1 pathology of malaria david p. humber school of biosciences university of east london
TRANSCRIPT
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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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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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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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Cerebral Malaria
Coma 6- 96 hours• shorter in children
20% fatality Hepatoslenomegaly common Retinal haemorrhages
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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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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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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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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