Pathology of Malaria

1
Pathology of Malaria

• David P. Humber
• School of Biosciences
• University of East London

2
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

3
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

4
The Parasite - Taxonomy

• Phylum - Apicomplexa (Sporozoa)
• Class - Haemosporidea (Sporozoea)
• Order - Haemosporidia
• Genus - Plasmodium

5
Species Infecting Humans

• Common Severe
• Rare Mild

• Plasmodium falciparum
• Malignant tertian (Cerebral)
• Plasmodium vivax
• Tertian
• Plasmodium ovale
• Tertian
• Plasmodium malariae
• Quartan

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Species Infecting Humans

• Relapses Fevers
• No 24-48
• Yes 48
• Yes 48
• No 72
• Rare Mild

• Plasmodium falciparum
• Tropical Africa, Asia, Latin America
• Plasmodium vivax
• Worldwide
• Plasmodium ovale
• Tropical West Africa
• Plasmodium malariae
• Worldwide but very patchy

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Epidemiology

• gt400 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 lt300m
• 64oN to 32oS

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Distribution of Malaria
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Life Cycle
Liver Schizont
Sporozoite
Trophozoite
Oocyst
RBC
Merozoite
Ookinete
Gametocytes
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Infected Liver CellHepatocyte
Pre-erythrocytic schizonts
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Erythrocytic forms (signet)
Young ring form trophozoites
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Gametocytes
P.falciparum
Macro
Micro
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Exflagellation
P. vivax produces 8 microgamentes in mosquitos
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

• Cold stage ???hr
• Headache/shiver/rapid weak pulse
• Hot stage 6hrs
• Intense headache/nausea/thirst/distress
• Sweating stage 4hrs
• Profuse sweating
• Sleep!

• Prepatent period
• Flu-like initially
• Intermittent fever
• Recurrence
• Coma/death
• Chronic infection
• Relapses

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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 _at_ 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 often
with splenomegaly
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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
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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 1940s
• selective uptake by food vacuole
• intefers with haem polymersiation/detox reactive
  oxygen species
• Resistance in humans early 1960s

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Other Antimalarials

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

Resistant strains by late 1960s
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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 RBCs
• 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