The Pathogenic Basis of Malaria

Dr Kartun SpA MSc

Clinical Outcome
 Level of endemicity: Acquired immunity

• High malaria transmission area:

– greatest disease burden in underfives and
pregnant women
– High number of asymptomatic malaria and
chronic anaemia in older children and adults

• Low malaria transmission area:

– All age groups are at risk of severe disease
– Mostly symptomatic
 Topics
• Red Blood Cells (RBCs) Invasion
• Binding of parasitized RBCs to vascular
endothelium and placenta
• Pro-inflammatory immune response

(Nature: Miller et al, 2002)

 Red Blood Cells Invasion
• P. falciparum:
– Invade rapidly all stages of RBCs
– Posses alternative invasion pathways

• P. vivax:
– mainly invade Duffy positive and target young RBCs
(reticulocytes)
– Gametocytes are released earlier than Pf
– Pv has hypnozoites form that remains dormant and
maintain transmission
 (Nature: Miller et al, 2002)
PfEMP1: P. falciparum erythrocytes membrane proteins-1
(Nature: Miller et al, 2002)
 Binding of parasitized RBCs to vascular
endothelium and placenta
• P. falciparum:
– Asexual parasites and gametocytes can adhere in
the endothelium and asexual parasite can adhere
in the placenta (trophozoits and schizonts)
– Only ring form found in the circulating blood

• Protective mechanism to avoid parasite

destruction by the spleen
 Pro inflammatory immune response and
pathogenesis

• T cells produce: TNF α, IFN γ and IL 2 (major

role in Pf infections)
• Monocytes/macrophages releases TNF α and
NO
• High TNF α in Pf is associated with disease
severity
• High TNF α in Pv infections is due to chronic
untreated Pv malaria (also associated with
thrombocytopenia)
• Inducer of pro-inflammatory cytokines: GPI
(Glycosilphosphatidylinositol) anchor from
MSP1 and MSP2 (Parasites proteins:
Merozoite surface proteins)
• Antibody to GPI are associated with clinical
immunity
• Interaction of innate and adaptive immunity
 Nitric Oxide
• Monocytes: Nitric Oxide synthase (NOS2) gene
modulates NO productions
• Antimicrobial activity
• Reduce TNF α activity to reduce cyto adherence and
tissue damage
• Higher NO production was considered to have protective
effect from cerebral malaria in Tanzanian children
• L-Arginine (substrate for NO synthesis): adjunctive Tx for
severe malaria

(Hobbs et al., 2002; Anstey et al, 1996; Yeo et al, 2008)

 Severe Malaria

• Rapid expansion of infected RBCs

• Destruction of both infected and uninfected RBCs
• Micro-vascular obstruction
• Inflammatory processes

Reduced tissue perfusion

 WHO Criteria of Severe Malaria
1. Cerebral Malaria
2. Pulmonary Edema/Respiratory distress
3. Severe Anaemia (Hb<5 g/dl)
4. Renal failure
5. Hypoglicemia
6. Hypotension/Shock
7. Spontaneous bleeding
8. Convulsion
9. Acidemia
10.Black Water Fever
WHO (2000) Severe falciparum malaria. Trans R Soc Trop Med Hyg 94
Suppl 1: S1-90.
1. GCS < 11/15 or Blantyre<2 / 5,
2. Hb<5g/dl,/Hct<15%
3. Visible Jaundice and >100,000 parasites /ul, or Cr>1.5
4. Cr>3mg/dl +/- Urine Output <400ml day-1
5. Plasma Glucose < 40mg/dl
6. Asexual Parasitaemia > 10%.
7. BPs <80mmHg and cool peripheries
8. Blackwater fever
9. Acidosis HCO3<15
10. Resp Insufficiency (central cyanosis or RR>32min or
deep breathing in children)
11. Prostration
 Severe Vivax Malaria
• Risk of severe disease are greater in Pv (23%,
675/2937) than in Pf (20%, 1570/7817)
malaria, p=0.001
• Severe anaemia accounted for 87% (589/675)
of severe disease in Pv vs 73% (1144/1570) in
Pf (p<0.001)
• 78 patients with pure Pv had respiratory
distress and 42 had coma
 Severe Vivax Malaria
Pathophysiology
• Severe anaemia: recurrent hemolysis of
predominantly uninfected erythrocytes with
increased fragility
• Lung: Pv may sequester within pulmonary
vasculatures and associated with
inflammatory increases in alveolar capillary
membrane permeability
• Coma: requires further understanding in
pathobiology of Pv infections
 Severe Vivax Malaria

• Price RN, Tjitra E, Guerra CA, Yeung S, White NJ, et al. (2007) Vivax
malaria: neglected and not benign. Am J Trop Med Hyg 77: 79-87.

• Tjitra E, Anstey NM, Sugiarto P, Warikar N, Kenangalem E, et al. (2008)

Multidrug-resistant Plasmodium vivax associated with severe and fatal
malaria: a prospective study in Papua, Indonesia. PLoS Med 5: e128.
• Anstey NM, Russell B, Yeo TW, Price RN (2009) The pathophysiology of
vivax malaria. Trends Parasitol 25: 220-227.
 Clinical Importance

• Define malaria treatment and prevention

strategy
 How can we reduce mortality
from severe malaria?

1) Malaria prevention at community level

2) Better case management of uncomplicated malaria
• ACT antimalarials:
• more rapid cure
• higher cure rates
3) Better case management of severe malaria
Better case management of severe malaria

1) Kill parasites faster

• IV Artesunate (SEAQUAMAT Study)
2) Adjunctive Rx: reducing tissue
damage caused by blood
vessel obstruction
• L-Arginine
3) Better management of
complications
• Dialysis, fluids etc…
 Antimalarials for
Uncomplicated Malaria
• Each infections can consist of 2-3 asexual
cycles, each cycle take 48 hours (2 days)

Day 0 1 2 3 4 5 6 7-20 days

Infected asexual cycle Gametocytes

• 3 day Artemisinin treatment: dealing with 2

asexual cycles (Parasite reduction rate of 10,000)
• The slow acting partner drug is required to delay
the emergence of resistance
 Antimalarials for severe malaria
• Death in severe malaria : within 48 hours of
presentation (one asexual cycle of blood stage
infection)
• IMPORTANT: prevention of the development
from less pathogenic ring stages (0-16 hours)
to more pathogenic sequestered stages

Rapid acting antimalarials:

artesunate
TERIMAKASIH