The pathogenesis of severe falciparum malaria

Over a quarter of the world's population remains at risk of malaria and up to 250 million clinical cases occur each year of which over 1 million will die of Plasmodium falciparum infection. Why so many individuals are infected, but only relatively few proceed to severe disease such as cerebral malaria, severe anaemia or respiratory distress, remains poorly understood. A number of parasite-host interactions are important in the pathogenesis of severe falciparum malaria. One of the major determinants of parasite density, often related to disease severity, is the ability of the merozoite to invade red cells. The red cell glycophorins and at least one parasite component, EBA 175, appear to be involved. Adherence of parasitized red cells to endothelium (cytoadherence) is a feature of falciparum malaria and may serve to concentrate the effects of the parasite locally. The binding of uninfected red cells to parasitized red cells (rosetting) is one parasite phenotype that shows an association with disease severity. Whilst rosetting may increase sequestration of the parasitized cell in small vessels, it does not appear to enhance invasion. The production of a toxin (or toxins) by the parasite is currently favoured as a major pathogenic mechanism, but the conclusive identity and characterization of such molecules have yet to be resolved. Falciparum malaria in man occurs against the background of many genetic polymorphisms involving the red cell variants, the MHC complex, the TNF promoter and doubtless many others as yet undiscovered. Acquired factors such as the state of immunity of the individual, age, pregnancy, superinfection, mixed malarial infections and nutrition may influence disease severity and outcome. However, in a consideration of why patients with falciparum malaria continue to die, human factors which include a delay in seeking treatment, failure of prophylaxis and iatrogenically induced disease, cannot be omitted. In the pathogenesis of severe disease a number of anomalies exist. In cerebral malaria there is no consistent reduction in total cerebral blood flow, no marked inflammatory cell response, no tissue invasion or necrosis, no breakdown in the blood-brain barrier, no cerebral oedema, no disseminated intravascular coagulation or hypoglycaemia. Instead schizont-infected cells are packed or sequestered into the capillaries of the brain as a result of cytoadherence, rosetting and changes in red cell deformability. Raised intracranial pressure may also play a role leading to herniation of the brainstem and death. The role of NO in the coma of cerebral malaria remains an attractive hypothesis. Malarial anaemia, whilst primarily a result of haemolysis, also encompasses impaired red cell production. Respiratory distress, a newly identified feature of severe disease, will almost certainly prove to have a number of underlying causes and be of importance in assessing prognosis.