Evidence from a natural experiment that malaria parasitemia is pathogenic in retinopathy-negative cerebral malaria

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). DOI: http://dx.doi.org/10.7554/eLife.23699.001 eLife digest Malaria is a life-threatening disease caused by a parasite that is transferred between people by infected mosquitoes. Most infected individuals suffer flu-like symptoms, but in rare cases malaria can affect the brain, resulting in brain damage, coma or death. The World Health Organization defines a person as suffering from cerebral malaria if the person is in a coma, has malaria parasites in his or her blood, and has no known alternative cause of the coma. Patients suffering from cerebral malaria are categorized based on whether they have damage to the back of the eyes known as retinopathy. It had previously been found that children who died of “retinopathy-positive” cerebral malaria (i.e. those who had retinopathy) had malaria parasites stuck in small vessels in their brains, which likely caused the coma. By contrast, children who died of “retinopathy-negative” cerebral malaria lacked this parasitic condition, and often also had other infections that can cause a coma, such as meningitis or sepsis. Because hospitals in many of the areas most affected by malaria often lack the ability to identify what – other than malaria – caused a coma, it was not clear whether malaria parasites influence how retinopathy-negative cerebral malaria develops. People with certain genetic variants – such as those that underlie sickle cell disease – are protected against the symptoms of malaria infections, and so these variants should also protect against cerebral malaria cases caused by the parasites. Small et al. therefore looked through data that had been collected over several years from people who had been admitted to a hospital in Malawi for cerebral malaria. This revealed that the genetically inherited sickle cell trait is highly protective against retinopathy-negative (as well as retinopathy-positive) cerebral malaria. Therefore, malaria parasites do play a role in a substantial proportion of cases of retinopathy-negative cerebral malaria. Although Small et al. provide evidence that malaria parasites play a role in retinopathy-negative cerebral malaria, they may not be the only cause of the coma. In the future, the absence of retinopathy could be used as a sign to look for additional factors that contribute to the coma. Currently, all cerebral malaria patients are treated in the same way. Understanding how malaria parasites interact with other illnesses to produce a coma could lead to the development of targeted treatment plans for retinopathy-negative patients. DOI: http://dx.doi.org/10.7554/eLife.23699.002