Malaria Lecture Revised

8/8/2019 Malaria Lecture Revised

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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

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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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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

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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

Back


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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

Back


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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)

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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

Back


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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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Malaria Lecture Revised