Abstract
Cerebral malaria (CM) can be classified as retinopathy-positive or retinopathy-negative, based on the presence or absence of characteristic retinal features. While malaria parasites are considered central to the pathogenesis of retinopathy-positive CM, their contribution to retinopathy-negative CM is largely unknown. One theory is that malaria parasites are innocent bystanders in retinopathy-negative CM and the etiology of the coma is entirely non-malarial. Because hospitals in malaria-endemic areas often lack diagnostic facilities to identify non-malarial causes of coma, it has not been possible to evaluate the contribution of malaria infection to retinopathy-negative CM. To overcome this barrier, we studied a natural experiment involving genetically inherited traits, and find evidence that malaria parasitemia does contribute to the pathogenesis of retinopathy-negative CM. A lower bound for the fraction of retinopathy-negative CM that would be prevented if malaria parasitemia were to be eliminated is estimated to be 0.93 (95% confidence interval: 0.68, 1).
Highlights
Cerebral malaria (CM) is responsible for a substantial proportion of the approximately 500,000 annual malaria deaths and 2,000,000 severe malaria cases (WHO, 2014, World Health Organization (WHO), 2015)
Using data gathered from 1996 to 2007 in a study of CM pathogenesis in Blantyre, Malawi (Taylor et al, 2004; Seydel et al, 2015) as well as the MalariaGEN consortium (Malaria Genomic Epidemiology Network, 2008), we compared children with CM to two types of controls – (1) community controls; (2) hospital controls, children who were admitted to the Paediatric Research Ward with a known non-malarial cause of illness – meningitis, non-malarial anemia or other non-malaria illness
We have studied a natural experiment that alters the level of malaria illness and found evidence that children with genetic traits associated with resistance to malaria illness are underrepresented in admissions with both Ret+ and Ret- CM (HbAS) or in admissions with Ret+ CM only (BGO)
Summary
Cerebral malaria (CM) is responsible for a substantial proportion of the approximately 500,000 annual malaria deaths and 2,000,000 severe malaria cases (WHO, 2014, WHO, 2015). Based on the presence or absence of malaria-specific retinal changes, CM can be classified as retinopathy-positive (Ret+) or retinopathy-negative (Ret-) (Lewallen et al, 1999; Beare et al, 2006). Ret- CM is a common and devastating condition – 40% of CM cases in our cohort were Ret- and of these, 12% died and 10% developed neurological problems (Table 1). Autopsy data show that children dying of Ret+ CM have a high degree of sequestration of parasitized red blood cells in cerebral vasculature (Taylor et al, 2004), considered the pathological hallmark of CM.
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