Improving the diagnosis of severe malaria in African children using platelet counts and plasma PfHRP2 concentrations

Background Severe falciparum malaria is difficult to diagnose accurately in children in high transmission settings. Platelet counts and plasma concentrations of P. falciparum histidine-rich protein-2 (PfHRP2) are potential biomarkers to increase diagnostic accuracy. Methods We fitted Bayesian latent class models to platelet counts and PfHRP2 concentrations in 2,649 patients enrolled in four studies of severe illness in three countries (Bangladesh, Kenya, and Uganda). We estimated receiver operating characteristic curves and compared parasite densities, haematocrits, total white blood cell counts, blood culture positivity rates, and haemoglobin S genotypes (HbAS and HbSS) across the subgroups defined by the probabilistic models. Findings The platelet count and the plasma PfHRP2 concentration have substantial diagnostic value in severe malaria. In severely ill patients with clinical features consistent with severe malaria, a combined platelet count [≤]150,000 per L and a plasma PfHRP2 concentration [≥]1,000 ng/mL had an estimated sensitivity of 74% and specificity of 93% in identifying `true' severe falciparum malaria. We estimate one third of African children enrolled in the two clinical studies of severe malaria had another cause of severe illness. Under the model, patients with severe malaria had higher parasite densities, lower haematocrits, lower rates of invasive bacterial disease, and a lower prevalence of both HbAS and HbSS than children misdiagnosed. Mortality in `true' severe malaria was consistent across the African sites at {approx}10%. Interpretation Studies of severe falciparum malaria in African children would be improved by including only patients with platelet counts [≤]150,000 per L and plasma PfHRP2 concentrations [≥]1,000 ng/mL. Funding Wellcome