-
Malaria Journal Jun 2023In sub-Saharan Africa (SSA), malaria remains a public health problem despite recent reports of declining incidence. Severe malaria is a multiorgan disease with...
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.
Topics: Child; Male; Humans; Infant; Adolescent; Child, Preschool; Female; Prospective Studies; Blackwater Fever; Uganda; Malaria, Cerebral; Anemia; Lactic Acid; Epidemics; Seizures; Jaundice; Respiratory Distress Syndrome
PubMed: 37259110
DOI: 10.1186/s12936-023-04586-3 -
Case Reports in Infectious Diseases 2023Blackwater fever (BWF) is a severe clinical syndrome occurring as a complication of malarial infection characterized by intravascular hemolysis, hemoglobinuria, and...
BACKGROUND
Blackwater fever (BWF) is a severe clinical syndrome occurring as a complication of malarial infection characterized by intravascular hemolysis, hemoglobinuria, and acute renal failure in people exposed to and, to some extent, in people who were exposed to medications like quinine and mefloquine. The exact pathogenesis of classic BWF remains unclear. The mechanism leading to damage to the red blood cells (RBCs) can be immunologic nonimmunologic, leading to massive intravascular hemolysis. . We present a case of classic blackwater fever in a 24-year-old otherwise previously healthy male without any history of antimalarial prophylaxis use, returning from recent travel to Sierra Leone. He was detected to have malaria in the peripheral smear test. He was treated with artemether/lumefantrine combination therapy. Unfortunately, his presentation was complicated by renal failure and was managed with plasmapheresis and renal replacement therapy.
CONCLUSION
Malaria continues to be a parasitic disease that can have devastating effects and continues to be a challenge globally. Although cases of malaria in the United States are rare and cases of severe malaria, mainly attributed to , are even more uncommon. Care should be taken to retain a high level of suspicion to consider the diagnosis, especially in returning travelers from endemic areas.
PubMed: 37179741
DOI: 10.1155/2023/5796881 -
Emerging Infectious Diseases Jul 2005Blackwater fever is characterized by acute intravascular hemolysis with hemoglobinuria in patients with Plasmodium falciparum malaria. Its pathogenesis and management...
Blackwater fever is characterized by acute intravascular hemolysis with hemoglobinuria in patients with Plasmodium falciparum malaria. Its pathogenesis and management are still debated. Nine cases of this syndrome occurred in 2003 at Kiremba Hospital in Burundi in children receiving multiple quinine treatments.
Topics: Adolescent; Adrenal Cortex Hormones; Antimalarials; Artemether; Artemisinins; Blackwater Fever; Burundi; Child; Humans; Infant; Male; Quinine; Sesquiterpenes
PubMed: 16022794
DOI: 10.3201/eid1107.041237 -
British Journal of Pharmacology and... Jun 1958Quinine produces haemolysis of rabbit and human red blood cells in concentrations up to 1 in 700. In a concentration of 1 in 10,000 it increases the degree of haemolysis...
Quinine produces haemolysis of rabbit and human red blood cells in concentrations up to 1 in 700. In a concentration of 1 in 10,000 it increases the degree of haemolysis produced by various haemolytic agents like saponin, bile salts and digitonin in vitro. Quinine when injected intravenously in 35 mg./kg. dose in rabbits increases the susceptibility of red blood cells to the haemolytic action of saponin. Intravascular haemolysis following the administration of quinine is seen in cases of blackwater fever, and on the basis of experimental work described in the paper it is suggested that quinine precipitates these haemolytic episodes by rendering the red blood cells more susceptible to the action of tissue lytic factors.
Topics: Animals; Blackwater Fever; Cell Death; Erythrocyte Count; Erythrocytes; Hemolysis; Hemolytic Agents; Humans; Pharmaceutical Preparations; Quinine; Rabbits; Saponins
PubMed: 13536282
DOI: 10.1111/j.1476-5381.1958.tb00213.x -
Clinical Infectious Diseases : An... Apr 2017In the Fluid Expansion as a Supportive Treatment (FEAST) trial, an unexpectedly high proportion of participants from eastern Uganda presented with blackwater fever (BWF).
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.
Topics: Age Factors; Biomarkers; Blackwater Fever; Child, Preschool; Erythrocytes; Female; Glucosephosphate Dehydrogenase; Hemoglobinopathies; Humans; Infant; Male; Mutation; Patient Outcome Assessment; Phenotype; Polymorphism, Genetic; Prevalence; Severity of Illness Index; Symptom Assessment; Uganda; Urinalysis
PubMed: 28362936
DOI: 10.1093/cid/cix003 -
British Medical Journal Mar 1945
PubMed: 20785946
DOI: 10.1136/bmj.1.4392.325 -
British Medical Journal Apr 1953
Topics: Blackwater Fever; Cortisone; Humans; Malaria
PubMed: 13032514
DOI: 10.1136/bmj.1.4814.819-a -
Indian Journal of Medical Microbiology 2016
Topics: Administration, Intravenous; Adult; Antimalarials; Artemisinins; Artesunate; Blackwater Fever; Blood; Humans; Male; Plasmodium falciparum
PubMed: 27514973
DOI: 10.4103/0255-0857.188373 -
BMJ Open Jul 2023Acute kidney injury (AKI) has in the past been considered a rare complication of malaria in children living in high-transmission settings. More recently, however, a...
PARIST study protocol: a phase I/II randomised, controlled clinical trial to assess the feasibility, safety and effectiveness of paracetamol in resolving acute kidney injury in children with severe malaria.
BACKGROUND
Acute kidney injury (AKI) has in the past been considered a rare complication of malaria in children living in high-transmission settings. More recently, however, a growing number of paediatric case series of AKI in severe malaria studies in African children have been published (Artesunate vs Quinine in the Treatment of Severe Malaria in African children and Fluids Expansion as Supportive Therapy trials). The Paracetamol for Acute Renal Injury in Severe Malaria Trial (PARIST) therefore, aims to assess feasibility, safety and determine the effective dose of paracetamol, which attenuates nephrotoxicity of haemoproteins, red-cell free haemoglobin and myoglobin in children with haemoglobinuric severe malaria.
METHODS
PARIST is a phase I/II unblinded randomised controlled trial of 40 children aged >6 months and <12 years admitted with confirmed haemoglobinuric severe malaria (blackwater fever), a positive blood smear for malaria and either serum creatinine (Cr) increase by ≥0.3 mg/dL within 48 hours or to ≥1.5 times baseline and elevated blood urea nitrogen (BUN) >20 mg/dL. Children will be randomly allocated on a 1:1 basis to paracetamol intervention dose arm (20 mg/kg orally 6-hourly for 48 hours) or to a control arm to receive standard of care for temperature control (ie, tepid sponging for 30 min if fever persists give rescue treatment). Primary outcome is renal recovery at 48 hours as indicated by stoppage of progression and decrease of Cr level below baseline, BUN (<20 mg/dL). Data analysis will be on the intention-to-treat principle and a per-protocol basis.Results from this phase I/II clinical trial will provide preliminary effectiveness data of this highly potential treatment for AKI in paediatric malaria (in particular for haemoglobinuric severe malaria) for a larger phase III trial.
ETHICS AND DISSEMINATION
Ethical and regulatory approvals have been granted by the Mbale Hospital Institutional Ethics Review Committee (MRRH-REC OUT 002/2019), Uganda National Council of Science and Technology (UNCST-HS965ES) and the National drug Authority (NDA-CTC 0166/2021). We will be disseminating results through journals, conferences and policy briefs to policy makers and primary care providers.
TRIAL REGISTRATION NUMBER
ISRCTN84974248.
Topics: Humans; Child; Acetaminophen; Feasibility Studies; Uganda; Malaria; Malaria, Falciparum; Acute Kidney Injury; Treatment Outcome; Randomized Controlled Trials as Topic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic
PubMed: 37524553
DOI: 10.1136/bmjopen-2022-068260 -
Malaria Journal Jun 2013The naturally occurring alkaloid drug, quinine is commonly used for the treatment of severe malaria. Despite centuries of use, its metabolism is still not fully...
BACKGROUND
The naturally occurring alkaloid drug, quinine is commonly used for the treatment of severe malaria. Despite centuries of use, its metabolism is still not fully understood, and may play a role in the haemolytic disorders associated with the drug.
METHODS
Incubations of quinine with CYPs 1A2, 2C9, 2C19, 2D6, and 3A4 were conducted, and the metabolites were characterized by accurate mass UPLC-MS(E) analysis. Reactive oxygen species generation was also measured in human erythrocytes incubated in the presence of quinine with and without microsomes.
RESULTS
The metabolites 3-hydroxyquinine, 2'-oxoquininone, and O-desmethylquinine were observed after incubation with CYPs 3A4 (3-hydroxyquinine and 2'-oxoquininone) and 2D6 (O-desmethylquinine). In addition, multiple hydroxylations were observed both on the quinoline core and the quinuclidine ring system. Of the five primary abundance CYPs tested, 3A4, 2D6, 2C9, and 2C19 all demonstrated activity toward quinine, while 1A2 did not. Further, quinine produced robust dose-dependent oxidative stress in human erythrocytes in the presence of microsomes.
CONCLUSIONS
Taken in context, these data suggest a CYP-mediated link between quinine metabolism and the poorly understood haemolytic condition known as blackwater fever, often associated with quinine ingestion.
Topics: Blackwater Fever; Chromatography, Liquid; Cytochrome P-450 Enzyme System; Erythrocytes; Humans; Malaria; Mass Spectrometry; Microsomes; Quinine; Reactive Oxygen Species
PubMed: 23800033
DOI: 10.1186/1475-2875-12-214