Background: Artesunate (AS) is the WHO first-line treatment of severe malaria in endemic countries, in adults and children. However, despite solid evidence that AS is safe and more effective than quinine in endemic areas, its deployment in non-endemic areas has been slow, due in part to the absence of a full good manufacturing practice (GMP) qualification (although prequalification has been granted in 2010). Prospective comparative trials were not conducted in travellers, but several retrospective studies and case reports are providing insights into the efficacy and safety of AS in imported severe malaria.

Methods: We performed a systematic review on AS use in non-endemic areas for the treatment of imported severe malaria, using the Prisma method for bibliographic reports. Post-AS delayed haemolysis (PADH) was defined by delayed haemolytic episodes occurring 7–30 days after treatment initiation. We summarized prescription guidelines and generated answers to frequently asked questions regarding the use of AS in travellers with severe malaria.

Results: We analysed 12 retrospectives and 1 prospective study as well as 7 case reports of AS treatment in 624 travellers. Of 574 patients with reported outcome, 23 died (4%). No death was attributed to AS toxicity. Non-haematological side effects were uncommon and mainly included mild hepatitis, neurological, renal, cutaneous and cardiac manifestations. PADH occurred in 15% of the treated patients. No death or sequelae were reported. Overall blood transfusion was administered in 50% of travellers with PADH.

Conclusion: AS is highly efficacious in travellers with severe malaria. The frequency of PADH supports the need of weekly follow-up of haematological parameters during 1 month. Full GMP qualification for the drug and rapid approval by drug agencies is warranted, backed by clear recommendations for optimal use.

Introduction

‘A handful of qinghao immersed with 2 l of water, wring out the juice and drink it all’. Here is how Ge Hong (284–346 CE) first referred to medicinal herb Artemisia annua L. (qinghao in Chinese) for treatment of malaria symptoms in his Handbook of Prescriptions for Emergencies. More than 1600 years later, the Chinese project 523 led by Pr Tu Youyou, drawing on traditional Chinese medicine, has isolated from A.annua a non-toxic, neutral extract that induced 100% parasite clearance in animal models of malaria. In 1972, this team isolated and purified by crystallization the active component of the extract: the qinghaosu (or artemisinin) and determined the stereo-structure (a sesquiterpene lactone) in 1975. They then discovered that reducing the ketone component (forming dihydroartemisinin) led to a more stable and 10 times more effective molecule than artemisinin, with much less frequent malaria recurrences during treatment with these derivatives.1 In 2015, the work conducted by the project 523 was internationally recognized and its team leader Pr Tu Youyou was awarded the Nobel Prize in Physiology and Medicine ‘for her discoveries concerning a novel therapy against Malaria’.

The use of artesunate (AS), a derivative from artemisinin compound, in severe malaria was introduced in endemic areas on the basis of two large randomized clinical trials that showed a 35% reduction in death rates in adults in Asia and a 22.5% reduction in children in Africa when AS was compared with quinine.2,3 In contrast to quinine, AS action on early circulating ring-stages reduces the risk of sequestration of red blood cell (RBC) infected with mature forms of Plasmodium falciparum and related clinical manifestations of severe malaria.4 The anti-malarial activity is linked to the endoperoxide moiety (artemisinin derivatives that lack this moiety are devoid of parasite-killing effect)5 but the exact mechanisms of action are still controversial. A widespread assumption is that artemisinin derivatives are pro-drugs activated by the cleavage of the endoperoxide bridge in the presence of ferrous iron or haem (Fenton-type reaction) that generates reactive oxygen species and carbon-centred radicals directly toxic on the intra-erythrocytic parasite.6 The rapid activity of these drugs on circulating ring stages stops their development to the trophozoite stages and therefore inhibits in a few hours the sequestration process (rosetting and cytoadherence).4,7 In contrast with other anti-malarial drugs (quinine, mefloquine, pyrimethamin), artemisinin derivatives act on almost all intra-erythrocytic parasite stages, including early rings, in addition to late trophozoites and schizonts (responsible for cytoadherence), and have also an action on immature sexual forms (but not on stage V gametocytes responsible for transmission) but have no killing activity on hepatic stages. Artemisinins induce a rapid and early clearance with up to a 10 000-fold reduction in parasite biomass per asexual cycle.7

In 2010, WHO has introduced the clear recommendations of using intravenous (IV) AS in all patients with severe malaria—adults, children and pregnant women—including those infected with non-falciparum species.8,9 Despite solid evidence that AS is superior to quinine, its deployment in non-endemic areas has been slowed by the lack of a full WHO good manufacturing practice (GMP) qualification, although prequalification has been granted in 2010 (Guilin Pharmaceutical Company, Guilin, China), and the absence of prospective clinical safety trials including travellers. Several studies have supported the use of AS in severe imported malaria, despite the description of a new adverse event in travellers, consisting in delayed haemolytic episodes termed post-AS delayed haemolysis (PADH). We conducted here a systematic review to assess the efficacy and the safety of AS in travellers with a focus on the occurrence of haematological adverse events.

Methods

We performed a systematic analysis on the use of AS in non-malaria endemic areas for the treatment of imported severe malaria. Clinical reports, in English or French where selected according to PRISMA guidelines.10 The literature search was made in Pubmed/Medline and Web of science in July 2016 using the following keywords: ‘AS’ and ‘travellers’ or ‘imported malaria’ or ‘anaemia’ or ‘haemolysis’. Reports were then selected according to relevance of title and abstract, and finally full-text articles were assessed for eligibility.

Case definition for PADH was a delayed haemolytic episode occurring 7–30 days after treatment initiation. Based on this analysis and on published recommendations, we summarized prescription guidelines and generated answers to frequently asked questions (FAQ) regarding the use of AS in travellers with severe malaria.

Results

We identified 20 relevant articles reporting a total of 624 travellers treated with AS for imported malaria.11–30,Table 1 presents the results and details of a systematic review on the use of AS in travellers. Data available in the literature were mostly case-reports (7)16,18,22–24,28,29 and retrospectives studies (12),11–15,17,19–21,26,27,30 except for one prospective study.25

Table 1

Systematic review of imported malaria treated with AS

 Reference Year(s) Country Number of AS-treated patients Clinical presentation Follow-up duration Study design Treatment detail Outcome Haemolytic anaemia (PADH lato sensu) PADH-related transfusion Other AEs PADH case definition 
 Tang et al.11 1991–2002 Taiwan Severe falciparum malaria (cerebral) N/A Retrospective AS IV + Q + Doxy ± PQ Recovery 2/2 (100%) N/A na N/A na 
 Mørch et al.12 2006–08 Norway Severe falciparum malaria 4 weeks Retrospective 
  • IV AS + Doxy (7/9)

  • IV AS (1/9)

  • IV AS + Clinda (1/9)

 
  • Recovery 9/9 (100%)

  • no sequelae, no recrudescence

 
0/9 (0%) na No (1 pregnant women— 3rd trimester—delivered a healthy child at term) na 
 Kano13 2001–07 Japan Severe or drug resistant falciparum malaria N/A Retrospective IV AS + MQ Recovery 5/5 (100%) 2/5 (40%) 2/2 (100%) Post-malaria neurological syndrome (1/5) na 
 Bartoloni et al.14 2008–09 Italy 8 (5 children) Severe falciparum malaria 2–25 days in hospital, follow-up duration N/A Retrospective IV AS + IV Q 
  • Recovery with no sequelae 7/8 (87.5%)

  • Mortality rate 1/8 (12.5%) Recrudescence 5 days after the end of treatment 1/8 (12.5%)

 
0/8 (0%) na Cinchonism (2/8) hypoglycaemia (2/8) attributed to quinine na 
 Mali et al.15, (MMWR) Morbidity and Mortality weekly report 2010 USA 39 Severe falciparum malaria N/A Retrospective IV AS 1st line or 2nd line after IV Q Mortality rate 5/39 (12.8%) N/A na N/A na 
 Callender and Hsue16 2009 Hawai’i Severe falciparum malaria 6 months Case report IV AS Recovery 1/1 (100%) 0/1 (0%) na No na 
 Zoller17 2006–10 Europe 25 (1 child) Severe falciparum malaria N/A Retrospective 
  • IV AS 1st line (22/25)

  • IV AS 2nd line (3/25)

 
Recovery 25/25 (100%) 
  • 6/25 (24%)

  • 3 persistent

  • 3 PADH stricto sensu

 
5/6 (83%) No N/A 
 Caramello et al.18 2011 Italy Severe falciparum malaria 40 days Case report IV AS 2nd line Recovery 1/1 (100%) 1/1 (100%) 1/1 (100%) No N/A 
 Eder et al.19 2009–11 UK 24 Severe falciparum malaria N/A Retrospective comparative study IV AS vs IV Q 
  • IV AS 1st line (16/24)

  • IV AS after 1 dose of IV Q (8/24)

 
Recovery 24/24 (100%) 1/24 (4%) delayed haemolysis Day 15 with Coombs + 1/1 (100%) No N/A 
 Kreeftmeijer- Vegter et al.20 2007–10 Netherlands, Belgium 68 Severe falciparum malaria (55/68) non-severe malaria (13) (1/68 = P. vivax, 1/68 = P. ovaleN/A Retrospective IV AS 1st line monotherapy or in association (43/68) IV AS in 2nd (25/68) Mortality rate in severe malaria 2/55 (3.6%) 7/55 (13%) 4/7 (57%) 1 Neurological syndrome concomitant to haemolysis at D30. No other AEs reported to AS N/A 
 Rolling et al.21 2006–12 Germany Severe falciparum malaria 4 weeks Retrospective comparative study IV AS/IV Q IV AS (4/8) or Rectal AS + IV Q (4/8) vs IV Q Recovery 8/8 100% 5/8 (63%) delayed haemolysis 3/5 (60%) temporary deterioration in renal function (3/5) Any decrease in median Hb and any increase in median LDH between Weeks 2 and 3 
 Paczkowski et al.22, (MMWR) 2008–13 USA Severe falciparum malaria 13 and 26 days Case report IV AS Recovery 2/2 (100%) 2/2 (100%) 2/2 (100%) No N/A 
 Boillat et al.23 2012–15 Switzerland Severe falciparum malaria At least 4 weeks Case report IV AS Recovery 4/4 (100%) 4/4 (100%) (uncertain diagnostic for 1 case with multifactorial anaemia) 3/4 (75%) N/A Hb drop + haemolysis (low haptoglobin, increased LDH) after Day 7 or continuing haemolysis starting from and around Day 7 and persisting beyond Day 14 
 Lee et al.24 2012 Canada Severe falciparum malaria 6 weeks Case report IV AS Recovery 1/1 (100%) 1/1 (100%) 1/1 (100%) No Decrease in Hb combined with an increase in LDH between Weeks 2 and 3 
 Jauréguiberry et al.25 2011–13 France 123 Severe falciparum malaria >8 days for 78/123 Prospective IV AS Mortality rate 6/123 (4.8%) 21/78 (27%) 1/21 (<5%) 
  • Cutaneous 3/123 (2.4%)

  • Neurological 4/123 (3.2%)

  • Cardiac 4/123 (3.2%)

  • Hypertension 1/123 (0.8%)

  • Elevated level of ALT 8/123 (6.5%) Hyperkaliaemia 1/123 (0.8%)

 
>10% decrease in Hb level + >10% increase in LDH level after Day 8 
 Kurth et al.26 2006–14 Europe 70 Severe falciparum malaria  Retrospective comparative study IV AS/IV Q 
  • IV AS 1st line (60/70)

  • IV AS 2nd line (3/70)

  • IV AS + IV Q (7/70)

 
Mortality rate 1/70 (1.4%) 19/70 (27%) N/A N/A N/A 
 McCarthy et al.27 2001–13 Canada 129 Severe falciparum malaria N/A Retrospective comparative study IV AS/IV Q IV AS Mortality rate 1/92 (1%) 2/89 (2.2%) at least 1 (data N/A for the second case) minor 2/89 (2.2%), Serious 1/89 (1.1%) (early haemolysis) Other 2/89 (2.2%) (determined retrospectively as unrelated to the treatment) N/A (one case of ‘delayed haemolysis’ occured at Day 6) 
 Chavada et al.28 N/A Australia Severe falciparum malaria N/A Case report IV AS Recovery 1/1 (100%) 1/1 (100%) 1/1 (100%) N/A Decline in Hb level ≥ 10%, haptoglobin level ≤ 0.1 g/l and LDH level > 390 U/l at least 7 days after initiation of IV AS 
 Charles et al.29 2013–14 Canada Severe falciparum malaria 3.5 months (1/2), 20 days (1/2) Case report IV AS Recovery 2/2 (100%) 2/2 (100%) 2/2 (100%) No Decline in Hb level ≥ 10%, haptoglobin level ≤ 0.1 g/l and LDH level > 390 U/l at least 7 days after initiation of IV AS 
 Twomey et al.30 2007–10 USA 102 Severe malaria 7 days Retrospective IV AS alone (56/102) or in association (46/102) Mortality rate 7/102 (6.9%) 0/102 (0%) na 92.2% of patients (most of them attributed to the disease). No grade 4 AEs was considered ‘definitively’ related to AS 2 pregnant women delivered healthy infants na 
Total 20 (13 studies, 7 case reports)   624   Retrospective (12/20), prospective (1/20), case reports (7/20)  Mortality rate 23/574 (4%) 74/485 (15.3%) 27/54 (50%) 129/465 (27.7%) 28/465 (6%) attributed to AS or not specified  
 Reference Year(s) Country Number of AS-treated patients Clinical presentation Follow-up duration Study design Treatment detail Outcome Haemolytic anaemia (PADH lato sensu) PADH-related transfusion Other AEs PADH case definition 
 Tang et al.11 1991–2002 Taiwan Severe falciparum malaria (cerebral) N/A Retrospective AS IV + Q + Doxy ± PQ Recovery 2/2 (100%) N/A na N/A na 
 Mørch et al.12 2006–08 Norway Severe falciparum malaria 4 weeks Retrospective 
  • IV AS + Doxy (7/9)

  • IV AS (1/9)

  • IV AS + Clinda (1/9)

 
  • Recovery 9/9 (100%)

  • no sequelae, no recrudescence

 
0/9 (0%) na No (1 pregnant women— 3rd trimester—delivered a healthy child at term) na 
 Kano13 2001–07 Japan Severe or drug resistant falciparum malaria N/A Retrospective IV AS + MQ Recovery 5/5 (100%) 2/5 (40%) 2/2 (100%) Post-malaria neurological syndrome (1/5) na 
 Bartoloni et al.14 2008–09 Italy 8 (5 children) Severe falciparum malaria 2–25 days in hospital, follow-up duration N/A Retrospective IV AS + IV Q 
  • Recovery with no sequelae 7/8 (87.5%)

  • Mortality rate 1/8 (12.5%) Recrudescence 5 days after the end of treatment 1/8 (12.5%)

 
0/8 (0%) na Cinchonism (2/8) hypoglycaemia (2/8) attributed to quinine na 
 Mali et al.15, (MMWR) Morbidity and Mortality weekly report 2010 USA 39 Severe falciparum malaria N/A Retrospective IV AS 1st line or 2nd line after IV Q Mortality rate 5/39 (12.8%) N/A na N/A na 
 Callender and Hsue16 2009 Hawai’i Severe falciparum malaria 6 months Case report IV AS Recovery 1/1 (100%) 0/1 (0%) na No na 
 Zoller17 2006–10 Europe 25 (1 child) Severe falciparum malaria N/A Retrospective 
  • IV AS 1st line (22/25)

  • IV AS 2nd line (3/25)

 
Recovery 25/25 (100%) 
  • 6/25 (24%)

  • 3 persistent

  • 3 PADH stricto sensu

 
5/6 (83%) No N/A 
 Caramello et al.18 2011 Italy Severe falciparum malaria 40 days Case report IV AS 2nd line Recovery 1/1 (100%) 1/1 (100%) 1/1 (100%) No N/A 
 Eder et al.19 2009–11 UK 24 Severe falciparum malaria N/A Retrospective comparative study IV AS vs IV Q 
  • IV AS 1st line (16/24)

  • IV AS after 1 dose of IV Q (8/24)

 
Recovery 24/24 (100%) 1/24 (4%) delayed haemolysis Day 15 with Coombs + 1/1 (100%) No N/A 
 Kreeftmeijer- Vegter et al.20 2007–10 Netherlands, Belgium 68 Severe falciparum malaria (55/68) non-severe malaria (13) (1/68 = P. vivax, 1/68 = P. ovaleN/A Retrospective IV AS 1st line monotherapy or in association (43/68) IV AS in 2nd (25/68) Mortality rate in severe malaria 2/55 (3.6%) 7/55 (13%) 4/7 (57%) 1 Neurological syndrome concomitant to haemolysis at D30. No other AEs reported to AS N/A 
 Rolling et al.21 2006–12 Germany Severe falciparum malaria 4 weeks Retrospective comparative study IV AS/IV Q IV AS (4/8) or Rectal AS + IV Q (4/8) vs IV Q Recovery 8/8 100% 5/8 (63%) delayed haemolysis 3/5 (60%) temporary deterioration in renal function (3/5) Any decrease in median Hb and any increase in median LDH between Weeks 2 and 3 
 Paczkowski et al.22, (MMWR) 2008–13 USA Severe falciparum malaria 13 and 26 days Case report IV AS Recovery 2/2 (100%) 2/2 (100%) 2/2 (100%) No N/A 
 Boillat et al.23 2012–15 Switzerland Severe falciparum malaria At least 4 weeks Case report IV AS Recovery 4/4 (100%) 4/4 (100%) (uncertain diagnostic for 1 case with multifactorial anaemia) 3/4 (75%) N/A Hb drop + haemolysis (low haptoglobin, increased LDH) after Day 7 or continuing haemolysis starting from and around Day 7 and persisting beyond Day 14 
 Lee et al.24 2012 Canada Severe falciparum malaria 6 weeks Case report IV AS Recovery 1/1 (100%) 1/1 (100%) 1/1 (100%) No Decrease in Hb combined with an increase in LDH between Weeks 2 and 3 
 Jauréguiberry et al.25 2011–13 France 123 Severe falciparum malaria >8 days for 78/123 Prospective IV AS Mortality rate 6/123 (4.8%) 21/78 (27%) 1/21 (<5%) 
  • Cutaneous 3/123 (2.4%)

  • Neurological 4/123 (3.2%)

  • Cardiac 4/123 (3.2%)

  • Hypertension 1/123 (0.8%)

  • Elevated level of ALT 8/123 (6.5%) Hyperkaliaemia 1/123 (0.8%)

 
>10% decrease in Hb level + >10% increase in LDH level after Day 8 
 Kurth et al.26 2006–14 Europe 70 Severe falciparum malaria  Retrospective comparative study IV AS/IV Q 
  • IV AS 1st line (60/70)

  • IV AS 2nd line (3/70)

  • IV AS + IV Q (7/70)

 
Mortality rate 1/70 (1.4%) 19/70 (27%) N/A N/A N/A 
 McCarthy et al.27 2001–13 Canada 129 Severe falciparum malaria N/A Retrospective comparative study IV AS/IV Q IV AS Mortality rate 1/92 (1%) 2/89 (2.2%) at least 1 (data N/A for the second case) minor 2/89 (2.2%), Serious 1/89 (1.1%) (early haemolysis) Other 2/89 (2.2%) (determined retrospectively as unrelated to the treatment) N/A (one case of ‘delayed haemolysis’ occured at Day 6) 
 Chavada et al.28 N/A Australia Severe falciparum malaria N/A Case report IV AS Recovery 1/1 (100%) 1/1 (100%) 1/1 (100%) N/A Decline in Hb level ≥ 10%, haptoglobin level ≤ 0.1 g/l and LDH level > 390 U/l at least 7 days after initiation of IV AS 
 Charles et al.29 2013–14 Canada Severe falciparum malaria 3.5 months (1/2), 20 days (1/2) Case report IV AS Recovery 2/2 (100%) 2/2 (100%) 2/2 (100%) No Decline in Hb level ≥ 10%, haptoglobin level ≤ 0.1 g/l and LDH level > 390 U/l at least 7 days after initiation of IV AS 
 Twomey et al.30 2007–10 USA 102 Severe malaria 7 days Retrospective IV AS alone (56/102) or in association (46/102) Mortality rate 7/102 (6.9%) 0/102 (0%) na 92.2% of patients (most of them attributed to the disease). No grade 4 AEs was considered ‘definitively’ related to AS 2 pregnant women delivered healthy infants na 
Total 20 (13 studies, 7 case reports)   624   Retrospective (12/20), prospective (1/20), case reports (7/20)  Mortality rate 23/574 (4%) 74/485 (15.3%) 27/54 (50%) 129/465 (27.7%) 28/465 (6%) attributed to AS or not specified  

IV AS, intravenous artesunate; IV Q, intravenous quinine; Doxy, doxycycline; Clinda, clindamycine; PQ, primaquine; MQ, mefloquine; N/A, not available; na, not applicable; PADH, post-AS delayed haemolysis; AEs, adverse events; Hb, haemoglobin; LDH, lactate dehydrogenase; ALT, alanine aminotransferase.

Efficacy of AS in Imported Severe Malaria

In 2008 in Norway, Mørch et al. published the first description of the use of IV AS in Europe in nine travellers with severe falciparum malaria. All patients survived with no sequelae and no adverse events were reported.12 Through the published studies, on the 574 cases where outcome was reported, 23 patients died (4%) but no death attributed to the treatment was reported. Treatment regimen differed depending on the study but consisted essentially in IV AS (except for the use of rectal route in one study),21 in first or second line (mostly after IV Quinine) alone or in association with several anti-malarial drugs. In a vast majority of cases, patients were treated for severe malaria (expect for 13 patients in one study who were treated for uncomplicated malaria).20

Safety of AS in Imported Severe Malaria

Studies conducted in travellers reported a good overall tolerance despite a high proportion of delayed haemolytic episodes (PADH). Data on other adverse events were reported in 15 studies12–14,16–22,24,25,27,29,30 (in only a subset of patients in two studies),21,27 information was thus available for 465 patients. In total, 27.7% of patients (129/465) declared at least one adverse event during treatment or after receiving AS but most of those were retrospectively attributed to malaria or to a concomitant treatment (mainly quinine). Of note, one study reported adverse events in 92.2% (94/102) of patients, including anaemia (65% of patients) and increased hepatic enzyme level (49%), most of them being considered malaria-related whereas no grade four events were considered ‘definitively’ related to AS.30 Finally, 28 (6%) adverse events were considered as possibly related to AS: 5 neurological syndromes (1%), 3 temporary deteriorations in renal function (0.6%), 3 cutaneous (0.6%) and 3 cardiac (0.6%) manifestations (including QTc lengthening episode and transient bradycardia in 1 and 2 patients, respectively),25 1 severe arterial ischaemia (0.2%), 1 episode of hypertension (0.2%), 8 cases of elevation of liver enzymes (1.7%) and 1 of hyperkaliaemia (0.2%), 2 ‘minor adverse events’ not specified (0.4%) and 1 case of early haemolysis (0.2%). Three studies have reported the use of AS during pregnancy (7 cases)12,25,30 without reported fetal or maternal toxicity for six of them and one case of miscarriage.25 Follow-up duration varied from 7 days30 to 6 months16 whereas it was not mentioned in 10 studies.

The most frequent reported adverse event was PADH. This complication seems AS-related as it was not described in quinine-treated patients21 and as search for conventional causes for haemolysis was usually negative when performed.13,18,20,31,32 The very first case was probably described in 2002 in Japan.13,33 The patient had haemolysis and jaundice at Day 11 and survived without sequelae but needed RBC concentrates transfusion. No other cases were reported until 2011 when the use of AS for severe malaria started to spread in non-endemic countries. Zoller et al.17 described the first case series (6 cases) of late or persistent haemolysis following treatment. Definition of PADH is, however, not univocal through published studies. Most of them did not use a precise case definition. The first34 and currently accepted35 objective definition of PADH associates a decrease in haemoglobin (Hb) level > 10% associated with an increase in lactate dehydrogenase (LDH) level > 10% after Day 8 post-treatment initiation. Others,36 used a broader definition including any decrease in median Hb and any increase in median LDH between the second and the third week after treatment associated with low haptoglobin at the end of the second week. The incidence of delayed haemolysis varies widely depending on the studies (and case definition) from 0%12,14,16,30 to 63%.21 In our systematic analysis PADH occurred in 15.3% (74/485) of patients with available follow-up data, 50% (27/54 patients with available transfusion data) requiring transfusion. In the only prospective study to date in travellers, PADH occurred in 27% of patients followed after D8 (21/78) but only 15% of those cases had haemoglobin levels < 7 g/dl and < 5% (1 patient) required transfusion.25 No death or sequelae have been attributed to the occurrence of PADH so far. No specific treatment for PADH was published. Corticosteroids were two times used19,20 but with unclear influence on the natural course of the haemolytic episode.

Factsheets and Frequently Asked Questions

AS is a new therapeutic for most clinicians in non-endemic countries for malaria. Table 2 summarizes answers to FAQ and information published about the use of AS in severe malaria9,37 and practical implications.

Table 2

FAQ and factsheets about IV AS for imported severe malaria

FAQ? and factsheets Answers 
How to prescribe AS? WHO recommends IV or IM AS to be administrated at 2.4 mg/kg/dose for at least 24 h and as long as oral route is not possible for all patients with severe malaria (at list one criterion).9 
In children under 20 kg, WHO recommends to increase the dose of parenteral AS to 3 mg/kg/dose to ensure equivalent drug exposure.9 
Which formulations of AS? Available AS formulation in Europe is a powder of 60 mg to be reconstituted (with bicarbonate de sodium 1ml) and diluted (saline serum 5ml) to reach 10 mg/ml final concentration. 
Concentration of the final reconstitution solution must be 10 mg/ml for IV solution or 20 mg/ml for the IM use. 
Blood DHA peak is reached more rapidly with IV than IM route. 
Which regimen? Conventional regimen consists on an injection at 0, 12 and 24 h after admission and then every 24 h until 7 days. 
Duration of injection should be maintained below 3–4 ml/min on each infusion. 
How many doses? Parenteral administration will be continued until treatment can be administered orally or if severe criteria persist (i.e. consciousness impairment, renal failure). 
How to switch? A switch to oral therapy by an ACT (artemether-lumefantrine or DHA-piperaquine) for 3 days is mandatory after completion of at least 24 h of AS IV (3 doses) to prevent recrudescence of parasitaemia and symptoms, a risk related in part to the short half-life of AS. 
A time interval (8–12 h) seems to be necessary between the end of AS and the first dose of oral ACT. 
How to manage AS with multiorgan failure during severe malaria? No dosing adjustment is necessary for patient with renal or hepatic function impairment as the half-life is very short. 
However, no data are available to date on pharmacokinetics and dynamics in those patients (especially patients requiring dialysis) and other specific categories (obesity, elderly). 
What about pregnant women? AS could be used for pregnant women in all trimesters.9 
A recent review of the literature suggests lower-maximum concentrations and exposure of DHA, after oral administration of artemether, AS and DHA in pregnant women59 with uncomplicated malaria but very few data are available to date for IV AS in severe malaria. 
Treatment with parenteral AS in pregnant women should thus be monitored very closely for safety but also for efficacy as pharmacokinetics and dynamics could be modified by pregnancy. 
How to monitor the efficacy and safety of AS during and after severe malaria attack? Patient follow-up should be performed on Days 3, 7, 14, 21 and 28 to assess treatment efficacy and safety and should consist in physical examination and measure of haemolysis bio-markers (Haemoglobin, LDH, haptoglobin, reticulocytes) to detect the occurrence of PADH. Parasitaemia determination (thin and/or thick smear) should be performed on Days 3, 7 and 28.37 
Patient should be informed of the PADH and warning signs and symptoms that warrant immediate referral to the hospital. 
How to manage overdose of AS? There are few data about overdosing of AS. 
A case of overdose has been documented by Guilin (http://guilinpharma.com/en/en/new_drug/Artesun_Clinical_Data.html) in a 5-year-old child who was inadvertently administered rectal AS at a dose of 88 mg/kg/day over 4 days. The overdose was associated with pancytopenia, melena, seizures, multiorgan failure and death. 
There is no specific treatment for overdose but blood count and EKG should be closely monitored and treatment consists in general supportive measures. 
FAQ? and factsheets Answers 
How to prescribe AS? WHO recommends IV or IM AS to be administrated at 2.4 mg/kg/dose for at least 24 h and as long as oral route is not possible for all patients with severe malaria (at list one criterion).9 
In children under 20 kg, WHO recommends to increase the dose of parenteral AS to 3 mg/kg/dose to ensure equivalent drug exposure.9 
Which formulations of AS? Available AS formulation in Europe is a powder of 60 mg to be reconstituted (with bicarbonate de sodium 1ml) and diluted (saline serum 5ml) to reach 10 mg/ml final concentration. 
Concentration of the final reconstitution solution must be 10 mg/ml for IV solution or 20 mg/ml for the IM use. 
Blood DHA peak is reached more rapidly with IV than IM route. 
Which regimen? Conventional regimen consists on an injection at 0, 12 and 24 h after admission and then every 24 h until 7 days. 
Duration of injection should be maintained below 3–4 ml/min on each infusion. 
How many doses? Parenteral administration will be continued until treatment can be administered orally or if severe criteria persist (i.e. consciousness impairment, renal failure). 
How to switch? A switch to oral therapy by an ACT (artemether-lumefantrine or DHA-piperaquine) for 3 days is mandatory after completion of at least 24 h of AS IV (3 doses) to prevent recrudescence of parasitaemia and symptoms, a risk related in part to the short half-life of AS. 
A time interval (8–12 h) seems to be necessary between the end of AS and the first dose of oral ACT. 
How to manage AS with multiorgan failure during severe malaria? No dosing adjustment is necessary for patient with renal or hepatic function impairment as the half-life is very short. 
However, no data are available to date on pharmacokinetics and dynamics in those patients (especially patients requiring dialysis) and other specific categories (obesity, elderly). 
What about pregnant women? AS could be used for pregnant women in all trimesters.9 
A recent review of the literature suggests lower-maximum concentrations and exposure of DHA, after oral administration of artemether, AS and DHA in pregnant women59 with uncomplicated malaria but very few data are available to date for IV AS in severe malaria. 
Treatment with parenteral AS in pregnant women should thus be monitored very closely for safety but also for efficacy as pharmacokinetics and dynamics could be modified by pregnancy. 
How to monitor the efficacy and safety of AS during and after severe malaria attack? Patient follow-up should be performed on Days 3, 7, 14, 21 and 28 to assess treatment efficacy and safety and should consist in physical examination and measure of haemolysis bio-markers (Haemoglobin, LDH, haptoglobin, reticulocytes) to detect the occurrence of PADH. Parasitaemia determination (thin and/or thick smear) should be performed on Days 3, 7 and 28.37 
Patient should be informed of the PADH and warning signs and symptoms that warrant immediate referral to the hospital. 
How to manage overdose of AS? There are few data about overdosing of AS. 
A case of overdose has been documented by Guilin (http://guilinpharma.com/en/en/new_drug/Artesun_Clinical_Data.html) in a 5-year-old child who was inadvertently administered rectal AS at a dose of 88 mg/kg/day over 4 days. The overdose was associated with pancytopenia, melena, seizures, multiorgan failure and death. 
There is no specific treatment for overdose but blood count and EKG should be closely monitored and treatment consists in general supportive measures. 

IV, intravenous; IM, intramuscular; ACT, artemisinin-based combination therapies; DHA, dihydroartemisinin, active compound of artemisinine; AS, artesunate; PADH, post-AS delayed haemolysis; LDH, lactate dehydrogenase; EKG, electrocardiography.

Discussion

This review reports the high efficacy and reasonable safety of AS in the treatment of severe malaria in non-endemic areas.

No comparative randomized and controlled trials have been conducted in travellers for ethical reasons,38 but studies reviewed here, reporting the use of AS in travellers in several countries, confirmed that the drug is well tolerated and efficient. Clinical impact of AS on mortality is, however, difficult to assess in high level of care countries, as mortality of severe malaria is already very low in quinine-treated patients (5.2% in a recently published prospective trial).39 In our review, 4% of patients with reported outcome died, which is close to 5% mortality rate reported in the only prospective study conducted in travellers.25 Four non-randomized studies have compared retrospectively quinine with AS in travellers19,21,26,27 but the number of AS-treated patients with reported outcome was not sufficient to conclude on the improvement of mortality while the design of these studies were not appropriate.

The efficacy of artemisinins seems to be principally due to the peak concentration (Cmax) while the drug exposure level (Area under the curve AUC) and drug exposure time (half-life) would be of minor significance. Furthermore, the parasite-killing activity is dose-dependent.40 In travellers treated with AS, parasite clearance is mainly due to pitting.41 Pitting is an original process whereby the parasite, which has been killed by the drug, is removed from its host RBC without haemolysis when passing through the inter-endothelial slits of the spleen. The dead parasite is thus retained in the spleen and eliminated by resident phagocytic cells while the ‘once-infected’ RBC returns to general circulation.42 Thus, AS treatment leads to a rapid decrease in parasitaemia and the inhibition of cytoadherence4 without destruction (at least initially) of hosts RBC.42 In splenectomized patients treated with AS, because of the absence of pitting, complete clearance of RBC containing dead parasite remnants is much longer (days or even weeks) than in patients with a spleen.43 These observations on splenectomized patients confirm that pitting is a spleen-specific process. Pitting can be observed without treatment but usually at a low rate (<5%). In quinine-treated patients, the pitting rate generally does not exceed 20–25%. However, in African immune populations, while pitting contributes substantially to parasite clearance, passively and naturally acquired immune mechanisms operating faster than pitting do exist.41

Several hypotheses have been proposed to explain the pathogenesis of PADH, including late toxicity due to manufacturing problems, suppressive effect on the bone marrow, auto-immune haemolysis or host factors (enzymes deficiencies, haemoglobinopathies or differences in pharmacokinetics). None of these have been solidly substantiated by data so far.44 Recent observations in a cohort of patients with severe imported malaria strongly suggest that PADH is related to pitting. Typical delayed haemolytic episodes were indeed linked to the delayed clearance of once-infected RBC that were initially spared by pitting during AS treatment.34 PADH can thus be predicted by the determination of the peak concentration of once-infected RBC (between Days 2 and 8). The threshold 0.18 g/l predicts PADH with 89% sensitivity and 83% specificity.34 This quantification is currently performed by flow cytometry at reference centres. Development of a simpler test is now needed to allow the prediction of PADH in endemic areas. The occurrence of PADH is not an immuno-allergic reaction and should not contraindicate the use of AS in case of a subsequent access.

PADH is a matter of concern for management of patients but does not undermine the survival benefit provided by this new class of compound, if accurate prediction and management are implemented, including weekly follow-up during 4 weeks post-treatment.37 Thus, close supervision of haematological parameters is absolutely necessary following the treatment as long as no predictive marker for PADH is available (Table 2). In October 2013, WHO published an information note which stated that ‘the therapeutic benefits far outweigh the risk of artemisinin-related adverse events, including post-treatment delayed haemolytic anaemia’.45

The incidence of PADH in this review was 15%. This proportion can be overestimated as the most severe cases are more likely to be reported. On another hand it can also be underestimated by a short follow-up.30,31 Of note the incidence reached 27% in the prospective study conducted in travellers.25

The haemolysis generally corrects spontaneously in a few days to few weeks (usually <6, personal data) and the only treatment that can be required is transfusion according to haemoglobin level and patient tolerance to anaemia. Although decrease in haemoglobin level is generally mild, cases of severe anaemia with severe complications have been reported including a case of renal impairment by haemoglobinuria in endemic area.46 These episodes were not previously described in large clinical trials conducted in endemic areas.2,3 Since then, Rolling et al. conducted a prospective study in 72 African children treated with IV AS and found an incidence of PADH of 7%.47 Patients with PADH were younger and had higher-initial parasitaemia. A second study enrolling children and adults in Democratic Republic of the Congo found delayed haemolysis in 11.4% of cases, all clinically manageable and rapidly resolving.48 Simple biological parameters such as high parasitaemia and high level of haemoglobin at Day 0 could be major risk factors but there are not sufficient to provide risk assessment for PADH.22,24,27,29 The responsibility of the Chinese product has been debated as no cases of PADH were described in north America until recently but since 2014 several cases have been reported both in USA and Canada.22,24,27,29 Late haemolysis depends of generated once-infected RBC, the time onset of treatment regarding parasitaemia and stage of development of the parasite.

Since PADH has been shown to be linked to the pitting process, all artemisin derivatives can theoretically be responsible for the occurrence of a delayed haemolysis. Cases have been reported in patient treated with artemisinin-based combination therapies (ACT) but the intensity of haemolysis was mild.49–52 ACT are mostly used for the treatment of uncomplicated malaria with generally low initial parasitaemia which makes the risk of a severe PADH low. In our opinion, the risk for PADH after ACT should be considered in case of treatment for a patient with high parasitaemia without any other signs for severe malaria.

Except from the recently described PADH, non-haematological adverse events (hepatic, neurological or cardiac) were previously described or published by the manufacturer (Summary of product characteristics Guilin). In a meta-analysis on artemisinin derivatives including 108 trials (9241 patients), no drug-related serious adverse event or severe significant toxicity were reported.53 One of the most frequent adverse event reported in travellers is liver toxicity. It is well known but it is infrequent (0.9–4.5%), mild and regresses in all cases without sequelae.53,54 It reaches almost 2% in our review. However, most of these reported elevated liver enzyme cases can also be malaria-related. AS showed a good cardiac tolerance in current practice55,56 but can cause bradycardia when used at high dose (15 mg/kg).57 Here, we found three cases of cardiac toxicity.25

In Europe, AS is not licenced but was recently granted an orphan drug compassionate use status (European Medicines Agency EMA). To our knowledge, there is no available AS manufactured under GMP in Europe. In the USA, a GMP formulation developed by the Walter Reed Army Institute of Research is available since 2004. Since 2011 with the help of Medicine for Malaria Venture to improve the manufacturing process the Chinese product is prequalified by the WHO.58 This is not, however, a full GMP certification and AS does not have marketing approval in the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) zone. In France, Belgium and Netherlands the product is available through a named patient program.20,25 Considering the emergency context for use of AS to treat severe malaria, AS should be stocked ahead of time in local hospitals and infectious diseases units for immediate availability upon request by clinicians. Any centre regularly treating malaria patients should stock AS and follow local policy to get the product. If AS is not available, IV quinine should be used instead as any delay in the treatment of severe malaria can increase the risk of mortality. Lack of GMP manufactured AS is one major disincentive to the use of this new class treatment for all imported severe malaria. It is now time to get and deploy a full GMP qualified AS, as the medical benefit of this new treatment is priceless.

Conflict of Interest

C.R, A.N and S.J. collaborate with Guilin Laboratories; P.B. provided expertise and collaborates with Fast-Track Drugs & Biologics LLC and Sigma-Tau Pharmaceuticals, is engaged in a collaboration with Guilin Laboratories and has provided expertise to Sanofi Aventis Research & Development. The remaining authors declare no competing financial interests.

Funding statement:

CR was supported by a fellowship from the Laboratory of excellence GR-Ex. The labex GR-Ex, reference ANR-11-LABX-0051 is funded by the program “Investissements d'avenir"” of the French National Research Agency, reference ANR-11-IDEX-0005-02

References

1
Tu
Y.
The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine
.
Nat Med
 
2011
;
17
:
1217
20
.
2
Dondorp
A
Nosten
F
Stepniewska
K
et al.  .
Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial
.
Lancet
 
2005
;
366
:
717
25
.
3
Dondorp
AM
Fanello
CI
Hendriksen
ICE
et al.  .
Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial
.
Lancet
 
2010
;
376
:
1647
57
.
4
Udomsangpetch
R
Pipitaporn
B
Krishna
S
et al.  .
Antimalarial drugs reduce cytoadherence and rosetting Plasmodium falciparum
.
J Infect Dis
 
1996
;
173
:
691
8
.
5
Krishna
S
Uhlemann
A-C
Haynes
RK.
Artemisinins: mechanisms of action and potential for resistance
.
Drug Resist Updat Rev Comment Antimicrob Anticancer Chemother
 
2004
;
7
:
233
44
.
6
Klonis
N
Creek
DJ
Tilley
L.
Iron and heme metabolism in Plasmodium falciparum and the mechanism of action of artemisinins
.
Curr Opin Microbiol
 
2013
;
16
:
722
7
.
7
White
NJ.
Assessment of the pharmacodynamic properties of antimalarial drugs in vivo
.
Antimicrob Agents Chemother
 
1997
;
41
:
1413
22
.
8
WHO. WHO Guidelines for the Treatment of Malaria, 2nd edn.
2010
.
9
WHO Guidelines for the treatment of malaria, third edition
2015
. Available at: http://apps.who.int/iris/bitstream/10665/162441/1/9789241549127_eng.pdf. (11 March 2016, date last accessed)
10
Moher
D
Liberati
A
Tetzlaff
J
et al.  .
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
.
Open Med Peer-Rev Indep Open-Access J
 
2009
;
3
:
e123
30
.
11
Tang
J-S
Chen
C-L
Ko
W-C
et al.  .
Imported malaria in southern Taiwan from 1991 to 2002: a single hospital’s experience
.
Kaohsiung J Med Sci
 
2003
;
19
:
398
405
.
12
Mørch
K
Strand
Ø
Dunlop
O
et al.  .
Severe malaria and artesunate treatment, Norway
.
Emerg Infect Dis
 
2008
;
14
:
1816
8
.
13
Kano
S.
Artemisinin-based combination therapies and their introduction in Japan
.
J Infect Chemother Off J Jpn Soc Chemother
 
2010
;
16
:
375
82
.
14
Bartoloni
A
Tomasoni
L
Bartalesi
F
et al.  .
Combined intravenous treatment with artesunate and quinine for severe malaria in Italy
.
Am J Trop Med Hyg
 
2010
;
83
:
274
6
.
15
Mali
S
Kachur
SP
Arguin
PM
et al.  .
Malaria surveillance–United States, 2010
.
Morb Mortal Wkly Rep Surveill Summ
 
2012
;
61
:
1
17
.
16
Callender
DM
Hsue
G.
Artesunate: investigational drug for the treatment of severe falciparum malaria in Hawai’i
.
Hawaii Med J
 
2011
;
70
:
77
9
.
17
Zoller
T
Junghanss
T
Kapaun
A
et al.  .
Intravenous artesunate for severe malaria in travelers, Europe
.
Emerg Infect Dis
 
2011
;
17
:
771
7
.
18
Caramello
P
Balbiano
R
De Blasi
T
et al.  .
Severe malaria, artesunate and haemolysis
.
J Antimicrob Chemother
 
2012
;
67
:
2053
4
.
19
Eder
M
Farne
H
Cargill
T
et al.  .
Intravenous artesunate versus intravenous quinine in the treatment of severe falciparum malaria: a retrospective evaluation from a UK centre
.
Pathog Glob Health
 
2012
;
106
:
181
7
.
20
Kreeftmeijer-Vegter
AR
van Genderen
PJ
Visser
LG
et al.  .
Treatment outcome of intravenous artesunate in patients with severe malaria in the Netherlands and Belgium
.
Malar J
 
2012
;
11
:
102
.
21
Rolling
T
Wichmann
D
Schmiedel
S
et al.  .
Artesunate versus quinine in the treatment of severe imported malaria: comparative analysis of adverse events focussing on delayed haemolysis
.
Malar J
 
2013
;
12
:
241
.
22
Paczkowski
MM
Landman
KL
Arguin
PM
et al.  .
Update on cases of delayed hemolysis after parenteral artesunate therapy for malaria - United States, 2008 and 2013
.
MMWR Morb Mortal Wkly Rep
 
2014
;
63
:
753
5
.
23
Boillat
O
Spechbach
H
Chalandon
Y
et al.  .
Post-artesunate delayed haemolysis ‒ report of four cases and review of the literature
.
Swiss Med Wkly
 
2015
;
145
:
w14181
.
24
Lee
J
Krajden
S
Graham
C
et al.  .
Severe delayed hemolysis associated with regulated parenteral antimalarial drug
.
Emerg Infect Dis
 
2015
;
21
:
164
6
.
25
Jauréguiberry
S
Thellier
M
Ndour
PA
et al.  .
Delayed-onset hemolytic anemia in patients with travel-associated severe malaria treated with artesunate, France, 2011-2013
.
Emerg Infect Dis
 
2015
;
21
:
804
12
.
26
Kurth
F
Develoux
M
Mechain
M
et al.  .
Intravenous artesunate reduces parasite clearance time, duration of intensive care, and hospital treatment in patients with severe malaria in Europe: the TropNet severe malaria study
.
Clin Infect Dis Off Publ Infect Dis Soc Am
 
2015
;
61
:
1441
4
.
27
McCarthy
AE
Morgan
C
Prematunge
C
et al.  .
Severe malaria in Canada, 2001-2013
.
Malar J
 
2015
;
14
:
151
.
28
Chavada
R
Hui
SH
O’connor
S
et al.  .
Post-artesunate delayed haemolysis in severe imported Plasmodium falciparum malaria
.
Med J Aust
 
2015
;
203
:
364
.
29
Charles
M
Patterson
JM
Asadi
L
et al.  .
Delayed hemolysis after parenteral artesunate therapy for severe malaria in two returning Canadian travelers
.
Am J Trop Med Hyg
 
2015
;
93
:
819
21
.
30
Twomey
PS
Smith
BL
McDermott
C
et al.  .
Intravenous artesunate for the treatment of severe and complicated malaria in the United States: clinical use under an investigational new drug protocol
.
Ann Intern Med
 
2015
;
163
:
498
506
.
31
Centers for Disease Control and Prevention (CDC)
.
Published reports of delayed hemolytic anemia after treatment with artesunate for severe malaria–worldwide, 2010-2012
.
MMWR Morb Mortal Wkly Rep
 
2013
;
62
:
5
8
.
32
Rolling
T
Schmiedel
S
Wichmann
D
et al.  .
Post-treatment haemolysis in severe imported malaria after intravenous artesunate: case report of three patients with hyperparasitaemia
.
Malar J
 
2012
;
11
:
169
.
33
Itoda
I
Yasunami
T
Kikuchi
K
et al.  .
[Severe falciparum malaria with prolonged hemolytic anemia after successful treatment with intravenous artesunate]
.
Kansenshōgaku Zasshi J Jpn Assoc Infect Dis
 
2002
;
76
:
600
3
.
34
Jauréguiberry
S
Ndour
PA
Roussel
C
et al.  .
Postartesunate delayed hemolysis is a predictable event related to the lifesaving effect of artemisinins
.
Blood
 
2014
;
124
:
167
75
.
35
Arguin
PM.
Case definition: postartemisinin delayed hemolysis
.
Blood
 
2014
;
124
:
157
8
.
36
Rolling
T
Agbenyega
T
Krishna
S
et al.  .
Delayed haemolysis after artesunate treatment of severe malaria - review of the literature and perspective
.
Travel Med Infect Dis
 
2015
;
13
:
143
9
.
37
Recommandation du Haut Conseil de la Santé Publique (HCSP). Place de l’artésunate injectable dans le traitement du paludisme grave de l’adulte et de l’enfant. 2013 Available at: http://www.hcsp.fr/Explore.cgi/Telecharger?NomFichier=hcspa20130201_palugraveartesunate.pdf. (11 March 2016, date last accessed)
38
Shanks
GD.
For severe malaria, artesunate is the answer
.
Lancet
 
2010
;
376
:
1621
2
.
39
Bruneel
F
Tubach
F
Mira
J-P
et al.  .
Imported falciparum malaria in adults: host- and parasite-related factors associated with severity. The French prospective multicenter PALUREA cohort study
.
Intensive Care Med
 
2016
;
42
(
10
):
1588
96
.
40
Miller
RS
Li
Q
Cantilena
LR
et al.  .
Pharmacokinetic profiles of artesunate following multiple intravenous doses of 2, 4, and 8 mg/kg in healthy volunteers: phase 1b study
.
Malar J
 
2012
;
11
:
255
.
41
Ndour
PA
Lopera-Mesa
TM
Diakité
SAS
et al.  .
Plasmodium falciparum clearance is rapid and pitting independent in immune Malian children treated with artesunate for malaria
.
J Infect Dis
 
2015
;
211
:
290
7
.
42
Angus
BJ
Chotivanich
K
Udomsangpetch
R
et al.  .
In vivo removal of malaria parasites from red blood cells without their destruction in acute falciparum malaria
.
Blood
 
1997
;
90
:
2037
40
.
43
Chotivanich
K
Udomsangpetch
R
McGready
R
et al.  .
Central role of the spleen in malaria parasite clearance
.
J Infect Dis
 
2002
;
185
:
1538
41
.
44
Rehman
K
Lötsch
F
Kremsner
PG
et al.  .
Haemolysis associated with the treatment of malaria with artemisinin derivatives: a systematic review of current evidence
.
Int J Infect Dis IJID Off Publ Int Soc Infect Dis
 
2014
;
29
:
268
73
.
45
WHO Information Note on Delayed Haemolytic Anaemia following Treatment with Artesunate - who_note_delayed_haemolytic_anaemia_oct13.pdf. Available from: http://www.who.int/malaria/publications/atoz/who_note_delayed_haemolytic_anaemia_oct13.pdf (11 March 2016, date last accessed).
46
Plewes
K
Haider
MS
Kingston
HWF
et al.  .
Severe falciparum malaria treated with artesunate complicated by delayed onset haemolysis and acute kidney injury
.
Malar J
 
2015
;
14
:
246
.
47
Rolling
T
Agbenyega
T
Issifou
S
et al.  .
Delayed hemolysis after treatment with parenteral artesunate in African children with severe malaria–a double-center prospective study
.
J Infect Dis
 
2014
;
209
:
1921
8
.
48
Burri
C
Ferrari
G
Ntuku
HM
et al.  .
Delayed anemia after treatment with injectable artesunate in the Democratic Republic of the Congo: a manageable issue
.
Am J Trop Med Hyg
 
2014
;
91
:
821
3
.
49
De Nardo
P
Oliva
A
Giancola
ML
et al.  .
Haemolytic anaemia after oral artemether-lumefantrine treatment in a patient affected by severe imported falciparum malaria
.
Infection
 
2013
;
41
:
863
5
.
50
Corpolongo
A
De Nardo
P
Ghirga
P
et al.  .
Haemolytic anaemia in an HIV-infected patient with severe falciparum malaria after treatment with oral artemether-lumefantrine
.
Malar J
 
2012
;
11
:
91
.
51
Kurth
F
Lingscheid
T
Steiner
F
et al.  .
Hemolysis after oral artemisinin combination therapy for uncomplicated Plasmodium falciparum malaria
.
Emerg Infect Dis
 
2016
;
22
:
1381
6
.
52
Gray
AM
Arguin
PM
Hamed
K.
Surveillance for the safety and effectiveness of artemether-lumefantrine in patients with uncomplicated Plasmodium falciparum malaria in the USA: a descriptive analysis
.
Malar J
 
2015
;
14
:
349.
53
Ribeiro
IR
Olliaro
P.
Safety of artemisinin and its derivatives. A review of published and unpublished clinical trials
.
Médecine Trop Rev Corps Santé Colon
 
1998
;
58
:
50
3
.
54
Price
R
van Vugt
M
Phaipun
L
et al.  .
Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives
.
Am J Trop Med Hyg
 
1999
;
60
:
547
55
.
55
Efferth
T
Kaina
B.
Toxicity of the antimalarial artemisinin and its dervatives
.
Crit Rev Toxicol
 
2010
;
40
:
405
21
.
56
Maude
RJ
Plewes
K
Faiz
MA
et al.  .
Does artesunate prolong the electrocardiograph QT interval in patients with severe malaria?
.
Am J Trop Med Hyg
 
2009
;
80
:
126
32
.
57
Hess
KM
Goad
JA
Arguin
PM.
Intravenous artesunate for the treatment of severe malaria
.
Ann Pharmacother
 
2010
;
44
:
1250
8
.
58
WHO List of Prequalified Medicinal Products. Available from: http://apps.who.int/prequal/query/productregistry.aspx (13 December 2016, date last accessed).
59
Burger
RJ
Visser
BJ
Grobusch
MP
et al.  .
The influence of pregnancy on the pharmacokinetic properties of artemisinin combination therapy (ACT): a systematic review
.
Malar J
 
2016
;
15
.
Epub ahead of print 18 February 2016. Feb 18, 15: 99
.