Post-treatment haemolysis is common following oral artemisinin combination therapy of uncomplicated malaria in travellers

Abstract

Background: Artemisinin-based combination therapy (ACT) for the treatment of malaria is highly effective, well tolerated and safe. Episodes of delayed haemolysis occur in up to 57.9% of patients with severe malaria treated with intravenous artesunate, mainly caused by 'pitting' of infected red blood cells in the spleen and the delayed loss of these once-infected RBCs (oiRBCs). Several reports indicate that post-treatment haemolysis (PTH) also occurs in uncomplicated malaria treated with oral ACT, calling for systematic investigation.

Methods: A prospective observational study to identify the incidence of PTH after oral ACT, defined as increased lactate dehydrogenase activity and low haptoglobin level on Day 14 after treatment. Patients were enrolled at two study centres in Germany and Italy. Study visits took place on Days 1, 3, 7, 14 and 28. Laboratory investigations included extended clinical routine laboratory tests, quantitative PfHRP2, anti-RBC antibodies and oiRBCs. The state of semi-immunity to malaria was assessed from childhood and ongoing exposure to Plasmodium spp. as per patient history.

Results: A total of 134 patients with uncomplicated malaria and 3-day ACT treatment were recruited. Thirty-seven (37.4%) of 99 evaluable patients with Pf and none of 9 patients with non-Pf malaria exhibited PTH on d14. Patients with PTH had higher initial parasitaemia, higher oiRBC counts on d3 and a 10-fold decrease in oiRBCs between d7 and d14 compared with patients without PTH. In patients with PTH, loss of haemoglobin was 4-fold greater in non-Africans than in Africans (-1.3 vs -0.3 g/dl). Semi-immune African patients with PTH showed markedly increased erythropoiesis on d14 compared with not semi-immune African and non-African patients with PTH.

Conclusions: PTH is common in patients with uncomplicated malaria and oral ACT. While the observed loss of haemoglobin will often not be clinically relevant, it could aggravate pre-existing anaemia, warranting follow-up examinations in populations at risk.

Keywords: Artemisinin combination therapy; Post-treatment haemolysis; malaria; once-infected red blood cells; uncomplicated malaria.

Figure 1

Laboratory data over time for patients with and without PTH; (A) changes in Hb levels during the post-treatment phase (d3–14) for patients with and without PTH and subgroups; boxes indicate median and interquartile range; whiskers indicate min to max values; points are individual patient data; (B) RPI, Hb and LDH were measured on d0, d3 and d7 (±2 days), d14 (±3 days) and d28 (±4 days) in all patients (n = 99); haematologic parameters for patient subgroups (non-African and African patients, non-immune and semi-immune African patients) are shown; mean and standard error of the mean are depicted; closed blue symbols, patients with PTH; open black symbols, patients without PTH; (C) exemplary laboratory values over time in three representative patients without, with compensated and with uncompensated PTH; Pf, Plasmodium falciparum; statistical significance was investigated by t-test, ^*P < 0.05, ^**P < 0.01, ^***P < 0.001

Figure 2

RPI, occurrence of oiRBCs and antigen screening test differ in patients with and without PTH; (A) RPI on Day 14 in patients with and without PTH and in subgroups; (B) initial parasitaemia (✕) and oiRBCs (○) during follow-up in patients without and with PTH; parasitaemia was determined by microscopy, oiRBCs were measured per μl of blood by fluorescence microscopy on thin blood smears; (C) occurrence of positive antibody screening test with papain-treated RBCs (AST-E) in patients with and without PTH in different subgroups; in (A) and (C), patients were classified as of African or non-African descent and semi-immune or non-immune according to their ancestry and history of exposure to Plasmodium spp., respectively; blue symbols, PTH; black symbols, no PTH; crosses, parasites d0 per μl