Risk Factors for Mortality in Children Hospitalized with Severe Malaria in Northern Zambia: A Retrospective Case-Control Study

Severe malaria, caused by the protozoan Plasmodium, is the leading parasitic cause of mortality worldwide. Plasmodium falciparum, the most lethal among human malaria parasites, predominates in sub-Saharan Africa where it causes a disconcerting 1,200 child deaths per day concentrated in regions where malaria has proven recalcitrant to control measures or where control measures are tenuous or absent.1,2 In Zambia, there were an estimated 3.1 million cases of malaria (severe and uncomplicated) in 2016 among its population of 16.7 million and it was most prevalent in northern Zambia where it persists year round despite the recent scale-up of vector control efforts.2,3 Severe malaria can feature one or more of severe anemia (hemoglobin < 5 g/dL), cerebral edema, lactic acidosis, respiratory failure, or shock. In high-transmission, resource-limited settings, malaria evades easy case definition and is often clinically indistinguishable from bacterial meningitis, pneumonia, bacteremia, and other febrile diseases which can conflate or confuse diagnosis.4 Only a small proportion (∼2%) of P. falciparum infections progress to severe malaria, but in highly malarious regions where children may experience several infections a year, the absolute number of cases is large.5 Prompt initiation of treatment is vital. Rapid disease progression is fueled by an exponential expansion of parasites and an exuberant host immune response, and hospital deaths occur most often within 24 hours of admission.5,6 The preferred treatment is intravenous artesunate and supportive care as indicated (e.g., fluid resuscitation, blood transfusion, anticonvulsants, and ventilator and vasopressor support), but even with appropriate care, mortality can reach 20%.5 Delayed presentation to allopathic health providers on account of logistical constraints or health-seeking behaviors compounds the danger.7 Distinguishing factors that contribute to poor outcomes for children with malaria can inform clinical and programmatic strategies to lessen its toll. However, research is limited by the inherent challenges of conducting intrahospital epidemiologic studies in rural centers where malaria prevalence is greatest. We present results of a retrospective, time-matched, case-control study of hospitalized children with malaria who died (cases) and those who survived (controls) at a rural, district-level hospital in a high-transmission region of northern Zambia to identify and evaluate demographic and clinical factors associated with increased risk of death.