Physiopathology and clinical management of blackwater fever: a scoping review.

BACKGROUND: Blackwater fever (BWF) is a severe syndrome occurring in patients with malaria upon antimalarial treatment, characterized by massive intravascular haemolysis and haemoglobinuria. BWF is a neglected condition and management recommendations are unavailable. OBJECTIVES: We performed a scoping review to appraise available data on clinical picture, treatment and physiopathology of BWF, which could guide rationally its clinical management. METHODS: MEDLINE, EMBASE, LILACS, Web of Science, and Scopus databases, and the reference list of relevant publications, were searched. Papers reporting original data on BWF cases or investigating the physiopathology of BWF were eligible. Data regarding case characteristics, trigger event, clinical management and outcome were extracted. For papers investigating the physiopathology of BWF, study design and principal findings were extracted. No quality assessment was performed. Data are presented as numbers and percentages, and summary of findings, grouped by paper focus (clinical description or physiopathology). RESULTS: 101 papers were included. The majority of BWF cases were observed in autochthonous children (75.7%) and adults (15.3%), in contrast with historical perception that BWF patients were typically expatriates. Clinical management was described for 794 cases; corticosteroids were used in 23. Outcome was reported for 535 patients, with 18.1% mortality. The trigger was reported for 552 (47.5%) cases; in 70.4% identified as quinine. However, two RCT comparing artesunate and quinine for falciparum malaria treatment did not find significant difference in BWF occurrence after their administration. Two case-control studies did not find significant difference in G6PDH deficiency between malaria patients with and without BWF. CONCLUSIONS: The physiopathology and optimal treatment of BWF remain similarly unknown as they were over a century ago. Empirical supporting treatment approach seems reasonable, while change of antimalarial drug and use of corticosteroids remain object of debate.

Unusual clinical spectra of childhood severe malaria during malaria epidemic in eastern Uganda: a prospective study.

BACKGROUND: In sub-Saharan Africa (SSA), malaria remains a public health problem despite recent reports of declining incidence. Severe malaria is a multiorgan disease with wide-ranging clinical spectra and outcomes that have been reported to vary by age, geographical location, transmission intensity over time. There are reports of recent malaria epidemics or resurgences, but few data, if any, focus on the clinical spectrum of severe malaria during epidemics. This describes the clinical spectrum and outcomes of childhood severe malaria during the disease epidemic in Eastern Uganda. METHODS: This prospective cohort study from October 1, 2021, to September 7, 2022, was nested within the 'Malaria Epidemiological, Pathophysiological and Intervention studies in Highly Endemic Eastern Uganda' (TMA2016SF-1514-MEPIE Study) at Mbale Regional Referral Hospital, Uganda. Children aged 60 days to 12 years who at admission tested positive for malaria and fulfilled the clinical WHO criteria for surveillance of severe malaria were enrolled on the study. Follow-up was performed until day 28. Data were collected using a customized proforma on social demographic characteristics, clinical presentation, treatment, and outcomes. Laboratory analyses included complete blood counts, malaria RDT (SD BIOLINE Malaria Ag P.f/Pan, Ref. 05FK60-40-1) and blood slide, lactate, glucose, blood gases and electrolytes. In addition, urinalysis using dipsticks (Multistix® 10 SG, SIEMENS, Ref.2300) at the bedside was done. Data were analysed using STATA V15.0. The study had prior ethical approval. RESULTS: A total of 300 participants were recruited. The median age was 4.6 years, mean of 57.2 months and IQR of 44.5 months. Many children, 164/300 (54.7%) were under 5 years, and 171/300 (57.0%) were males. The common clinical features were prostration 236/300 (78.7%), jaundice in 205/300 (68.3%), severe malarial anaemia in 158/300 (52.7%), black water fever 158/300 (52.7%) and multiple convulsions 51/300 (17.0%), impaired consciousness 50/300(16.0%), acidosis 41/300(13.7%), respiratory distress 26/300(6.7%) and coma in 18/300(6.0%). Prolonged hospitalization was found in 56/251 (22.3%) and was associated with acidosis, P = 0.041. The overall mortality was 19/300 (6.3%). Day 28 follow-up was achieved in 247/300 (82.3%). CONCLUSION: During the malaria epidemic in Eastern Uganda, severe malaria affected much older children and the spectrum had more of prostration, jaundice severe malarial anaemia, black water fever and multiple convulsions with less of earlier reported respiratory distress and cerebral malaria.

Blackwater Fever Treated with Steroids in Nonimmune Patient, Italy.

Causes of blackwater fever, a complication of malaria treatment, are not completely clear, and immune mechanisms might be involved. Clinical management is not standardized. We describe an episode of blackwater fever in a nonimmune 12-year-old girl in Italy who was treated with steroids, resulting in a rapid clinical resolution.

Resurgence of blackwater fever among children in sub-Saharan Africa: a scoping review protocol.

INTRODUCTION: Blackwater fever (BWF), a complication of malaria, has in the past been considered as a rare complication of malaria in children living in high transmission settings. More recently, however, a growing number of paediatric clusters of BWF cases have been reported predominantly in sub-Saharan Africa (SSA). The aim of this study is to map evidence on BWF among children in SSA from 1 January 1960 to 31 December 2021. METHODS AND ANALYSIS: This review will be guided by Arksey and O' Malley's methodological framework for scoping reviews with methodological refinements by Levac et al and will comply with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews' guidelines. Five electronic databases (MEDLINE via PubMed, Embase, the Cochrane Library, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and PsycINFO) will be systematically searched using predefined keywords. In addition, reference lists of included articles will be searched. Our multidisciplinary team has formulated search strategies and two reviewers will independently complete study eligibility screening, final selection and data extraction. A third reviewer will adjudicate the final decision on disputed articles. Bibliographic data and abstract content will be collected and analysed using a data-charting tool developed iteratively by the research team. ETHICS AND DISSEMINATION: This scoping review being a secondary analysis does not require ethics approval. We anticipate results of this review will broaden understanding of paediatric BWF in SSA and identify its research gaps in SSA. We will be disseminating results through journals and conferences targeting primary care providers.

Blackwater fever and acute kidney injury in children hospitalized with an acute febrile illness: pathophysiology and prognostic significance.

BACKGROUND: Acute kidney injury (AKI) and blackwater fever (BWF) are related but distinct renal complications of acute febrile illness in East Africa. The pathogenesis and prognostic significance of BWF and AKI are not well understood. METHODS: A prospective observational cohort study was conducted to evaluate the association between BWF and AKI in children hospitalized with an acute febrile illness. Secondary objectives were to examine the association of AKI and BWF with (i) host response biomarkers and (ii) mortality. AKI was defined using the Kidney Disease: Improving Global Outcomes criteria and BWF was based on parental report of tea-colored urine. Host markers of immune and endothelial activation were quantified on admission plasma samples. The relationships between BWF and AKI and clinical and biologic factors were evaluated using multivariable regression. RESULTS: We evaluated BWF and AKI in 999 children with acute febrile illness (mean age 1.7 years (standard deviation 1.06), 55.7% male). At enrollment, 8.2% of children had a history of BWF, 49.5% had AKI, and 11.1% had severe AKI. A history of BWF was independently associated with 2.18-fold increased odds of AKI (95% CI 1.15 to 4.16). When examining host response, severe AKI was associated with increased immune and endothelial activation (increased CHI3L1, sTNFR1, sTREM-1, IL-8, Angpt-2, sFlt-1) while BWF was predominantly associated with endothelial activation (increased Angpt-2 and sFlt-1, decreased Angpt-1). The presence of severe AKI, not BWF, was associated with increased risk of in-hospital death (RR, 2.17 95% CI 1.01 to 4.64) adjusting for age, sex, and disease severity. CONCLUSIONS: BWF is associated with severe AKI in children hospitalized with a severe febrile illness. Increased awareness of AKI in the setting of BWF, and improved access to AKI diagnostics, is needed to reduce disease progression and in-hospital mortality in this high-risk group of children through early implementation of kidney-protective measures.

Mystery of blackwater fever from an Australian perspective.

Blackwater fever is a haemolytic syndrome associated with malaria that coincided with the use of quinine chemoprophylaxis. Once quinine was no longer chronically used to prevent malaria, blackwater fever largely disappeared and its aetiology remains poorly understood. Blackwater fever is representative of classical tropical medicine and its history was reflected in Australia's colonial development of Papua New Guinea particularly as reported in the Australian medical literature.

Predictors of prolonged hospitalisation and mortality among children admitted with blackwater fever in eastern Uganda.

Our study aimed at determining clinical factors associated with prolonged hospitalisation and death among children admitted with blackwater fever (BWF). We analysed 920 eligible records for the period January - December 2018 from Mbale and Soroti Regional Referral Hospitals in Eastern Uganda. The median hospitalisation was 3 (IQR: 2-5 days) days. Prolonged hospitalisation was in 251/920 (27.3%). Clinical features independently associated with prolonged hospitalisation included abdominal tenderness, body pain and mild fever. 29/920 (3.2%) died, of these 20 (69.0%) within 48 h of admission. Features of severity associated with mortality were noisy or interrupted breathing, tachypnoea, chest pain, convulsions, delayed capillary refill time (≥3 s), severe pallor, high fever (>38.5°C), altered level of consciousness, prostration and acidotic breathing.

Exploring association between MBL2 gene polymorphisms and the occurrence of clinical blackwater fever through a case-control study in Congolese children.

BACKGROUND: Blackwater fever (BWF), one of the most severe and life-threatening forms of falciparum malaria, is characterized by acute massive intravascular haemolysis, often leading to acute renal failure. Thus far, the genetics of the underlying susceptibility to develop BWF is not fully elucidated. Deficiency in the MBL protein, an important component of the innate immune system, has previously been suggested to be a susceptibility factor for the development of severe malaria. This study aimed to evaluate the association between MBL2 gene polymorphisms, known to affect the MBL protein level/activity, and the occurrence of BWF among Congolese children. METHODS: This is a case-control study. Cases were patients with BWF, whereas controls, matched for gender and age, had uncomplicated malaria (UM). Dried blood spot was collected for genotyping. RESULTS: A total of 129 children were screened, including 43 BWF and 86 UM. The common allele in BWF and UM was A, with a frequency of 76.7 and 61.0%, respectively (OR: 2.67 (0.87-829) and p = 0.079). The frequency of the C allele was 18.6 and 29.1% in BWF and UM groups, respectively, with p = 0.858. Not a single D allele was encountered. Genotype AA was at higher risk for BWF whereas genotypes A0 (AB and AC) were over-represented in UM group (OR: 0.21 (0.06-0.78)) with p = 0.019. Nine haplotypes were observed in this study: 3 high MBL expression haplotypes and 6 low MBL expression haplotype. One new haplotype HYPC was observed in this study. None of these haplotypes was significantly associated with BWF. CONCLUSION: This pilot study is a preliminary research on MBL2 gene and infectious diseases in DRC. The study results show a higher risk for BWF in AA. This suggests that future studies on BWF should further investigate the contribution of a strong immune response to the occurrence of BWF.

Blackwater Fever in Ugandan Children With Severe Anemia is Associated With Poor Postdischarge Outcomes: A Prospective Cohort Study.

BACKGROUND: Blackwater fever (BWF), one of the complications of severe malaria, has recently re-emerged as a cause of severe anemia (SA) in African children. However, postdischarge morbidity in children with BWF has previously not been described. METHODS: This was a descriptive cohort study in which children, aged 0-5 years, admitted to Jinja Regional Referral Hospital with acute episodes of SA (hemoglobin ≤5.0 g/dL) were followed up for 6 months after hospitalization. Incidence of readmissions or deaths during the follow-up period was compared between SA children with BWF and those without BWF. RESULTS: A total of 279 children with SA including those with BWF (n = 92) and no BWF (n = 187) were followed for the duration of the study. Overall, 128 (45.9%) of the study participants were readmitted at least once while 22 (7.9%) died during the follow-up period. After adjusting for age, sex, nutritional status, and parasitemia, SA children with BWF had higher risk of readmissions (hazard ratio [HR], 1.68; 95% confidence interval [CI], 1.1-2.5) and a greater risk of death (HR. 3.37; 95% CI, 1.3-8.5) compared with those without BWF. Malaria and recurrence of SA were the most common reasons for readmissions. CONCLUSIONS: There is a high rate of readmissions and deaths in the immediate 6 months after initial hospitalization among SA children in the Jinja hospital. SA children with BWF had increased risk of readmissions and deaths in the postdischarge period. Postdischarge malaria chemoprophylaxis should be considered for SA children living in malaria endemic areas.

Blackwater fever in a non-immune patient with Plasmodium falciparum malaria after intravenous artesunate.

Blackwater fever was typically reported after quinine administration, although it is poor recognized in patients receiving artesunate. This case describes a blackwater fever in a non-immune patient after artesunate for severe malaria. It highlights the importance of monitoring haemolytic parameters in severe malaria to avoid renal impairment or severe anaemia.

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

BACKGROUND: Blackwater 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 PRESENTATION: This 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. CONCLUSION: To 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.

Severe delayed haemolytic anaemia associated with artemether-lumefantrine treatment of malaria in a Japanese traveller.

Delayed haemolytic anaemia has been reported in association with intravenous artesunate treatment in patients with severe Plasmodium falciparum malaria, and furthermore, oral artemisinin-based combination therapies including artemether-lumefantrine (AL) have also been incriminated. However, definite cases of delayed haemolytic anaemia associated with AL appear to be scarce, as reported cases were often treated concomitantly with other anti-malarials. In this study, we report a severe case of delayed haemolytic anaemia following AL alone in a Japanese traveller with severe parasitaemia caused by numerous P. falciparum parasites and a few P. vivax parasites. We also stress the need by further studies to differentiate between delayed haemolytic anaemia and blackwater fever, the latter being another malaria-related haemolytic condition, more clearly than they are now.

The Multifactorial Epidemiology of Blackwater Fever.

Blackwater fever is a massive hemolytic event usually occurring in the context of repeated falciparum malaria infections and intermittent quinine use. Its etiology is poorly understood, and it is rarely seen today. Historical epidemiological observations from the 20th century demonstrated variable patterns in prisoners in Andaman Islands, refugees in Macedonia, canal workers in Panama, expatriates in Rhodesia, and Second World War soldiers. Rates of blackwater fever per 1,000 malaria cases varied over two orders of magnitude. Islands, such as the Andaman Islands and New Guinea, had lower blackwater fever rates than continental areas. During the Second World War, blackwater fever rates in British soldiers in West Africa and Australian soldiers in New Guinea differed by a factor of 40 despite similar treatment regimens and falciparum malaria transmission risks. Blackwater fever is a complex interaction between host erythrocyte, falciparum malaria, and antimalarial drugs which remains poorly understood.

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

BACKGROUND: In the Fluid Expansion as a Supportive Treatment (FEAST) trial, an unexpectedly high proportion of participants from eastern Uganda presented with blackwater fever (BWF). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A MINI OVERVIEW OF MALARIA IN PREGNANCY.

Human malaria is caused by five species of Plasmodia: P. falciparum, P. vivax, P. ovale, P. malariae and P. knowlesi. Most infections are due to either P. falciparum or P. vivax, but mixed infections with more than one malarial species also occur. The majority of malaria-related deaths are due to P. falciparum. Generally, the pregnant women are a high risk group, as malaria can be a life threatening infection for both mother and fetus. Risk of stillbirth, spontaneous abortion, and other adverse pregnancy outcomes is increased in the setting of malaria, and pregnant travelers should be advised to defer travel until after delivery whenever feasible.

Blackwater Fever Followed by Severe Falciparum Malaria in a Child

Blackwater fever is a serious clinical syndrome manifested by acute intravascular hemolysis, fever, and the passage of black or red urine, which is classically associated with falciparum malaria and irregular administration of quinine. In Korea, Plasmodium vivax is the only endemic malaria circulating; a number of imported cases of falciparum malaria have been reported in patients following return from international travel to a malaria endemic area. Therefore, it is important for health care professionals including pediatricians to be aware of the falciparum malaria and its clinical courses. Herein, we report a case of a 14-year-old girl with severe falciparum malaria that was complicated by blackwater fever.

Historical Review: Problematic Malaria Prophylaxis with Quinine.

Quinine, a bitter-tasting, short-acting alkaloid drug extracted from cinchona bark, was the first drug used widely for malaria chemoprophylaxis from the 19th century. Compliance was difficult to enforce even in organized groups such as the military, and its prophylaxis potential was often questioned. Severe adverse events such as blackwater fever occurred rarely, but its relationship to quinine remains uncertain. Quinine prophylaxis was often counterproductive from a public health viewpoint as it left large numbers of persons with suppressed infections producing gametocytes infective for mosquitoes. Quinine was supplied by the first global pharmaceutical cartel which discouraged competition resulting in a near monopoly of cinchona plantations on the island of Java which were closed to Allied use when the Japanese Imperial Army captured Indonesia in 1942. The problems with quinine as a chemoprophylactic drug illustrate the difficulties with medications used for prevention and the acute need for improved compounds.

[A Case of Blackwater Fever after Treatment for Plasmodium falciparum Malaria].

Blackwater fever (BWF), which causes massive intravascular hemolysis and the passage of black-colored urine, is a poorly understood condition that is rarely seen during the course of malaria. Here, we present a case of BWF that developed after treatment for falciparum malaria complicated by hyperparasitemia in a Japanese traveler. A 29-year-old woman returning from Ghana visited our travel clinic with complaints of sudden fever and headache on the third day of illness. She had taken anti-malarial drugs for intermittent malaria prophylaxis and the treatment of malaria while in Ghana. Falciparum malaria was diagnosed based on the results of a blood smear and was confirmed using PCR. She was successfully treated with a single artesunate suppository and one dose of intravenous quinine followed by artemether-lumefantrin for 3 days. She was discharged without complications on the 11th day of illness. However, she was re-admitted for fever and headache on the 16th day of illness. The recrudescence of malaria was excluded by peripheral blood smear results. BWF was diagnosed based on the presence of fever, black-colored urine, and laboratory findings suggesting intravascular hemolysis. She was treated with supportive care, including the transfusion of 10 packs of red blood cells and the maintenance of fluid and electrolyte balance, and she gradually improved within two weeks. BWF is a rare but severe complication induced by severe falciparum malaria and/or the use of the aryl-amino alcohol group of antimalarial drugs. Thus, consideration of BWF is particularly important for a rapid and accurate diagnosis.

Blood Trials: Transfusions, Injections, and Experiments in Africa, 1890-1920.

From about 1880 to 1920, a culture of medical experimentation promoted blood transfusion as a therapy for severe anemia in Europe, which was applied in German East Africa in 1892 for a case of blackwater fever, a complication of malaria afflicting mainly Europeans. This first case of blood transfusion in Africa, in which an African's blood was transfused into a German official, complicates the dominant narrative that blood transfusions in Africa came only after World War I. Medical researchers moreover experimented with blood serum therapies on human and animal subjects in Europe and Africa, injecting blood of different species, "races" and ethnicities into others to demonstrate parasite transmissibility and to discover vaccines for diseases such as malaria, sleeping sickness, and yellow fever. While research in German colonies is highlighted here, this was a transnational medical culture that crossed borders and oceans. This research is of interest as a possible early pathway for the epidemic spread of HIV and other zoonoses in Africa and the world, which biomedical researchers have identified as emerging in West-Central Africa sometime around the turn of the twentieth century.