Severe malaria, artesunate and haemolysis

Sir, Intravenous artesunate is the treatment of choice for severe and complicated malaria, according to the WHO 2010 guidelines, after large clinical trials in Africa (AQUAMAT) and South-East Asia (SEAQUAMAT) demonstrated a substantial benefit in terms of survival when this drug was compared with quinine; artesunate also proved to be very well tolerated. We report the case of a 22-year-old Italian woman who presented to Amedeo di Savoia Hospital in Turin in September 2011, with fever, chills and headache after a 4 week stay in Sierra Leone, without taking malaria chemoprophylaxis. Her physical examination showed a temperature of 408C, dehydration and splenomegaly. Blood tests showed a normal leucocyte count, haemoglobin 14.4 g/dL, thrombocyte count 32000/mm, lactate dehydrogenase (LDH) 2722 U/L and total bilirubin 5.7 mg/dL. Peripheral thick and thin blood films showed Plasmodium falciparum trophozoites (3.8% parasitized red blood cells). A treatment with oral artemether/lumefantrine was started. The following day, the parasitaemia was 6.9%; since the parasitaemiawas increasing and the patient was fulfilling WHO 2010 criteria for severe malaria (hyperparasitaemia and jaundice), intravenous artesunate (Guilin Pharmaceutical Co., Shanghai, China) dosed at 2.4 mg/kg every 12 h was started. After 6 h, the parasitaemia had dropped to 2% and was 0.01% after 24 h. After 36 h, the patient was switched to oral artemether/lumefantrine. On day 4, parasitaemia was absent and LDH was 1449 U/L. On day 8 she had another febrile peak and laboratory signs of haemolytic anaemia (haemoglobin 8.1 g/dL, LDH 2406 U/L, bilirubin 3.1 mg/dL, reticulocytes 150/1000 and haptoglobin ,2 mg/dL). No parasites were found on the blood smear. Immunohaematological haemolysis and glucose-6-phosphate dehydrogenase deficiency were ruled out by a cold agglutinins test, Coombs test, autoantibodies and glucose-6-phosphate dehydrogenase test. On day 14 (haemoglobin 5.6 g/dL), a blood transfusion was prescribed. In the following days the patient’s condition improved and she was discharged on day 18. On day 40, the patient was asymptomatic, thin and thick blood films were negative, and haematological and biochemical parameters were within the normal range. The patient gave written informed consent for the publication of these data. Haemolysis is not reported as a side effect of artesunate treatment in the cited trials (only some expected cases of blackwater fever occurred immediately after treatment). Nonetheless, subclinical haemolysis could be undiagnosed in such settings. Zoller et al. recently published a case series in European travellers with artesunate-treated imported malaria, including six cases with haemolysis occurring 14–31 days and resolving 3–6 weeks after treatment. The event was more frequent when high doses were used. In the reported case, an LDH flare and decrease in haemoglobin reappeared after parasite and fever clearance, and were associated with fever (37.5–388C) and conjunctival jaundice, indicating a haemolytic syndrome. A direct drug toxicity is unlikely, given the short half-life of the molecule (time to final detection: 2 h); although, due to the drug’s production outside European standards of good manufacturing practice, the presence of contaminants cannot be excluded. A further possibility is haemolysis due to lumefantrine, which has a longer half-life; however, this has never been reported, despite the long-term worldwide use of artemether/lumefantrine. Overall, a clear explanation for the haemolysis in this reported case is lacking. Since unexplained haemolysis has been repeatedly observed, specific surveillance in artesunate-treated patients is required.