Post-artesunate delayed haemolysis in severe imported Plasmodium falciparum malaria

We report a case of post-artesunate delayed haemolysis (PADH) in severe Plasmodium falciparum malaria.

A female wildlife conservation worker based in South Africa presented with severe malaria (hypotensive shock and 30% parasitaemia level). She had not been on malaria prophylaxis. Six months earlier she had a febrile illness after a tick bite, which was treated with doxycycline with complete resolution. Blood tests revealed renal impairment, abnormal liver function tests with coagulopathy and thrombocytopenia without intravascular haemolysis. Systemic examination was unremarkable.

In the intensive care unit she was given intravenous artesunate for 5 days and supportive platelet transfusion. Blood cultures and serologies for dengue, leptospirosis, schistosomiasis, rickettsia and HIV were negative. Oral artemether-lumefantrine was prescribed to complete malaria treatment. Recurrence of haemolysis was observed on Day 10 of admission (1 week after artesunate treatment). Extravascular haemolysis was confirmed by low haptoglobin and elevated lactate dehydrogenase (LDH) levels. Other causes of haemolysis such as viral haemorrhagic fever (Rift Valley and Crimean–Congo fevers), drugs and viral infections were excluded.

A literature search of haemolytic causes alluded to the possibility of PADH.1 Proposed criteria by the United States Centers for Disease Control and Prevention (CDC) for PADH (a decline in haemoglobin levels of ≥ 10%, haptoglobin levels of ≤ 0.1 g/L and an increase in LDH levels of > 390 U/L) were present.1 Supportive therapy with blood transfusion led to restabilisation of haemoglobin. Convalescent serological testing found an increase in Rickettsia typhi titre from < 128 to 256 before discharge. This was consistent with murine typhus likely caused by flea bites when cleaning her room. Empirical therapy with doxycycline given earlier in the current admission would have treated this.

Artesunate is the drug of choice to treat severe P. falciparum infection due to concerns of drug resistance and mortality benefit.2 PADH is a rare but significant complication of artesunate, with 23 confirmed and 15 probable cases.3 Although there has been heterogeneity in the criteria for diagnosis of PADH in the past, the CDC optimised the definition in 2014.1,4 PADH typically occurs 1 to 3 weeks after administration of intravenous artesunate treatment.1 Artesunate supplied in Australia is manufactured overseas (China) and sourced by a local company. Although controversy remains around artesunate manufactured overseas due to non-adherence to Good Manufacturing Practice (GMP) guidelines, whether PADH is caused by direct toxicity from the drug in non-GMP settings remains speculative as it has also been described in three patients who received the drug made in the US and Canada.4,5 There are two proposed mechanisms of PADH: (i) rapid clearance of parasite from the infected red blood cells causes them to “pit”, which causes haemolysis; and (ii) activation of the pro-inflammatory cytokines.3,4 Higher parasitaemia levels in non-immune patients are more frequently associated with PADH.1,4 PADH is also known to occur with oral artemisinin derivatives.1

Clinicians using artesunate to treat patients diagnosed with falciparum malaria need to be aware of the risk of PADH, especially if haemolysis develops after treatment. Based on the current literature, we recommend a follow-up of at least 1 month after treatment.1,2