Sickle cell anaemia and severe Plasmodium falciparum malaria: a secondary analysis of the Transfusion and Treatment of African Children Trial (TRACT)
Issued Date
2022-09-01
Resource Type
eISSN
23524642
Scopus ID
2-s2.0-85136342034
Pubmed ID
35785794
Journal Title
The Lancet Child and Adolescent Health
Volume
6
Issue
9
Start Page
606
End Page
613
Rights Holder(s)
SCOPUS
Bibliographic Citation
The Lancet Child and Adolescent Health Vol.6 No.9 (2022) , 606-613
Suggested Citation
Uyoga S., Olupot-Olupot P., Connon R., Kiguli S., Opoka R.O., Alaroker F., Muhindo R., Macharia A.W., Dondorp A.M., Gibb D.M., Walker A.S., George E.C., Maitland K., Williams T.N. Sickle cell anaemia and severe Plasmodium falciparum malaria: a secondary analysis of the Transfusion and Treatment of African Children Trial (TRACT). The Lancet Child and Adolescent Health Vol.6 No.9 (2022) , 606-613. 613. doi:10.1016/S2352-4642(22)00153-5 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/85581
Title
Sickle cell anaemia and severe Plasmodium falciparum malaria: a secondary analysis of the Transfusion and Treatment of African Children Trial (TRACT)
Author's Affiliation
Other Contributor(s)
Abstract
Background: Sickle cell anaemia (SCA) has historically been associated with high levels of childhood mortality in Africa. Although malaria has a major contribution to this mortality, to date, the clinical pathology of malaria among children with SCA has been poorly described. We aimed to explore the relationship between SCA and Plasmodium falciparum malaria in further detail by investigating the burden and severity of malaria infections among children recruited with severe anaemia to the TRACT trial of blood transfusion in Africa. Methods: This study is a post-hoc secondary analysis of the TRACT trial data, conducted after trial completion. TRACT was an open-label, multicentre, factorial, randomised controlled trial enrolling children aged 2 months to 12 years who presented with severe anaemia (haemoglobin <6·0 g/dL) to four hospitals in Africa. This secondary analysis is restricted to Uganda, where the birth prevalence of SCA is approximately 1% and malaria transmission is high. Children were classified as normal (HbAA), heterozygous (HbAS), or homozygous (HbSS; SCA) for the rs334 A→T sickle mutation in HBB following batch-genotyping by PCR at the end of the trial. To avoid confounding from SCA-specific medical interventions, we considered children with an existing diagnosis of SCA (known SCA) separately from those diagnosed at the end of the trial (unknown SCA). The outcomes considered in this secondary analysis were measures of P falciparum parasite burden, features of severe malaria, and mortality at day 28 in malaria-positive children. Findings: Between Sept 17, 2014, and May 15, 2017, 3944 children with severe anaemia were enrolled into the TRACT trial. 3483 children from Uganda were considered in this secondary analysis. Overall, 1038 (30%) of 3483 Ugandan children had SCA. 1815 (78%) of 2321 children without SCA (HbAA) tested positive for P falciparum malaria, whereas the prevalence was significantly lower in children with SCA (347 [33%] of 1038; p<0·0001). Concentrations of plasma P falciparum histidine-rich protein 2 (PfHRP2), a marker of the total burden of malaria parasites within an individual, were significantly lower in children with either known SCA (median 8 ng/mL; IQR 0–57) or unknown SCA (7 ng/mL; 0–50) than in HbAA children (346 ng/mL; 21–2121; p<0·0001). In contrast to HbAA children, few HbSS children presented with classic features of severe and complicated malaria, but both the frequency and severity of anaemia were higher in HbSS children. We found no evidence for increased mortality at day 28 in those with SCA compared with those without SCA overall (hazard ratios 1·07 [95% CI 0·31–3·76] for known SCA and 0·67 [0·15–2·90] for unknown SCA). Interpretation: The current study suggests that children with SCA are innately protected against classic severe malaria. However, it also shows that even low-level infections can precipitate severe anaemic crises that would likely prove fatal without rapid access to blood transfusion services. Funding: UK Medical Research Council, Wellcome, and UK National Institute for Health and Care Research.