背景:严重贫血与幼儿住院死亡率高相关。在疟疾流行地区,存活儿童出院后死亡或再次入院的风险也增加.我们进行了系统评价和个体患者数据荟萃分析,以确定每月出院后化学预防对从严重贫血中恢复的儿童的疗效。
方法:根据PRISMA-IPD指南进行分析。我们在2023年8月28日搜索了多个数据库,没有日期或语言限制,对于在疟疾流行的非洲接受严重贫血的儿童(年龄<15岁)中比较每月出院后疟疾化学预防与安慰剂或标准护理的随机对照试验。使用每日或每周预防疟疾的试验不合格。所有符合条件的试验的研究者共享假名数据集,它们被标准化和合并以进行分析。主要结果是干预期间的全因死亡率。在改良的意向治疗人群中进行了分析,包括为端点做出贡献的所有随机分配的参与者。使用风险比(RR)的固定效应两阶段荟萃分析来生成死亡率的汇总效应估计。使用一阶段混合效应Prentice-Williams-Peterson总时间模型分析了经常性的事件发生时间数据(再入院或临床就诊),以获得风险比(HR)。这项研究在PROSPERO注册,CRD42022308791。
结果:我们的搜索确定了91篇文章,其中78个被标题和摘要排除在外,另有10人不符合资格标准。三个双盲,安慰剂对照试验,包括3663名患有严重贫血的儿童,纳入系统评价和荟萃分析;3507(95·7%)对改良的意向治疗分析做出了贡献。参与者每月接受磺胺多辛-乙胺嘧啶治疗,直至疟疾传播季节结束(平均每名儿童3·1疗程[范围1-6];n=1085;冈比亚),出院后第4周和第8周(n=1373;马拉维)结束时每月给予蒿甲醚-lumefantrine,或在出院后第2、6和10周结束时每月给予双氢青蒿素-哌喹(n=1049;乌干达和肯尼亚)。干预期间,出院后疟疾化学预防与死亡率降低77%相关(RR0·23[95%CI0·08-0·70],p=0·0094,I2=0%),全因再入院率降低55%(HR0·45[95%CI0·36-0·56],p<0·0001)与安慰剂相比。保护作用仅限于干预期,在药物的直接药效学作用减弱后不能持续。少量的试验限制了我们评估异质性的能力,其来源,和出版偏见。
结论:在疟疾流行的非洲,出院后的疟疾化学预防降低了刚从严重贫血中恢复的出院儿童的死亡率和再入院率.出院后的疟疾化学预防可能是管理高危人群的宝贵策略。未来的研究应该集中在交付方法上,延长保护持续时间的选项,其他高危住院群体,和针对出院后发病的非疟疾原因的干预措施。
背景:挪威研究理事会和比尔-梅林达-盖茨基金会通过全球抗疟药研究网络。
BACKGROUND: Severe anaemia is associated with high in-hospital mortality among young children. In malaria-endemic areas, surviving children also have an increased risk of mortality or readmission after hospital discharge. We conducted a systematic
review and individual patient data meta-analysis to determine the efficacy of monthly post-discharge malaria
chemoprevention in children recovering from severe anaemia.
METHODS: This analysis was conducted according to PRISMA-IPD guidelines. We searched multiple databases on Aug 28, 2023, without date or language restrictions, for randomised controlled trials comparing monthly post-discharge malaria chemoprevention with placebo or standard of care among children (aged <15 years) admitted with severe anaemia in malaria-endemic Africa. Trials using daily or weekly malaria prophylaxis were not eligible. The investigators from all eligible trials shared pseudonymised datasets, which were standardised and merged for analysis. The primary outcome was all-cause mortality during the intervention period. Analyses were performed in the modified intention-to-treat population, including all randomly assigned participants who contributed to the endpoint. Fixed-effects two-stage meta-analysis of risk ratios (RRs) was used to generate pooled effect estimates for mortality. Recurrent time-to-event data (readmissions or clinic visits) were analysed using one-stage mixed-effects Prentice-Williams-Peterson total-time models to obtain hazard ratios (HRs). This study is registered with PROSPERO, CRD42022308791.
RESULTS: Our search identified 91 articles, of which 78 were excluded by title and abstract, and a further ten did not meet eligibility criteria. Three double-blind, placebo-controlled trials, including 3663 children with severe anaemia, were included in the systematic
review and meta-analysis; 3507 (95·7%) contributed to the modified intention-to-treat analysis. Participants received monthly sulfadoxine-pyrimethamine until the end of the malaria transmission season (mean 3·1 courses per child [range 1-6]; n=1085; The Gambia), monthly artemether-lumefantrine given at the end of weeks 4 and 8 post discharge (n=1373; Malawi), or monthly dihydroartemisinin-piperaquine given at the end of weeks 2, 6, and 10 post discharge (n=1049; Uganda and Kenya). During the intervention period, post-discharge malaria
chemoprevention was associated with a 77% reduction in mortality (RR 0·23 [95% CI 0·08-0·70], p=0·0094, I2=0%) and a 55% reduction in all-cause readmissions (HR 0·45 [95% CI 0·36-0·56], p<0·0001) compared with placebo. The protective effect was restricted to the intervention period and was not sustained after the direct pharmacodynamic effect of the drugs had waned. The small number of trials limited our ability to assess heterogeneity, its sources, and publication bias.
CONCLUSIONS: In malaria-endemic Africa, post-discharge malaria chemoprevention reduces mortality and readmissions in recently discharged children recovering from severe anaemia. Post-discharge malaria
chemoprevention could be a valuable strategy for the management of this group at high risk. Future research should focus on methods of delivery, options to prolong the protection duration, other hospitalised groups at high risk, and interventions targeting non-malarial causes of post-discharge morbidity.
BACKGROUND: The Research-Council of Norway and the Bill-&-Melinda-Gates-Foundation through the Worldwide-Antimalarial-Research-Network.