Delayed-onset hemolytic anemia in patients with travel-associated severe malaria treated with artesunate, France, 2011-2013

Abstract

Artesunate is the most effective treatment for severe malaria. However, delayed-onset hemolytic anemia has been observed in ≈20% of travelers who receive artesunate, ≈60% of whom require transfusion. This finding could discourage physicians from using artesunate. We prospectively evaluated a cohort of 123 patients in France who had severe imported malaria that was treated with artesunate; our evaluation focused on outcome, adverse events, and postartesunate delayed-onset hemolysis (PADH). Of the 123 patients, 6 (5%) died. Overall, 97 adverse events occurred. Among the 78 patients who received follow-up for >8 days after treatment initiation, 76 (97%) had anemia, and 21 (27%) of the 78 cases were recorded as PADH. The median drop in hemoglobin levels was 1.3 g/dL; 15% of patients with PADH had hemoglobin levels of <7 g/dL, and 1 required transfusion. Despite the high incidence of PADH, the resulting anemia remained mild in 85% of cases. This reassuring result confirms the safety and therapeutic benefit of artesunate.

Keywords: France; Plasmodium falciparum; artesunate; delayed-onset; hemolysis; hemolytic anemia; imported; incidence; malaria; outcome; parasites; safety; therapeutic benefit; travel-associated; travelers; vector-borne infections.

Figure 1

Distribution of PADH and non-PADH patterns of anemia in a prospective analysis of delayed-onset hemolytic anemia in patients with severe imported malaria treated with artesunate, France, 2011–2013. Of 123 patients who received treatment, 6 died and 39 were lost to follow-up after day 8, leaving a total of 78 patients with sufficient clinical and/or biologic information to fulfill the anemia definition criteria for PADH or non-PADH classification. Indeterminate pattern, cases of anemia for which information was lacking or with an evolution pattern that did not fit PADH or non-PADH patterns; PADH, postartesunate delayed-onset hemolysis.

Figure 2

Nadir and last hemoglobin levels for 78 patients in a prospective analysis of delayed-onset hemolytic anemia in patients with severe imported malaria treated with artesunate, France, 2011–2013. Gray dots, hemoglobin level for patients with the postartesunate delayed-onset hemolysis (PADH) pattern of anemia; black dots, hemoglobin level for patients with non-PADH pattern of anemia, indeterminate pattern and nonanemic patients. Dotted lines represent hemoglobin level thresholds of 8 or 7 g/dL.

Figure 3

Typical features of postartesunate delayed-onset hemolysis and anemia for 21 patients followed in a prospective analysis of delayed-onset hemolytic anemia in patients with severe imported malaria treated with artesunate, France, 2011–2013. During the second and third weeks of late hemolytic anemia, a drop in hemoglobin occurred along with a reoccurrence of markers of hemolysis (defined as >10% drop in hemoglobin level or >10% rise in LDH concentration). Reticulocyte regeneration occurred during week 3 (delayed in comparison with other patterns of anemia, in which regeneration usually occurs during week 2 [not shown]). Values are means (SEMs). LDH, lactate dehydrogenase.