Pathology of Malaria

David P. Humber
School of Biosciences
University of East London

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Learning Outcomes

 Know the parasites, vector & epidemiology

 Understand of the life cycle
 Know the principal clinical features and
pathology and the basis of diagnosis
 Appreciate the difficulties of control

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 The Problem

 At Risk
• More than 40% of the world population
 Deaths
• More than 2 million per year
 Chemotherapy
• Limited Drugs & drug resistance
 Vector control
 Vaccination 3
The Parasite - Taxonomy

• Phylum - Apicomplexa (Sporozoa)

• Class - Haemosporidea (Sporozoea)
• Order - Haemosporidia
• Genus - Plasmodium

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Species Infecting Humans
Common & Severe
 Plasmodium falciparum
• Malignant tertian (Cerebral)
 Plasmodium vivax
• Tertian
 Plasmodium ovale
• Tertian
 Plasmodium malariae
• Quartan Rare & Mild

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Species Infecting Humans
Relapses Fevers
 Plasmodium falciparum No 24-48

• Tropical Africa, Asia, Latin America Yes 48

 Plasmodium vivax Yes 48
• Worldwide
No 72
 Plasmodium ovale
• Tropical West Africa
 Plasmodium malariae
• Worldwide but very patchy
Rare & Mild

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Epidemiology
>400 million cases annually
3 million deaths
majority 2-5 years
103 endemic countries
most in Africa
most due to P.falicparum
Need 15oCfor 4 weeks <300m
64oN to 32oS
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Distribution of Malaria

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Life Cycle

Sporozoite Liver Schizont

Trophozoite
Oocyst
RBC
Merozoite

Ookinete

Gametocytes 9
Infected Liver CellHepatocyte

Pre-erythrocytic schizonts

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Erythrocytic forms (signet)

Young ring form trophozoites 11

Gametocytes

P.falciparum

Macro
Micro

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Exflagellation

P. vivax produces 8 microgamentes

in mosquito’s midgut
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Clinical Features

 Pre-patent Period
• Time taken from infection to symptoms
– P. falciparum 6-12 days
– P. vivax 10-17days
– P ovale 14 days
– P. malariae 28-30 days

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Clinical Features of Malaria

 Prepatent period  Cold stage hr

• Headache/shiver/rapid
 Flu-like initially weak pulse
 Intermittent fever  Hot stage 6hrs
 Recurrence • Intense
 Coma/death headache/nausea/thirst/di
stress
 Sweating stage 4hrs
 Chronic infection • Profuse sweating
 Relapses Sleep!
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Tertian Malaria - P. vivax & P. ovale

 Rarely fatal- relapses common

 Prodrome
• myalgia, headache, chilliness, low grade irregular
fever (no sync maturation cycle)
 Synchronisation @ 5-7 days - paroxysms on
alternate days
 Spleen palpable 10-14 days
 P. ovale milder with shorter initial attacks
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Qartan Malaria - P. malariae

 Paroxysms every third day

 Mildest and most chronic of the 4
 immune complex nephropathy
 seasonal variation with P.f (wet season)

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Falciparum Malaria

 Cause of virtually all malaria deaths

• asynchronous cycle
• onset insidious - fever variable
• Rapid onset of splenomegaly
 Severe anaemia, jaundice,
hyperventilation, cns dysfunction
(delirium, stupor, coma) . . . . . . . . .

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Fever Charts

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Untreated P. falciparum malaria

 Sequestration - (schizogony completed)

• Bind to endothelia cells surface receptors eg
ICAM1 - via membrane “knobs” with histidine
rich protein
• Reduced in some individuals - splenectomy &
genetic background
• Clumping also occurs (platelets involved?)

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Site Specific Sequestration

 Brain
• measurable reduction in blood flow
 Intestines
• diarrhoea
 Placenta
• intervillus space

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Hepatosplenomegaly

 Hepatic dysfunction
 Hyperplasia of splenic/liver macrophages
 Normally transient
• related to parasite load
 Tropical splenomegally
• Proportion of adult develop very large spleens
• Genotype/IR genes
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Hepato-splenomegaly

10-15% die - survivors partially immune

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often with splenomegaly
Cerebral Malaria

 Coma 6- 96 hours
• shorter in children
 20% fatality
 Hepatoslenomegaly common
 Retinal haemorrhages

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Cerebral Malaria

Numerous small haemorrhages

of grey matter
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Brain section - P. falciparum

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Nephrosis

 Renal failure common in adults

• poor prognosis
 Transient Nephrosis
• all species
 Nephrotic Syndrome
• P. malariae - IC mediated

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Nephrosis

P. Malariae
quarten nephrosis 28
Blackwater Fever

 Massive intra vascular haemolysis

• haemoglobinuria
• acute renal failure
– tubule necrosis
• parasitemia may be absent
• nonimmune or G6PD deficiency + treatment -
autoimmuninty?
 Mortality 20-30%
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Pregnancy

 Serious complication in pregnancy

• maternal deaths, foetal death (x10) & foetal
retardation
 Placental sequestration & clumping
• accumulation of intervillus macrophages &
fibrin deposits

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Section of Placenta

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 Diagnosis

 Clinical symptoms
– Regular fevers / possible exposure
 Stained fixed blood smear
– Thick film - presence/absence
– Thin film - morphology/species
 Blood
– Capillary - fluorescence
– Antigen capture
– PCR/Mabs
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Chemotherapy

 Quinine
• Extract of tree bark
• used since 17th century
• 1.3 - 2.0g/day for 7 -10 days
• Tonic water!
– Methylene blue
– pamaquine
– mepacrine
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Synthetic antmalarials

 Chloroquine
• Developed by Bayer in 1934 (toxic!)
• Rediscoved in the mid 1940’s
– selective uptake by food vacuole
– intefers with haem polymersiation/detox reactive
oxygen species
• Resistance in humans early 1960’s

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Other Antimalarials

 Proguanil - 1948
 Primaquine - 1951
 Pyrimethamine - 1952
 Cycloquanil - 1963

Resistant strains by late 1960’s

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Treatment v Prophylaxis

 Monotherapy
 Treatment
• high dose short term
 Prophylaxis
• low dose long term

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 Immune Mechanisms
 Antibody blocks merozoite infection of RBC’s
• passive transfer experiment in the Gambia
 Enhance clearance through opsonisation
 ADCC likely
 NK activity
 Decrease in circulating T cells
 Down regulation of T cell function
Spleen - spleenectomy!
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Cytokines

 IL1

 TNF

 IL10

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Stage specific

 Anti sporozoite antibodies in adults in

endemic areas- blocks liver invasion
 Anti sporozoite/merozoite antibodies -
block rbc invasion
 TNF blocks merozoite development
 Erythrocyte clearance - liver and spleen
 Block cyto-adherence
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Immunomodulation

 Poly clonal T & B activation

• auto antibodies - anaemia?
 Immunodepression
• humoral & cellular - T, B & macrophage

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Immunopathology

 Fever
• correlates with schizont rupture
• IL1 & TNF
 Anaemia
• common complication exceeds parasitemia &
may worsen after treatment
• T cell control of spllenomegally/bone marrow

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Immunopathology 2

 Cerebral malaria
• highly reversible
• Under T cell control - IL1/TNF
 Glomerulonephritis
• Not very common - acute nephritis reversed by
treatment
• IgM, IgG & C3 - autoimmune?
• treatment mediated
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