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Severe and fatal vivax malaria challenges 'benign tertian malaria' dogma

The report by Parakh and colleagues in this issue of Annals of Tropical Paediatrics (pp. 253–6) details six patients having vivax malaria with syndromes of severe malaria typically linked to falciparum malaria. The finding of cerebral or renal complications in addition to severe anaemia in patients found to be infected only by Plasmodium vivax raises questions that strike at the very foundations of our presumed understanding of pathogenesis by the plasmodial parasites that cause malaria. Malariologists have long viewed the two dominant plasmodia of humans, Plasmodium falciparum and P. vivax, through a malignant versus benign prism. No contemporary texts of medicine attribute to P. vivax the ability to provoke cerebral, pulmonary, hepatic, renal or haematological syndromes that threaten life. Most authoritative voices describe death by vivax malaria as exceedingly rare and almost always a consequence of rupture or infarct of the spleen. Consequently, distinctions in the respective cellular and molecular behaviours of P. falciparum versus P. vivax constituted a means of identifying putative determinants of lethal infection. Likewise, shared characteristics fell away from consideration as factors of virulence. This analytical lever delivered much of what today lies at the foundation of theory regarding the pathogenesis of falciparum malaria. Reports over the past 5 years challenge the notion of vivax malaria as a rare and fastidious killer. In patients where falciparum malaria and other endemic infections have been reliably excluded, vivax malaria appears to be the cause of cerebral malaria, severe anaemia, lung injury, respiratory distress, renal failure, hepatic dysfunction, sepsis and shock. The malignant–benign dichotomy between falciparum and vivax malaria, and much of the dogma on pathogenesis derived from it, seem positioned to fall. To take just one example, if a species of parasite lacking the molecular machinery of adherence to the walls of deep vasculature kills by the same set of syndromes as a species having arrays of such machinery, one may reasonably question the direct relevance of cyto-adherance processes to lethal pathogenesis. The description of severe disease syndromes in vivax malaria remains, at best, a very rough sketch. The science is very much incomplete, and the drawing of conclusions regarding pathogenesis would be very much premature. One of the principal questions is risk of severe disease relative to falciparum malaria. Do the case reports of severe vivax malaria represent clinical aberrations and biological outliers, or do they represent more typical courses of infection? Hospital-based studies that offer reliable denominators for assessing risk point to the typical end of that spectrum of possibility. However, one might ask whether those hospitals themselves represent epidemiological extremes atypical for most vivax patients. Addressing this question of risk relative to falciparum malaria will require broader reporting from care providers treating patients with vivax and falciparum malaria. Parakh and colleagues describe their six patients as a set of ‘uncommon manifestations’, but is this really so? Are these manifestations uncommon or simply unexpected? We are given no sense of denominators below the six. Over what period were they seen? How many vivax malaria patients were seen in that interval? Was severe falciparum malaria more common and more lethal in that interval? Whether severe disease syndromes in vivax malaria are Annals of Tropical Paediatrics (2009) 29, 251–252