Haemolysis associated with the treatment of malaria with artemisinin derivatives: a systematic review of current evidence

• Haemolysis following treatment of severe malaria with artemisinin drugs is a common clinical phenomenon typically occurring in the second week after initiation of antimalarial therapy.
• The observed decrease of haemoglobin is clinically significant and the majority of reported cases required repeated administration of blood transfusions.
• All artemisinin derivatives and all routes of administration (intravenous, intra-muscular, intra-rectal and even oral administration) may be associated with late haemolysis.
• Hyperparasitaemia is the most consistent risk factor for haemolysis, however not all patients with hyperparasitaemia will develop haemolysis following treatment with artemisinins.
• Despite the occurrence of haemolysis following treatment with artemisinin drugs, parenteral artesunate remains the first line treatment for severe malaria.
• Patients treated with artemisinin derivatives for severe malaria should be followed-up for clinical and laboratory investigations at least once weekly for a 4 to 6 week period to screen for signs of haemolysis.

SummaryBackgroundArtemisinin derivatives are the mainstay of antimalarial treatment, both for uncomplicated malaria and for severe disease. Artemisinins are known for their rapid onset of action, good tolerability, and safety. However, besides the sporadic but worrying reports of delayed parasite clearance after treatment with artemisinins, there have been an increasing number of reports of acute haemolytic anaemia following their use and the safety of this class of antimalarials is being questioned.MethodsIn this systematic review, all reports of patients experiencing haemolysis following the use of artemisinins for the treatment of malaria were identified and collated into an electronic database. Summary statistics were calculated to characterize the epidemiology and clinical features of this safety concern related to artemisinin derivatives.ResultsA total of 37 patients were identified suffering from haemolysis following the treatment of severe malaria with artemisinin derivatives. Thirty-one cases had received intravenous artesunate, while the remaining cases were attributed to other parenteral or oral regimens of artemisinin derivatives. The majority of patients were returning travellers (n = 30), and six clinical cases had been reported in paediatric patients. The median onset of haemolysis was 15 (interquartile range (IQR) 13–15) days after the initiation of treatment for the ‘delayed-onset’ pattern and 17 (IQR 13–22) days for the ‘persistent’ haemolysis pattern. The median reduction in haemoglobin due to haemolysis was 6 g/dl (IQR 4–8 g/dl). The estimated proportion of patients suffering from severe malaria experiencing haemolysis after treatment with artemisinin derivatives was 13% (95% confidence interval 9–18%), and 73% of these (i.e., 9% of the total population) required blood transfusions. No fatal outcome has been reported in the literature to date.ConclusionsHaemolysis is commonly associated with the class of artemisinin drugs when used for the treatment of severe malaria. Potential causes of this safety issue are discussed. Although no deaths attributed to haemolysis have been reported so far, this safety issue may lead to life-threatening anaemia and is particularly worrying for regions where safe blood products are not readily available.