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Haemoparasite-Malaria
A Detailed Study
Dr. Mohamed Iqbal Musani, MD
Professor of Pathology
Ibn Sina Medical College Jeddah
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Introduction
1
Malaria
Malaria is a major public healthproblem in warm climatesespecially in developing countries.
It is a leading cause of diseaseand death among children underfive years, pregnant women andnon-immunetravellers/immigrants.
Children under 5 are the major at risk group in malariousregions. Inset: An Anopheles mosquito taking a blood meal
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Wh
at 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 casesworldwide 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 reportedin South America and Asia
P. malariae Responsible for only 7% of malaria cases
Occurs mainly in sub-tropical climates
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The burden of malaria
The direct burden of malaria
morbidity and mortality
Every year, there are about 500million clinical attacks of malaria.
Of these, 2-3 million are severeand about 1 million people die(about 3000 deaths every day).
Malaria in pregnancy accounts forabout 25% of cases of severematernal anaemia and 10-20% oflow birthweight. Low birthweightdue to malaria accounts for about5-10% of neonatal and infants
deaths.
The indirect burden of malaria
Human development: Impairedintellectual development,developmental abnormalities(especially following cerebralmalaria), lost school attendanceand productivity at work
Economics: Malaria retardseconomic development in thedeveloping world. The cost of asingle bout of malaria is equivalentto over 10 working days in Africa.
The cost of treatment is between$US0.08 and $US5.30, dependingon the type of drugs prescribed asrequired by the local pattern ofdrug resistance.
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Geographical Distribution of Malaria
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 inhot, humid areas and below altitudes of 2000 meters. Development of the malaria parasite occursoptimally between 25-30oC and stops below 16oC. Indigenous malaria has been recorded as far as64oN and 32oS.
Malaria has actually increased in sub-Saharan Africa in recent years. The major factor has been thespread of drug-resistant parasites. Other important factors include the persistence of poverty,HIV/AIDS, mosquito resistance to insecticides, weak health services, conflict and populationmigration.
Although previously
widespread, today
malaria is confined
mainly to Africa, Asia and
Latin America. About
40% of the worlds
population is at risk of
malaria. It is endemic in91 countries, with small
pockets of transmission
occurring in a further 8
countries.
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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 ofendemicity include :
A. Hypoendemicity - little transmission and the disease has little effect on thepopulation.
B. Mesoendemicity - varying intensity of transmission; typically found in thesmall, rural communities of the sub-tropics.
C. Hyperendemicity - intense but seasonal transmission; immunity is insufficientto prevent the effects of malaria on all age groups.
D. Holoendemicity - intense transmission occurs throughout the year. As peopleare continuously exposed to malaria parasites, they gradually develop immunityto the disease. In these areas, severe malaria is mainly a disease of children fromthe first few months of life to age 5 years. Pregnant women are also highlysusceptible because the natural immune defence mechanisms are impairedduring pregnancy.
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Female Anopheles mosquito taking a blood meal
Source:http://phil.cdc.gov/phil/quicksearch.asp
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
are able to transmit malaria.
Like all mosquitoes, anopheles breed
in water - hence accumulation of water
favours the spread of the disease.
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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 bloodstream. 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 cellslyse 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 whenanother female anopheles mosquito feeds. These develop into sporozoites inthe gut of the insect host and travel to its salivary glands. Then the cycle startsagain
The life cycle of the malaria parasite is shown on the next slide
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In e ion Spo o oi e
Li e
A e ualle
Ga e o e
e o oi e
T an i iono o qui o
The ala ia Pa a i e Li e C le
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The clinical course ofP. falciparum
Following a bite by an infected mosquito, many people do notdevelop 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:
A. Asymptomatic parasitaemia (clinical immunity)B. Acute, uncomplicated malariaC. Severe malaria
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This is usually seen in older children and adults who haveacquired natural immunity to clinical disease as aconsequence of living in areas with high malariaendemicity. There are malaria parasites in the peripheralblood but no symptoms. These individuals may beimportant reservoirs for disease transmission.
Some individuals may even develop anti-parasite
immunity so that they do not develop parasitaemiafollowing infection.
A. Asymptomatic parasitaemia
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B. Simple, uncomplicated malaria
Children with malaria waiting to be seen at amalaria clinic in the south western part ofNigeria. Identifying children with severe malaria,and giving them prompt treatment, is a majorchallenge when large numbers attend clinics.
This can occur at any age butit is more likely to be seen inindividuals with some degreeof immunity to malaria. Theaffected person, though ill,does not manifest life-threatening disease.
Feveris the most constantsymptom of malaria. It may
occur in paroxysms when lysisof red cells releasesmerozoites resulting in fever,chills and rigors(uncontrollable shivering).
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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. vivaxandP. 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)
3rd day in P. vivaxand P. ovale
(tertian malaria)
4th day in P. malariae infections,
(quartan malaria)
Note how the frequency of spikes of feverdiffer according to the Plasmodium species.
In practice, spikes of fever in P. falciparum,occur irregularly - probably because of thepresence of parasites at various stages ofdevelopment.
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Other features of simple,
uncomplicated malaria include:o Vomiting
o Diarrhoea more commonly seen in young children and, when vomiting also occurs, may bemisdiagnosed as viral gastroenteritis
o Convulsions commonly seen in young children. Malaria is the leading cause of convulsions withfever 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 acheso Splenomegaly
o Tenderhepatomegaly
These clinical features occur in mild malaria. However, the infection requires urgentdiagnosis and management to prevent progression to severe disease.
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C. Severe and complicated malaria
1. Cerebral malaria
2. Severe malaria anaemia
3. Hypoglycaemia
4. Metabolic acidosis
5. Acute renal failure
6. Pulmonary oedema
7. Circulatory collapse, shock oralgid malaria
8. Blackwater fever
Nearly all severe disease and the estimated >1 million deaths frommalaria are due to P. falciparum. Although severe malaria is bothpreventable and treatable, it is frequently a fatal disease.
The following are 8 important severe manifestations of malaria:
Note: It is common for an individual patient to have more thanone severe manifestation of malaria!
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Summary of differences in the clinical featuresof severe malaria in adults and children
Clinical Manifestation Children Adults
Similar in adults and children
Prostration
Circulatory collapse
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+
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+
More common in children
Cerebral malaria
Severe anaemia
Multiple convulsions
Metabolic acidosis
Hypoglycaemia
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+++
++
++
+
+
+
+ / -
More common in adults Jaundice
Pulmonary oedema
Haemoglobinuria
Abnormal bleeding
Renal failure
+
+ / -
+ / -
+ / -
+ / -
+++
++
+
+
+
Frequency of occurrence
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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 achesand pains and malaise and are initially misdiagnosed as having flu.
P. falciparum malaria can be rapidly progressive and fatal. Prompt diagnosis saves lives andrelies 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 anyunwell person who has been in a malarious area recently
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Investigations
Blood Film Examination
Thick and thin blood films (or smears) haveremained the gold standard for thediagnosis of malaria. The films are stainedand examined by microscopy.
Thick blood film - Used for detectingmalaria: a larger volume of blood isexamined allowing detection of even lowlevels of parasitaemia. Also used fordetermining parasite density and monitoringthe response to treatment.
Thin blood film ives more informationabout the parasite morphology and,therefore, is used to identify the particularinfecting species of Plasmodium.
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A drop of blood is spread over a
small area. When dry, the slide isstained with Fields or iemsastains. The red cells lyse leavingbehind the parasites.
Used to detect parasites,even if parasitaemia is low
Less useful for speciation
Thick blood film
Back
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A small drop of blood isspread across a microscopeslide, fixed in methanol andstained with iemsa stain.
The microscopist finds thearea of the film where redcells are lying next to eachother. The fine details of theparasites can be examined todetermine the species.
Used for speciation Does not detect low
parasitaemia
Thin blood film
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Ring forms or trophozoites; manyred cells infected some with morethan one parasite
ametocytes (sexual stages); After a bloodmeal, these forms will develop in themosquito gut
Appearance ofP. falciparum in thin
blood films
http://phil.cdc.gov/phil/quicksearch.asp
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Other methods of diagnosis of malaria
These are not routinely used in clinical practice. They include :
a) Antigen capture kits. Uses a dipstick and a finger prick bloodsample. Rapid test - results are available in 10-15 minutes.
Expensive and sensitivity drops with decreasing parasitaemia.b) PCR based techniques. Detects DNA or mRNA sequences
specific to Plasmodium. Sensitivity and specificity high but test isexpensive, takes several hours and requires technical expertise.
c) Fluorescent techniques. Relatively low specificity and sensitivity.Cannot identify the parasite species. Expensive and requiresskilled personnel.
d) Serologic tests. Based on immunofluorescence detection ofantibodies against Plasmodium species. Useful for epidemiologicand not diagnostic purposes.
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Malaria in pregnancy
More than 45 million women (30 million inAfrica) become pregnant in malaria endemic areaseach year.
Common adverse effects of malaria in pregnancy include:
Maternal anaemia
Stillbirths
Premature delivery and intrauterine growth retardationresult in the delivery of low birth weight infants
The WHO now recommends intermittent preventivetreatment (IPT): the administration of anti-malarialdrugs (e.g. sulphadoxine-pyrimethamine) duringantenatal 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 inthe newborn.
Previously, chemoprophylaxis (e.g. with chloroquine) wasrecommended for all women living in malaria endemicareas.
Source:http://phil.cdc.gov/phil/quicksearch.asp
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Sources of information Malaria. reenwood BM, Bojang K, Whitty CJ, Targett A. Review; Lancet2005;
365:1487-98.
http://mosquito.who.int/cmc_upload/0/000/015/372/RBMInfosheet_1.htmThese WHO fact sheets developed by the Roll Back Malaria Partnershipcover many different aspects of malaria including prevention withinsecticide-treated bed nets and treatment with atemesinin-basedcombination 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 Foundations 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 bymicroscopy that are set in the context of clinical cases.
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1. Cerebral malaria - clinical
A 4 year old boy who was deeplycomatose and had persistentdeviation of the eyes
The most well-known severe manifestation ofmalaria
Defined as: unarousable coma persisting for more than
one hour with asexual forms ofP. 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 isbetween 20-30%.
In survivors, resolution of coma usually occurswithin 1-2 days in children and within 2-4 days inadults but may be complicated by neurologicalsequelae in ~5% adults and >10% of children.
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 beseen on fundoscopy.
* None of the clinical features are pathognomonic, malaria parasitaemia is common in peopleliving in endemic areas and coma may complicate many illnesses. Therefore, a clinicaldiagnosis of cerebral malaria is made only after other common causes of coma (e.g.meningitis) have been excluded.
NextBack
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A young girl with cerebral malaria. Note theabnormal, decerebrate posturing
The exact pathogenesis of cerebral malaria is notwell understood. It is believed to result fromsequestration of parasitised red cells in the smallblood vessels in the brain. The consequences ofthis include: reduced cerebral blood flow cerebral hypoxia release of cytokines which in turn induce therelease of nitrous oxide, a known depressor ofconsciousness
Cerebral malaria - pathophysiology
A 3 year old boy with impairedconsciousness, grimacing and markedextensor posturing of the arms
Sequestration of parasitised red
cells in different tissues probably
underlies most severe
manifestations of malaria
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2. Severe malaria anaemia
Defined as a haematocrit of
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Blood sugar
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Lactic acidosis is a major contributor and probably
results from tissue anoxia and anaerobic glycolysis
Presents with deep, rapid respirations (as in diabetic
ketoacidosis)
Back
4. Metabolic acidosis
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occurs almost exclusively in adults and older children in
areas of unstable malaria
affected patients are usually oliguric (urinary output
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Acute pulmonary oedema, developing shortly after
delivery in a woman with severe P. falciparummalaria
6. Acute pulmonary oedema
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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
condition is commonly
associated with hypoglycaemia
and metabolic acidosis.
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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 characterisedby hypotension, vomiting,
diarrhoea, rapid respiration and oliguria. This condition is
associated with a poor prognosis.
7. Circulatory collapse, shock, algid
malaria
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This results from massive intravascularhaemolysis. The condition presents withsevere pallor, jaundice and passage ofdark urine due to haemoglobinuria. It maybe associated with acute renal failure.
Typical, dark urine of haemoglobinuria onday 0 which has cleared by day 3
8. Haemoglobinuria or Blackwater Fever
A 3 year old boy with severe anaemia(Hb 3.3 g/dl) and dark urine (shown inthe container)
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