Describe the malarial parasites, their life cycle and the pathogenesis of malaria.

The Parasites and the Vector

• The vector is the female anopheles mosquito, which bites from dusk to dawn; the male does not take blood meals. In India the principal vectors are An. Culicifacies (rural), An. Stephensi (urban, breeding in overhead tanks and construction sites), An. Fluviatilis and An. Dirus
• The mosquito is the definitive host, because the sexual cycle occurs in it; man is the intermediate host. This is the reverse of what intuition suggests

Life Cycle

• An infected female Anopheles injects sporozoites in saliva while feeding → Sporozoites reach the liver within 30 minutes and invade hepatocytes — pre-erythrocytic (exo-erythrocytic) schizogony → Each liver schizont ruptures to release thousands of merozoites. In P.
• Vivax and P.
• Ovale some sporozoites instead become dormant hypnozoites → Merozoites invade red cells — erythrocytic schizogony: ring → trophozoite → schizont → The schizont ruptures, releasing merozoites that invade fresh red cells.
• synchronous rupture is what produces the paroxysm of fever, and its interval determines the periodicity → Some merozoites develop into male and female gametocytes — the only form infective to the mosquito, and the form responsible for transmission → In the mosquito gut: gametogony and fertilisation → ookinete → OOCYST on the gut wall → sporogony → Sporozoites migrate to the salivary glands, and the mosquito is infective for life

Pathogenesis

• Fever — caused by the synchronous rupture of schizonts releasing merozoites, malarial pigment (haemozoin) and glycosylphosphatidylinositol, which trigger TNF-alpha and other cytokines. The classical paroxysm has a cold stage (rigor), a hot stage and a sweating stage
• Anaemia — multifactorial and often out of proportion to the parasitaemia: lysis of infected cells, destruction of uninfected cells (the major component), splenic clearance, dyserythropoiesis and marrow suppression, and in P. Falciparum also blackwater fever (massive intravascular haemolysis with haemoglobinuria)
• Splenomegaly from reticuloendothelial hyperplasia; and hyperreactive malarial splenomegaly in chronic exposure
• Sequestration — the key to severe falciparum malaria: infected red cells express PfEMP1 on surface knobs, which binds endothelial receptors (ICAM-1, CD36, chondroitin sulphate A) — cytoadherence. They also bind uninfected cells (rosetting) and each other (autoagglutination)
• The consequences of sequestration — microvascular obstruction with tissue hypoxia and acidosis; it explains cerebral malaria, and it explains why schizonts are absent from the peripheral film in falciparum malaria and why the peripheral parasite count underestimates the true burden
• Placental malaria — sequestration in the placenta through chondroitin sulphate A binding causes maternal anaemia, low birth weight and fetal loss; primigravidae are particularly affected because they lack specific antibody

Genetic Protection and Immunity

• Immunity is slow, incomplete and species- and strain-specific, requiring repeated infection over years. It reduces severity rather than preventing infection, and it wanes when exposure ceases
• Premunition — immunity that persists only while a low-grade infection continues
• The practical consequences — in a high-transmission area severe disease is confined to young children and pregnant women; in a low-transmission area all ages are susceptible; and someone who leaves an endemic area and returns after some years has lost their protection

Distinguishing the Species on a Blood Film

Applied Aspects

• Ask the species before deciding the treatment; vivax needs radical cure with primaquine and falciparum needs an artemisinin combination, and mixed infection is common in India
• Sequestration means the peripheral count understates severity in falciparum malaria; a modest parasitaemia with clinical severity should not be reassuring
• Suspect malaria in any fever in an endemic area, and in a returning traveller for at least a year afterwards; the classical periodicity is often absent early in the illness
• Malaria in pregnancy requires particular vigilance, since placental sequestration may cause severe maternal anaemia and fetal loss with a low or even negative peripheral film
• India has both P. Vivax and P. Falciparum in large numbers, with falciparum predominating in the north-east and in tribal districts; the National Framework aims at elimination
• Screen for G6PD deficiency before primaquine, since the drug causes severe haemolysis in deficient individuals — and G6PD deficiency is itself common in malarious populations for the same evolutionary reason
• The mosquito is the definitive host, which is worth stating explicitly because it is counterintuitive and is a favourite examination point
• Banana-shaped gametocytes identify P. Falciparum even when ring forms are scanty, and they may persist for weeks after cure without indicating treatment failure
• Thrombocytopenia is present in most patients with malaria and is a useful early pointer in an undifferentiated fever, though it is not specific
• Anaemia is often disproportionate to the parasitaemia, because most of the destruction falls on uninfected red cells; so a low count on the film does not explain away a severe anaemia
• Malaria can be transmitted by transfusion and by shared needles, since the blood stages are directly infective; donor screening matters in endemic areas
• Transfusion-transmitted malaria has NO liver stage, so no hypnozoites form and primaquine radical cure is unnecessary even for P. Vivax
• Congenital malaria occurs and should be considered in a neonate with fever, anaemia and jaundice born to a mother from an endemic area
• Sickle trait persists because it protects against malaria, and this balanced polymorphism is the clearest example in human genetics of a lethal gene maintained by selection
• Immunity wanes when exposure stops, so a person who has lived abroad for some years and returns to visit family is at real risk despite having grown up in an endemic area — a group that frequently omits prophylaxis
• Splenomegaly rates in children were historically used to measure endemicity, and the spleen rate remains a simple field index of transmission
• Placental sequestration may give a negative peripheral film in a pregnant woman with significant malaria, so a normal film does not exclude it where suspicion is high