Circulating Immune Complexes and Glucose-6-Phosphate Dehydrogenase Deficiency Predict Recurrent Blackwater Fever in Ugandan Children With Severe Malaria

Background Recently, there has been an unexplained increase in the incidence of blackwater fever (BWF) in Eastern Uganda. In this study, we evaluated the association between immune complexes, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and the occurrence and recurrence of BWF in children with severe malaria (SM). Methods Between 2014 and 2017, children aged 6 months to <4 years hospitalized with SM and community children (CC) were recruited at 2 hospitals in Central and Eastern Uganda. We measured serum circulating immune complexes (cIC) and their relationship to SM complications and postdischarge outcomes, and evaluated effect mediation through G6PD deficiency. Results In total, 557 children with SM and 101 CC were enrolled. The mean age was 2.1 years. Children with SM had higher cIC levels than CC (P <. 001). After controlling for age, sex, and site, cIC were associated with severe anemia, jaundice, and BWF: adjusted odds ratio (aOR), 7.33 (95% confidence interval [CI], 3.45-15.58), P <. 0001; aOR, 4.31 (95% CI, 1.68-11.08), P =. 002; and aOR, 5.21 (95% CI, 2.06-13.18), P <. 0001, respectively. cIC predicted readmissions for SM, severe anemia, and BWF: adjusted incidence rate ratios (aIRR), 2.11 (95% CI, 1.33-3.34), P =. 001; aIRR, 8.62 (95% CI, 2.80-26.59), P <. 0001; and aIRR, 7.66 (95% CI, 2.62-22.45), P <. 0001, respectively. The relationship was most evident in boys where the frequency of the G6PD African allele (A^-) was 16.8%. G6PD deficiency was associated with increases in cIC in boys (P =. 01) and mediation analysis suggested G6PD deficiency contributes to recurrent severe anemia and BWF via increased cIC. Conclusions Immune complexes are associated with hemolytic complications and predict recurrences in SM survivors.