Transcript Pathology of Malaria - University of East London

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
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The Parasite - Taxonomy
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•
•
•
Phylum - Apicomplexa (Sporozoa)
Class - Haemosporidea (Sporozoea)
Order - Haemosporidia
Genus - Plasmodium
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Species Infecting Humans

Plasmodium falciparum
Common & Severe
• Malignant tertian (Cerebral)

Plasmodium vivax
• Tertian

Plasmodium ovale
• Tertian

Plasmodium malariae
• Quartan
Rare & Mild
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Species Infecting Humans

Plasmodium falciparum
• Tropical Africa, Asia, Latin America

Plasmodium vivax
• Worldwide

Plasmodium ovale
Relapses
Fevers
No
24-48
Yes
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Yes
48
No
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• Tropical West Africa

Plasmodium malariae
• Worldwide but very patchy
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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
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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 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 sweating
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
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 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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