MALARIA

Preamble

 Malaria is the most important parasitic disease

of humans
 It is the cause of 30-40% of all outpatient
hospital attendance in Africa
 It is responsible for about 25% of all childhood
deaths
Preamble

 Although respiratory disease also accounts for

about 25% of all childhood deaths
 Malaria is the most important single infectious
agent causing death in young children
 Repeated episodes of fever and illness reduce
appetite and restrict play, social interaction and
educational opportunities, thereby contributing
to poor development.
Preamble

 Malaria transmission is intense and stable in

Nigeria
 Malaria related economic losses in Nigeria has
been estimated to be about 132 billion Naira
 In Nigeria and rest of endemic Africa, the bulk
of malaria episodes are attributable to P.
falciparum
Life cycle Plasmodium
 In humans life cycle starts with inoculation of
sporozoites
 These disappears into the hepatocytes within 30-60
minutes
 Development in the liver requires about 7-14 days
*

 The mature schizonts releases merozoites into blood

stream when erythrocytic stage begins
 The erythrocytic stage takes about 36-48 hours for P.
falciparum, P.vivax and P. ovale (and 72h for malariae)
* ovale and vivax have hypnozoites
Malaria Life Sporogony
Cycle Oocyst

Life Cycle Sporozoites

Mosquito Salivary
Zygote Gland

Hypnozoites
Exo- (for P. vivax
and P. ovale)
erythrocytic
(hepatic) cycle
Gametocytes

Erythrocytic
Cycle

Schizogony
 Malaria Transmission Cycle
Exo-erythrocytic (hepatic) Cycle:
Sporozoires injected Sporozoites infect liver cells and
into human host during develop into schizonts, which release
blood meal merozoites into the blood

Parasites
mature in
mosquito
midgut and Dormant liver stages
MOSQUITO HUMAN
migrate to (hypnozoites) of P.
salivary vivax and P. ovale
glands

Erythrocytic Cycle:
Merozoites infect red
blood cells to form
Some merozoites schizonts
Parasite undergoes
sexual reproduction in differentiate into male or
the mosquito female gametocyctes
Life cycle Plasmodium

In the mosquito genus Anopheles:

 Life cycle begins with the fusion of ingested
gametocytes
 The formation of zygote and O Ökinette occurs
in the intestinal wall
 OÖcyst subsequently undergoes nuclear
fission to produce sporozoites ( an average of 7 days is
required)
Presentation

May be:
 Acute uncomplicated: = acute febrile illness
 Severe/complicated malaria: when there are:
 Encephalopathy
 Severe anaemia
 Hyperpyrexia
 Metabolic derangement
 Acute renal or respiratory syndrome etc
Diagnosis
 Both clinical and laboratory means are employed.
 About 50% of clinical Δ is incorrect even by the
physicians (detection of the parasite is paramount)
 Laboratory methods include:
1.Antigen detection
2. Antibody detection
3. QBC
4. PCR
5. Thick/thin blood film
Diagnosis
 Antibody detection: using enzymatic immunoassay or
immunoflourescence may be used in surveys but not
useful in acute malaria (antibodies develop days or weeks after onset)
 Antigen detection: e.g. parasight F, OptiMAL
 The former detects histidine rich protein-2 whereas the
latter detects parasite specific lactate dehydrogenase.
-available as dipsticks and easy to use
-but antigen may remain in circulation for sometime after
the parasite has been cleared (esp HRP-2)
Diagnosis

Quantitative Buffy Coat

 - uses specialized capillary tube pre-coated
with acridine orange (AO) and potassium oxalate
 -the parasite DNA is stained by AO
 -parasitized RBC occupies the top of the tube
and are pressed against the wall by a float
 -these cells are viewed with florescence
microscope
pLDH detection

 LDH is produced by the parasite

 Thus the enzyme is released by the parasitized
cells
 Isoforms of the enzymes are species specific
 Monoclonal antibodies detect the enzymes in
blood of infected patients
Detection of HRP-2*

 Another form of antigen detection test

 Monoclonal immunoglobulin raised against
falciparum specific histidine rich antigen-2
 The immunoglobulin is immobilized on the
nitrocellulose strip
 Positive sample: control dashed line and solid
pink line are visible
* Implicated in the formation of Hemozoin
Diagnosis

Thick and thin blood film

 -the ‘gold standard’
 Thick film tends to concentrate parasite
 Thin film is better for assessing morphology
Diagnosis
 Characteristics of P. falciparum
 Red cells not enlarged
 Rings are fine and may be >1 per cell
 Some rings may have 2 chromatin dots
 Presence of marginal form
 Crescent shaped gametocytes*
 Maurer’s dot may be present
*Only an evidence of recent infection
 Gametocytes P.falciparum

Macro
Micro
Diagnosis

P. malariae
 Ring form may have squarish appearance
 Characteristics band forms
 Mature schizont has daisy head appearance
 Chromatin dot may be on the inner surface of
the ring
 Red cell not enlarged
Diagnosis

P. ovale
 Red cell enlarged
 Comet form common
 Rings large and coarse
 Schuffner’s dots prominent
 Mature schizont similar to that of P. malariae
Current status of drug

 Chloroquine: has been widely used since the end of 2nd

World war.
 The onslaught by P. falciparum on this cheap and safe
drug dated back 1959
 It however, remains the drug of first choice for P.
vivax+, P. ovale and P. malariae
 Resistance to chloroquine results from reduced drug
accumulation and/or increased efflux.
+ problems with this also
Current status of drug
 Resistance of Plasmodium falciparum to chloroquine
stood at about 65% in Thailand since 1990
 In Nigeria, response varies in the different geo-political
regions ( < 10% in South-south and 77% in North-
west). Next slide
 Resistance can be induced experimentally by repeated
exposure of parasites to sub inhibitory concentrations
of the drug.
 Amodiaquine+ may be efficacious in chloroquine
resistant malaria.
+ Amodiaquine was dropped because of agranulocytosis, hepatitis; it has come back
fully now! will Dipyrone too?
Efficacy study of CQ, P-S, Art-L and
As-Aq 02&04*

100

80 NC
NE
60
NW
40
SE
20 SS
SW
0
CQ P-S Art-Lu As=Aq
Current status of drug
 Mefloquine: introduced in 1984 for acute
uncomplicated malaria and by 1990 significant
resistance has been reported in Thailand.
 This drug is still very efficacious in Nigeria,
although in vitro testing of some isolates
suggested reduced sensitivity.
 Was combined with P-S in the hope that
mefloquine could be protected same idea
exported to Africa.
Current status of drug
 The combination with P-S did not have any advantage
over mefloquine monotherapy in Nigeria.
 Mefloquine resistance mirrors that of quinine and
halofantrine but bears an inverse relationship to that of
chloroquine in any given area.
 Resistance has been attributed to an ATP-dependent
P-glycoprotein pump, a product of Pfmdr gene.
Current status of drug

 Substantial drop in response to quinine has

been reported from Thailand as far back as
1982
 The drug is still very useful in ALL grades and
types of malaria in Nigeria
 In fact this drug remains first line in the
treatment of severe malaria in Nigeria.
Current status of drug
The Antifolates antimalarials include:
 Pyrimethamine, proguanil (dihydrofolate reductase or
DHFR inhibitors)
 Sulphadoxine, sulphalene and dapsone (dihdropteroate
synthase or DHPS inhibitors).
 Pyrimethamine, proguanil are causal chemoprophylactic
agents but in combination with DHPS inhibitors, they are
schizonticides, for example P-S, Chlorproguanil-Dapsone
(lapdap)*

*A new formulation
Current status of drug
 Resistance to P-S has become established in Thailand
and Indochina since the early 1970s.
 East African countries were also the first to be affected
in Africa.
 Pyrimethmine-sulphadoxine was used as second line
drug in Nigeria and most African countries until
recently.
 Cure rate may be as low as 8% in South-south Nigeria
Current status of drug

 Resistance is usually due to point mutations in

DHFR and/or DHPS gene
 Mutations at position 164 (common in Southeast Asia)
results in highly resistant mutants.

However, mutations at positions 51, 59 and 108 show relative resistance

(common in Africa)
Current status of drug

 Atovaquone: A relatively new agent usually

presented in combination with Proguanil
 single point mutations in the cytochrome b
gene of P. falciparum confers marked
reduction in susceptibility to the drug.
Current status of drug

Artemisinin and its derivatives

 Reduced susceptibility was found against isolates from
Southwest Nigeria and Central Africa*
 Stable resistance has not been documented clinically.
 Artemether and other artemisinin derivatives are useful
in all grades and types of malaria all over the World.
*Reported in 1992
There are genuine apprehensions that P. falciparum may become resistant to this group of drugs
reputed to be the fastest schizonticides, indeed one the reasons for advocating combination
therapy.
Treatment options

 The problem of drug resistance has compelled

the use of combination chemotherapy
 The major premise is to ensure cure and delay
or prevent development of drug resistance.
 In the past pyrimethamine-sulphadoxine, mefloquine, quinine with
or without antibiotics provided alternative remedies in Nigeria.
Treatment options

 Nowadays, the option is basically what combination of

drugs to administer
 Combination chemotherapy in malaria involves the
use of two or more drugs that affect different
biochemical processes in the parasite. ++
 The parasite biomass during an acute malaria infection
is usually between 109 and 1014

++Theoretically, if two drugs are used and for each one a single mutational event confers complete
resistance and such events occur with a frequency of 1:10 10 nuclear divisions, the probability
of a mutation resistant to both drugs is 1:10 20
Treatment options
 Combination chemotherapy may either be:
 ACT or Non-ACTion
Artemisinin based Combination Therapy: especially
favoured because
 artemisinin derivatives reduce parasite biomass very fast
 Rapid relief of symptoms
 Good safety profile
 Have short half-lives*

* less likely to exert drug pressure

Treatment options
Examples of artemisinin based combination therapy are:
 Artemether-lumefantrine
 Artesunate Amodiaquine
 Artesunate-pyrimethamine-sulphadoxine
 Pyronaridine plus artesunate
 Pyronaridine plus artemether
 Pyronaridine dihydroartemisinin
 Mefloquine plus artemether
 Artesunate plus chlorproguanil-dapsone*

* Not yet available for general use here

Treatment options

Nonartemisinin based combinations include:

 Chloroquine plus pyrimethamine-sulphadoxine**
 Amodiquine plus pyrimethamine-sulphadoxine
 Mefloquine plus pyrimethamine-sulphadoxine

**Not recommended because the 2 drugs are failing

Reversal phenomenon
 In vitro, reversal of resistance in P. falciparum
has been demonstrated for chloroquine,
mefloquine, quinine and quinidine.
 In vivo CQ resistance has been successfully
reversed by chlorpheniramine, a histamine H-1
receptor antagonist*.
 Perhaps, this could be further explored by
some of us.
*probenecid has also been used for P-S
Management of severe malaria
 Always consider appropriate ΔΔ
 Prompt treatment improves prognosis
 Severe anaemia – transfusion may be life-saving
 Cerebral malaria
– IV QN or IM artemether
 Later, oral medication
– + Anticonvulsant
– Close monitoring is essential
 Fluid
 Parasitaemia
 Urine output and Specific Gravity
 Hypoglycaemia
Management of severe malaria

 Haemoglobinuria: correct fluid, haematocrit,

– Osmotic diuretic or dialysis may be necessary
 Renal impairment
– Pre-renal* (conc urine + normal microscopy) vs renal
– Dialysis may be necessary
 Hypoglycaemia
– Esp. in pregnant women, QN therapy (hyper-insulinism)
– Confirm with RBG or simply treat!
– Glucose infusion
 Hyperpyrexia – antipyretic, tepid sponging, fanning, ??cooling
blanket
* Fluid challenge may be helpful
Management of severe malaria
 Pulmonary edema
 Caused by:
 Over-hydration
 Renal failure, pregancy, hyper-parasitaemia
– Nurse propped up, O2
 Circulatory collapse
– Hypovolemia, sepsis
– Tx: fluid replacement, +dopamine, +antibiotics
Malaria Prevention

 Malaria vaccine
 Vector control: avoid mosquito bite, use ITN
 Chemoprophylaxis
– Traditional/conventional
– Intermittent preventive treatment
Vector control

 Mosquito repellant: N N di-etheyl meta-

toluamide (DEET)
 Pyrethrin impregnated nets
 Interfering with vector life cycle
– Anti-larval measures
– Environmental sanitation
Traditional chemoprophylaxis

 Drugs:
 Mefloquine
 Chloroquine
 Doxycycline
 Proguanil
 Atovaquone-proguanil
Malaria prophylaxis

 Who need prophylaxis?

 Pregnant women
 Non immune visitors
 Haemoglobinopathy
 The under 5s??
Some practical points

 Remember
 Febrile illness ≠ malaria!
 Severe or complicated malaria ≠ drug resistant
malaria!
 Failure of symptom resolution does not always
mean that there is drug resistance
 Your lab. may be wrong!
Failure of symptom resolution
 Re-evaluate your patient including history and physical
examination
 Was there an initial blood film, what was the finding?
 Repeated blood film, this time both thick and film
should be done
 You may have to request to look at film!
 If positive, is this ETF, LTF or a NEW INFECTION?
Failure of symptom resolution

 Responses are now classified as: adequate

clinical response (ACR) or early (ETF) and late
treatment failure (LTF).
 The ETF is defined as persistence or
deterioration of symptoms and presence of
parasitaemia during the first 3 days of follow
up.
Failure of symptom resolution
 Late treatment failure is defined as
reappearance of symptoms during days 4-14 of
follow up.
 ACR is defined as the either the absence of
parasitaemia on day 14 (irrespective of axillary
temperature) or the absence of symptoms on
day 14 (irrespective of parasitaemia) in
patients who did not meet criteria for ETF or
LTF.
BLOOD FILM ‘POSITIVE’ but patient
is well
 First, seek reassurance from the lab., NOT all
that is read as PLASMODIUM turn out to be
right!
 Watch the patient and repeat the film twenty-
four and/or forty-eight hours after
 Re-evaluate patient, symptom-wise if repeat is
positive
 Treat, especially if a child and symptomatic!
BLOOD FILM ‘NEGATIVE’ in clinical
malaria
 Competence of the lab. - parasite on the film but not
identified!
 Plasmodium falciparum sometimes ‘hide’ especially in
the perfectly synchronous infection
 Either case: Your clinical judgement is paramount
Remember:
 You may have to treat certain ‘at risk’ patients even
before and/or without the benefit of ancillary
investigation BUT also remember that your subsequent
mgt. in such instance may not benefit significantly from
the same ‘rejected’ or ‘unavailable’ lab.!
Thank you
For your attention!