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.

中文翻译：

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镰状细胞性贫血和严重恶性疟原虫疟疾：非洲儿童输血和治疗试验 (TRACT) 的二次分析

背景

镰状细胞性贫血 (SCA) 历来与非洲儿童的高死亡率有关。尽管疟疾对这种死亡率有很大贡献，但迄今为止，对 SCA 儿童中疟疾的临床病理学描述很少。我们旨在通过调查非洲输血 TRACT 试验招募的患有严重贫血的儿童的疟疾感染负担和严重程度，进一步详细探讨 SCA 和恶性疟原虫疟疾之间的关系。

方法

本研究是对 TRACT 试验数据的事后二次分析，在试验完成后进行。TRACT 是一项开放标签、多中心、因子、随机对照试验，在非洲四家医院招募 2 个月至 12 岁患有严重贫血（血红蛋白 <6·0 g/dL）的儿童。该次要分析仅限于乌干达，那里 SCA 的出生患病率约为 1%，疟疾传播率很高。对于HBB中的 rs334 A→T 镰状突变，儿童被分类为正常 (HbAA)、杂合子 (HbAS) 或纯合子 (HbSS; SCA)在试验结束时通过 PCR 进行批量基因分型。为避免与 SCA 特异性医疗干预混淆，我们将现有诊断为 SCA（已知 SCA）的儿童与试验结束时诊断出的儿童（未知 SCA）分开考虑。该次要分析中考虑的结果是恶性疟原虫寄生虫负担、严重疟疾特征和疟疾阳性儿童第 28 天死亡率的测量值。

发现

2014 年 9 月 17 日至 2017 年 5 月 15 日期间，3944 名患有严重贫血的儿童参加了 TRACT 试验。本次分析考虑了来自乌干达的 3483 名儿童。总体而言，3483 名乌干达儿童中有 1038 名（30%）患有 SCA。在 2321 名无 SCA (HbAA) 的儿童中，有 1815 名 (78%) 的恶性疟原虫疟疾检测呈阳性，而患有 SCA 的儿童的患病率明显较低（1038 名儿童中的 347 名 [33%]；p<0·0001）。血浆恶性疟原虫浓度富含组氨酸的蛋白质 2 (PfHRP2) 是个体体内疟疾寄生虫总负担的标志物，在已知 SCA（中位数 8 ng/mL；IQR 0-57）或未知 SCA（7 ng/mL）的儿童中显着降低。 mL；0-50）高于 HbAA 儿童（346 ng/mL；21-2121；p<0·0001）。与 HbAA 儿童相比，HbSS 儿童很少出现重症和复杂疟疾的典型特征，但 HbSS 儿童贫血的频率和严重程度均较高。我们没有发现 SCA 患者在第 28 天的死亡率高于总体上没有 SCA 的患者（已知 SCA 的风险比为 1·07 [95% CI 0·31-3·76] 和 0·67 [0·15- 2·90] 对于未知的 SCA)。

解释

目前的研究表明，患有 SCA 的儿童天生就可以抵抗典型的重症疟疾。然而，它也表明，即使是低水平的感染也会引发严重的贫血危机，如果没有快速获得输血服务，这可能会致命。

资金

英国医学研究委员会、惠康和英国国家健康与护理研究所。