Elevated levels of nitric oxide and low levels of haptoglobin are associated with severe malarial anaemia in African children

Severe malarial anaemia (SA) is a major complication of malaria and an important cause of child mortality and morbidity. However, the pathogenesis behind SA is poorly understood. Nitric oxide (NO) is known to play a protective role against clinical malaria but is also suggested to have a pathogenic role in cerebral malaria (CM). Erythrophagocytosis by splenic macrophages has been implicated in the pathogenesis of SA. In this study, plasma levels of NO, neopterin, haptoglobin and C-reactive protein (CRP) were measured in paediatric patients with CM, n=77, SA (n=28) and uncomplicated malaria (UM n=53). Haptoglobin levels were significantly lower in SA (median (interquartile range) 25 (17–59) mg/l) than in both CM and UM (40 (24–80) mg/l and 110 (60–160) mg/l, respectively, P<0.001). In contrast, NO levels were higher in SA (38 (28–51) μmol/l) than in CM and UM (21 (15–32) μmol/l and 10.3 (5.6–17) μmol/l, respectively, P<0.001). A significant negative correlation between haptoglobin and NO was seen in the SA group. No such correlation was observed within the UM or CM groups. No significant differences in neopterin levels were observed between any of the three groups, neither was there any correlation between parasitaemias and neopterin levels. The low haptoglobin and high levels of NO in this SA group may contribute to haemolysis. Taken together our results support the hypothesis that immune-mediated erythrocyte destruction is involved in the pathogenesis of malarial anaemia.