Malaria, anaemia and antimalarial drug resistance in African children

Abstract

Malaria-associated anaemia is a potentially preventable cause of severe morbidity and mortality in children < 5years of age, in areas of high malaria transmission in sub-Saharan Africa. In a cross-sectional study of 3586 children, 80% were anaemic (haemoglobin [Hb]<11g/dL) and 3% had severe anaemia (Hb<5g/dL). Risk factors for anaemia included age < 3years, malaria parasitaemia, previous ineffective therapy and lack of bednet use. Since the emergence of drug-resistant parasite strains, the frequency of occurrence of severe anaemia is rising. In a review of 1116 randomly selected hospital records for children hospitalized in 2002, we found that 90% had anaemia, 20% were severely anaemic and 20% received a blood transfusion. Twelve percent of severely anaemic children died and 52% of the malaria-related mortality was due to severe anaemia. Artemisinin-based combination therapy (ACT) has been advocated to prevent the development of antimalarial drug resistance, but ACT is expensive and currently in limited supply. In a meta-analysis of 4472 African children, Amodiaquine plus sulfadoxine-pyrimethamine, an alternative non-ACT, was as effective as ACT in some settings. We conducted a randomized controlled trial of 600 Kenyan children with uncomplicated malaria whom we treated with either one or three days of artesunate [AS] plus sulfadoxine-pyrimethamine [SP] or SP alone. The parasitological failure rates on day 28 after excluding new infections by parasite genotyping were 33%, 21%, and 43%, for those treated with SP+AS for one day, SP+ AS for 3 days or SP alone, respectively. Adding AS to SP, in a setting with high SP resistance did not markedly improve the efficacy of the combination. The impact of introducing effective antimalarial therapy on case fatality was investigated using 4 years of surveillance data. When increasing proportions of children received an effective antimalarial therapy the case fatality rates decreased markedly (from 11 to 3.5%). We used data from the randomized trial described above to evaluate the effect of therapy on haematological recovery and anaemia prevalence. By 28 days after treatment, only 18% of the children had achieved haematological recovery and there was a modest reduction in the prevalence of anaemia in all treatment arms. AS+SP did not result in better haematological outcomes compared to SP alone. A possible explanation for this is the high failure rates in all treatment arms and the short follow-up period. The treatment of severe malaria-related anaemia includes administration of blood transfusion, an intervention that carries a substantial risk for HIV transmission in sub-Saharan Africa. Three key factors were found to determine the beneficial effect of a transfusion using a decision analysis. These were, a high risk of mortality without a transfusion, a low risk of HIV contaminating the blood supply and high transfusion effectiveness. Children who have survived an episode of severe anaemia stand a higher chance of getting another more severe and sometimes fatal, episode of severe anaemia. For this risk group, the rebound phenomenon may be prevented by repeated administration of curative doses of an effective antimalarial therapy regardless of the presence of malaria parasites.