageal echocardiography. An ECG in the context of massive PE most commonly reveals only a sinus tachycardia, but may show new right axis deviation, right bundle branch block or a dominant R wave in V1 . The classical nding of S1 Q3 T3 (a deep S wave in Ischaemic cardiac chest pain Non-cardiac chest pain Relieving factors Respiratory, gastrointestinal, locomotor or psychological Rest Quick response to nitrates Precipitation Spontaneous, not related to exertion, provoked by posture, respiration or palpation Precipitated by exertion and/or emotion Character Tight, squeezing, choking Radiation Other or no radiation Jaw/neck/shoulder/arm (occasionally back) Location Peripheral, localised Central, diffuse Associated features Not relieved by rest Variable or no response to nitrates Breathlessness Fig. 9.1 Identifying ischaemic cardiac pain: the ‘balance’ of evidence.
- 213. Presenting problems inacute medicine 181 9 lead I, with a Q wave and T wave inversion in lead III) is rare. If massive PE is suspected and the patient is haemodynamically unstable, a transthor- acic echocardiogram, to seek evidence of right heart strain and exclude alternative diagnoses such as tamponade, is extremely useful. If the patient is deemed to be at low risk of PE, a D-dimer test can be informative, as a negative result effectively excludes the diagnosis. The D-dimer test should be performed only if there is clinical suspicion of PE, as false-positive results can lead to unnecessary investigations. If the D-dimer is positive, there is high clinical suspicion, or there is other convincing evidence of PE (such as features of right heart strain on the ECG), prompt imaging should be arranged (p. 546 and Fig. 17.67). Acute breathlessness In acute breathlessness, the history, along with a rapid but careful exam- ination, will usually suggest a diagnosis that can be conrmed by routine investigations including chest X-ray, 12-lead ECG and arterial blood gas (ABG) sampling. Presentation A key feature of the history is the speed of onset of breathlessness. Acute severe breathlessness (over minutes or hours) has a distinct differential diagnosis list to chronic exertional breathlessness. The presence of asso- ciated cardiovascular (chest pain, palpitations, sweating and nausea) or respiratory (cough, wheeze, haemoptysis, stridor) symptoms can narrow the differential diagnosis yet further. A previous history of left ventricular dysfunction, asthma or exacerbations of chronic obstructive pulmonary disease (COPD) is important. A high temperature, cough (productive or non-productive) and/or viral prodrome may indicate respiratory infection and, if so, relevant infection control precautions should be taken from ini- tial assessment. In the severely ill patient, it may be necessary to obtain the history from accompanying witnesses. In children, the possibility of inhalation of a foreign body (Fig. 9.2) or acute epiglottitis should always be considered. There is often more than one underlying diagnosis; a thorough assessment should continue, even after a possible diagnosis has been reached, particularly if the severity of symptoms does not seem to be ade- quately explained. The causes of acute severe breathlessness are covered here; chronic exertional dyspnoea is discussed further on page 489). Clinical assessment Airway obstruction, anaphylaxis and tension pneumothorax require immediate identication and treatment. If any of these is suspected, treatment should not be delayed while additional investigations are per- formed, and anaesthetic support is likely to be required. In the absence of an immediately life-threatening cause, the following should be assessed and documented: level of consciousness degree of central cyanosis work of breathing (rate, depth, pattern, use of accessory muscles) adequacy of oxygenation (SpO2 ) ability to speak (in single words or sentences) cardiovascular status (heart rate and rhythm, blood pressure (BP) and peripheral perfusion). Pulmonary oedema is suggested by a raised jugular venous pressure and bi-basal crackles or diffuse wheeze, while asthma or COPD is charac- terised by wheeze and prolonged expiration. A hyper-resonant hemithorax with absent breath sounds raises the possibility of pneumothorax, while severe breathlessness with normal breath sounds may indicate PE. Leg swelling may suggest cardiac failure or, if asymmetrical, venous thrombosis. The presence of wheeze is not always indicative of bronchospasm. In acute left heart failure, an increase in the left ventricular diastolic pressure causes the pressure in the left atrium, pulmonary veins and pulmonary capillaries to rise. When the hydrostatic pressure of the pulmonary capil- laries exceeds the oncotic pressure of plasma (about 25–30mmHg), uid moves from the capillaries into the interstitium. This stimulates respiration through a series of autonomic reexes, producing rapid, shallow respira- tion, and congestion of the bronchial mucosa may cause wheeze (some- times known as cardiac asthma). Sitting upright or standing may provide some relief by helping to reduce congestion at the apices of the lungs. The patient may be unable to speak and is typically distressed, agitated, sweaty and pale. Respiration is rapid, with recruitment of accessory muscles, coughing and wheezing. Sputum may be profuse, frothy and blood-streaked or pink. Extensive crepitations and rhonchi are usually audible in the chest and there may also be signs of right heart failure. Any arrhythmia may cause breathlessness, but usually does so only if the heart is structurally abnormal, such as with the onset of atrial bril- lation in a patient with mitral stenosis. In such cases, the classic mid-di- astolic rumbling murmur may be heard. Patients sometimes describe chest tightness as ‘breathlessness’. However, myocardial ischaemia may also induce true breathlessness by provoking transient left ventricular dysfunction. When breathlessness is the dominant or sole feature of 9.3 Causes of elevated serum troponin other than acute coronary syndrome Cardiorespiratory causes Pulmonary embolism Acute pulmonary oedema Tachyarrhythmias Myocarditis/myopericarditis Aortic dissection Cardiac trauma Cardiac surgery/ablation Non-cardiorespiratory causes Prolonged hypotension Severe sepsis Severe burns Stroke Subarachnoid haemorrhage End-stage renal failure A B Fig. 9.2 Inhaled foreign body. covering mucous lm.
- 214. 182 ACUTEMEDICINE AND CRITICAL ILLNESS myocardial ischaemia, it is known as ‘angina equivalent’. A history of chest tightness or close correlation with exercise should be sought. Initial investigations As shown in Box 9.4, amalgamation of a clear history and thorough clinical examination with chest X-ray, ECG and ABG ndings will usu- ally indicate the primary cause of breathlessness. In cases of suspected infection, a viral throat swab should be obtained early in the course of the assessment; increasingly point-of-care testing of viral throat swabs is available, providing important and rapid diagnostic information. If avail- able, sputum should be sent for culture. If bronchospasm is suspected, measurement of peak expiratory ow will assist in the assessment of severity and should be performed whenever possible. An ABG will often provide additional information to SpO2 measure- ment alone, particularly if there is clinical evidence (drowsiness, delirium, asterixis) or a strong likelihood of hypercapnia. An acute rise in PaCO2 will increase the HCO3 by only a small amount, resulting in inadequate buffering and acidaemia. Renal compensation and a large rise in HCO3 will take at least 12hours. In acute type II respiratory failure (p. 496), the rate of rise of PaCO2 is a better indicator of severity than the absolute value. An ABG can also give a carboxyhaemoglobin level after smoke inhalation (although this can also be measured on a venous sample), and is central to the identication of metabolic acidosis or the diagnosis of psychogenic hyperventilation (see Box 9.4). If pulmonary embolism is suspected, calculating pre-test probability (Ch. 1) is key. In a patient with a pre-test probability of less than 15%, the pulmonary embolism rule-out criteria (PERC) can rule out pulmonary embolism clinically, negating the need for further imaging, if none of the criteria listed in Box 9.5 is met. Further detail on the investigation and management of pulmonary embolus is given on page 546. Procalcitonin (PCT) and N-terminal pro-hormone brain natriuretic pro- tein (NT-proBNP) can be measured in venous blood. While these bio- markers can give an indication of aetiology in shortness of breath, they are probably of more value in tracking clinical progression and response to treatment. Elevated PCT is a biomarker for bacterial infection and may be useful, in addition to clinical assessment, in helping decide the need for and duration of antibiotic therapy in patients with conrmed viral res- piratory disease (such as COVID-19) who may have additional bacterial super-infection. Elevated NT-proBNP is suggestive of underlying left ven- tricular failure (p. 393), although it can be elevated in other conditions such as renal failure, COPD, pulmonary hypertension and pulmonary embolism. Measurement of NT-proBNP may be considered if there is no clear-cut evidence of pulmonary oedema on a chest X-ray and can be particularly useful as a ‘rule-out’ test, as a normal NT-proBNP has high negative predictive value for heart failure. Individuals with suspected heart failure should undergo early echocardiography (p. 402). CT imaging (with or without pulmonary angiography) is a useful investigation in many respiratory conditions as interstitial changes, tumours or consolidation may not be evident on chest X-ray. If breath- lessness is suspected to be an ‘angina equivalent’, objective evidence 9.5 PERC rule for pulmonary embolism Rules out PE if none of the eight criteria is present and pre-test probability is less than or equal to 15% (1.8% was chosen as the point of equipoise between the benets and risks of further investigations for PE, and the benets and risks of not investigating further). Age ≥50 Heart rate ≥100 Oxygen saturation on room air <95% Unilateral leg swelling Haemoptysis Recent surgery or trauma (≤4 weeks ago requiring hospitalisation) Prior venous thromboembolism (VTE) Hormone use (oral contraceptives), hormone replacement or oestrogenic hormone use in male or female patients 9.4 Clinical features in acute breathlessness Condition History Signs Chest X-ray ABG ECG Pulmonary oedema Chest pain, palpitations, orthopnoea, cardiac history* Central cyanosis, ↑JVP, sweating, cool extremities, basal crackles* Cardiomegaly, oedema/pleural effusions* ↓PaO2 ↓PaCO2 Sinus tachycardia, ischaemia*, arrhythmia Massive pulmonary embolus Risk factors, chest pain, pleurisy, syncope*, dizziness* Central cyanosis, ↑JVP*, absence of signs in the lung*, shock (tachycardia, hypotension) Often normal Prominent hilar vessels, oligaemic lung elds* ↓PaO2 ↓PaCO2 Sinus tachycardia, RBBB, S1 Q3 T3 pattern↑T(V1 –V4 ) Acute severe asthma History of asthma, asthma medications, wheeze* Tachycardia, pulsus paradoxus, cyanosis (late), →JVP*, ↓peak ow, wheeze* Hyperination only (unless complicated by pneumothorax)* ↓PaO2 Normal PaCO2 (↑PaCO2 in extremis) Sinus tachycardia (bradycardia in extremis) Acute exacerbation of COPD Previous episodes*, smoker. If in type II respiratory failure, may be drowsy Cyanosis, hyperination*, signs of CO2 retention (apping tremor, bounding pulses)* Hyperination*, bullae, complicating pneumothorax ↓ or ↓↓PaO2 ↑PaCO2 in type II failure ± ↑H+ , ↑HCO3 in chronic type II failure Normal, or signs of right ventricular strain Pneumonia/ lower respiratory tract infection Prodromal illness*, fever*, rigors*, pleurisy* Fever, delirium, pleural rub*, consolidation*, cyanosis (if severe) Pneumonic consolidation* ↓PaO2 ↓PaCO2 (↑ in extremis) Tachycardia Metabolic acidosis Evidence of diabetes mellitus or renal disease, aspirin or ethylene glycol overdose Fetor (ketones), hyperventilation without heart or lung signs*, dehydration*, air hunger Normal PaO2 normal ↓↓PaCO2 , ↑H+ ↓HCO3 Psychogenic Previous episodes, digital or perioral dysaesthesia No cyanosis, no heart or lung signs, carpopedal spasm Normal PaO2 normal* ↓↓PaCO2 , ↓H+ * *Valuable discriminatory feature. (ABG = arterial blood gas; COPD = chronic obstructive pulmonary disease; JVP = jugular venous pressure; RBBB = right bundle branch block)
- 215. Presenting problems inacute medicine 183 9 of myocardial ischaemia from stress testing may help to establish the diagnosis, although coronary artery angiography (either by CT or car- diac catheterisation) is often performed early in the investigation path- way (p. 432). Anaphylaxis Anaphylaxis is a potentially life-threatening, systemic allergic reaction characterised by a variable combination of circulatory collapse, bron- chospasm, laryngeal stridor, angioedema and urticaria. The risk of death is increased in patients with pre-existing asthma, particularly if this is poorly controlled, and in situations where treatment with adrenaline (epi- nephrine) is delayed. Presentation Anaphylaxis occurs when an allergen binds to and cross-links mem- brane-bound IgE on mast cells in a susceptible individual, causing release of histamine, tryptase and other vasoactive mediators from mast cells. These mediators have a variety of effects, including vasodilatation, increased capillary permeability leading to hypotension, and broncho- constriction. It can be difcult to distinguish IgE-mediated anaphylaxis clinically from non-specic degranulation of mast cells on exposure to drugs, chemicals or other triggers where IgE is not involved, previously known as anaphylactoid reactions. Clinical assessment The clinical features of anaphylaxis are summarised in Figure 9.3. Several other conditions can mimic anaphylaxis and these are listed in Box 9.6 It is important to assess the severity of the reaction, and the time between allergen exposure and onset of symptoms provides a guide. Enquiry should be made about potential triggers. If a trigger is immedi- ately obvious, a detailed history of the previous 24hours may be helpful. The most common triggers of anaphylaxis are foods, latex, insect venom and drugs. A history of previous local allergic responses to the offending agent is common. The route of allergen exposure may inuence the prin- cipal clinical features of a reaction; for example, if an allergen is inhaled, the major symptom is frequently wheezing. Features of anaphylaxis may overlap with the direct toxic effects of drugs and venoms (Chs 7 and 8). Potentiating factors, such as exercise alcohol or fatigue, can lower the threshold for an anaphylactic event. It is important to identify precipitating factors so that appropriate avoidance measures may be taken in the longer term. Investigations and management Measurement of serum mast cell tryptase concentrations is useful to conrm the diagnosis. It is important to measure tryptase in serial tests to demonstrate the temporal relationship to the triggering event. Specic IgE tests may be useful in conrming hypersensitivity and may be prefer- able to skin-prick tests when investigating patients with a history of ana- phylaxis. The cornerstone of management of a severe case is the early administration of adrenaline (epinephrine), which supports the cardiovas- cular system, reduces bronchospasm and has some disease-modifying effects. Secondary management depends upon which organs are most affected. The emergency management of anaphylaxis is summarised in Box 9.7. If present, angioedema of the orofacial area requires careful observation and timely intervention, possibly with endotracheal intuba- tion. The investigation and management of angioedema is discussed further on page 82. Individuals who have recovered from an anaphylactic event should be referred for specialist assessment. The aims are to identify the trig- ger, educate the patient regarding avoidance and management of sub- sequent episodes, and to establish whether specic treatment, such as immunotherapy, is indicated. If the trigger factor cannot be identi- ed or avoided, recurrence is common. Patients who have previously Itching of palms, soles of feet and genitalia Feeling of impending doom, loss of consciousness Conjunctival injection Flushing Sweating Hypotension Urticaria Wheeze, bronchoconstriction Angioedema of lips and mucous membrane Abdominal pain Diarrhoea Cardiac arrhythmias Laryngeal obstruction Stridor Wasp sting Fig. 9.3 Clinical manifestations of anaphylaxis. In this example, the response is to an insect sting containing venom to which the patient is allergic. This causes release of histamine and other vasoactive mediators, which lead to the characteristic features of anaphylaxis that are illustrated. 9.6 Differential diagnosis of anaphylaxis Causes of hypotension Vasovagal syncope Cardiac arrhythmia Cardiogenic shock Causes of respiratory distress Status asthmaticus Pulmonary embolus Causes of laryngeal obstruction C1 inhibitor deciency Idiopathic angioedema Causes of generalised ushing Systemic mastocytosis Carcinoid syndrome
- 216. 184 ACUTEMEDICINE AND CRITICAL ILLNESS experienced an anaphylactic event should be prescribed self-injectable adrenaline (epinephrine) and they and their families or carers should be instructed in its use (Box 9.8). The use of a MedicAlert (or similar) brace- let will increase the likelihood of the injector being administered in an emergency. There is an important role for a specialist dietitian when a food trigger is the suspected allergen. Allergy in adolescence requires additional consideration and management, as set out in Box 9.9 Syncope/presyncope The term ‘syncope’ refers to sudden loss of consciousness due to reduced cerebral perfusion. ‘Presyncope’ refers to lightheadedness, in which the individual thinks he or she may ‘black out’. Dizziness and pre- syncope are particularly common in old age (Box 9.10). Symptoms are disabling, undermine condence and independence, and can affect a person's ability to work or to drive. There are three principal mechanisms that underlie recurrent presyn- cope or syncope: cardiac syncope due to mechanical cardiac dysfunction or arrhythmia neurocardiogenic syncope (also known as vasovagal or reex syn- cope), in which an abnormal autonomic reex causes bradycardia and/or hypotension postural hypotension, in which physiological peripheral vasocon- striction on standing is impaired, leading to hypotension. There are, however, other causes of loss of consciousness, and dif- ferentiating syncope from seizure is a particular challenge. Psychogenic blackouts (also known as non-epileptic seizures or pseudoseizures) also need to be considered in the differential diagnosis. Presentation The history from the patient and a witness is the key to establishing a diagnosis. The terms used for describing the symptoms associated with syncope vary so much among patients that they should not be taken for granted. Some patients use the term ‘blackout’ to describe a purely visual symptom, rather than loss of consciousness. Some may under- stand ‘dizziness’ to mean an abnormal perception of movement (vertigo), 9.8 How to prescribe self-injectable adrenaline (epinephrine) Prescription (normally initiated by an immunologist or allergist) Specify the brand of autoinjector, as they have different triggering mechanisms Prescribe two devices Indications Anaphylaxis to allergens that are difcult to avoid: Insect venom Foods Idiopathic anaphylactic reactions History of severe localised reactions with high risk of future anaphylaxis: Reaction to trace allergen Likely repeated exposure to allergen History of severe localised reactions with high risk of adverse outcome: Poorly controlled asthma Lack of access to emergency care Patient and family education Know when and how to use the device Carry the device at all times Seek medical assistance immediately after use Wear an alert bracelet or necklace Include the school in education for young patients Other considerations Caution with β-adrenoceptor antagonists (β-blockers) in anaphylactic patients as they may increase the severity of an anaphylactic reaction and reduce the response to adrenaline (epinephrine) 9.9 Allergy in adolescence Resolution of childhood allergy: most children affected by allergy to milk, egg, soybean or wheat will grow out of their food allergies by adolescence, but allergies to peanuts, tree nuts, sh and shellsh are frequently life-long. Risk-taking behaviour and fatal anaphylaxis: serious allergy is increasingly common in adolescents and this is the highest risk group for fatal, food-induced anaphylaxis. This is associated with increased risk-taking behaviour, and food-allergic adolescents are more likely than adults to eat unsafe foods, deny reaction symptoms and delay emergency treatment. Emotional impact of food allergies: some adolescents may neglect to carry a prescribed adrenaline (epinephrine) autoinjector because of the associated nuisance and/or stigma. Surveys of food-allergic teenagers reveal that many take risks because they feel socially isolated by their allergy. 9.10 Dizziness in old age Prevalence: common, affecting up to 30% of people aged >65 years. Symptoms: most frequently described as a combination of unsteadiness and lightheadedness. Most common causes: postural hypotension and cardiovascular disease. Many patients have more than one underlying cause. Arrhythmia: can present with lightheadedness either at rest or on activity. Anxiety: frequently associated with dizziness but rarely the only cause. Falls: multidisciplinary workup is required if dizziness is associated with falls. 9.7 Emergency management of anaphylaxis Treatment Comment Prevent further contact with allergen Prevents ongoing mast cell activation Ensure airway patency Prevents hypoxia Administer adrenaline (epinephrine) promptly: 0.3–0.5mL 1:1000 solution IM in adults (0.3–0.5mg) Repeat at 5–10min intervals if initial response is inadequate Intramuscular route important because of peripheral vasoconstriction Acts within minutes Increases blood pressure Reverses bronchospasm Administer antihistamines: Chlorphenamine 10mg IM or slow IV injection Blocks effect of histamine on target cells Administer glucocorticoids: Hydrocortisone 200mg IV Reduces cytokine release Prevents rebound symptoms in severe cases Provide supportive treatment: Nebulised adrenaline (epinephrine) (e.g. 3mg) Nebulised β2 -agonists (e.g. salbutamol 5mg) IV uids Oxygen Reduces airway oedema Reverses bronchospasm Restores plasma volume Reverses hypoxia (IM = intramuscular; IV = intravenous) some will consider this a feeling of faintness, and others will regard it as unsteadiness. The clinician thus needs to elucidate the exact nature of the symptoms that the patient experiences. The potential differential diagnosis of syncope and presyncope, on the basis of the symptoms described, is shown in Figure 9.4. The history should always be supplemented by a direct eye-witness account if available. Careful history with corroboration will usually establish whether there has been full consciousness, altered consciousness, vertigo, transient amnesia or something else. Attention should be paid to potential triggers (e.g. medication, micturition, exertion, prolonged standing), the
- 217. Presenting problems inacute medicine 185 9 patient's appearance (e.g. colour, seizure activity), the duration of the epi- sode, and the speed of recovery (Box 9.11). Cardiac syncope is usually sudden, but can be associated with premonitory lightheadedness, palpita- tion or chest discomfort. The blackout is usually brief and recovery rapid. Exercise-induced syncope can be the presenting feature of a number of serious pathologies (such as hypertrophic obstructive cardiomyopathy or exercise-induced arrhythmia) and always requires further investigation. Neurocardiogenic syncope will often be associated with a situational trig- ger (such as pain or emotion), and the patient may experience ushing, nausea, malaise and clamminess for several minutes afterwards. Recovery is usually quick and without subsequent delirium, provided the patient has assumed a supine position. There is often some brief stiffening and limb-twitching, which requires differentiation from seizure-like movements. It is rare for syncope to cause injury or to cause amnesia after regaining awareness. Patients with seizures do not exhibit pallor, may have abnormal movements, usually take more than 5 minutes to recover and are often confused. Aspects of the history that can help to differentiate seizure from syncope are shown in Box 9.12 A diagnosis of psychogenic blackout (also known as non-epileptic seizure, pseudoseizure or psychogenic seizure) may be suggested by specic emotional triggers, dramatic movements or vocalisation, or by very prolonged duration (hours). A history of rotational vertigo is sug- gestive of a labyrinthine or vestibular disorder (p. 1143). Postural hypo- tension is normally obvious from the history, with presyncope or, less commonly, syncope occurring within a few seconds of standing. The history should include enquiry about predisposing medications (diuretics, vasodilators, antidepressants) and conditions (such as diabetes mellitus and Parkinson's disease). Clinical assessment Examination of the patient may be entirely normal, but may reveal clinical signs that favour one form of syncope. The systolic murmurs of aortic Labyrinthine dysfunction Infection Benign positional vertigo Ménière’s disease Ischaemia/infarction Trauma Other (e.g. drugs, otosclerosis) Central vestibular dysfunction ‘Physiological’ (visual– vestibular mismatch) Demyelination Migraine Posterior fossa mass lesion Vertebro-basilar ischaemia Other (e.g. disorders of cranio-vertebral junction) Ataxia Weakness Loss of joint position sense Gait dyspraxia Joint disease Visual disturbance Fear of falling (Chs 26 and 28) Impaired cerebral perfusion Cardiac disease Arrhythmia Left ventricular dysfunction Aortic stenosis Hypertrophic obstructive cardiomyopathy Other causes Vasovagal syncope Postural hypotension Micturition syncope Cough syncope Carotid sinus sensitivity Hypoglycaemia (Ch. 21) Anxiety* Hyperventilation Post-concussive syndrome Panic attack Non-epileptic attack Epileptic seizure Presyncope (reduced cerebral perfusion) Syncope (loss of cerebral perfusion) Sensation of movement? (vertigo) Loss of balance? Lightheaded? Other description ‘Funny turn’ or blackout * Anxiety is the most common cause of dizziness in those under 65 years Loss of consciousness (‘blackout’) Fig. 9.4 The differential diagnosis of syncope and presyncope.
- 218. 186 ACUTEMEDICINE AND CRITICAL ILLNESS to bradycardia, but the key to establishing a diagnosis is to obtain an ECG recording while symptoms are present. Since minor rhythm distur- bances are common, especially in older adults, symptoms must occur at the same time as a recorded arrhythmia before a diagnosis can be made. Ambulatory ECG recordings are helpful only if symptoms occur several times per week. Patient-activated ECG recorders are useful for examining the rhythm in patients with recurrent dizziness, but are not helpful in assessing sudden blackouts. When these investigations fail to establish a cause in patients with presyncope or syncope, an implantable ECG recorder can be sited subcutaneously over the upper left chest. This device continuously records the cardiac rhythm and will activate automatically if extreme bradycardia or tachycardia occurs. The ECG memory can also be tagged by the patient, using a hand-held activator as a form of ‘symptom diary’. Stored ECGs can be accessed by the implanting centre, using a telemetry device in a clinic, or using a home monitoring system via an online link. Head-up tilt-table testing is a provocation test used to establish the diagnosis of vasovagal syncope. It involves positioning the patient supine on a padded table that is then tilted to an angle of 60–70° for up to 45minutes, while the ECG and BP responses are monitored. A pos- itive test is characterised by bradycardia (cardio-inhibitory response) and/or hypotension (vasodepressor response), associated with typical symptoms. Headache Headache is common and causes considerable worry amongst both patients and clinicians, but rarely represents sinister disease. The causes may be divided into primary or secondary, with primary headache syn- dromes being vastly more common (Box 9.13). Presentation The primary purpose of the history and clinical examination in patients presenting with headache is to identify the small minority of patients with serious underlying pathology. Key features of the history include the tem- poral evolution of a headache; a headache that reached maximal inten- sity immediately or within 5 minutes of onset requires rapid assessment for possible subarachnoid haemorrhage. Other ‘red ag’ symptoms are shown in Box 9.14 It is important to establish whether the headache comes and goes, with periods of no headache in between (usually migraine), or whether it is present all or almost all of the time. Associated features, such as preceding visual symptoms, nausea/vomiting or photophobia/phono- phobia, may support a diagnosis of migraine but others, such as pro- gressive focal symptoms or constitutional upset like weight loss, may suggest a more sinister cause. The headache of cerebral venous throm- bosis may be ‘throbbing’ or ‘band-like’ and associated with nausea, vomiting or hemiparesis. Raised intracranial pressure (ICP) headache 9.11 Typical features of cardiac syncope,neurocardiogenic syncope and seizures Cardiac syncope Neurocardiogenic syncope Seizures Premonitory symptoms Often none Lightheadedness Palpitation Chest pain Breathlessness Nausea Lightheadedness Sweating Delirium Hyperexcitability Olfactory hallucinations ‘Aura’ Unconscious period Extreme ‘death- like’ pallor Pallor Prolonged (>1min) unconsciousness Motor seizure activity* Tongue-biting Urinary incontinence Recovery Rapid (< 1min) Flushing Rapid Nausea Lightheadedness Prolonged delirium (>5mins) Headache Focal neurological signs *N.B. Cardiac syncope can also cause convulsions by inducing cerebral anoxia. 9.12 How to differentiate seizures from syncope Seizure Syncope Aura (e.g. olfactory) + − Cyanosis + − Lateral tongue-biting + −/+ Post-ictal delirium + − Post-ictal amnesia + − Post-ictal headache + − Rapid recovery − + 9.13 Primary and secondary headache syndromes Primary headache syndromes Migraine (with or without aura) Tension-type headache Trigeminal autonomic cephalalgia (including cluster headache) Primary stabbing/coughing/exertional/sex-related headache Thunderclap headache New daily persistent headache syndrome Secondary causes of headache Medication overuse headache (chronic daily headache) Intracranial bleeding (subdural haematoma, subarachnoid or intracerebral haemorrhage) Raised intracranial pressure (brain tumour, idiopathic intracranial hypertension) Infection (meningitis, encephalitis, brain abscess) Inammatory disease (temporal arteritis, other vasculitis, arthritis) Referred pain from other structures (orbit, temporomandibular joint, neck) stenosis or hypertrophic obstructive cardiomyopathy are important nd- ings, particularly if paired with a history of lightheadedness or syncope on exertion. BP taken when supine and then after 1 and 3minutes of standing may, when combined with symptoms, provide robust evidence of symptomatic postural hypotension. Clinical suspicion of hypersensitive carotid sinus syndrome (sensitiv- ity of carotid baroreceptors to external pressure such as a tight collar) should prompt monitoring of the ECG and BP during carotid sinus pres- sure, provided there is no carotid bruit or history of cerebrovascular dis- ease. A positive cardio-inhibitory response is dened as a sinus pause of 3seconds or more; a positive vasodepressor response is dened as a fall in systolic BP of more than 50mmHg. Carotid sinus pressure will produce positive ndings in about 10% of older adults, but fewer than 25% of these experience spontaneous syncope. Symptoms should not, therefore, be attributed to hypersensitive carotid sinus syndrome unless they are reproduced by carotid sinus pressure. Initial investigations A 12-lead ECG is essential in all patients presenting with syncope or presyncope. Lightheadedness may occur with many arrhythmias, but blackouts (Stokes–Adams attacks) are usually due to profound brady- cardia or malignant ventricular tachyarrhythmias. The ECG may show evidence of conducting system disease (e.g. sinus bradycardia, atrioven- tricular block, bundle branch block), which would predispose a patient
- 219. Presenting problems inacute medicine 187 9 retro-orbital pain, clouding of the cornea, decreased visual acuity and, often, systemic upset. Temporal headaches in patients over 60 should prompt examination for enlarged or tender temporal arteries and palpa- tion of temporal pulses (often absent in temporal arteritis). Visual acuity should be assessed promptly, as visual loss is an important complication of temporal arteritis. Initial investigations If there is any alteration of conscious level, focal neurological signs, new-onset seizures or a history of head injury, then CT scanning of the head is indicated. The urgency of scanning will depend on the clinical picture and trajectory but in many circumstances will be immediately 9.14 ‘Red ag’ symptoms in headache Symptom Possible explanation Sudden onset (maximal immediately or within 5min) Subarachnoid haemorrhage Cerebral venous sinus thrombosis Pituitary apoplexy Meningitis Focal neurological symptoms (other than for typically migrainous) Intracranial mass lesion: Vascular Neoplastic Infection Constitutional symptoms: Weight loss General malaise Pyrexia Meningism Rash Meningitis Encephalitis Neoplasm (lymphoma or metastases) Inammation (vasculitis) Raised intracranial pressure (worse on waking/lying down, associated vomiting) Intracranial mass lesion New-onset aged >60 years Temporal arteritis 9.15 Identification of bacterial meningitis In patients presenting with headache, identication of those with bacterial meningitis is a top priority to facilitate rapid antibiotic treatment. In almost all cases there will be one of the following features: meningism (neck stiffness, photophobia, positive Kernig's sign) fever >38°C signs of shock (tachycardia, hypotension, elevated serum lactate) rash (not always petechial). Hello, Mr XXX. Can you open your eyes, please? Score best eyes/ motor/verbal response Trapezius pinch Score response looking at arms for localisation/ flexion/abnormal flexion Pressure on supra-orbital ridge Score response Firm nail-bed pressure Score if withdrawal present or any eye/verbal response No response No response No response Fig. 9.5 Assessment of the Glasgow Coma Scale (GCS) score in an obtunded patient. Avoid using a sternal rub, as it causes bruising. tends to be worse in the morning and when lying at or coughing, and associated with nausea and/or vomiting. A description of neck stiffness along with headache and photophobia should raise the suspicion of meningitis (Box 9.15), although this may present in atypical ways in immunosuppressed, alcoholic or pregnant patients. The behaviour of the patient during headache is often instruc- tive; migraine patients typically retire to bed to sleep in a dark room, whereas cluster headache often induces agitated and restless behaviour. The pain of a subarachnoid haemorrhage frequently causes signicant distress. Headache duration is also important to elicit; headaches that have been present for months or years are almost never sinister, whereas new-onset headache, especially in older adults, is more of a concern. In a patient over 60 years with head pain localised to one or both temples, scalp tenderness or jaw claudication, temporal arteritis (Ch. 26) should be considered. Clinical assessment An assessment of conscious level (using the Glasgow Coma Scale (GCS); Fig. 9.5) should be performed early and constantly reassessed. A decreased conscious level suggests raised ICP and urgent CT scan- ning (with airway protection if necessary) is indicated. A full neurological examination may provide clues as to the pathology involved; for example, brainstem signs in the context of acute-onset occipital headache may indicate vertebrobasilar dissection. Neurological signs may, however, be ‘falsely localising’, as in large subarachnoid haemorrhage or bacte- rial meningitis. Care should be taken to examine for other evidence of meningitis such as a rash (not always petechial), fever or signs of shock. Unilateral headache with agitation, ipsilateral lacrimation, facial sweat- ing and conjunctival injection is typical of cluster headache. Conjunctival injection may also be seen in acute glaucoma, accompanied by peri- or
- 220. 188 ACUTEMEDICINE AND CRITICAL ILLNESS required. Intracranial haemorrhage or a space-occupying lesion with mass effect should prompt urgent neurosurgical referral. If bacterial men- ingitis is suspected (see Box 9.15), cerebrospinal uid (CSF) analysis is required to make a denite diagnosis. Antibiotics should not be delayed for lumbar puncture (LP), which needs to be preceded by CT scanning only if raised ICP is suspected. In cases of thunderclap headache (peak intensity within 5 minutes and lasting over an hour), a normal CT scan should be followed by an LP performed more than 12 hours after head- ache onset, to look for evidence of xanthochromia. A negative CT scan within 6 hours of headache onset has a high degree of sensitivity for detecting subarachnoid blood. In such cases, a discussion of risks and benets with the patient may conclude that an LP is not necessary to exclude subarachnoid haemorrhage, although a CT angiogram may be considered to exclude other pathology, such as arterial dissection. Many headaches require prompt involvement of specialists. Features of acute glaucoma, for example, require immediate ophthalmological review for measurement of intraocular pressures. Suspected temporal arteritis with an erythrocyte sedimentation rate (ESR) of >50mm/hr should prompt immediate glucocorticoid therapy and rheumatological referral (see Ch. 26 for management). Features of raised ICP in the absence of a mass lesion on neuroimaging may indicate idiopathic intracranial hyper- tension; CSF opening pressure is likely to be informative. Unilateral leg swelling Most leg swelling is caused by oedema, the accumulation of uid within the interstitial space. There are three explanatory mechanisms for devel- opment of oedema, which are described in Box 9.16. Unilateral swelling usually indicates a localised pathology in either the venous or the lym- phatic system, while bilateral oedema often represents generalised uid overload combined with the effects of gravity. However, all causes of unilateral leg swelling may present bilaterally, and generalised uid over- load may present with asymmetrical (and therefore apparently unilateral) oedema. Fluid overload may be the result of cardiac failure, pulmonary hypertension (even in the absence of right ventricular failure), renal failure, hypoalbuminaemia or drugs (calcium channel blockers, glucocorticoids, mineralocorticoids, non-steroidal anti-inammatory drugs (NSAIDs) and others); see Box 16.14 for other causes. The remainder of this section focuses on the causes of ‘unilateral’ oedema. Presentation Any patient who presents with unilateral leg swelling should be assessed with the possibility of deep vein thrombosis (DVT) in mind. The pain and swelling of a DVT is often fairly gradual in onset, over hours or even days. Sudden-onset pain in the posterior aspect of the leg is more consistent with gastrocnemius muscle tear (which may be traumatic or spontane- ous) or a ruptured Baker's cyst. Leg swelling and pain associated with paraesthesia or paresis, or in the context of lower limb injury or reduced conscious level, should always prompt concern regarding the possibility of compartment syndrome (Box 9.17). Clinical assessment Lower limb DVT characteristically starts in the distal veins, causing an increase in temperature of the limb and dilatation of the supercial veins. Often, however, symptoms and signs are minimal. Cellulitis is usually characterised by erythema and skin warmth local- ised to a well-demarcated area of the leg and may be associated with an obvious source of entry of infection (e.g. leg ulcer or insect bite). The patient may be febrile and systemically unwell. Supercial thrombophle- bitis is more localised; erythema and tenderness occur along the course of a rm, palpable vein. Examination of any patient presenting with leg swelling should include assessment for malignancy (evidence of weight loss, a palpable mass or lymphadenopathy). Malignancy is a risk factor for DVT, but pelvic or lower abdominal masses can also produce leg swelling by compress- ing the pelvic veins or lymphatics. Early lymphoedema is indistinguish- able from other causes of oedema. More chronic lymphoedema is rm and non-pitting, often with thickening of the overlying skin, which may develop a ‘cobblestone’ appearance. Chronic venous insufciency is a cause of long-standing oedema that, particularly when combined with another cause of leg swelling, may acutely worsen. Characteristic skin changes (haemosiderin depo- sition, hair loss, varicose eczema, ulceration) and prominent varicosities are common, and sometimes cause diagnostic confusion with cellulitis. See Box 9.17 for the examination ndings associated with compartment syndrome. Initial investigations Factors predisposing to venous thromboembolism are covered in detail in Chapter 25. Clinical criteria can be used to rank patients according to their likelihood of DVT, by using scoring systems that determine pre-test probability (see Ch. 1), such as the Wells score (Box 9.18). Figure 9.6 gives an algorithm for investigation of suspected DVT based on initial Wells score. In patients with a low (‘unlikely’) pre-test probability of DVT, D-dimer levels can be measured; if these are normal, further investiga- tion for DVT is unnecessary. Further information on the interpretation of D-dimer is given in Box 9.19. In those with a moderate or high (‘likely’) probability of DVT or with elevated D-dimer levels, objective diagnosis of DVT should be obtained using appropriate imaging, usually a Doppler ultrasound scan. Therefore, in the same way as for pulmonary embo- lus, the investigative pathway for DVT differs according to the pre-test probability of DVT. For low-probability DVT, the negative predictive value of the D-dimer test (the most important parameter in this context) is over 99%; if the test is negative, the clinician can discharge the patient with condence. In patients with a high probability of DVT, the negative predictive value of a D-dimer test falls to somewhere in the region of 97%–98%. While this may initially appear to be a high gure, to discharge 2 or 3 patients in every 100 incorrectly would generally be considered an unacceptable error rate. Hence, with the exception of pregnancy (Box 9.20), a combination of clinical probability and blood test results should be used in the diagnosis of DVT. If cellulitis is suspected, serum inammatory markers, skin swabs and blood cultures should be sent, ideally before antibiotics are given. Ruptured Baker's cyst and calf muscle tear can both be readily diag- nosed on ultrasound. If pelvic or lower abdominal malignancy is sus- pected, a prostate-specic antigen (PSA) level should be measured in males and appropriate imaging with ultrasound (transabdominal or trans- vaginal) or CT should be undertaken. 9.16 Mechanisms of oedema There are three explanatory mechanisms for the development of oedema that may occur in isolation or combination: increased hydrostatic pressure in the venous system due to increased intravascular volume or venous obstruction decreased oncotic pressure secondary to a decrease in the plasma proteins that retain uid within the circulation obstruction to lymphatic drainage (‘lymphoedema’). 9.17 Identification of compartment syndrome Compartment syndrome classically occurs following extrinsic compression of a limb due to trauma or reduced conscious level (especially when caused by drugs or alcohol). It usually presents with a tense, rm and exquisitely painful limb. The pain is characteristically exacerbated by passive muscle stretching or squeezing the compartment. Altered sensation may be evident distally. Absent peripheral pulses are a late sign and their presence does not exclude the diagnosis. Clinical suspicion of compartment syndrome should prompt measurement of creatine kinase and urgent surgical review.
- 221. Presenting problems inacute medicine 189 9 it becomes localised. Movement exacerbates the pain; abdominal rigidity and guarding occur. Perforation. When a viscus perforates, pain starts abruptly; it is severe and leads to generalised peritonitis. Obstruction. Pain is colicky, with spasms that cause the patient to writhe around and double up. Colicky pain that does not disappear between spasms suggests complicating inammation. Ischaemia. Signs are variable; pain may come on acutely or more gradually and the abdomen can be soft or rigid. A raised venous lactate is usually only a late sign once hepatic lactate clearance is overwhelmed (see Fig. 9.14). Clinical assessment If there are signs of peritonitis (guarding and rebound tenderness with rigidity), the patient should be resuscitated with titrated oxygen, intrave- nous uids and antibiotics; urgent surgical input is required. In other cir- cumstances, further investigations may be necessary, as detailed below (Fig. 9.7). Initial investigations Patients should have a full blood count, urea and electrolytes, glucose and amylase taken to look for evidence of dehydration, leucocytosis and 9.18 Predicting the pre-test probability of deep vein thrombosis (DVT) using the Wells score* Clinical characteristic Score Previous documented DVT 1 Active cancer (patient receiving treatment for cancer within previous 6 months or currently receiving palliative treatment) 1 Paralysis, paresis or recent plaster immobilisation of lower extremities 1 Recently bedridden for ≥3 days, or major surgery within previous 12 weeks 1 Localised tenderness along distribution of deep venous system 1 Entire leg swollen 1 Calf swelling at least 3cm larger than that on asymptomatic side (measured 10cm below tibial tuberosity) 1 Pitting oedema conned to symptomatic leg 1 Collateral supercial veins (non-varicose) 1 Alternative diagnosis at least as likely as DVT –2 Clinical probability Total score DVT low probability <1 DVT moderate probability 1–2 DVT high probability >2 *A dichotomised revised Wells score, which classies patients as ‘unlikely’ or ‘likely’, may also be used. From Wells PS. Evaluation of D-dimer in the diagnosis of suspected deep vein thrombosis. N Engl J Med 2003; 349:1227; copyright © 2003 Massachusetts Medical Society. Pre-test probability (see Box 9.18) Low D-dimer ve D-dimer +ve +ve +ve ve ve Probability low, or moderate with ve D-dimer Probability high, or moderate with +ve D-dimer Repeat compression ultrasound in 7 days Treat Exclude Compression ultrasound Moderate or high Fig. 9.6 Investigation of suspected deep vein thrombosis. Pre-test probability is calculated in Box 9.18. See also page 10. 9.19 D-dimer D-dimers are specic cross-linked brin degradation products which are small protein fragments present in blood after a blood clot is degraded by brinolysis. D-dimers are present in human blood when the coagulation system has been activated, usually because of the presence of thrombosis, disseminated intravascular coagulation or venom-induced consumptive coagulopathy. As the sensitivity of D-dimer decreases with time, it should not be used in the assessment of patients who present with symptoms for 7 days or more. D-dimer increases with age; for patients aged over 50 years with suspected venous thromboembolism (VTE), a cut-off equal to the patient’s age in years × 10µg/L (or × 0.056nmol/L) has therefore been proposed. Although their safety is still being evaluated, age-adjusted D-dimers appear to decrease the false-positive rate without substantially increasing the false- negative rate 9.20 Swollen legs in pregnancy Benign swollen legs: common in pregnancy; this is usually benign. DVT: pregnancy is a signicant risk factor; however D-dimer: should not be measured in pregnancy; it has not been validated in this group. Imaging: should be arranged on the basis of clinical suspicion alone, and the threshold for undertaking a denite diagnostic test should be low. 9.21 Causes of acute abdominal pain Inflammation Appendicitis Diverticulitis Cholecystitis Pelvic inammatory disease Pancreatitis Pyelonephritis Intra-abdominal abscess Perforation/rupture Peptic ulcer Diverticular disease Ovarian cyst Aortic aneurysm Obstruction Intestinal obstruction Biliary colic Ureteric colic Other (rare) See Box 23.22 Acute abdomen The acute abdomen accounts for approximately 50% of all urgent admis- sions to general surgical units, but a signicant proportion of patients present via acute medicine. Presentation The acute abdomen is a consequence of one or more of the following pathological processes (Box 9.21): Inammation. Pain develops gradually, usually over several hours. It is initially rather diffuse until the parietal peritoneum is involved, when
- 222. 190 ACUTEMEDICINE AND CRITICAL ILLNESS Symptoms and signs of peritonitis Resuscitation Pain No clear evidence of peritonitis Blood tests ↑ Amylase/lipase Acute pancreatitis Free air Perforation Dilated loops of bowel Intestinal obstruction/ileus Gallstones and thickened gallbladder wall Cholecystitis Pseudo-obstruction CT scan Pancreatitis Abscess Aortic aneurysm Malignancy Erect chest X-ray Abdominal X-ray Ultrasound Contrast radiology Abnormality detected Abnormality detected Perforation Inconclusive investigations No diagnosis No free air No abnormality No abnormality No abnormality No abnormality Symptoms persist Symptoms settle Laparotomy Laparoscopy Observe Fig. 9.7 Management of acute abdominal pain: an algorithm. pancreatitis. Urinalysis is useful in suspected renal colic and pyelone- phritis. An erect chest X-ray may show air under the diaphragm, sug- gestive of perforation, and a plain abdominal lm may show evidence of obstruction or ileus (see Fig. 23.11). An abdominal ultrasound may help in identifying gallstones, renal stones, free uid or an intra-abdominal abscess. Abdominal CT scanning is the most useful investigation, and is essential in differentiating pseudo-obstruction and mechanical large bowel obstruction. Concerns regarding contrast-induced nephropathy should be secondary to the imperative to reach an early diagnosis. CT may also be useful to seek evidence of pancreatitis, retroperitoneal col- lections or masses, including aortic aneurysm. Diagnostic laparotomy should be considered when the diagnosis has not been revealed by other investigations. All patients must be carefully and regularly reassessed (every 2–4 hours) so that any change in condi- tion that might alter both the suspected diagnosis and clinical decision can be observed and acted on early. Management The general approach is to close perforations, treat inammatory condi- tions with antibiotics or resection, and relieve obstructions. Aspiration of gastric contents is a major risk in all acute abdominal conditions, espe- cially intestinal obstruction. This occurs once the laryngeal reexes are overwhelmed by the volume of regurgitated material, and is particularly common in frailer individuals or where there is a coexisting reduction in conscious level. The placement of a large-bore nasogastric tube should therefore be considered whenever bowel obstruction is suspected. The speed of intervention and the necessity for surgery depend upon vari- ous factors, of which the presence of peritonitis is the most pertinent. A treatment summary of some of the more common surgical conditions follows: Acute appendicitis: This should be treated by early surgery, since there is a risk of perforation and recurrent attacks with non-operative treatment. The appendix can be removed through a conventional right iliac fossa skin crease incision or by laparoscopic techniques. Acute cholecystitis: This can be successfully treated non-operatively but the high risk of recurrent attacks and the low morbidity of sur- gery have made early laparoscopic cholecystectomy the treatment of choice unless there are other considerations (such as pregnancy). Acute diverticulitis: Conservative therapy is standard, but if perfora- tion has occurred, resection is advisable. Depending on peritoneal contamination and the degree of shock (risk of anastomotic leak correlates with severity of shock), primary anastomosis is pref- erable to a Hartmann's procedure (oversew of rectal stump and end-colostomy). Small bowel obstruction: If the cause is obvious and surgery inevita- ble (such as with a strangulated hernia), an early operation is appro- priate. If the suspected cause is adhesions from previous surgery, only those patients who do not resolve within the rst 48 hours or who develop signs of strangulation (colicky pain becoming constant, peritonitis, tachycardia, fever, leucocytosis) should have surgery. Large bowel obstruction: Pseudo-obstruction should be treated non-operatively. Some patients benet from colonoscopic decom- pression, but mechanical obstruction merits resection, usually with a primary anastomosis. Differentiation between the two can be made by water-soluble contrast enema.
- 223. Common presentations ofdeterioration 191 9 Mesenteric ischaemia: This can be due to an arterial or venous throm- bosis, or a structural abnormality of the gut such as a volvulus. Early surgery can be successful in revascularisation of the gut or removing ischaemic tissue, although acute mesenteric arterial thrombosis has a poor prognosis, especially when the diagnosis is delayed. Acute pancreatitis: CT scanning can be useful to rule out other pathologies that may be amenable to operative management (e.g. ret- roperitoneal perforation), but is not essential in the early management of the disease. Management is usually conservative, and the majority of patients will improve. A minority will develop pancreatic necro- sis that will require prolonged supportive care and organ support. Antibiotics are not usually indicated in the early phase of the disease. Perforated peptic ulcer: Surgical closure of the perforation is stand- ard practice, but some patients without generalised peritonitis can be treated non-operatively once a water-soluble contrast meal has conrmed spontaneous sealing of the perforation. Adequate and aggressive resuscitation with intravenous uids, antibiotics and anal- gesia is mandatory before surgery. For a more detailed discussion of acute abdominal pain, the reader is referred to the companion volume of this text, Principles and Practice of Surgery Identification and assessment of deterioration Early warning scores and the role of the medical emergency team There are many systems that have been developed with the aim of rapidly identifying and managing physiological deterioration. These are referred to as ‘rapid response systems’. One popular example of a rapid response system is a medical emergency team (MET). A MET system operates on the basis that when a patient meets certain physiological criteria, the team is alerted. The team is expected to make a rapid assessment and institute immediate management. This may include escalation to critical care or, fol- lowing liaison with the parent clinical team, ongoing ward-based care. The trigger for a ‘MET’ call may be a single parameter – such as a low BP or tachycardia – or may consist of a composite early warning score. Early warning score systems function by the observer allocating a value between 0 and 3 for abnormalities in respiratory rate, SpO2 , tempera- ture, BP, heart rate and neurological response (Fig. 9.8). The values are summed and the composite score gives an indication of the severity of physiological derangement. Early warning systems can be automated into an electronic format that calculates the score and even alerts the responsible clinician(s) by email or text message. There are advantages and disadvantages to having a separate MET system, compared with allowing the responsible clinical team to manage deterioration, and to having a composite score or a single parameter detection system. These are outlined in Box 9.22 Immediate assessment of the deteriorating patient An approach to assessment of the deteriorating patient can be summa- rised by the mnemonic ‘C-A-B-C-D-E’. C – Control of obvious problem For example, if the patient has ventricular tachycardia on the monitor or signicant blood loss is apparent, immediate action is required. A and B – Airway and breathing If the patient is talking in full sentences, then the airway is clear and breathing is adequate. A rapid history should be obtained while the initial assessment is undertaken. Breathing should be assessed with a focused respiratory examination. Oxygen saturations and ABGs should be checked early (p. 194). C – Circulation A focused cardiovascular examination should include heart rate and rhythm, blood pressure, jugular venous pressure, evidence of bleeding, signs of shock and abnormal heart sounds. The carotid pulse should be palpated in the collapsed or unconscious patient, but peripheral pulses also should be checked in conscious patients. The radial, brachial, foot and femoral pulses may disappear as shock progresses, and this indi- cates the severity of circulatory compromise. D – Disability Conscious level should be assessed using the GCS (see Fig. 9.5 and Box 9.29). A brief neurological examination looking for focal signs should be performed. Capillary blood glucose should always be measured to exclude hypoglycaemia or severe hyperglycaemia. E – Exposure and evidence ‘Exposure’ indicates the need for targeted clinical examination of the remaining body systems, particularly the abdomen and lower limbs. ‘Evidence’ may be gathered via a collateral history from other health-care professionals or family members, recent investigations, prescriptions or monitoring charts. Selecting the appropriate location for ongoing management and anticipatory care planning Two groups of patients frequently gain benet from admission to criti- cal care: those with organ dysfunction severe enough to require organ support and those in whom the disease process is clearly setting them on a downward trajectory and in whom early, aggressive manage- ment may alter the outcome. Whether an individual patient should be admitted to the intensive care or high-dependency unit (ICU/HDU) will depend on local arrangements. A useful tool to assist with the decision regarding location is the ‘level of care’ required (Box 9.23). Many inten- sive care units are a mix of level 2 and level 3 beds, which streamlines the admission process. When a patient requires admission with a sus- pected transmissible disease that poses a risk to other patients and staff, the patient should be admitted to an isolated room located within an appropriate area of the hospital that can provide an appropriate level of care. Anticipatory care planning (ACP) refers to the process of decision-mak- ing relating to treatments or support that would be appropriate if a patient’s condition was to deteriorate. Admission can be a valuable opportunity for discussion with the patient and family members/carers about the appro- priate ‘ceiling of care’; for example, would resuscitation in the event of a cardiac arrest and/or admission to a critical care area be appropriate. Such discussions may result in the placement of a ‘do not resuscitate order’ and a decision that ‘ward-level’ care may be the ‘ceiling’ for that individual. It is important that discussions and decisions are clearly documented in the patient record. Further details of ACP decision-making are found on page 206. Common presentations of deterioration As patients become critically unwell, they usually manifest physiological derangement. The principle underpinning critical care is the simultane- ous assessment of illness severity and the stabilisation of life-threatening physiological abnormalities. The goal is to prevent deterioration and
- 224. 192 ACUTEMEDICINE AND CRITICAL ILLNESS Full Name NEWS key A+B 0 1 2 3 Date of Birth A+B C C D E SpO2 Scale 2† Oxygen saturation (%) Date Time ≥25 21–24 18–20 15–17 12–14 9–11 ≤8 Date of Admission 3 2 1 1 1 2 2 3 1 2 2 3 1 2 3 1 2 1 1 3 3 3 2 1 3 3 3 3 ≥25 21–24 18–20 15–17 12–14 9–11 ≤8 ≥97 on O2 95–96 on O2 93–94 on O2 ≥93 on air 88–92 86–87 84–85 ≤83% ≥220 201–219 181–200 161–180 141–160 121–140 111–120 101–110 91–100 81–90 71–80 61–70 51–60 ≤50 ≥131 121–130 111–120 101–110 91–100 81–90 71–80 61–70 51–60 41–50 31–40 ≤30 ≥131 121–130 111–120 101–110 91–100 81–90 71–80 61–70 51–60 41–50 31–40 ≤30 ≥220 201–219 181–200 161–180 141–160 121–140 111–120 1