Pathology of malaria
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Pathology of Malaria. David P. Humber School of Biosciences University of East London. Learning Outcomes. Know the parasites, vector & epidemiology Understand of the life cycle Know the principal clinical features and pathology and the basis of diagnosis

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Pathology of malaria l.jpg

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

  • Phylum - Apicomplexa (Sporozoa)

  • Class - Haemosporidea (Sporozoea)

  • Order - Haemosporidia

  • Genus - Plasmodium


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Plasmodium falciparum

Malignant tertian (Cerebral)

Plasmodium vivax

Tertian

Plasmodium ovale

Tertian

Plasmodium malariae

Quartan

Common & Severe

Rare & Mild

Species Infecting Humans


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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

Species Infecting Humans


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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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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 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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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!

Clinical Features of Malaria


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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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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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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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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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