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 mild blackwater fever]. / Une fièvre bilieuse hémoglobinurique de gravite moyenne.

We report a highly probable case of moderately severe blackwater fever. A French woman, living in Guinea Bissau, was used to taking self-medication halofantrine for malaria. On this occasion, she felt unusual chills and pyrexia after a non documented bout of malaria, followed by nausea, then jaundice with dark-red urines despite another treatment with halofantrine. A sepsis was eliminated by two negatives thick peripheral blood drop examinations. Hemolysis was noted with 8.1 g/dl of hemoglobin, Coombs positive, and LDH at 1,452 IU/l, associated to renal failure with 34 ml per minute of clearance. The outcome was favourable with rehydration. Blackwater fever has been described with the three aminoalcohols, but mainly in severe presentations. Clinicians are not familiar with this disease, even though it has major therapeutic implications: quinine, halofantrine, and mefloquine become strictly contra-indicated. Moderate forms may be unknown, and this observation should be taken into account to prevent mistreatment in future patients.

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.

[Methemalbuminnemia after massive hemolysis during blackwater fever]. / Methémmalbuminémie après hémolyse massive au cours d'une fièvre bilieuse hémoglobinurique.

We report a case of blackwater fever with brown plasma due to the presence of methemalbumin. The discovery of plasma with this color is a rare event at the laboratory. This compound appears during intravascular hemolysis or hemorrhagic pancreatitis when the ability of haptoglobin and hemopexin to bind free hemoglobin has been exceeded. In these cases some of heme is oxidized to hematin and taken up by serum albumin to form an albumin-hematin complex called methemalbumin. The major clinical problem is to evoke the diagnosis of methemalbuminemia and not confuse with methemoglobinemia. In our case, methemalbumin was detected and quantified using a scanning spectrophotometer. Its diagnostic and clinicals consequences are discussed.

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.

[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.

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.

Endotoxaemia in complicated falciparum malaria.

In a prospective hospital-based study, endotoxin was detected by amoebocyte limulus lysate test in the blood of 18 of 20 patients with complicated Plasmodium falciparum (16 with cerebral malaria, 2 with blackwater fever, one with acute malarial hepatitis and one with hepatorenal failure) and in all 5 patients with uncomplicated malaria tested, but in none of 5 healthy volunteers. There were 4 deaths among the 18 patients with complicated malaria and endotoxaemia. No correlation between endotoxaemia and presence of complications, clinical severity, or degree of parasitaemia was found. A concomitant bacterial infection could account for endotoxaemia in 11 of the 16 patients with cerebral malaria and endotoxaemia; in the other 5 patients with cerebral malaria, 4 with other complications, and 5 with uncomplicated malaria, endotoxin was detected in the blood without any evidence of bacterial infection.