Long-term health and socioeconomic impact of interventions targeting low-density malaria infection (LMI) among children in Tanzania

项目摘要/摘要 随着疟疾传播的下降，越来越多的感染持续在体内处于低水平。 低密度疟疾感染(LMI)通常是慢性的，在 社区中的儿童和发烧的儿童，但他们在很大程度上被忽视了，因为 标准的护理点诊断对检测它们的灵敏度有限，并且它们被认为是偶发的或 有益的是，它们可能会在未来的疟疾疾病中再次提供保护性免疫。然而，这些数据中的大部分 用于高变速箱设置，结果好坏参半。还有来自较低传输设置的数据 意味着负面的健康后果。越来越多的身体证据表明，LMI与 反复疟疾，慢性贫血，生长不良，合并侵袭性细菌疾病感染，以及认知 减损。间歇预防治疗(Ipt)和大规模给药(Mda)试验的数据 还建议治疗LMI的好处。然而，这些假定的治疗策略也可以促进药物 并且在低传输设置下不实用。更灵敏的检测方法包括 分子方法越来越多，但有证据表明它们在减轻疾病负担方面是有效的 是缺乏的。为了向政策和实践提供信息，迫切需要有证据证明 儿童LMI的检测和治疗。拟议项目的目标是确定长期的 检测和治疗儿童LMI的健康和社会经济影响。我们假设，与一个 在疟疾检测是被动的情况下，根据标准诊断(PCD)、检测和 在主动病例检测(ACDM)和被动病例(ACDM)中使用分子检测方法治疗LMI 儿童中的PCDm检测将改善各种原因的发病率，并具有认知和社会经济利益。 为了验证这一假设，我们建议在6个月大的儿童中进行一项开放标签的随机对照试验。 到10岁的儿童在坦桑尼亚巴加莫约的一个既定试验点，那里的传播率很低，我们有 研究发现，高比例的感染是低密度的。治疗恶性疟原虫LMI的效果观察 通过主动或被动案件侦破可能有所不同。因此，我们将把这些作为单独的干预措施进行研究 将每一项与护理标准进行比较。将招募总共600名儿童的具有人口代表性的样本 (n=每臂200，包括15%的随诊损失)使至少85%的功率(双侧a=0.05)能够检测到 与对照相比，每个干预措施的效应大小为20%。孩子们将被随机分成三组 研究武器：1)PCD(对照)护理标准，出现发烧的儿童将接受蒿甲醚治疗 基于快速诊断试验(RDT)阳性结果的Lumefantrine(AL)，2)ACDM(ARM 2)，儿童将 每年接受三次疟疾检测(使用RDT和qPCR)，并对RDT或 QPCR阳性，以及3)PCDm(第3臂)，儿童发烧时将接受疟疾检测 (使用RDT和qPCR)，对于RDT或qPCR阳性的患者给予AL。将在#年进行标准的PCD ARM 2和ARM 3将不进行ACD。为了捕捉亚急性或慢性影响，将在 2年。具体目标是：(1)评估标准PCD加ACDM与标准PCD的影响 对儿童长期健康的关注。我们假设加入ACDM将降低全因疾病的发生率 来访。次要结果包括贫血、生长发育、安全性、疟疾、抗生素使用、临床症状、发烧 发病、发热发作后的临床失败、免疫反应、认知和社会经济影响。(2)至 评估PCDm与标准PCD对儿童长期健康的影响。我们假设PCDm与 标准的PCD将降低全因疾病就诊的发生率。次级结果如目标1所述。(3) 评价ACDM和PCDm的成本-效果。为了告知干预的潜在可扩展性， 我们将使用目标1和目标2的社会经济成本数据来比较控制和计算每种干预措施 结果包括：避免的每次就诊费用、按残疾调整的生命年(DALY)和按经济情况 省了一块钱。我们从全因发病率和死亡率的角度应对LMI挑战的方法 社会经济影响是创新的，因为现状一直是考虑它们与疟疾的相关性- 具体结果和传递；我们还将利用创新的新工具来评估认知评估和 长期的社会经济影响。我们研究的意义在于全球范围内的相关性日益增强 LMI及其对儿童的相关发病率；儿童健康对全球健康、社会和 经济；以及这类第一次审判有可能导致政策和做法的变化。

Project Summary/Abstract As malaria transmission declines, an increasing proportion of infections persist in the body at low levels. Low-density malaria infection (LMI) are often chronic and represent a high proportion of infections among children in the community and children presenting with fever, but they have been largely ignored because standard point-of-care diagnostics have limited sensitivity to detect them, and they are considered incidental or beneficial in that they may provide protective immunity again future malaria illness. However, much of this data comes for high transmission settings and results are mixed. Also data from lower transmission settings suggests negative health consequences. There is a growing body evidence to suggest that LMI are associated with recurrent malaria, chronic anemia, poor growth, co-infection with invasive bacterial disease, and cognitive impairment. Data from trials of intermittent preventative therapy (IPT) and mass drug administration (MDA) also suggest benefits of treating LMI. However, these presumptive treatment strategies can also promote drug resistance and are not practical in low transmission settings. More sensitive detection methods including molecular approaches are increasingly available, but evidence of their effectiveness to reduce disease burden is lacking. To inform policy and practice, there is an urgent need for evidence on the impact and safety of detecting and treating LMI in children. The objective of the proposed project is to determine the long-term health and socioeconomic effects of detecting and treating LMI in children. We hypothesize that compared to a standard of care where malaria detection is passive and based on standard diagnostics (PCD), detecting and treating LMI through use molecular detection methods in active case detection (ACDm) and passive case detection (PCDm) in children will improve all-cause morbidity and have cognitive and socioeconomic benefits. To test this hypothesis, we propose to conduct an open-label randomized controlled trial in children 6 months to 10 years of age at an established trial site in Bagamoyo, Tanzania, where transmission is low and we have found that a high proportion of infections are low-density. The effects of treating Plasmodium falciparum LMI through active or passive case detection may differ. As such, we will study these as separate interventions and compare each to the standard of care. A population representative sample of 600 children total will be recruited (n=200 per arm, inclusive of 15% loss to follow-up) enabling at least 85% power (two-sided a=0.05) to detect a 20% effect size for each of the interventions compared to control. Children will be randomized into one of three study arms: 1) standard of care PCD (Control) whereby children presenting with fever will receive artemether lumefantrine (AL) based on positive rapid diagnostic test (RDT) result, 2) ACDm (Arm 2) whereby children will receive testing for malaria (using RDT and qPCR) three times annually, with AL administered for RDT or qPCR-positivity, and 3) PCDm (Arm 3), in which children, when they have fever, will receive testing for malaria (using RDT and qPCR) with AL administered for RDT or qPCR-positivity. Standard PCD will be conducted in Arm 2 and no ACD will be conducted in Arm 3. To capture subacute or chronic effects, follow-up will occur over 2 years. Specific aims are: (1) To assess the impact of standard PCD plus ACDm vs standard PCD alone on long-term child health. We hypothesize that adding ACDm will lower incidence of all-cause sick visits. Secondary outcomes include anemia, growth, safety, malaria, antibiotic use, clinical symptoms, fever episodes, clinical failure after fever episodes, immune responses, cognition, and socioeconomic effects. (2) To assess the impact of PCDm vs standard PCD on long-term child health. We hypothesize that PCDm vs standard PCD will lower incidence of all-cause sick visits. Secondary outcomes are as described in Aim 1. (3) To evaluate the cost-effectiveness of ACDm and PCDm. To inform potential scalability of the interventions, we will use socioeconomic cost data from Aims 1 and 2 to compare each intervention to control and calculate outcomes including: cost per sick visit averted, per disability adjusted life years (DALYs), and per economic dollar saved. Our approach to address the challenge of LMI from the perspective of all-cause morbidity and socioeconomic effects is innovative as the status quo has been to consider them for their relevance to malaria- specific outcomes and transmission; we will also utilize innovative new tools to assess cognitive evaluation and long-term socioeconomic impact. The significance of our study lies in the increasing worldwide relevance of LMI and its associated morbidity for children; the importance of child health for global health, society, and the economy; and the potential for this first trial of its kind to lead to policy and practice changes.