A part of an intra-departmental symposium on malaria. Epidemiology, Pathogenesis, life-cycle covered.

1. Malaria
DR ANDREA JOSEPHINE R,
1ST YEAR MD PG,
DEPT. OF PEDIATRICS,
ESIC MEDICAL COLLEGE &
PGIMSR,
CHENNAI.

2. Contents
1. Disease Burden
2. Etiology
3. Disease Transmission
4. Life – cycle
5. Pathogenesis

3. World Malaria Report 2014 - WHO
2014 – 97 countries – Ongoing transmission
3.2 bn at risk: 1.2 bn at high risk (>1 case/1000 popn)
198 mn cases of malaria world-wide
5.84 lakh deaths: 90% in Africa-
4.37lakh children died before their 5th birthday of malaria
4.53 lakh under-five deaths due to malaria
On the brighter side, 26% reduction in the prevalence of malaria
47% reduction in the malaria mortality rate.

4. World Malaria Report 2014

5. World Malaria Report 2014- India
1.2 bn at risk
275mn – high transmission (>1case/1000popn.) – 22%
839mn – low transmission (0-1cases/1000popn.) – 67%
138mn – Malaria-free – 11%
Reported confirmed cases – 8.81 lakhs
Reported deaths – 440
53% d/t Pl. falciparum, 47% d/t Pl. vivax

6. World Malaria Report - India

7. Plasmodium species
Pl. falciparum – Malignant tertian
Pl. vivax – Benign tertian
Pl. ovale – Benign tertian
Pl. malariae – Benign quartan
Pl. knowlesi – Severe quotidian in SEAR since 1965.

8. Transmission patterns
1. Stable endemic: Natural transmission occurring over many years with predictable
incidence & prevalence
2. Unstable: Transmission rates vary from year to year; Low immunity, Greater chance of
epidemics.
Regions are classified based on parasite rate in children 2-9yrs old:-
1. Hypoendemic (0-10%)
2. Mesoendemic (11-50%)
3. Hyperendemic (>50%; large proportion of adults with enlarged spleens)
4. Holoendemic (consistently >75%; low proportion of adults with enlarged spleens)

9. Terms
Autocthonous: Acquired locally; May be indigenous or introduced.
Introduced: Migrant populations with asymptomatic infections serve as source
of infection.
Induced: Blood-borne transmission by Exposure to infected blood by
transfusion, organ donation, needle-stick injury, lab accident.
Cryptic: No explanation can be found, No epidemiologic link to other cases
found.
Congenital: by Transplacental transmission or breakdown of placental barrier
during labour or delivery.

10. Anopheles species
1. A. culicifacies – Rural – 65%
2. A. stephensi – Urban
3. A. fluviatilis – 15% - Plains & foothills

11. Life-cycle of Plasmodium

12. Life-cycle of Plasmodium
1. Exo-erythrocytic schizogony : Liver – 5-16days
Sporozoites → Infect hepatocytes → Schizonts → Merozoites
2. Erythrocytic schizogony: RBCs – 1-3days
Mero → Trophozoites → Merozoites
↓ ↓
Gametocyte Hypnozoites
3. Sporogonic cycle: Mosquito gut – 8-15days
Micro + Macro-gametes → Zygotes → Ookinetes → Oocysts→Sporozoites

13. Malaria Life-cycle

14. Host-Parasite interaction
1. Intensity of exposure
2. Presence of acquired immunity : Low in non-endemic areas, Infants, children
and pregnant women of endemic areas → Severe disease
3. Genetic factors:
Duffy-negative blood group: lack receptors for invasion of P. vivax merozoites
– Resistant to P. vivax infection
Sickle cell: Heterozygous with HbAS – Protected against severe malaria &
mortality.
Specific human leucocyte antigens in west Africa – protect against severe
malaria.

15. Pathogenesis
Schizogony in RBCs
Release of merozoites by lysis of RBCs
Release of toxic waste products-
RBC membrane products, hemozoin pigment, GPI
Activate macrophages and endothelium
Release cytokines, inflammatory mediators,
viz. TNF, IFN-ϒ, IL-1,6,8, Macrophage-CSF, Lymphotoxin, superoxide, NO
Headache, fever, rigors, nausea, diarrhea, anorexia, fatigue, myalgia,
thrombocytopenia, immunosuppression, coagulopathy

16. Pathogenesis
GPI: Glycosyl Phosphatidyl Inositol
GPI tail is common to several Merozoite Surface Proteins MSP-1,2 & 4.
Pl. vivax : More pyrogenic at lower levels of parasitemia –
Structural difference of GPI
Greater concentration of TLR-9 – stimulating motifs within P. vivax hemozoin

17. Pathogenesis
Hemozoin → Apoptosis of BM erythroid cells → Anemia
Plasmodial DNA: Also highly pro-inflammatory
Presented by hemozoin
Internalized, interacts with intracellular receptors
↓
NF-ĸß receptors
↓
Protein synthesis → COX-2 → Fever

18. Pathogenesis of Severe Malaria
1. Parasite bio-mass:
Pl. falciparum infects RBCs of all ages (up to 20-30% parasitemia)
Pl. vivax infects only young RBCs (<2% parasitemia)
2. Role of cytokines:
Initial response helps to limit the infection
Failure to down-regulate this response l/t excess cytokines
Cytokines → ↓Mitochondrial O2 use → ↑ Lactate production

19. Pathogenesis of Severe Malaria
2. Role of cytokines:
Increased cyto-adherence → Microvascular obstruction → Hypoxia
Loss of auto-regulation of local blood flow →Poor circulation↗
Dyserythropoiesis, Poor RBC deformability → Anemia
Decreased gluconeogenesis → Hypoglycemia
Myocardial depression → Cardiac insufficiency
Loss of endothelial integrity → Vascular damage in lungs & brain
Selective upregulation of ICAMs in Brain & placenta – Cerebral malaria & Placental
dysfunction
Activation of leucocytes & platelets → Pro-coagulant activity

20. Pathogenesis of severe malaria
3. Increased adhesiveness:
Knob protrusions appear on surface of infected RBCs – Areas of contact between infected
RBC and endothelium
Rosetting →Infected RBCs adhere to uninfected RBCs
Cyto-adherence → Sequestration by adherence to endothelium in heart, lung, liver,
kidney, intestines, subcutaneous tissues, adipose tissues and placenta → Micro-
aerophilic environ better suited to their maturation → Escape clearance by spleen and
immune destruction→
Unbridled multiplication →Blocks blood flow → ↓d O2 supply →
↓d mitochondrial ATP synthesis → Cytokine production → Severe disease

21. Pathogenesis of Severe Malaria
3. Increased adhesiveness:
P. Falciparum Erythrocyte Membrane Protein 1(PfEMP1)
Bind to ICAM-1, CD36, CSA(placenta)
Rosetting – Binding of PfEMP1 to CD31, complement receptor 1, Heparan
sulphate-like glycosaminoglycans of uninfected RBCs.
Rosetting less in blood group O RBCs – Protected from severe malaria.

22. Pathogenesis of Severe Malaria
4. RBC rigidity & deformability:
Hemin-induced oxidative damage of RBC membrane
Temperature-induced membrane fluctuations due to fever
Alteration in Phospholipid bilayer & attached spectrin network
Inhibition of Na/K pump
RBC rigidity & deformability → ↑ Clearance by spleen→Anemia
Hemolysis, Suppression of erythropoiesis by cytokines, Hemozoin-induced apoptosis in
developing RBCs → Anemia

23. Thank You