1. Haemoparasite-Malaria
A Detailed Study
Dr. Mohamed Iqbal Musani, MD
Professor of Pathology
Ibn Sina Medical College Jeddah

2. Introduction
1
Malaria
Malaria is a major public health
problem in warm climates
especially in developing countries.
It is a leading cause of disease
and death among children under
five years, pregnant women and
non-immune
travellers/immigrants.
Children under 5 are the major at risk group in malarious
regions. Inset: An Anopheles mosquito taking a blood meal

3. What is malaria ?
Malaria is a disease caused by the protozoan parasites of the genus Plasmodium.
The 4 species that commonly infect man are:
Species Major features
P. falciparum  The most important species as it is responsible for 50% of all malaria cases
worldwide and nearly all morbidity and mortality from severe malaria
 Found in the tropics & sub-tropics
P. vivax  The malaria parasite with the widest geographical distribution
 Seen in tropical and sub-tropical areas but rare in Africa
 Estimated to cause 43% of all malaria cases in the world
P. ovale  This species is relatively rarely encountered
 Primarily seen in tropical Africa, especially, the west coast, but has been reported
in South America and Asia
P. malariae  Responsible for only 7% of malaria cases
 Occurs mainly in sub-tropical climates

4. The burden of malaria
The “direct” burden of malaria The “indirect” burden of malaria
– morbidity and mortality
• Human development: Impaired
• Every year, there are about 500 intellectual development,
million clinical attacks of malaria. developmental abnormalities
Of these, 2-3 million are severe (especially following cerebral
and about 1 million people die malaria), lost school attendance
(about 3000 deaths every day). and productivity at work
• Malaria in pregnancy accounts for
about 25% of cases of severe • Economics: Malaria retards
maternal anaemia and 10-20% of economic development in the
low birthweight. Low birthweight developing world. The cost of a
due to malaria accounts for about single bout of malaria is equivalent
5-10% of neonatal and infants to over 10 working days in Africa.
deaths. The cost of treatment is between
$US0.08 and $US5.30, depending
on the type of drugs prescribed as
required by the local pattern of
drug resistance.

5. Geographical Distribution of Malaria
Although previously
widespread, today
malaria is confined
mainly to Africa, Asia and
Latin America. About
40% of the world’s
population is at risk of
malaria. It is endemic in
91 countries, with small
pockets of transmission
occurring in a further 8
countries.
Malaria is transmitted by the female anopheles mosquito. Factors which affect mosquito ecology,
such as temperature and rainfall, are key determinants of malaria transmission. Mosquitoes breed in
hot, humid areas and below altitudes of 2000 meters. Development of the malaria parasite occurs
optimally between 25-30oC and stops below 16oC. Indigenous malaria has been recorded as far as
64oN and 32oS.
Malaria has actually increased in sub-Saharan Africa in recent years. The major factor has been the
spread of drug-resistant parasites. Other important factors include the persistence of poverty,
HIV/AIDS, mosquito resistance to insecticides, weak health services, conflict and population
migration.

6. Endemicity
 Endemicity refers to the amount or severity of malaria in an area or community.
Malaria is said to be endemic when there is a constant incidence of cases over a
period of many successive years.
Endemic malaria may be present in various degrees. Recognised categories of
endemicity include :
A. Hypoendemicity - little transmission and the disease has little effect on the
population.
B. Mesoendemicity - varying intensity of transmission; typically found in the small,
rural communities of the sub-tropics.
C. Hyperendemicity - intense but seasonal transmission; immunity is insufficient
to prevent the effects of malaria on all age groups.
D. Holoendemicity - intense transmission occurs throughout the year. As people
are continuously exposed to malaria parasites, they gradually develop immunity
to the disease. In these areas, severe malaria is mainly a disease of children from
the first few months of life to age 5 years. Pregnant women are also highly
susceptible because the natural immune defence mechanisms are impaired
during pregnancy.

7. How is malaria transmitted?
• Malaria parasites are transmitted from
one person to another by the bite of a
female anopheles mosquito.
• The female mosquito bites during dusk
and dawn and needs a blood meal to
feed her eggs.
• Male mosquitoes do not transmit
malaria as they feed on plant juices
and not blood.
• There are about 380 species of
anopheles mosquito but only about 60 Female Anopheles mosquito taking a blood meal
are able to transmit malaria.
Source:http://phil.cdc.gov/phil/quicksearch.asp
• Like all mosquitoes, anopheles breed in
water - hence accumulation of water
favours the spread of the disease.

8. How does infection develop ?
• Plasmodium infects the human and insect host alternatively and several
phases of the parasite life cycle are described.
• During feeding, saliva from the mosquito is injected into the human blood
stream. If the mosquito is carrying malaria, the saliva contains primitive stages
of malaria parasites called sporozoites.
• Hepatic, tissue or pre-erythrocytic phase: Sporozoites invade and develop
in liver cells. The infected hepatocyte ruptures to release merozoites.
• Erythrocytic phase: Merozoites then invade red blood cells. The red cells
lyse and this causes bouts of fever and the other symptoms of the disease.
This cycle repeats as merozoites invade other red cells.
• Sexual phase: Sexual forms of the parasites develop and are ingested when
another female anopheles mosquito feeds. These develop into sporozoites in
the gut of the insect host and travel to its salivary glands. Then the cycle starts
again…
• The life cycle of the malaria parasite is shown on the next slide

9. The Malaria Parasite Life Cycle
In fe ctio n S p o ro zo ite s
Click on the diagram
to explore different
areas of the life
cycle
L ive r
M e ro zo ite s A se xu a l
cycle
Tra n sm issio n
to m o sq u ito
G a m e to cyte s

10. The Malaria Parasite Life Cycle
1. Transmission
In fe ctio n S p o ro zo ite s
Female anopheles
mosquito bites and
releases sporozoites
into the blood stream.
These circulate for about
30 mins and then invade
the liver.
L ive r
M e ro zo ite s A se xu a l
cycle
Tra n sm issio n
to m o sq u ito
G a m e to cyte s

11. The Malaria Parasite Life Cycle
2. Pre-erythrocytic phase
In fe ctio n S p o ro zo ite s
Also called the “tissue” or “hepatic”
phase
Takes place in hepatocytes. The
sporozoites mature into schizonts
which rupture to release merozoites.
Duration of this phase depends on the
species.
In P. vivax and P. ovale, the schizont
may also differentiate into hypnozoites.
L ive r
These are dormant forms of the
parasite which may remain in the liver
M e ro zo ite s for several months or years and cause
A se xu a l
cycle relapse in the human host.
Tra n sm issio n
to m o sq u ito
G a m e to cyte s

12. The Malaria Parasite Life Cycle
In fe ctio n S p o ro zo ite s
L ive r
3a. Asexual phase (Erythrocytic schizogony)
M e ro zo ite s Merozoites invade red blood cells. Here they
A se xu a l
grow and mature into trophozoites which
cycle
appear as ring forms. The trophozoites
Tra n sm issio n develop into schizonts. The infected red
to m o sq u ito blood cells then rupture to release numerous
merozoites from the schizont to infect other
red cells. Merozoite release results in fever,
G a m e to cyte s
chills, rigours and other symptoms of malaria
infection.

13. The Malaria Parasite Life Cycle
In fe ctio n S p o ro zo ite s
L ive r
M e ro zo ite s A se xu a l
cycle
3b. Sexual phase
Tra n sm issio n
Some merozoites differentiateu ito male
into
to m o sq
and female gametocytes, the forms of
Plasmodia infective to mosquitoes. These
are taken up by a mosquito during G a m e to cyte s
another blood meal. These fuse to form
an ookinette in the gut lumen of the
mosquito. The ookinette invades the
stomach wall to form the oocyst. This in
turn develops and releases sporozoites
which migrate to the salivary gland of the
mosquito. This mosquito then goes on to
infect another human host.

14. Severity of disease and host factors
In addition to parasite factors, several host factors determine the outcome of exposure to malaria:
• Naturally-acquired immunity. People who are constantly exposed to malaria gradually acquire
immunity, firstly against clinical disease and later against parasite infection. Clinical manifestations of
malaria are most severe in the non-immune. In holoendemic areas, these are children aged <5 years
and pregnant women (especially primagravidae). People of any age from areas that are free from
malaria, or have limited malaria transmission, are at risk when they are exposed to malaria.
• Red cell and haemoglobin variants. Well known examples of inherited factors that protect against
malaria are Haemoglobin S carrier state, the thalassaemias and Glucose-6-phosphate
dehydrogenase (G6PD) deficiency. Malaria provides the best known example whereby an
environmental factor (malaria) has selected human genes because of their survival advantage.
• Foetal haemoglobin (HbF): High levels of HbF occur in neonates, and in some people with inherited
haemoglobin variants, protect against severe forms of P. falciparum malaria.
• Duffy blood group: P. vivax requires the Duffy blood receptor to enter red blood cells. Therefore,
people who do not carry the Duffy blood group are resistant to this malaria species. This explains the
rarity of P. vivax in Africa, as most Africans are Duffy blood group negative.

15. The clinical course of P. falciparum
Following a bite by an infected mosquito, many people do not
develop any signs of infection. If infection does progress,
the outcome is one of three depending on the host and
parasite factors enumerated in the previous slides:
• Asymptomatic parasitaemia (“clinical immunity”)
• Acute, uncomplicated malaria
• Severe malaria

16. A. Asymptomatic parasitaemia
This is usually seen in older children and adults who have
acquired natural immunity to clinical disease as a
consequence of living in areas with high malaria
endemicity. There are malaria parasites in the peripheral
blood but no symptoms. These individuals may be
important reservoirs for disease transmission.
Some individuals may even develop anti-parasite
immunity so that they do not develop parasitaemia
following infection.

17. B. Simple, uncomplicated malaria
This can occur at any age but
it is more likely to be seen in
individuals with some degree
of immunity to malaria. The
affected person, though ill,
does not manifest life-
threatening disease.
Fever is the most constant
symptom of malaria. It may
occur in paroxysms when lysis Children with malaria waiting to be seen at a
of red cells releases malaria clinic in the south western part of
Nigeria. Identifying children with severe malaria,
merozoites resulting in fever, and giving them prompt treatment, is a major
challenge when large numbers attend clinics.
chills and rigors
(uncontrollable shivering).

18. The periodicity of malaria fever
Erythrocytic schizogony is the time
taken for trophozoites to mature into
merozoites before release when the
cell ruptures.
It is shortest in P. falciparum (36
hours), intermediate in P. vivax and
P. ovale (48 hours) and longest in P.
malariae (76 hours).
Typical paroxysms thus occur every
• 2nd day or more frequently in P.
falciparum (“sub-tertian” malaria) Note how the frequency of spikes of fever
• 3 day in P. vivax and P. ovale
rd differ according to the Plasmodium species.
(“tertian” malaria) In practice, spikes of fever in P. falciparum,
• 4th day in P. malariae infections, occur irregularly - probably because of the
presence of parasites at various stages of
(“quartan” malaria)
development.

19. Other features of simple,
uncomplicated malaria include:
o Vomiting
o Diarrhoea – more commonly seen in young children and, when vomiting also occurs, may be
misdiagnosed as viral gastroenteritis
o Convulsions – commonly seen in young children. Malaria is the leading cause of convulsions
with fever in African children.
o Pallor – resulting mainly from the lysis of red blood cells. Malaria also reduces the synthesis of
red blood cells in the bone marrow.
o Jaundice – mainly due to haemolysis.
Malaria is a multisystem disease. Other common clinical features are:
o Anorexia
o Cough
o Headache
o Malaise
o Muscle aches
o Splenomegaly
o Tender hepatomegaly
These clinical features occur in “mild” malaria. However, the infection requires urgent
diagnosis and management to prevent progression to severe disease.

20. C. Severe and complicated malaria
Nearly all severe disease and the estimated >1 million deaths from malaria
are due to P. falciparum. Although severe malaria is both preventable and
treatable, it is frequently a fatal disease.
The following are 8 important severe manifestations of malaria:
Click on each severe manifestation for details
1. Cerebral malaria 1. Acute renal failure
2. Severe malaria anaemia 2. Pulmonary oedema
3. Circulatory collapse, shock or “algid
3. Hypoglycaemia
4. Blackwater fever
4. Metabolic acidosis
Note: It is common for an individual patient to have more than
one severe manifestation of malaria!

21. Summary of differences in the clinical features
of severe malaria in adults and children
Frequency of occurrence
Clinical Manifestation Children Adults
Similar in adults and children
• Prostration +++ +++
• Circulatory collapse + +
More common in children
• Cerebral malaria +++ ++
• Severe anaemia +++ +
• Multiple convulsions +++ +
• Metabolic acidosis +++ +
• Hypoglycaemia ++ +/-
More common in adults
• Jaundice + +++
• Pulmonary oedema +/- ++
• Haemoglobinuria +/- +
• Abnormal bleeding +/- +
• Renal failure +/- +

22. Diagnosis
Malaria is a multisystem disease. It presents with a wide variety of non-specific clinical features:
there are no pathognomonic symptoms or signs. Many patients have fever, general aches
and pains and malaise and are initially misdiagnosed as having “flu”.
P. falciparum malaria can be rapidly progressive and fatal. Prompt diagnosis saves lives and
relies on astute clinical assessment:
• A good history
– Residence or a recent visit (in the preceding 3 months) to a malaria endemic area
– History of fever (may be paroxysmal in nature)
– Recognise significance of non-specific clinical features such as vomiting, diarrhoea,
headache, malaise
• Physical examination
– Identify signs consistent with malaria: fever, pallor, jaundice, splenomegaly
– Exclude other possible causes of fever (e.g. signs of viral and bacterial infections)
The diagnosis of malaria should be considered in any
unwell person who has been in a malarious area recently

23. Investigations
Blood Film Examination
Thick and thin blood films (or “smears”) have
remained the gold standard for the
diagnosis of malaria. The films are stained
and examined by microscopy.
Thick blood film - Used for detecting malaria:
a larger volume of blood is examined
allowing detection of even low levels of
parasitaemia. Also used for determining
parasite density and monitoring the
response to treatment. Show Me
Thin blood film – Gives more information
about the parasite morphology and,
therefore, is used to identify the particular
infecting species of Plasmodium. Show Me

24. Thick blood film
A drop of blood is spread over a
small area. When dry, the slide is
stained with Field’s or Giemsa
stains. The red cells lyse leaving
behind the parasites.
• Used to detect parasites,
even if parasitaemia is low
• Less useful for speciation
Back

25. A small drop of blood is
Thin blood film spread across a microscope
slide, fixed in methanol and
stained with Giemsa stain.
The microscopist finds the
area of the film where red cells
are lying next to each other.
The fine details of the
parasites can be examined to
determine the species.
• Used for speciation
• Does not detect low
parasitaemia
Back

26. Appearance of P. falciparum in thin
blood films
Ring forms or trophozoites; many
red cells infected – some with more
than one parasite
Gametocytes (sexual stages); After a blood
meal, these forms will develop in the
mosquito gut
http://phil.cdc.gov/phil/quicksearch.asp

27. Other methods of diagnosis of malaria
These are not routinely used in clinical practice. They include :
• Antigen capture kits. Uses a dipstick and a finger prick blood
sample. Rapid test - results are available in 10-15 minutes.
Expensive and sensitivity drops with decreasing parasitaemia.
• PCR based techniques. Detects DNA or mRNA sequences
specific to Plasmodium. Sensitivity and specificity high but test is
expensive, takes several hours and requires technical expertise.
• Fluorescent techniques. Relatively low specificity and sensitivity.
Cannot identify the parasite species. Expensive and requires
skilled personnel.
• Serologic tests. Based on immunofluorescence detection of
antibodies against Plasmodium species. Useful for epidemiologic
and not diagnostic purposes.

28. Malaria in pregnancy
More than 45 million women (30 million in
Africa) become pregnant in malaria endemic areas
each year.
Common adverse effects of malaria in pregnancy include:
• Maternal anaemia
• Stillbirths
• Premature delivery and intrauterine growth retardation
result in the delivery of low birth weight infants
The WHO now recommends intermittent preventive
treatment (IPT): the administration of anti-malarial
drugs (e.g. sulphadoxine-pyrimethamine) during
antenatal care whether or not women show symptoms.
IPT has been shown to substantially reduce the risk of
maternal anaemia in the mother and low birth weight
in the newborn.
Previously, chemoprophylaxis (e.g. with chloroquine) was
recommended for all women living in malaria endemic Source:
areas. http://phil.cdc.gov/phil/quicksearch.asp

29. Sources of information
• Malaria. Greenwood BM, Bojang K, Whitty CJ, Targett GA. Review; Lancet 2005;
365:1487-98.
• http://mosquito.who.int/cmc_upload/0/000/015/372/RBMInfosheet_1.htm
These WHO fact sheets developed by the Roll Back Malaria Partnership
cover many different aspects of malaria – including prevention with
insecticide-treated bed nets and treatment with atemesinin-based
combination therapies
• http://www.cdc.gov/malaria/
The US Centre for Disease Control and Prevention site for malaria
• http://www.malaria.org/
Follow the “Learn about malaria” link on the Malaria Foundation’s website.
This contains numerous useful and accessible resources.
• http://www.rph.wa.gov.au/labs/haem/malaria/
An interactive resource from the Royal Perth Hospital, Western Australia.
Contains useful self-assessment exercises in malaria diagnosis by
microscopy that are set in the context of clinical cases.

30. 1. Cerebral malaria - clinical
• The most well-known severe manifestation of
malaria
• Defined as:
– unarousable coma persisting for more than
one hour
– with asexual forms of P. falciparum in the
peripheral blood
– other common causes of encephalopathy
excluded*
• Occurs most commonly in young children
although non-immune adults are also at risk
• Cerebral malaria can rapidly progress to death,
even with appropriate treatment. Case fatality is
between 20-30%.
• In survivors, resolution of coma usually occurs A 4 year old boy who was deeply
within 1-2 days in children and within 2-4 days in comatose and had persistent
adults but may be complicated by neurological
sequelae in ~5% adults and >10% of children. deviation of the eyes
The illness may start with drowsiness and confusion and then progress to coma. The loss of
consciousness is often preceded by repeated convulsions. Retinal haemorrhages may be
seen on fundoscopy.
* None of the clinical features are pathognomonic, malaria parasitaemia is common in people
living in endemic areas and coma may complicate many illnesses. Therefore, a clinical
diagnosis of cerebral malaria is made only after other common causes of coma (e.g.
meningitis) have been excluded.
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31. Cerebral malaria - pathophysiology
The exact pathogenesis of cerebral malaria is not
well understood. It is believed to result from
sequestration of parasitised red cells in the small
blood vessels in the brain. The consequences of
this include:
• reduced cerebral blood flow
• cerebral hypoxia
• release of cytokines which in turn induce the
release of nitrous oxide, a known depressor of
A young girl with cerebral malaria. Note the consciousness
abnormal, decerebrate posturing
Sequestration of parasitised red
cells in different tissues probably
underlies most severe
manifestations of malaria
A 3 year old boy with impaired
consciousness, grimacing and marked
extensor posturing of the arms
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32. 2. Severe malaria anaemia
Defined as a haematocrit of <15% or haemoglobin
concentration <5 g/dl.
Occurs commonly in young children and pregnant
women.
Anaemia in malaria results from a combination of
factors:
• Destruction of parasitised red blood cells
• Destruction of unparasitised red cells by
complement-mediated lysis
• Bone marrow suppression by cytokines produced
by malaria parasites
• Haemolysis induced by medications in individuals
with glucose-6-phosphate dehydrogenase
deficiency
Marked pallor in an African child with
severe anaemia due to P. falciparum
Many patients require urgent transfusion. The infection
condition may be rapidly fatal when blood
transfusion is delayed.
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33. 3. Hypoglycaemia
• Blood sugar <2.5 mmol/L
• Increases the risk of mortality and sequelae in children
with cerebral malaria; may present with convulsions or a
deterioration in level of consciousness.
• Results from a combination of factors:
– reduced glycogen stores because of reduced food
intake
– increased metabolism due to fever and repeated
convulsions
– glucose consumption by malaria parasites
– cytokine or quinine-stimulated hyperinsulinaemia
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34. 4. Metabolic acidosis
• Lactic acidosis is a major contributor and probably
results from tissue anoxia and anaerobic glycolysis
• Presents with deep, rapid respirations (as in diabetic
ketoacidosis)
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35. 5. Acute renal failure
• occurs almost exclusively in adults and older children in
areas of unstable malaria
• affected patients are usually oliguric (urinary output <400
ml/day) or anuric (<50 ml/day)
• serum creatinine levels are elevated
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36. 6. Acute pulmonary oedema
This is a grave and usually fatal
manifestation of severe
falciparum malaria and occurs
mainly in adults.
Hyperparasitaemia, renal failure
and pregnancy are recognised
predisposing factors and the
Acute pulmonary oedema, developing shortly after
condition is commonly delivery in a woman with severe P. falciparum
malaria
associated with hypoglycaemia
and metabolic acidosis.
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37. 7. Circulatory collapse, shock, “algid
malaria”
Features of circulatory collapse (cold/clammy skin,
hypotension, peripheral cyanosis, weak/thready pulses) may
be seen in patients with severe P. falciparum malaria.
“Algid malaria” is characterised by hypotension, vomiting,
diarrhoea, rapid respiration and oliguria. This condition is
associated with a poor prognosis.
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38. 8. Haemoglobinuria or “Blackwater Fever”
This results from massive intravascular Typical, dark urine of haemoglobinuria on
day 0 which has cleared by day 3
haemolysis. The condition presents with
severe pallor, jaundice and passage of
dark urine due to haemoglobinuria. It may
be associated with acute renal failure.
A 3 year old boy with severe anaemia
(Hb 3.3 g/dl) and dark urine (shown in
the container)
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