Pathology of Malaria

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

Learning Outcomes
Know the parasites, vector & epidemiology a Understand of the life cycle a Know the principal clinical features and pathology and the basis of diagnosis a Appreciate the difficulties of control
a

2

The Problem
a

At Risk
• More than 40% of the world population

a

Deaths
• More than 2 million per year

a

Chemotherapy
• Limited Drugs & drug resistance

Vector control a Vaccination
a
3

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

4

Species Infecting Humans
a

Plasmodium falciparum
• Malignant tertian (Cerebral)

Common & Severe

a

Plasmodium vivax
• Tertian

a

Plasmodium ovale
• Tertian

a

Plasmodium malariae
• Quartan
Rare & Mild
5

Species Infecting Humans
a

Plasmodium falciparum
• Tropical Africa, Asia, Latin America

Relapses

Fevers

No Yes Yes No

24-48 48 48 72

a

Plasmodium vivax
• Worldwide

a

Plasmodium ovale
• Tropical West Africa

a

Plasmodium malariae
• Worldwide but very patchy
Rare & Mild

6

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

7

Distribution of Malaria

8

Life Cycle
Sporozoite Liver Schizont

Oocyst

Trophozoite RBC Merozoite

Ookinete Gametocytes
9

Infected Liver CellHepatocyte
Pre-erythrocytic schizonts

10

Erythrocytic forms (signet)

Young ring form trophozoites

11

Gametocytes
P.falciparum

Micro

Macro

12

Exflagellation

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

Clinical Features
a

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

14

Clinical Features of Malaria
a a a a a

Prepatent period Flu-like initially Intermittent fever Recurrence Coma/death Chronic infection Relapses

a

Cold stage ≅ 1hr
• Headache/shiver/rapid weak pulse

a

Hot stage 6hrs
• Intense headache/nausea/thirst/di stress

a

Sweating stage 4hrs
• Profuse sweating Sleep!
15

a a

Tertian Malaria - P. vivax & P. ovale
Rarely fatal- relapses common a Prodrome
a

• myalgia, headache, chilliness, low grade irregular fever (no sync maturation cycle)

Synchronisation @ 5-7 days - paroxysms on alternate days a Spleen palpable 10-14 days a P. ovale milder with shorter initial attacks
a
16

Qartan Malaria - P. malariae
Paroxysms every third day a Mildest and most chronic of the 4 a immune complex nephropathy a seasonal variation with P.f (wet season)
a

17

Falciparum Malaria
a

Cause of virtually all malaria deaths
• asynchronous cycle • onset insidious - fever variable • Rapid onset of splenomegaly

a

Severe anaemia, jaundice, hyperventilation, cns dysfunction (delirium, stupor, coma) . . . . . ....
18

Fever Charts

19

Untreated P. falciparum malaria
a

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?)

20

Site Specific Sequestration
a

Brain
• measurable reduction in blood flow

a

Intestines
• diarrhoea

a

Placenta
• intervillus space

21

Hepatosplenomegaly
Hepatic dysfunction a Hyperplasia of splenic/liver macrophages a Normally transient
a

• related to parasite load
a

Tropical splenomegally
• Proportion of adult develop very large spleens • Genotype/IR genes
22

Hepato-splenomegaly

10-15% die - survivors partially immune often with splenomegaly

23

Cerebral Malaria
a

Coma 6- 96 hours
• shorter in children

20% fatality a Hepatoslenomegaly common a Retinal haemorrhages
a

24

Cerebral Malaria

Numerous small haemorrhages of grey matter

25

Brain section - P. falciparum

26

Nephrosis
a

Renal failure common in adults
• poor prognosis

a

Transient Nephrosis
• all species

a

Nephrotic Syndrome
• P. malariae - IC mediated

27

Nephrosis

P. Malariae quarten nephrosis

28

Blackwater Fever
a

Massive intra vascular haemolysis
• haemoglobinuria • acute renal failure
– tubule necrosis

• parasitemia may be absent • nonimmune or G6PD deficiency + treatment autoimmuninty?
a

Mortality 20-30%
29

Pregnancy
a

Serious complication in pregnancy
• maternal deaths, foetal death (x10) & foetal retardation

a

Placental sequestration & clumping
• accumulation of intervillus macrophages & fibrin deposits

30

Section of Placenta

31

Diagnosis
a a

Clinical symptoms
– Regular fevers / possible exposure

Stained fixed blood smear
– Thick film - presence/absence – Thin film - morphology/species

a

Blood
– Capillary - fluorescence – Antigen capture – PCR/Mabs
32

Chemotherapy
a

Quinine • Extract of tree bark • used since 17th century • 1.3 - 2.0g/day for 7 -10 days • Tonic water!
– Methylene blue – pamaquine – mepacrine
33

Synthetic antmalarials
a

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

34

Other Antimalarials
Proguanil - 1948 a Primaquine - 1951 a Pyrimethamine - 1952 a Cycloquanil - 1963
a

Resistant strains by late 1960’s
35

Treatment v Prophylaxis
Monotherapy a Treatment
a

• high dose short term
a

Prophylaxis
• low dose long term

36

Immune Mechanisms
a

Antibody blocks merozoite infection of RBC’s
• passive transfer experiment in the Gambia

Enhance clearance through opsonisation a ADCC likely a NK activity a Decrease in circulating T cells a Down regulation of T cell function Spleen - spleenectomy!
a
37

Cytokines
a

IL1 TNF IL10

a

a

38

Stage specific
Anti sporozoite antibodies in adults in endemic areas- blocks liver invasion a Anti sporozoite/merozoite antibodies block rbc invasion a TNF blocks merozoite development a Erythrocyte clearance - liver and spleen a Block cyto-adherence
a
39

Immunomodulation
a

Poly clonal T & B activation
• auto antibodies - anaemia?

a

Immunodepression
• humoral & cellular - T, B & macrophage

40

Immunopathology
a

Fever
• correlates with schizont rupture • IL1 & TNF

a

Anaemia
• common complication exceeds parasitemia & may worsen after treatment • T cell control of spllenomegally/bone marrow
41

Immunopathology 2
a

Cerebral malaria
• highly reversible • Under T cell control - IL1/TNF

a

Glomerulonephritis
• Not very common - acute nephritis reversed by treatment • IgM, IgG & C3 - autoimmune? • treatment mediated
42

Sign up to vote on this title
UsefulNot useful