Severe delayed autoimmune haemolytic anaemia following artesunate administration in severe malaria: a case report

Abstract

BackgroundParenteral artesunate is recommended as first-line therapy for severe and complicated malaria. Although its efficacy has been proven, long-term safety profile is still under evaluation. Several cases of delayed haemolytic anaemia occurred after initial clinical improvement and resolution of parasitaemia in non-immune travellers and children living in endemic areas. Reports have generated concern that this phenomenon might be related to the treatment itself, either by direct toxicity or immune-related mechanism. This is a report of the first case of autoimmune haemolytic anaemia following treatment of severe malaria initially managed with parenteral artesunate with strong indication for drug-immune related mechanism.CaseA 17-year old Ivoirian female travelling in France presented with fever, headache and abdominal pain seven days after her arrival. Physical examination was indicative of septic shock while blood analysis showed normal haemoglobin level, but profound thrombocytopaenia and hyperlactataemia. Blood smear analysis showed Plasmodium falciparum infection with a parasitaemia of 0.8%. Severe malaria was diagnosed according to the WHO criteria. The patient was initially managed with artemether/lumefantrine combination and then parenteral artesunate for 48 hours. Empiric antibiotic course was also initiated with ceftriaxone, metronidazole, gentamycin, and then piperacillin and ciprofloxacin. At day 14, haemoglobin dropped to 4.6 g/dL with biologic features indicative of haemolysis (LDH 658 U/L, haptoglobin <0.15 g/L). At that time, parasitaemia was negative and other infections or hereditary disorders were excluded, while Coombs’ direct antiglobulin test was positive for IgG and C3d. Antinuclear antibodies were absent. Further investigations evidenced drug-induced antibodies related to artesunate. It was concluded a drug-mediated autoimmune haemolytic anaemia. A corticosteroids regimen was initiated at 1 mg/kg/day. Outcome was favourable and corticosteroids were progressively tapered during two months. At present the patient’s condition remains stable without recurrence of haemolytic anaemia.ConclusionThis is the first case of delayed haemolytic anaemia related to artesunate with a strong indication for drug-immune related mechanism. Further research is warranted to better characterize this plausible cause of post-treatment haemolysis following parenteral artesunate administration in severe malaria patients.Electronic supplementary materialThe online version of this article (doi:10.1186/1475-2875-13-398) contains supplementary material, which is available to authorized users.

Development of Delayed Hemolytic Anemia After Treatment with Oral Artemether–Lumefantrine in Two Patients with Severe Falciparum Malaria

“…23 Furthermore, artesunate-dependent antibodies were recently reported in a French patient. 13 Similar to our patients, most patients with delayed hemolysis described to date have recovered naturally. Several patients with severe anemia, however, required blood transfusions to support their recovery.…”

“…Among the 39 previously reported PADH cases, 14 had switched to oral artemether-lumefantrine following initial treatments such as parenteral artesunate or parenteral artesunate plus tetracyclines. 3,[12][13][14] Other combinations of ACTs included artesunate-amodiaquine following artesunate injection, 5 dihydroartemisinin-piperaquine following intramuscular artemether, 6 and artemether-lumefantrine following quinine injection plus doxycycline. 8 Only one previous case of PADH was associated with artemetherlumefantrine as the sole regimen.…”

Artemisinin-induced delayed hemolysis after administration of artesunate and artesunate-amodiaquine in malaria-free Wistar rats

“…Artesunate have been previously reported to be associated with neutropenia at doses higher than doses administered in our study (Bethell et al, 2010), however neutropenia was not observed with AS, ASQ or AQ during the study. This study lends support to a case report of artesunate induced auto-immune post-treatment delayed hemolysis, although this occurred in a malaria patient (Raffray et al, 2014).…”

Evidencing the Role of Erythrocytic Apoptosis in Malarial Anemia

“…In vitro studies performed by Alzoubi et al (2014a,b) showed that the antimalarial drugs artesunate and lumefantrine have proapoptotic effect on erythrocytes, possibly through generation of oxidative stress, a feature already reported for both drugs (Xie et al, 2005; Abolaji et al, 2013). Thus, the proapoptotic effect of artesunate and lumefantrine could explain the reduction of erythrocytic blood parameters reported in healthy rats and humans (Xie et al, 2005; Kongpatanakul et al, 2009) as well as in occurrence of acute anemia in malarial patients following antimalarial drug treatment (De Nardo et al, 2013; Raffray et al, 2014; Sowunmi et al, 2015). …”