Specific Biomarkers Differentiate Cerebral Malaria From Other Causes of Coma in African Children

BACKGROUND: Cerebral malaria (CM) is a serious complication of Plasmodium falciparum malaria that causes coma and, frequently, death. In malaria-endemic settings, a large percentage of the population presents with incidental P falciparum malaria parasitemia. In the absence of specific biomarkers for CM, when these individuals suffer from bacterial or viral infections causing coma, they are frequently misdiagnosed with CM. METHODS: We have tested the specificity for CM of 2 candidate biomarkers for severe malaria, angiopoietin-like 4 (ANGPTL4) and inhibin-βE (INHBE), which are secreted by endothelial cells in response to P falciparum-infected erythrocytes. The levels of these biomarkers were determined retrospectively in the plasma of a cohort of 379 Kenyan children including cases of severe malaria caused by CM, respiratory distress, or severe anemia, as well as cases of nontraumatic coma of unknown cause. RESULTS: ANGPTL4 and INHBE showed high specificity for severe malaria, including CM (area under the curve [AUC] 0.82), respiratory distress (AUC 0.86), and severe anemia (AUC 0.85), when compared to acute nontraumatic coma of nonmalarial etiology. Specificity was further increased when the biomarkers were used in combination with platelet levels (AUC 0.96). ANGPTL4 and INHBE are also predictors of death by CM (AUC 0.85). CONCLUSIONS: ANGPTL4 and INHBE could be developed as a diagnostic tool for the differentiation of comatose patients with CM from other causes of coma.