Hemolysis after Oral Artemisinin Combination Therapy for Uncomplicated Plasmodium falciparum Malaria

Abstract

Episodes of delayed hemolysis 2-6 weeks after treatment of severe malaria with intravenous artesunate have been described. We performed a prospective observational study of patients with uncomplicated malaria to investigate whether posttreatment hemolysis also occurs after oral artemisinin-based combination therapy. Eight of 20 patients with uncomplicated malaria who were given oral artemisinin-based combination therapy met the definition of posttreatment hemolysis (low haptoglobin level and increased lactate dehydrogenase level on day 14). Five patients had hemolysis persisting for 1 month. Patients with posttreatment hemolysis had a median decrease in hemoglobin level of 1.3 g/dL (interquartile range 0.3-2.0 g/dL) in the posttreatment period, and patients without posttreatment hemolysis had a median increase of 0.3 g/dL (IQR -0.1 to 0.7 g/dL; p = 0.002). These findings indicate a need for increased vigilance for hemolytic events in malaria patients, particularly those with predisposing factors for anemia.

Keywords: Plasmodium falciparum; anemia; artemisinin; clinical study; haptoglobin; hemoglobin; hemolysis; lactate dehydrogenase; malaria; oral artemisinin combination therapy; parasites; uncomplicated malaria.

Figure 1

Changes in hemoglobin levels (ΔHb) for patients with and without posttreatment hemolysis after treatment with oral artemisinin-based combination therapy for uncomplicated Plasmodium falciparum malaria. A) Day (d) 0 to d 14 (overall); B) d 0 to d 3 (treatment period); C) d 3 to d 14 (posttreatment period). Horizontal lines indicate median values, boxes indicate interquartile ranges, whiskers indicate ranges, and solid squares and circles indicate individual patient data points. The Mann-Whitney U test was used for comparative analysis. *p<0.05; †p<0.01; NS, not significant.

Figure 2

Changes in hemoglobin levels (ΔHb) for patients without posttreatment hemolysis, with compensated posttreatment hemolysis, and with uncompensated posttreatment hemolysis after treatment with oral artemisinin-based combination therapy for uncomplicated Plasmodium falciparum malaria. A) day (d) 0 to d 14 (overall); B) d 0 to d 3 (treatment period); C) d 3 to d 14 (posttreatment period). Horizontal lines indicate median values, boxes indicate interquartile ranges, whiskers indicate ranges, and solid squares, circles, and triangles indicate individual patient data points.

Figure 3

Laboratory values over time for exemplary patients with and without posttreatment hemolysis after treatment with oral artemisinin-based combination therapy for uncomplicated Plasmodium falciparum malaria. A) Patient without posttreatment hemolysis, B) patient with compensated posttreatment hemolysis, and C) patient with uncompensated posttreatment hemolysis. Hb, hemoglobin; LDH, lactate dehydrogenase.