FEVER

A Clinical Approach
By

Assisstant Prof.
Dr. Elzahraa Mohammed Megheizel
 What we should learn in this
lecture?
• What is Tropical Medicine
• Definition of fever, patterns of fever
• How to measure body temperature?
• Pathogenesis and causes of fever
• Types of pyrogens
• Mechanism of action of antipyretics
• Definition and causes of PUO
• Diagnostic approach of PUO
 What is Tropical Medicine?
• It is an interdisciplinary branch of medicine
that deals with health issues that occur
uniquely, are more widespread, or are
more difficult to control in tropical
and .subtropical regions
The Father of Tropical Medicine

• Sir Patrick Manson

is recognized as
the ‘Father of
Tropical Medicine’.
He founded the
London School of
Tropical Medicine
& Hygiene in 1899.
 Fever (pyrexia)

• Raised core body temperature due to an

alteration in the heat regulating
mechanisms resulting in body temperature
being set at a level higher than normal.
What is the normal body
temperature? and how to
measure?
• Normal temperarure ranges from:
36.6ºC to 37.2ºC.
• Body temperature measured by medical
thermometer.
• The thermometer must be left for about
1-2 minutes.
• You could put the thermometer
- in the mouth under the tongue
- in the axilla (add 0.5 degree)
- in the rectum ( subtract 0.5 degree)
• Fever is a useful marker of inflammation:
usually the height of fever reflects the
severity of the inflammatory process.
pathophysiology
 Heat production
Heat production is a principal by-product of
metabolism. The rate of heat production is
determined by
Basal metabolic rate of all the cells of the body
Extra rate of metabolism caused by muscle activity,
thyroxin,epinephrin, NE
and sympathetic stimulation on the cells
Extra metabolism caused by increased chemical
activity in the cells themselves, especially when the
cell temperature increases.
 Pathogenesis of Fever

• Core body temperature (the temperature of blood in

the right atrium) is determined by two opposing
processes, each of which is determined by the CNS.
• Energy (heat) is generated by living tissues
(thermogenesis). It may be passively absorbed from
the environment as well.
• Energy is lost to the environment, chiefly through the
emission of infrared radiation and through transfer of
energy to a surrounding medium (conduction,
convection and evaporation)
 Types of pyrogens
• exogenous pyrogens:
endotoxins ( high molecular weight, heat
stable, act after a latent period).
• Endogenous pyrogens:
leucocytic pyrogens (heat labile, act on the
centre for thermoregulation).
• Un-identified muscle cell pyrogens:
unknown chemicals ( explain pyrexia of
collegen D., myocardial infarction, and non
infective diseases.
 Fever
• Pyrogens

Elevated set-point

Maintaining an abnormally elevated Temperature

BMR(basal metabolic rate) increases

T  = Elevated set-point
 Causes of fever
• Physiologic causes: after meals, vigorous exercise,
hot bath, pregnancy,during ovulation and hot weather.
• Infections.
• Immune reaction e.g. collagen diseases.
• Inflammation e.g. gout.
• Endocrinal e.g. thyrotoxicosis.
• Tissue damage e.g. myocardial infarction.
• Tumours, lymphomas, leukaemias
• Toxins e.g. drugs.
 Terminology of abnormal variation
• Abnormally high:
Ø 37.3ºC- 38ºC low grade
Ø 38.1ºC - 39ºC moderate grade
Ø 39.1ºC - 40ºC high grade
Ø > 40ºC hyperpyrexia
• Abnormally low:
Ø 36.5ºC subnormal
Ø 36ºC hypothermia
Ø 35.5ºC collapse
 Hyperthermia
Ø fever due to a disturbance of thermal regulatory
control

• excessive heat production

(e.g. vigorous exercise, a reaction to some
anesthetics)
• decreased dissipation (e.g. dehydration)
• loss of regulation
(injury to the hypothalamic regulatory center)
 Causes of hyperpyrexia
(hyperthermia)
• Heat stroke .
• Encephalitis.
• Pontine Hge.
• Status epilepticus.
• Thyrotoxic crisis.
• Trauma to the region of hypothalamus.

• Drugs e.g. halothane(malignant hyperthermia),

phenothiazines (neuroleptic malignat syndrome).
 Causes of hypothermia
• Shock.
• Hypothyroid coma.
• Panhypopituitarism.
• Starvation.
• Chronic depilating disease.
• Damage to the anterior hypothalamus.
• Hypoglycemia
• Drugs (e.g. alcohol)
Patterns of fever
 continuous
Temp. variation does not
exceed 1ºC

e.g. 2nd week of typhoid fever

Meningitis
 Remittent
Temp. variation more than 1ºC,
not reach base line.

e.g. Pus under tension

Septicaemia
empyema
 Hectic
Temp. variation more than 1ºC, not
reach base line, ossilation is very
large.
 Intermittent
Temp. variation more than 1ºC, and
reach base line
Quotidian (24h): rise every day
Tertian (48h): rise every other day (P. vivax, P.
ovale)
Quartan (72): rise every two day (P. malariae)

Double quotidian : 2 rises and falls in 24hs.

e.g. kala azar, T.B.
 Relapsing
(Undulant)
Bouts of pyrexia separated by
bouts of normal or subnormal
temp. for days
e.g. Pel-Ebstein fever (lymphoma)
Brucellosis
 Saddle
back
2 peaks separated by less rise
for about 3 days
e.g. Dengue fever
 Onset of pyrexia
• Gradual over days e.g. tyophoid fever,
whooping cough.
• Gradual of a shorter period e.g. measles,
diphtheria.
• Sudden (associated with rigors), usually
of high grade e.g. influenza, pneumonia,
scarlet fever.
• Re-increase after subsidence of fever
usually points to relapse
 Offset of pyrexia

• Lysis:
gradual e.g. typhoid

• Crisis:
sudden e.g. pneumonia

• Premature drop may be due to

complications
Symptoms common with febrile
diseases:
• Anorexia
• Malaise
• Myalgias
• headache
• nausea and vomiting
• dry coated tongue
• oligurea with concentrated urine
• impaired physical and mental activities.
• Most febrile patients have pain, tenderness,
redness, swelling at the site of inflammation
and the cause of fever is readily identified.
 Complication of fever
• Severe dehydration

• Hallucinations

• Fever-induced seizure (febrile seizure), in a

small number of children ages 6 months to 5
years, usually involve loss of consciousness
and shaking of limbs on both sides of the
body.
 APPROACH TO FEVER
• Personal History:
– Age
– Occupation
– Place of origin, Travel History
– Habits
• Consumption of Unpasteurized Dairy Products
• Injection Drug Abuse
• Excessive Alcohol Use
• Underlying Diseases:
– Splenectomy
– Surgical Implantation of Prosthesis
– Immunodeficiency
– Chronic Diseases:
• Cirrhosis
• Chronic Heart Diseases
• Chronic Lung Diseases
• Drug History:
– Antipyretics
– Immunosuppressant
– Antibiotics
• Family History:
– TB in the Family
– Recent Infection in the Family
• Associated Symptoms:
– Shaking chills
– Ear pain,Ear drainage,Hearing loss
– Visual and Eye Symptoms
– Sore Throat
– Chest and Pulmonary Symptoms
– Abdominal Symptoms
– Back pain, Joint or Skeletal pain
 Course and patterns of pyrexia
• The fever pattern is determined by a
temperature chart in which body
temperature measures 4 times daily is
plotted against the days
• Physical Examination:
– Vital Signs

– Neurological Exam.

– Skin Lesions,Mucous Membrane

– Eyes

– ENT

– Lymphadenopathy

– Lungs and Heart

– Abdominal Region (Hepatomegaly,Splenomegaly)

– Musculoskeletal
 LABORATORY STUDY
IN PATIENT WITH FEBRILE ILLNESS
• Assess the extent and severity of the
inflammatory response to infection

• Determine the site(s) and complications of

organ involvement by the process

• Determine the etiology of the infectious

disease
 Treatment of fever
• Try water bath; remove blankets and
heavy clothing; keep room at comfortable
temp

• Antipyretics

• Management of the cause

 Mechanism of action of antipyretics
• Non-steroidal antipyretic agents (NSAIDs) inhibit
fever by blocking the synthesis of prostaglandins
within the endothelium of the hypothalamus through
inhibition of the cyclo-oxygenase. However, they do
not diminish the elaboration of endogenous
pyrogens.

• Glucocorticoid hormones directly impede the

production of endogenous pyrogens by
phagocytes. Cytokine synthesis is inhibited at more
than one level.
Fever presentations
(associations)
 Fever presenting by headache
• Meningitit, encephalitis, and meningeal
irritation (occipital and severe)
• Influenza and common cold.
• Typhoid fever (usually frontal dull
aching).
• Rift valley fever and dengue fever.
• Malaria.
 Fever presenting by chills or rigors
ØC h i l l s i s s e n s a t i o n o f c o l d n e s s , a n d
accompany marked rise of temp. in any fever.

ØRigors is tonic contraction of the muscles

with shaking and stucking of teeth, and it
usually accompanied by intermittent type of
fever.
ØRigors are found in:
• Malaria.
• Influenza.
• Urinary tract infection.
• Pus under tension.
• Pyaemia and septicaemia.
• After antipyeritcs
• I.V. fluids containing pyrogens.
• Any fever of sudden onset especially in
infant.
ØRigors are repeated in special fevers:
• Malaria (regular rigors).
• Pyelitis.
• Septicaemia.
• SBE.
• Acute milliary TB.
• Charcot’s intermittent fever.
• Closed abscess under tension.
Ø NB. When rigors occur in diseases not
known to cause rigors, it indicates
complications e.g.:

• With hydrothorax indicates extension

pyothorax.

• With valvular Ht. diseases indicates SBE.

ØRegular rigors of malaria can be
differentiated from irregular rigors by its
characteristic 4 stages:
• Cold stage 15 minutes.
• Rigors 15-30 minutes.
• Hot stage 15-30 minutes.
• Defervescence or sweating stage
(prostration and weakness).
30 minutes.
Ø Afebrile rigors:
• Blood transfusion.

• I.V. fluid therapy.

• Catheterization.
Pyrexia Of Unknown
Origin
(PUO)
 Definition
• Fever > 38.3 on several occasions

• It is a fever of more than three weeks with no

evident cause detected after doing the usual
investigations including chest x-ray. Most of
these cases are due to a common disorder with
an unusual presentation

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 New definition
Ø includes the outpatient setting (which reflects
current medical practice) is broader, stipulating:

• 3 outpatient visits or

• 3 days in the hospital without elucidation of a cause

or

• 1 week of "intelligent and invasive" ambulatory

investigation
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 Potential Etiologies

ØBased on patient population

• Classical

• Immunodeficient (Neutropenic)

• Nosocomial

• HIV related

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 Classic FUO
• This refers to the original classification

Ø there are five categories of conditions

• infections (e.g. abscesses, endocarditis,

tuberculosis, and complicated urinary tract
infections),

• neoplasms (e.g. lymphomas, leukaemias),

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• connective tissue diseases (e.g. temporal
arteritis and polymyalgia rheumatica, Still's
disease, systemic lupus erythematosus,
and rheumatoid arthritis),

• miscellaneous disorders (e.g. alcoholic

hepatitis, granulomatous conditions), and
undiagnosed conditions.

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 Categories of Illness Causing PUO

Infections 30 - 40 %

Malignancies 20 – 25 %

Collagen Vascular Disease 10 – 20 %

Miscellaneous 15 – 20 %

Undiagnosed 10 – 15 %
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 Infections
• Tuberculosis • Mononucleosis
(especially (EBV & CMV)
extrapulmonary) • Systemic viral
syndrome
• Abdominal
• Urinary tract
abscesses
infection
• Pelvic abscesses • Respiratory tract
• Dental abscesses infection
• Endocarditis • Bacterial
• Osteomyelitis meningitis
• Enteric infection
• Sinusitis
 Malignancies
• Chronic leukemia
• Lymphoma
• Metastatic cancers
• Myelodysplastic syndromes
• Pancreatic carcinoma
• Sarcomas
• Fever lasting > 1 yr
Malignancy } Decline in frequency
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Autoimmune (collagen vascular disease)

• Rheumatoid arthritis
• Rheumatoid fever
• Inflammatory bowel disease
• Reiter's syndrome
• Systemic lupus erythematosus
• Vasculitides
• Adult Still's disease
• Polymyalgia rheumatica
• Temporal arteritis
ed. 60
 Miscellaneous
• Drugs and nutritional supplements
• Hyperthyroidism
• Complications from cirrhosis
• Factitious fever
• Hepatitis (alcoholic, granulomatous, or
lupoid)
• Deep venous thrombosis
• Sarcoidosis
• Kawasaki disease 61
 Some important causes
• Extrapulmonary tuberculosis is the most
frequent cause of FUO
• Drug-induced hyperthermia, as an
adverse reaction to medication, should
always be considered (sulphonamides,
penicillin,..)
• Disseminated granulomatoses such as
Tuberculosis, Histoplasmosis,
Coccidioidomycosis, Blastomycosis and
Sarcoidosis
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• Lymphomas are common cause of FUO in
adults.
• Thromboembolic disease (i.e. pulmonary
embolism, deep venous thrombosis)
occasionally shows fever. Although infrequent,
its potentially lethal
• Others as familial Mediterranean fever, cyclic
neutropenia
• Endocarditis, although uncommon, is another
important etiology to consider.
• An underestimated reason is factitious fever.
Patients frequently are women that work, or
have worked, in the medical field and have
complex medical histories
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• Comprehensive history

• Repeated physical examinations

• Investigations

• Diagnostic trial

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 History
• Retake a detailed history
• Recent travel
• Exposure to pets and other animals
• Sexual history
• Work environment
• Contact with other people with similar
symptoms
• Family history
• Past medical history list of medications
– Include OTC
• Inspect the temperature chart for some
characteristic pattern
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 Physical Exam
• Re-examine the patient: new signs may
have appeared while others could have
been missed
• Skin
• Mucus membranes
• Lymphadenopathy
• Organomegaly
ØHospital admission: temperature chart,
temperature grade and pattern
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 Diagnosis

• A cost-effective individualized
approach is essential in the
evaluation of these patients to
prevent performing inappropriate
tests
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 Diagnostic Testing
Ø Review the results of laboratory
investigations and radiographs and
repeat if necessary.
• CBC
• LFTs
• ESR
• Urinalysis
• Blood cultures
• Further testing should be based on
abnormalities in the
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• PPD testing is inexpensive screening tool
that should be used on all FUO patients
that do not have a known positive reaction
• If initial testing is inconclusive- more
specific testing should be performed
based on clinical suspicion
• Serologies
• CT
• Ultrasounds
• MRI
• Nuclear Medicine Scans

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• Serological tests for IMN, CMV, Coxiella…..,
Widal and Malta should be repeated. Amoebic
and Toxoplasma serology may also be required.
• Blood , urine or other body fluid culture.
• Abdominal ultrsonography and CT
• Biopsy samples as liver, lymph node, peritoneal
or pleural biopsies
• Splenic aspirate is valuable in the diagnosis of
lymphomas or in cases of splenic focal lesions.
• Bone marrow aspirate for haematologic disorders
and malaria.
• Bone marrow culture is useful in typhoid
fever and brucellosis.
• Bone marrow biopsy is valuable in
dissiminated TB, Kala-azar, neoplastic
disorders
• Fundus examination may be useful in
Toxoplasmosis, sarcoidosi, TB
• Radiologic examination
• Exploratory laparotomy when an intra-
abdominal pathology is still suspected
• Chest radiograph
– Tuberculosis, malignancy, Pneumocystis
carinii pneumonia
• CT of abdomen or pelvis with contrast
agent
– Abscess, malignancy
• Gallium 67 scan
– Infection, malignancy
• Indium-labeled leukocytes
– Occult septicemia

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• Technetium Tc 99m
– Acute infection and inflammation of bones and
soft tissue
• MRI of brain
– Malignancy, autoimmune conditions
• PET scan
– Malignancy, inflammation
• Transthoracic or transesophageal
echocardiography
– Bacterial endocarditis
• Venous Doppler study
– Venous thrombosis
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 • Observation
Ø Therapeutic trial:
• In suspected cases of TB, a trial of anti-TB
drugs may be indicated
• In Malaria , a trial of anti-malarial drugs may
be given
• Empirical therapies are considered only for
the patient who is significantly compromised.
• Corticosteroid empirical therapy is
inappropriate
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 Case scenario
• A 40 years old worker presented to the
hospital feeling unwell, complaint of fever
since 1 month, associated with headache,
anorexia, malaise and myalgia, the patient
sought medical advice 3 times, he improved
for few day by antipyretics and empirical
antibiotics, and the fever recured again,
routine investigations was normal, done for
him 3 weeks ago, the patient not known to be
diabetic or hypertensive, and he has no
relevant past history
• What is the definition of PUO ?

• What is meant by “routine investigations” ?

• How could you determine the course and

pattern of fever ?

• Mention what is the symptoms and

complications associated with fever?

• What is your approach to diagnose this case ?