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Pathology of Malaria

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

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  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. Plasmodium falciparum Malignant tertian (Cerebral) Plasmodium vivax Tertian Plasmodium ovale Tertian Plasmodium malariae Quartan Common & Severe Rare & Mild Species Infecting Humans

  6. 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

  7. 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

  8. Distribution of Malaria

  9. Life Cycle Liver Schizont Sporozoite Trophozoite Oocyst RBC Merozoite Ookinete Gametocytes

  10. Infected Liver CellHepatocyte Pre-erythrocytic schizonts

  11. Erythrocytic forms (signet) Young ring form trophozoites

  12. Gametocytes P.falciparum Macro Micro

  13. Exflagellation P. vivax produces 8 microgamentes in mosquito’s midgut

  14. 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

  15. 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

  16. 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

  17. 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)

  18. 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) . . . . . . . . .

  19. Fever Charts

  20. 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?)

  21. Site Specific Sequestration • Brain • measurable reduction in blood flow • Intestines • diarrhoea • Placenta • intervillus space

  22. 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

  23. Hepato-splenomegaly 10-15% die - survivors partially immune often with splenomegaly

  24. Cerebral Malaria • Coma 6- 96 hours • shorter in children • 20% fatality • Hepatoslenomegaly common • Retinal haemorrhages

  25. Cerebral Malaria Numerous small haemorrhages of grey matter

  26. Brain section - P. falciparum

  27. Nephrosis • Renal failure common in adults • poor prognosis • Transient Nephrosis • all species • Nephrotic Syndrome • P. malariae - IC mediated

  28. Nephrosis P. Malariae quarten nephrosis

  29. 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%

  30. Pregnancy • Serious complication in pregnancy • maternal deaths, foetal death (x10) & foetal retardation • Placental sequestration & clumping • accumulation of intervillus macrophages & fibrin deposits

  31. Section of Placenta

  32. 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

  33. 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

  34. 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

  35. Other Antimalarials • Proguanil - 1948 • Primaquine - 1951 • Pyrimethamine - 1952 • Cycloquanil - 1963 Resistant strains by late 1960’s

  36. Treatment v Prophylaxis • Monotherapy • Treatment • high dose short term • Prophylaxis • low dose long term

  37. 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!

  38. Cytokines • IL1 • TNF • IL10

  39. 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

  40. Immunomodulation • Poly clonal T & B activation • auto antibodies - anaemia? • Immunodepression • humoral & cellular - T, B & macrophage

  41. Immunopathology • Fever • correlates with schizont rupture • IL1 & TNF • Anaemia • common complication exceeds parasitemia & may worsen after treatment • T cell control of spllenomegally/bone marrow

  42. 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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