Abstract
In the Fluid Expansion as a Supportive Treatment (FEAST) trial, an unexpectedly high proportion of participants from eastern Uganda presented with blackwater fever (BWF). We describe the prevalence and outcome of BWF among trial participants and compare the prevalence of 3 malaria-protective red blood cell polymorphisms in BWF cases vs both trial (non-BWF) and population controls. Of 3170 trial participants, 394 (12.4%) had BWF. The majority (318 [81.0%]) presented in eastern Uganda and were the subjects of further analysis. BWF cases typically presented with both clinical jaundice (254/318 [80%]) and severe anemia (hemoglobin level <5 g/dL) (238/310 [77%]). Plasmodium falciparum parasitemia was less frequent than in non-BWF controls, but a higher proportion were positive for P. falciparum histidine rich protein 2 (192/246 [78.0%]) vs 811/1154 [70.3%]; P = .014), suggesting recent antimalarial treatment. Overall, 282 of 318 (88.7%) received transfusions, with 94 of 282 (33.3%) and 9 of 282 (3.4%) receiving 2 or 3 transfusions, respectively. By day 28, 39 of 318 (12.3%) BWF cases and 154 of 1554 (9.9%) non-BWF controls had died (P = .21), and 7 of 255 (3.0%) vs 13/1212 (1%), respectively, had severe anemia (P = .036). We found no association with G6PD deficiency. The prevalence of both the sickle cell trait (10/218 [4.6%]) and homozygous α+thalassemia (8/216 [3.7%]) were significantly lower among cases than among population controls (334/2123 [15.7%] and 141/2114 [6.6%], respectively), providing further support for the role of malaria. We report the emergence of BWF in eastern Uganda, a condition that, according to local investigators, was rare until the last 7 years. We speculate that this might relate to the introduction of artemisinin-based combination therapies. Further studies investigating this possibility are urgently required.
Highlights
In the Fluid Expansion as a Supportive Treatment (FEAST) trial, an unexpectedly high proportion of participants from eastern Uganda presented with blackwater fever (BWF)
We report the emergence of BWF in eastern Uganda, a condition that, according to local investigators, was rare until the last 7 years
Blackwater fever (BWF), a syndrome comprising acute intravascular hemolysis, fever, and the passage of dark or red-colored urine, has been recognized most commonly as a complication of recent or concurrent Plasmodium falciparum malaria infection in nonimmune expatriate adults living in Africa, where it was frequently complicated by severe anemia, jaundice, and renal failure [1, 2]
Summary
We describe the prevalence and outcome of BWF among trial participants and compare the prevalence of 3 malaria-protective red blood cell polymorphisms in BWF cases vs both trial (non-BWF) and population controls. The methods and outcome of the FEAST trial have been described in detail previously [13]. A structured clinical case report form was completed at admission by study clinicians. Admission blood samples were collected from recruited children, and whole blood and plasma were stored at –80°C for subsequent analysis. Plasma P. falciparum histidine rich protein 2 (pfHRP2), a sensitive marker of recent malaria infection, was quantified using methods described in detail previously [14]. The red blood cell polymorphisms sickle cell trait (hemoglobin [Hb] AS), sickle cell anemia (HbSS), the common African variant of α+thalassemia, and the B, A, and A– allelic variants of G6PD were typed by polymerase chain reaction [15] from DNA extracted using proprietary methods (Qiagen DNA Blood Mini Kits, Crawley, United Kingdom). Hemoglobin estimation was repeated at 8 and 24 hours and at 28 days, and mortality was reported at 48 hours and 28 days postrandomization
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