1 Pathology of Malaria David P. Humber School of Biosciences University of East London.

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Pathology of Malaria

David P. HumberSchool of BiosciencesUniversity 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

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The Parasite - Taxonomy

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

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Species Infecting Humans

Plasmodium falciparum• Malignant tertian (Cerebral)

Plasmodium vivax• Tertian

Plasmodium ovale• Tertian

Plasmodium malariae• Quartan

Common & Severe

Rare & Mild

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Species Infecting Humans

Plasmodium falciparum• Tropical Africa, Asia, Latin

America Plasmodium vivax

• Worldwide Plasmodium ovale

• Tropical West Africa Plasmodium malariae

• Worldwide but very patchy

Relapses Fevers

No 24-48

Yes 48

Yes 48

No 72

Rare & Mild

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Epidemiology

>400 million cases annually3 million deaths

majority 2-5 years103 endemic countries

most in Africamost due to P.falicparum

Need 15oCfor 4 weeks <300m64oN to 32oS

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Distribution of Malaria

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Life Cycle

Sporozoite Liver Schizont

Oocyst

Ookinete

Trophozoite

Merozoite

Gametocytes

RBC

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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

MicroMacro

P.falciparum

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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 Flu-like initially Intermittent fever Recurrence Coma/death

Chronic infection Relapses

Cold stage hr• Headache/shiver/rapid

weak pulse Hot stage 6hrs

• Intense headache/nausea/thirst/distress

Sweating stage 4hrs• Profuse sweatingSleep!

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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 immuneoften 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 haemorrhagesof 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 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