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.

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.

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.

[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.

CYP450 phenotyping and metabolite identification of quinine by accurate mass UPLC-MS analysis: a possible metabolic link to blackwater fever.

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.

An imported case of P. falciparum malaria presenting as black water fever with acute renal failure.

This is a report of a case of blackwater fever in a 28-year-old Nigerian man who was admitted to hospital with fever, jaundice and passing dark urine. Abdominal examination revealed splenomegaly and an examination of the peripheral smear of the patient showed the ring form of the trophozoites of Plasmodium falciparum (P. falciparum). Serum creatinine was 200micromol/L. Treatment with quinine and doxycycline was started and intravenous fluids were administered with close monitoring of the urine output and serum electrolytes. Due to the alarming amount of fluid accumulation and his exacerbated azotaemia the decision was made to haemodialyse the patient; the patient required five haemodialysis sessions during his stay in the hospital. He was discharged on the sixteenth day after admission with a serum creatinine level of 160micromol/L.

Muscle cell injury, haemolysis and dark urine in children with falciparum malaria in Papua New Guinea.

During a prospective study of red cell variants and severe malaria in children, a surprising observation was the occurrence of dark urine. Children were grouped according to urine findings: 22 had dark urine that contained a haem protein (Group I), 93 had urine of normal colour that contained a haem protein (Group II) and 236 had normal urine (Group III). To investigate the cause of dark urine, haemolysis and muscle cell injury were assessed. Intravascular haemolysis was greater in Group I than in Groups II and III. However, anaemia was more severe in Group III and is likely to have resulted mainly from extravascular haemolysis. Median plasma myoglobin concentrations were greater in Groups I and II than Group III (P = 0.00060). Plasma myoglobin was greater in children with cerebral malaria, hyperlactataemia and those who died but was not associated with acidosis. Urine myoglobin was greater in Group I than Groups II and III (P = 0.00054). It is likely that both haemoglobin and myoglobin contributed to dark urine. The association between muscle cell injury and coma suggests sequestration of parasitized red cells as a common underlying pathology. In malaria, hyperlactataemia may result directly from breakdown of muscle protein as well as tissue hypoxia.

Fiebre amarilla: un peligro latente / Yellow fever: a latent danger

La fiebre amarilla es una zoonosis, aguda, febril que se encuentra catalogada como una fiebre hemorrágica potencialmente mortal. Es causada por un antrópodo del cual se conocen dos modalidades epidemiológicas, con un área endémica que corresponde a la mayoría de América del Sur y parte del continente africano. En Costa Rica la última epidemia de fiebre amarilla ocurrió a principios de los años cincuenta. La fisiopatología de la fiebre amarilla no es bien conocida. La mayoría de las infecciones son sintomáticas, y tienen una alta mortalidad que varía según la epidemia. El diagnóstico se confirma de forma definitiva con la serología y aunque éste examen no se realiza en el país, las muestras de los casos sospechosos son enviadas a laboratorios panameños. Con base en su gran mortalidad y a la ausencia de un tratamiento específico, es obvio que el camino a seguir en el manejo de la fiebre amarilla es la prevención mediante las vacunaciones masivas en las áreas endémicas y grupos de riesgo, así como el control del vector. La fiebre amarilla sigue siendo una entidad que afecta considerablemente la salud pública en varios países del mundo; Costa Rica reúne un conjunto de condiciones que facilitarían su aparición y propagación, por lo que es una patología cuyas características convendría mantener en mente. Descriptores: Arbovirus, fiebre amarilla, Costa Rica, zoonosis, fiebre hemorrágica.

Relationship between plasma Interleukin-12 (IL-12) and IL-18 levels and severe malarial anemia in an area of holoendemicity in western Kenya.

In this study, we investigated whether levels of interleukin-12 (IL-12) and IL-18 in plasma are associated with severe malarial anemia outcomes in an area of holoendemicity in western Kenya. We compared plasma IL-12 and IL-18 levels in six groups of children grouped into the categories aparasitemic, asymptomatic, mild malaria, high-density uncomplicated malaria (UC), moderate malarial anemia (MMA), or severe malarial anemia (SMA). IL-12 levels were significantly reduced in children with SMA (P < 0.05) but not in other groups compared to children in the aparasitemic control group. IL-18, a cytokine known to be critical for the induction of gamma interferon along with IL-12, was produced more frequently (70%) in children with UC (P = 0.06) than in children in the aparasitemic control group (32%). However, in the SMA group the IL-18 response rate declined to 30%, which was similar to that in the aparasitemic control group, which showed a 32% response rate. This finding suggests that the IL-18 response may be impaired in children with SMA. In summary, the results from this study support the hypothesis that impairment of IL-12 and/or IL-18 response may contribute to the development of severe malarial anemia in areas of holoendemicity for malaria.

In vitro RBC exposure to Plasmodium falciparum has no effect on RBC antigen expression.

Severe malarial anaemia is a leading cause of death in African children younger than 3 years of age who are infected with Plasmodium falciparum. The pathogenesis of this anaemia is not understood. The purpose of this study was to determine if P. falciparum induces changes in RBC membranes that contribute to the immune destruction of RBCs. RBCs were collected from healthy subjects and tested using standard haemagglutination assays for 45 antigens representing 21 blood group systems/collections before and after exposure to P. falciparum, strain FVO. Lectins were used to determine whether crypt or neoantigens were expressed on the RBC membrane. Polybrene was used to detect changes in sialic acid. RBCs were cultured in vitro with and without the parasite, and blinded serologic studies were completed. CD35 (complement receptor 1), CD55 (decay-accelerating factor), CD59 (membrane inhibitor of reactive lysis) and CD47 (integrin-associated protein) flow cytometric assays were compared for infected and uninfected RBCs. The percentage of parasitaemia was determined using Giemsa-stained thin blood films. Two (Ch, Lub) of the 45 antigens had differing strengths of agglutination between infected and uninfected RBCs, but these differences were resolved with a second source of antisera. Forty-three antigens showed no significant differences in the strength of agglutination between the infected and uninfected RBCs. Lectin and polybrene testing showed no differences. CD35, CD55, CD59 and CD47 levels showed no significant differences. P. falciparum does not appear to alter the expression of classified immunogenic antigens on the RBC membrane in this in vitro system. The pathogenesis of the haemolytic episode that occurs in these children remains unclear.

[Blackwater fever in adults with sickle cell anemia. Two fatal cases]. / Fièvre bilieuse hémoglobinurique chez l'adulte drépanocytaire. A propos de deux cas mortels.

Blackwater fever is characterized by severe intravascular hemolysis with renal failure caused by recurrent use of quinine for prophylaxis. Once described in European patients, sporadic cases have been reported more and more often in autochthonous Africans and Asians. Newer antimalarials including aminoalchohol mefloquine, and halofantrine have also been implicated in Blackwater fever. In this report we describe two cases of blackwater fever involving patients with sickle cell anemia (HbSS). Symptoms including fever, acute hemolytic anemia, emesis, back pain, and hemoglobinuria were characteristic of blackwater fever. Both patients died. Although the underlying mechanism of blackwater fever remains unclear, a likely explanation is an immunoallergic reaction to quinine. Association with glucose-6-phosphate dehydrogenase deficiency has often been reported. Our cases suggest that blackwater fever may also be correlated with hemoglobinopathy such as HbSS.

Recurrence of blackwater fever: triggering of relapses by different antimalarials.

Five cases of blackwater fever (BWF) are described, all of whom had a history of recent quinine therapy. In two cases a second haemolytic crisis was induced by halofantrine, in one case also a third. Increasing frequency of this syndrome with its dramatic clinical presentation is to be expected as imported P. falciparum infection, parasite resistance to chloroquine and the use of quinine and other related antimalarials become more frequent.

An etiologic study of hemoglobinuria and blackwater fever in the Kivu Mountains, Zaire.

Between January 1985 and March 1986, in the high altitude area of Kivu, Eastern Zaïre, 38 patients presenting with hemoglobinuria as main manifestation were investigated. Profound glucose-6-phosphate dehydrogenase deficiency was detected in 4 patients, leptospirosis in 2 and Hantaan virus infection in 2. Hemolysis was doubtful (haptoglobin > 40 mg/dl, Hemoglobin > 12 g/dl) in 2 patients. Other potential causes of hemoglobinuria such as hemoglobinopathy, toxic agents, infectious diseases or blood transfusion incompatibility were carefully screened and excluded. The syndrome observed in the remaining 28 cases was strongly suggestive of blackwater fever (BWF) as described in malaria patients by several authors under the french name "fièvre bilieuse hémoglobinurique". Quinine was used as curative treatment of malaria before admission in a significant greater proportion (p < 0.01) of patients with BWF compared to patients with uncomplicated malaria, suggesting that this drug might have played a triggering role in the genesis of BWF. However, quinine was usually administered at inadequate doses to malaria patients non responding to chloroquine and belonging to a population of whom 50% are non immune. It may thus also be hypothesized that BWF in our patients could result from a hyperparasitemic state that remained undetected because of an unusual synchronous lysis of infected erythrocytes. In the latter case BWF would correspond to a major complication of falciparum malaria only coincidentally related to the use of quinine.

Blackwater fever at the Kenyatta National Hospital in Kenya: a case report.

Blackwater fever was an important cause of morbidity and mortality in the beginning of this century particularly in West and Central Africa. There has been a marked reduction in the incidence of blackwater fever since 1950 and only sporadic cases occur nowadays. At the Kenyatta National Hospital, three cases of blackwater fever have been seen in the past four years whereas not a single case had been reported between 1975 and 1988. Two of the patients fit into the classical description of blackwater fever and one was possibly due to drug induced haemolysis in a G6PD deficiency patient.