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Journal of Tropical Pediatrics Advance Access originally published online on March 17, 2006
Journal of Tropical Pediatrics 2006 52(2):78-82; doi:10.1093/tropej/fml005
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© The Author [2006]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Clinical Review

Evidence behind the WHO Guidelines: Hospital Care for Children: Efficacy and Safety of Artemisinin Derivatives in Children with Malaria

Naor Bar-Zeeva and Nick White, Secondary reviewerb

a Royal Children's Hospital, Melbourne, Australiab Wellcome Trust South East Asia Unit, Thailand

For more information on this project to evaluate the evidence behind the WHO Hospital Care for Children, see J Trop Pediatr 2006; 52: 1–2. If you would like to suggest a topic or contribute a review, please contact Dr Julian Kelly. E-mail <julian.kelly{at}rch.org.au>.

The World Health Organization has produced guidelines for the management of common illnesses in hospitals with limited resources. This series of articles reviews the scientific evidence behind WHO's recommendations. The WHO guidelines, and more reviews are available at: http://www.who.int/child-adolescent-health/publications/CHILD_HEALTH/PB.htm

This review addresses the question: "How does the efficacy and safety of artemisinin derivatives compare with quinine in the treatment of severe falciparum malaria in children."

The WHO Pocketbook of Hospital Care for Children recommends quinine or artemisinin derivates (artemether or artesunate) for the treatment of severe malaria. Quinine is recommended for most countries, except those in Southeast Asia and the Amazon basin. Whatever first-line therapy is used WHO now strongly recommends combination therapy; using an additional drug to which there is no resistance (sulfadoxine-pyrimethamine, artemisinin-based combination therapy or clindamycin in combination with quinine).


   Background
Top
 Background
Methodology
 Results
 Conclusions
 References
 
Malaria causes 850 000 child deaths every year [1]. The majority of malaria-related morbidity and mortality is among children in Africa and Asia [4], where the parasite causes an estimated one billion episodes of fever [2]. In Africa one in five child deaths are due to malaria and the disease costs an estimated $12 billion annually [2, 3]. Despite vector control measures, malaria is making a resurgence and resistance to first-line therapies is an increasing problem [5, 6]. Child mortality from malaria continues to rise in sub-Saharan Africa [6–8] and has been predicted to continue to rise [9–11]. Artemisinin (qinghaosu) derivatives are a newly developed class of drug. These may be given orally, rectally, intravenously or intramuscularly. No resistance has yet been reported.


   Methodology
Top
 Background
 Methodology
Results
 Conclusions
 References
 
The Cochrane Database was searched for reviews and randomised trials and the Pubmed Clinical Queries tool was used to search 1966–2005 Medline database of the US National Library of Medicine using the search strategy (Artemisinin OR artemether OR artemotil OR artesunate OR artelinic acid OR dihydroartemisinin) AND (Quinine). This yielded 79 trials and 8 systematic reviews. Citations listed in retrieved trials were also hand-searched and reviewed, yielding a further 5 trials and 3 systematic review. Of these 1 was not randomized, 1 was non-comparative and 3 compared artemisinins with an agent other than quinine. Papers were excluded if they were non-randomised or non-comparative, if they compared artemisinin derivatives with agents other than quinine, if their outcomes related to non-clinical endpoints such as biochemical or pharmacokinetic studies or resistance prevalence studies, were cost-effectiveness analyses, did not include children or were in a language other than English. These exclusion criteria applied to 50 trials and 3 systematic reviews, leaving a total of 32 papers for review, 29 of which were from the original search strategy and 3 from secondary references. Methodological quality of included articles was type 1b according to the criteria of the Oxford Centre for Evidence-Based Medicine [12] (http://www.cebm.net/levels_of_evidence.asp). Primary outcomes assessed were mortality or adverse events (AEs). Secondary outcomes included fever clearance time (FCT), coma recovery time (CRT), neurological sequelae, parasite clearance time (PCT), 28-day cure rate and effect on gametocyte carriage. Heterogeneity among studies occurred in 6 domains: (i) the use of different drug regimens, durations and modes of administration, (ii) non-uniform methods of outcome reporting, (iii) background prevalence of resistance at the study site, (iv) the endemicity and seasonality of infections at the site, (v) the degree of illness severity of patients studied and (vi) age of study populations.


   Results
Top
 Background
 Methodology
 Results
Conclusions
 References
 
Mortality
In adults with severe falciparum malaria, artemisinin derivatives reduce mortality compared with quinine. This was proved conclusively in a trial of artesunate vs. quinine involving 1461 people from Southeast Asia. The odds ratio for mortality for those receiving artesunate was 0.6 (95 per cent CI 0.45–0.71), p = 0.0002. Of the study participants, 202 (13.8 per cent) were children younger than 15 years. When these children were analysed as a subgroup the resulting odds ratio was 0.43 (95 per cent CI 0.13–1.42) [13].

Eleven other trials found no significant difference in mortality between artemisinin derivatives and quinine [14–24]. Two other studies [25, 26] described lower mortality in artemether group than quinine, but statistical significance was not reported.

A meta-analysis based on individual patient data comparing mortality using intramuscular artemether and intravenous quinine showed odds ratio 0.80 (95 per cent CI 0.62–1.02), p = 0.08. When Asian adults were analysed, odds ratio (OR) was 0.59 (95 per cent CI 0.35–1.01), p = 0.012 suggesting an important clinical benefit [27]. It is possible that geographic differences exist and this may be a function of higher quinine resistance in Southeast Asia, though other factors cannot be excluded. In a global meta-analysis reported by geographic region, adults from Southeast Asia had lower mortality with artemether (40 per cent reduction) that trended towards statistical significance, OR 0.38 (95 per cent CI 0.14–1.02), but among African children there was no difference, OR 1.01 (95 per cent CI 0.73–1.40) [28]. Another meta-analysis conducted across Africa also showed no difference in mortality [29].

In only a single trial [30] was higher mortality found among patients treated with artemether compared with those treated with quinine (p < 0.05). This study of Kenyan children with cerebral malaria found that those with respiratory distress had higher and earlier mortality if given artemether (p < 0.05). It was postulated children with acidosis may have absorbed intramuscular artemether poorly. Concern was also raised about the consequences of rapid breakdown of parasites in the face of already severe illness. It is known, however, that respiratory distress is an independent risk factor for mortality in severe malaria [31] so distinguishing a drug effect from underlying disease effect is difficult. Importantly, the higher mortality in the artemether group that was apparent in the intention to treat analysis was confounded by many patients who did not in fact have cerebral malaria, and after their exclusion the difference was not significant. The concerning findings of higher mortality in the artemether group are likely confounded by these multiple and interacting factors.

A systematic review of studies of adults and children was conducted in 2000 [32]. Results were reported individually for the various artemisinin derivatives. Compared with quinine, mortality with artemisinin had an OR of 0.68 (95 per cent CI 0.28–1.65). For artemether OR 0.72 (95 per cent CI 0.57–0.91), however, excluding two studies which raised methodological concerns regarding allocation concealment resulted in OR 0.79 (95 per cent CI 0.59–1.05). For artesunate the OR was 0.35 (95 per cent CI 0.20–0.61). For all artemisinin derivatives combined, OR 0.61 (95 per cent CI 0.46–0.82), giving a relative risk reduction (RRR) of 48 per cent and number needed to treat of 25. Most of the studies in this meta-analysis used artemether. When only cases of cerebral malaria were studied, combining all artemisinin derivatives gave OR 0.63 (95 per cent CI 0.44–0.88) and RRR 31 per cent. Excluding studies with inadequate allocation concealment however, gave OR 0.78 (95 per cent CI 0.55–1.10) [32].

Summary: Compared with quinine, artesunate reduces mortality in adults with severe malaria, especially in Southeast Asia. Children in Southeast Asia are likely to have a similar benefit, but this has not yet been shown in African children. A definitive large scale multi-centre study of IV artesunate in African children is required. Rectal artesunate has been suggested for treatment of severe malaria in remote settings. No trial has shown this approach to be inferior to quinine.

Adverse events
Data regarding adverse events were not uniformly collected. The frequency of serious AEs was small in most studies and no statistical inferences can be drawn [9, 14–17, 19–22, 25, 26, 30, 33–39]. A meta-analysis found quinine to be associated with more frequent episodes of hypoglycaemia, but statistical significance was not stated [27]. A systematic review of all studies to 2000 claimed all AEs were mild and none led to discontinuation of treatment [32].

AEs reported included hypoglycaemia, pruritis and urticaria, tinnitus and dizziness. Prolongation of the QT-interval on the electrocardiograph was reported but no clinically relevant dysrrhythmias occurred. All these events were reported more frequently in patients treated with quinine but occurred with artemisinin derivatives also. Local pain at the site intramuscular injection occurred only with quinine. No tenesmus was reported in rectally administered medication. Artemsinins did not lead to neurological toxicity, though in one study more seizures occurred in artemether treated patients [40].

Summary. Mild AE occurred with both treatments. Overall both treatments were well tolerated. Uniformly-collected data in large studies with adequate power are needed.

Secondary outcomes
Fever clearance time
Although widely reported as a surrogate for efficacy, fever clearance time (FCT) is of doubtful clinical significance [40–42]. Most studies found no difference in FCT [9, 14–20, 22–25, 27, 30, 39, 43], though in some [21, 29, 33–36] but not all [26] FCT was shorter with artemisinin.

Coma recovery time
Heterogeneity exists among studies in the definition of CRT and many studies did not use standardized scales [44]. Most studies found no difference in CRT between artemisinin derivatives and quinine [13–16, 18, 20, 21, 23, 25, 27, 29, 30, 32, 36, 43]. CRT was significantly faster with artemisinin derivatives in some studies [22, 24, 26, 33] and faster with quinine in another [17]. Current evidence does not suggest an advantage to artemisinin derivatives over quinine in terms of coma recovery time.

Neurological sequelae
Concern was first raised about neurotoxicity of artemisinin derivatives in animal studies [45, 46]. Their safety in humans has repeatedly been demonstrated [47]. No significant difference in residual neurological deficits between those treated with artemisinin derivatives and quinine has been demonstrated [13, 15–17, 20, 21, 23, 24, 30, 32]. Two meta-analyses, one of which was an individual patient data analysis [27], suggested no significant difference in neurological outcome [27, 29]. Some papers showed prolonged coma and more seizures in artemether treated patients [32] but almost all neurological defects that were followed over months resolved with time. There is no clear advantage of artemisinin derivatives over quinine in terms of improved neurological outcomes. Artemisinin derivatives do not cause neurotoxicity in children.

Parasite clearance time
PCT is widely used as a marker of antimalarial efficacy. It is widely accepted that artemisinin derivatives clear parasitaemia faster than other antimalarial agents [6, 38] but this does not correlate with clinical recovery [16, 24, 30, 48]. The clinical significance of PCT has therefore been questioned [17, 21, 22, 40, 48, 49]. PCT has several definitions so comparing results across studies is difficult. In 13 studies artemisinin derivatives did clear parasitaemia significantly faster than quinine [9, 17, 19, 21, 22, 24, 27, 29, 30, 32–37, 39] but this was not the case in other studies [14–16, 18, 20, 23, 25, 26, 43].

28-day cure rate and recrudescence
The cure rate (absence of parasitaemia or clinical symptoms) depends not only on the initial drug used but also on adjunctive long-acting antimalarial drugs [32, 50]. There was heterogeneity among studies in the adjunctive drugs used (eg sulfadoxine-pyrimethamine, mefloquine, tetracycline) and often different adjuncts were used in the two treatment arms. Although many studies reported a 28-day cure rate, this should not be interpreted as reflecting differences between artemisinin derivatives and quinine in isolation of other agents. Cure rate depends on multiple factors, including background quinine resistance, initial parasite load and host immune factors. Several papers addressed cure [18, 20, 32, 35, 38] and recrudescence [9, 15, 16, 25, 34, 37, 39], but patient numbers in these studies were small and no definitive conclusion can be drawn in this review.

Gametocytaemia
The last stage in the lifecycle of P. falciparum is the development of gametocytes (sexual forms) in the blood which are taken up by a mosquito and are required for transmissibility [6]. Gametocytes are more likely to occur when treatment failure results in recrudescence, which can occur if the initial parasite burden is high or with drug resistance [6, 51]. Antimalarial drugs differ in their effect on gametocyte carriage [6, 40] and those that reduce gametocytes may reduce disease transmission [52], the public health impact will depend on local transmission rates [50]. In a study of 5193 patients of which 3241 were children, artemisinin derivatives markedly reduced gametocyte carriage compared with quinine. The relative risk of gametocytaemia after a treatment course with quinine compared with artemisinin derivatives was 6.8 (95 per cent CI 3.1–15.1), p < 0.0001 [51]. The same study also reported that after widespread introduction of artemisinin derivatives in 1994, there was a sudden reduction in malaria incidence by nearly half [51]. Similar and more detailed findings have been documented in adults [52–54]


   Conclusions
Top
 Background
 Methodology
 Results
 Conclusions
References
 
Artemisinin derivatives are highly effective, safe and well-tolerated in the treatment of malaria in children. All but one study confirm that artemisinins, given intravenously, orally or rectally were at least as effective as quinine for severe or cerebral malaria. Recrudescence and the development of drug resistance are risks if these agents are used as monotherapy, therefore dual formulations are important. Rectal administration is very useful in remote areas with inadequate access to medical facilities. Artemisinins lead to a reduction in transmission in Southeast Asia. Large scale multi-centre studies in African children are currently being undertaken [55] to definitively determine the impact of these agents on mortality.


   References
Top
 Background
 Methodology
 Results
 Conclusions
 References
 

  1. Korenromp E, Miller J, Nahlen B, Wardlaw T, Young M. World Malaria Report. 2005 World Health Organisation/Roll Back Malaria/United Nations Children's Fund.
  2. Arrow K, Panosian CB, Gelband H. Saving lives buying time: economics of malaria drugs in an age of resistance. 2004 Washington DC: National Academies Press.
  3. Arrow KJ, Gelband H, Jamison DT. Making antimalarial agents available in Africa. N Engl J Med 2005; 353 (4): 333–5.
  4. WHO/UNICEF The Africa Malaria Report 2003. 2003 Geneva.
  5. Hastings IM, D’Alessandro U. Modelling a predictable disaster: the rise and spread of drug-resistant malaria. Parasitol Today 2000; 16 (8): 340–7.
  6. White N, Antimalarial drug resistance and combination chemotherapy. Phil Trans R Soc Lond B Biol Sci 1999; 354 (1384): 739–49.
  7. Marsh K, Malaria disaster in Africa. Lancet 1998; 352(9132) : 924.
  8. World Health Organization Children and Malaria – Information Sheet Number 5 in Roll Back Malaria. 2005: Geneva.
  9. Hien TT, Tam DT, Cuc NT, Arnold K, Comparative effectiveness of artemisinin suppositories and oral quinine in children with acute falciparum malaria. Trans R Soc Trop Med Hyg 1991; 85 (2): 210–1.[CrossRef]
  10. Magill A, Panosian C, Making antimalarial agents available in the United States. N Engl J Med 2005; 353 (4): 335–7.
  11. Sidhu JS, Ashton M, Huong NV, et al. Artemisinin population pharmacokinetics in children and adults with uncomplicated falciparum malaria. Br J Clin Pharmacol 1998; 45 (4): 347–54.
  12. Oxford Centre for Evidence-Based Medicine Levels of Evidence and Grades of Recommendation. 1998.
  13. Dondorp A, Nosten F, Stepniewska K, Day N, White N. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005; 366 (9487): 717–25.
  14. Aceng JR, Byarugaba JS, Tumwine JK. Rectal artemether versus intravenous quinine for the treatment of cerebral malaria in children in Uganda: randomised clinical trial. BMJ 2005; 330(7487): 334.[CrossRef]
  15. Olumese PE, Bjorkman A, Gbadegesin RA, Adeyemo AA, Walker O. Comparative efficacy of intramuscular artemether and intravenous quinine in Nigerian children with cerebral malaria. Acta Trop 1999; 73 (3): 231–6.
  16. Walker O, Salako LA, Omokhodion SI, Sowunmi A. An open randomized comparative study of intramuscular artemether and intravenous quinine in cerebral malaria in children. Trans R Soc Trop Med Hyg 1993; 87 (5): 564–6.
  17. van Hensbroek MB, Onyiorah E, Jaffar S, et al. A trial of artemether or quinine in children with cerebral malaria. N Engl J Med 1996; 335 (2): 69–75.
  18. Moyou-Somo R, Tietche F, Ondoa M, et al. Clinical trial of beta-arteether versus quinine for the treatment of cerebral malaria in children in Yaounde Cameroon. Am J Trop Med Hyg 2001; 64 (5–6) : 229–32.
  19. Cao XT, Bethell DB, Pham TP, et al. Comparison of artemisinin suppositories intramuscular artesunate and intravenous quinine for the treatment of severe childhood malaria. Trans Roy Soc Trop Med Hyg 1997; 91 (3): 335–42.[CrossRef]
  20. Thuma PE, Bhat GJ, Mabeza GF, et al. A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria. Am J Trop Med Hyg 2000; 62 (4): 524–9.
  21. Taylor TE, Wills BA, Courval JM, Molyneux ME. Intramuscular artemether vs intravenous quinine: an open randomized trial in Malawian children with cerebral malaria. Trop Med Int Health 1998; 3 (1): 3–8.
  22. Huda SN, Shahab T, Ali SM, Afzal K, Khan HM. A comparative clinical trial of artemether and quinine in children with severe malaria. Indian Pediatr 2003; 40 (10): 939–45.
  23. Satti GM, Elhassan SH, Ibrahim SA. The efficacy of artemether versus quinine in the treatment of cerebral malaria. J Egypt Soc Parasitol 2002; 32 (2): 611–23.
  24. Taylor TE, Wills BA, Kazembe P, et al. Rapid coma resolution with artemether in Malawian children with cerebral malaria. Lancet 1993; 341 (8846): 661–2.
  25. Salako LA, Walker O, Sowunmi A, Omokhodion SJ, Adio R, Oduola AM. Artemether in moderately severe and cerebral malaria in Nigerian children. Trans Roy Soc Trop Med Hyg 1994; 88 (Suppl 1): S13–5.[CrossRef]
  26. Adam I, Idris HM, Mohamed-Ali AA, Aelbasit IA, Elbashir MI. Comparison of intramuscular artemether and intravenous quinine in the treatment of Sudanese children with severe falciparum malaria. East Afr Med J 2002; 79 (12): 621–5.
  27. Artemether-Quinine Meta-analysis Study Group A meta-analysis using individual patient data of trials comparing artemether with quinine in the treatment of severe falciparum malaria. Trans Roy Soc Trop Med Hyg 2001; 95 (6): 37–50.
  28. Pittler MH, Ernst E. Artemether for severe malaria: a meta-analysis of randomized clinical trials. Clin Infect Dis 1999; 28 (3): 597–601.
  29. Courval JM, et al. Meta-analysis of open randomized trials comparing artemether versus quinine for cerebral malaria in African children. Jap J Trop Med Hygiene 1996; 24 (Suppl 1): 97–100.
  30. Murphy S, English M, Waruiru C, et al. An open randomized trial of artemether versus quinine in the treatment of cerebral malaria in African children. Trans Roy Soc Trop Med Hyg 1996; 90 (3): 298–301.[CrossRef]
  31. Marsh K, Forster D, Waruiru C, et al. Indicators of life-threatening malaria in African children. N Engl J Med 1995; 332 (21): 1399–404.
  32. McIntosh HM, Olliaro P. Artemisinin derivatives for treating severe malaria. Cochrane Database Syst Rev 2000(2): CD000527.
  33. Mohanty AK, Rath BK, Mohanty R, Samal AK, Mishra K. Randomized control trial of quinine and artesunate in complicated malaria. Indian J Pediatr 2004; 71 (4): 291–5.
  34. Barnes KI, Mwenechanya J, Tembo M, et al. Efficacy of rectal artesunate compared with parenteral quinine in initial treatment of moderately severe malaria in African children and adults: a randomised study. Lancet 2004; 363 (9421): 1598–605.
  35. Luxemburger C, Nosten F, Raimond SD, Chongsuphajaisiddhi T, White NJ. Oral artesunate in the treatment of uncomplicated hyperparasitemic falciparum malaria. Am J Trop Med Hyg 1995; 53 (5): 522–5.
  36. Danis M, et al. Results obtained with I.M. artemether versus I.V. quinine in the treatment of severe malaria in a multicentre study in Africa. Jap J Trop Med Hygiene 1996. 24 (Suppl 1): 93–96.
  37. Bich NN, De Vries PJ, Van Thien H, et al. Efficacy and tolerance of artemisinin in short combination regimens for the treatment of uncomplicated falciparum malaria. Am J Trop Med Hyg 1996; 55 (4): 438–43.
  38. Ramharter M, Oyakhirome S, Klouwenberg PK, et al. Artesunate-clindamycin versus quinine-clindamycin in the treatment of Plasmodium falciparum malaria: a randomized controlled trial. Clin Infect Dis 2005. 40 (12): 1777–84.[CrossRef]
  39. de Vries PJ, Bich NN, Van Thien H, et al. Combinations of artemisinin and quinine for uncomplicated falciparum malaria: efficacy and pharmacodynamics. Antimicrob Agents Chemother 2000; 44 (5): 1302–8.[CrossRef]
  40. White NJ, Krishna S. Treatment of malaria: some considerations and limitations of the current methods of assessment. Trans Roy Soc Trop Med Hyg 1989; 83 (6): 767–77.[CrossRef]
  41. Kwiatkowski D. Febrile temperatures can synchronize the growth of Plasmodium falciparum in vitro. J Exp Med 1989; 169 (1): 357–61.
  42. Long HY, Lell B, Dietz K, Kremsner PG, Plasmodium falciparum: in vitro growth inhibition by febrile temperatures. Parasitol Res 2001; 87 (7): 553–5.
  43. Afolabi BB, Okoromah CN, Intramuscular arteether for treating severe malaria. Cochrane Database Syst Rev 2004 (4): CD004391.
  44. Newton CR, Chokwe T, Schellenberg JA, Winstanley PA, Forster D, Peshu N, Kirkham FJ, Marsh K. Coma scales for children with severe falciparum malaria. Trans Roy Soc Trop Med Hyg 1997; 91 (2): 161–5.
  45. Brewer TG, Peggins JO, Grate SJ, et al. Neurotoxicity in animals due to arteether and artemether. Trans Roy Soc Trop Med Hyg 1994; 88 (Suppl 1): S33–6.
  46. Nontprasert A, Nosten-Bertrand M, Pukrittayakamee S, Vanijanonta S, Angus BJ, White NJ, Assessment of the neurotoxicity of parenteral artemisinin derivatives in mice. Am J Trop Med Hyg 1998; 59 (4): 519–22.
  47. Newton PN, Day NP, White NJ. Misattribution of central nervous system dysfunction to artesunate. Clin Infect Dis 2005; 41(11): 1687–8; author reply 1688.
  48. White NJ. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob Agents Chemother 1997; 41 (7): 1413–22.
  49. Brewster DR, Kwiatkowski D, White NJ, Neurological sequelae of cerebral malaria in children. Lancet 1990; 336 (8722): 1039–43.
  50. Woodrow CJ, Haynes RK, Krishna S. Artemisinins. Postgrad Med J 2005; 81 (952): 71–8.
  51. Price RN, Nosten F, Luxemburger C, ter Kuile FO, Paiphun L, Chongsuphajaisiddhi T, White NJ. Effects of artemisinin derivatives on malaria transmissibility. Lancet 1996; 347 (9016): 1654–8.
  52. Pukrittayakamee S, et al. Activities of artesunate and primaquine against asexual- and sexual-stage parasites in falciparum malaria. Antimicrob Agents Chemother 2004; 48 (4): 1329–34.
  53. von Seidlein L, Jawara M, Coleman R, Doherty T, Walraven G, Targett G. Parasitaemia and gametocytaemia after treatment with chloroquine pyrimethamine/sulfadoxine and pyrimethamine/sulfadoxine combined with artesunate in young Gambians with uncomplicated malaria. Trop Med Int Health 2001; 6 (2): 92–8.
  54. Esamai F, Ayuo P, Owino-Ongor W, et al. Rectal dihydroartemisinin versus intravenous quinine in the treatment of severe malaria: a randomised clinical trial. East Afr Med J 2000; 77 (5): 273–8.
  55. Maitland K, Nadel S, Pollard AJ, Williams TN, Newton CR, Levin M. Management of severe malaria in children: proposed guidelines for the United Kingdom. BMJ 2005; 331 (7512): 337–43.

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