Fatal case of delayed-onset haemolytic anaemia after oral artemether–lumefantrine

Gustafsson, Lotta; James, Sunil; Zhang, Yimeng; Thozhuthumparambil, Karunakaran Pradeep

doi:10.1136/bcr-2021-245718

BMJ Case Rep

2021

DOI: 10.1136/bcr-2021-245718

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Fatal case of delayed-onset haemolytic anaemia after oral artemether–lumefantrine

Lotta Gustafsson

Sunil James

Yimeng Zhang

et al.

Abstract: Artemisinin derivatives are used globally in the management of falciparum malaria. Postartemisinin delayed haemolysis (PADH) is a recognised adverse event contributing to severe anaemia. To the best of our knowledge, we report the first recorded fatal case of PADH. A 60-year-old woman presented with two episodes of collapse at home and feeling generally unwell. She had recently been treated for uncomplicated falciparum malaria 1 month prior with artemether 80 mg/lumefantrine 480 mg in Congo. Her results on adm… Show more

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2021

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Post-artemisinin haemolytic anaemia, and lack of efficacy: case reportA 60-year-old woman developed post-artemisinin haemolytic anaemia following treatment with artemether/lumefantrine for falciparum malaria. Additionally, she exhibited a lack of efficacy during treatment with cobalamin, erythropoietin, folic acid, glucose and methylprednisolone for haemolytic anaemia [not all dosages and routes stated].The woman was admitted after experiencing two collapses at home and feeling unwell. Her medical history was significant for achalasia, migraine and hypertension. She was diagnosed with falciparum malaria one month prior in Congo, and was treated with oral artemether/lumefantrine 80/420mg. She then returned to the United Kingdom, and was admitted. At admission, she reported dark urination 1-2 weeks before the presentation. She was tachycardic with HR of 118 beats/min and her other vital signs were normal. Her lab test showed normocytic anaemia (Hb 43 g/L) and stage 1 acute kidney injury, blood test revealed iron level 41.1 µmol/L, transferrin 1.86 g/L, transferrin saturation 88%, ferritin 4252 µg/L, vitamin-B12 733 µg/L and folate 7.8 µg/L. Direct antiglobulin test was also found positive. An abdominal ultrasound showed normal liver and spleen. No bleeding was noted on head CT scan. She had received artemether/lumefantrine 20 days prior to the admission and there was no other evidence for acute or long-standing haemolysis. Based on all the findings, she was diagnosed with post-artemisinin haemolytic anaemia secondary to artemether/lumefantrine use.The woman was scheduled for blood transfusion; however, she denied blood products transfusion due to her personal beliefs. Therefore, she received a supportive care with erythropoietin, folic acid, cobalamin [vitamin-B12] along with empirical treatment unspecified antibacterial [antibiotics]. Despite the supportive care treatment, her condition continued to deteriorate. Hence, she was started on methylprednisolone but her Hb continued to decrease. Subsequently, her kidney function and WBC count worsened, and consciousness decreased with capillary sugar level of 1.1. Therefore, she received IV glucose replacement, but her blood gas showed a pH of 6.982, base excess of -25 mmol/L, lactate >25 mmoL and undetectable Hb. Eventually, she died due to post-artemisinin delayed haemolysis and haemolytic anaemia.

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

Kurth

Tober‐Lau

Lingscheid

et al. 2023

Journal of Travel Medicine

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Background Artemisinin combination therapy (ACT) for the treatment of malaria is highly effective, well tolerated and safe. Episodes of delayed hemolysis occur in up to 57.9% of patients with severe malaria treated with intravenous artesunate, mainly caused by ‘pitting’ of infected red blood cells (RBCs) in the spleen and delayed loss of these once-infected RBCs (oiRBCs). Several reports indicate that post-treatment hemolysis (PTH) also occurs in uncomplicated malaria treated with oral ACT, calling for systematic investigation. Methods Prospective observational study to identify the proportion of patients with 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, 28. Laboratory investigations included extended clinical routine laboratory tests, quantitative P.f.-HRP2, anti-RBC antibodies, and oiRBCs. 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 P.f. and none of nine patients with non-P.f. 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 to patients without PTH. In patients with PTH, loss of haemoglobin (Hb) 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 to 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 Hb will not be clinically relevant in most cases, it could aggravate pre-existing anaemia and warrants follow-up examinations in populations at risk.

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Imported severe Plasmodium falciparum infection in the first trimester of pregnancy complicated by post-artemisinin delayed hemolysis and intrauterine fetal death, a case report

et al. 2023

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Background Post-artemisinin delayed hemolysis (PADH) is a serious complication in patients who recover from severe malaria after receiving artemisinin-based combined therapy (ACT), including artemether-lumefantrine. In Japan, among the antimalarial drugs recommended by the World Health Organization (WHO) guideline for severe malaria, intravenous quinine gluconate is available only in 29 designated hospitals, and intravenous artesunate is unavailable. Therefore, oral artemether-lumefantrine is occasionally administered as an alternative, even though it may be a suboptimal treatment. In non-endemic settings like Japan, a lack of knowledge of malaria and the side effects, such as post-artemisinin delayed hemolysis caused by the ACT, can have critical consequences. Like our patient, being a primigravida in the early stages of pregnancy is a serious risk factor for severe malaria and must be carefully monitored. Case presentation This report describes a severe case of imported Plasmodium falciparum malaria complicated by fetal loss and prolonged anemia, requiring frequent blood transfusions. The patient was a previously healthy pregnant Japanese female in her 30 s. She developed a high fever 2 days after returning from Nigeria. The patient fulfilled the severe malaria criteria by WHO. On arrival, an abdominal ultrasound incidentally revealed a fetus of 5 week gestational age with a heartbeat in the uterus. Given her pregnancy and the severity of the disease, she was administered intravenous quinine 16 mg/kg as a loading dose. However, the second dose of quinine was not administered due to frequent vomiting and QTc prolongation. We initiated treatment with oral artemether-lumefantrine, and clearance of parasitemia was confirmed by microscopic observation on day 4. Miscarriage was noted on day 6 after admission. Moreover, the patient became feverish again up to 39 °C, and from days 14 to 22, the patient required multiple blood transfusions due to PADH. On day 40, follow-up was discontinued as the hemoglobin level exceeded 10 g/dL. Conclusions In patients who recover from severe malaria after ACT treatment, monitoring the hemoglobin level for at least a month is strongly recommended for prompt identification of PADH. Travelers to malaria-endemic countries, especially primigravida women, should be provided with adequate information on the risk and prevention of infection.

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Fatal case of delayed-onset haemolytic anaemia after oral artemether–lumefantrine

Cited by 3 publications

References 29 publications

Multiple drugs

Multiple drugs

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

Imported severe Plasmodium falciparum infection in the first trimester of pregnancy complicated by post-artemisinin delayed hemolysis and intrauterine fetal death, a case report

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