High Frequency of Blackwater Fever Among Children Presenting to Hospital With Severe Febrile Illnesses in Eastern Uganda

Engoru, Charles; Uyoga, Sophie; Muhindo, Rita; Macharia, Alex; Kiguli, Sarah; Opoka, Robert O.; Akech, Samuel; Ndila, Carolyne; Nyeko, Richard; Mtove, George; Nteziyaremye, Julius; Chebet, Martin; George, Elizabeth C; Babiker, Abdel; Gibb, Diana; Williams, Thomas N.; Maitland, Kathryn

doi:10.1093/cid/cix003

Cited by 46 publications

(73 citation statements)

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“…These findings are important and novel and demonstrate that β‐thalassemia mutations indeed exist in both East and Central Africa, and that HbS/β 0 or HbS/β + ‐thalassemia should be considered for patients with elevated %HbA 2 and decreased MCV. As previously described, there was a high frequency of both α–thalassemia and G6PD deficiency in our cohort, which may ameliorate the risk of severe malaria and sickle phenotype, but may also affect the responses to hydroxyurea therapy . Study participants with two α‐globin gene deletions had significantly higher hemoglobin concentrations and were less likely to have been transfused prior to study entry, in comparison to those with one or zero α‐globin gene deletions.…”

Section: Discussionsupporting

confidence: 58%

Realizing effectiveness across continents with hydroxyurea: Enrollment and baseline characteristics of the multicenter REACH study in Sub‐Saharan Africa

et al. 2018

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Despite its well-described safety and efficacy in the treatment of sickle cell anemia (SCA) in high-income settings, hydroxyurea remains largely unavailable in sub-Saharan Africa, where more than 75% of annual SCA births occur and many comorbidities exist. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) is a prospective, Phase I/II open-label trial of hydroxyurea designed to evaluate the feasibility, safety, and benefits of hydroxyurea treatment for children with SCA in four sub-Saharan African countries. Following comprehensive training of local research teams, REACH was approved by local Ethics Committees and achieved full enrollment ahead of projections with 635 participants enrolled over a 30-month period, despite half of families living >12 km from their clinical site. At enrollment, study participants (age 5.4 ± 2.4 years) had substantial morbidity, including a history of vaso-occlusive pain (98%), transfusion (68%), malaria (85%), and stroke (6%). Significant differences in laboratory characteristics were noted across sites, with lower hemoglobin concentrations (P < .01) in Angola (7.2 ± 1.0 g/dL) and the DRC (7.0 ± 0.9 g/dL) compared to Kenya (7.4 ± 1.1 g/dL) and Uganda (7.5 ± 1.1 g/dL). Analysis of known genetic modifiers of SCA demonstrated a high frequency of α-thalassemia (58.4% with at least a single α-globin gene deletion) and G6PD deficiency (19.7% of males and 2.4% of females) across sites. The CAR β-globin haplotype was present in 99% of participants. The full enrollment to REACH confirms the feasibility of conducting high-quality SCA research in Africa; this study will provide vital information to guide safe and effective dosing of hydroxyurea for children with SCA living in Africa.

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Section: Discussionsupporting

confidence: 58%

Realizing effectiveness across continents with hydroxyurea: Enrollment and baseline characteristics of the multicenter REACH study in Sub‐Saharan Africa

et al. 2018

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“…The urine is black and, if the haemolysis is extensive, the patient has a pale, slate-grey appearance. Blackwater fever may be part of severe malaria [ 124 – 126 ]. Death may occur from severe anaemia or from acute renal failure.…”

Section: Clinical Featuresmentioning

confidence: 99%

Anaemia and malaria

White

2018

Malar J

380

312

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Malaria is a major cause of anaemia in tropical areas. Malaria infection causes haemolysis of infected and uninfected erythrocytes and bone marrow dyserythropoiesis which compromises rapid recovery from anaemia. In areas of high malaria transmission malaria nearly all infants and young children, and many older children and adults have a reduced haemoglobin concentration as a result. In these areas severe life-threatening malarial anaemia requiring blood transfusion in young children is a major cause of hospital admission, particularly during the rainy season months when malaria transmission is highest. In severe malaria, the mortality rises steeply below an admission haemoglobin of 3 g/dL, but it also increases with higher haemoglobin concentrations approaching the normal range. In the management of severe malaria transfusion thresholds remain uncertain. Prevention of malaria by vector control, deployment of insecticide-treated bed nets, prompt and accurate diagnosis of illness and appropriate use of effective anti-malarial drugs substantially reduces the burden of anaemia in tropical countries.

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“…The authors have been unable to identify literature suggesting a direct link from persistent submicroscopic parasitaemia to clinical BWF and suggest that PCR methods should be undertaken prospectively in cases of BWF and treated controls to determine the frequency of this finding which, if universal, may point to an as yet unidentified mechanism involving the organism itself rather than simply the human response to infection and treatment. Recent reports of a rising incidence of BWF in endemic areas following the introduction of ACT [ 69 ] suggest that this research should be a priority.…”

Section: Discussionmentioning

confidence: 99%

A case of blackwater fever with persistent Plasmodium falciparum parasitaemia detected by PCR after artemether–lumefantrine treatment

Huggan

et al. 2018

Malar J

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BackgroundBlackwater fever is a complication of malaria infection consisting of a syndrome of febrile intra-vascular haemolysis with severe anaemia and intermittent passage of dark-red to black colour urine. Despite numerous reports and studies of this condition, its pathogenesis remains incompletely understood.Case presentationThis report describes a case of classic blackwater fever in a returning traveller, without prior history of malaria infection nor usage of anti-malarial prophylaxis, treated with two courses of oral artemether–lumefantrine combination therapy. Unusual persistence of submicroscopic Plasmodium falciparum parasitaemia was detected by PCR for 18 days after initiation of treatment.ConclusionTo the authors’ knowledge this is the first reported occurrence of a case of blackwater fever associated with prolonged submicroscopic parasitaemia. This unusual case challenges the current knowledge of the pathogenesis of this condition and opens questions that may have important diagnostic and treatment implications.Electronic supplementary materialThe online version of this article (10.1186/s12936-018-2180-1) contains supplementary material, which is available to authorized users.

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High Frequency of Blackwater Fever Among Children Presenting to Hospital With Severe Febrile Illnesses in Eastern Uganda

Abstract: SummaryWe have noted a recent upsurge in blackwater fever among children presenting to hospitals in eastern Uganda and speculate that this may relate to a change in policy toward new artemisinin-based combination therapies for malaria.

Cited by 46 publications

References 25 publications

Realizing effectiveness across continents with hydroxyurea: Enrollment and baseline characteristics of the multicenter REACH study in Sub‐Saharan Africa

Realizing effectiveness across continents with hydroxyurea: Enrollment and baseline characteristics of the multicenter REACH study in Sub‐Saharan Africa

Anaemia and malaria

A case of blackwater fever with persistent Plasmodium falciparum parasitaemia detected by PCR after artemether–lumefantrine treatment

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