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

针对坦桑尼亚儿童低密度疟疾感染（LMI）的干预措施的长期健康和社会经济影响

• 批准号: 10328848
• 负责人: Michelle Sang Hsiang
• 金额: $ 93.61万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328848
• 关键词: 10 year old; Address; African; Anemia; Antibiotics; Applied Research; Area; Bacterial Infections; Child; Child Health; Child Welfare; Childhood; Chronic; Clinical; Cognition; Cognitive; Cognitive deficits; Cohort Studies; Communicable Diseases; Communities; Country; Data; Detection; Diagnosis; Diagnostic; Diagnostic tests; Drug resistance; Economics; Effectiveness; Evaluation; Failure; Falciparum Malaria; Fever; Future; Growth; Health; Health care facility; Immune response; Immunity; Impaired cognition; Incidence; Infection; Intervention; Lead; Malaria; Methods; Microscopic; Microscopy; Mission; Molecular; Morbidity - disease rate; National Institute of Allergy and Infectious Disease; Outcome; Parasites; Patients; Pediatric cohort; Persons; Pharmaceutical Preparations; Plasmodium falciparum; Policies; Population; Prevalence; Preventive therapy; Privatization; Public Health; Randomized; Randomized Controlled Trials; Rapid diagnostics; Recommendation; Recurrence; Reporting; Risk; Role; Safety; Sampling; Side; Site; Societies; Symptoms; Tanzania; Test Result; Testing; Time; Toxic effect; Uganda; Visit; arm; artemether; base; benflumetol; burden of illness; co-infection; comparison intervention; cost; cost effectiveness; cost-effectiveness evaluation; density; detection method; disability-adjusted life years; efficacy evaluation; follow-up; global health; high risk; improved; innovation; malaria infection; malaria transmission; open label; overtreatment; point-of-care diagnostics; prevent; primary outcome; protective effect; recruit; secondary outcome; socioeconomics; standard of care; three-arm study; tool; transmission process; treatment strategy

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.

项目概要/摘要 随着疟疾传播的减少，体内持续存在低水平感染的比例不断增加。 低密度疟疾感染 (LMI) 通常是慢性的，并且在感染人群中所占比例很高。 社区里的孩子和发烧的孩子，但他们基本上被忽视了，因为 标准的护理点诊断检测它们的灵敏度有限，并且它们被认为是偶然的或 有益的是它们可以为未来的疟疾疾病提供保护性免疫力。然而，这些数据中的大部分 适用于高传输设置，结果好坏参半。还有来自较低传输设置的数据 表明对健康产生负面影响。越来越多的身体证据表明 LMI 与 患有复发性疟疾、慢性贫血、生长不良、合并感染侵袭性细菌性疾病和认知障碍 损害。间歇性预防性治疗 (IPT) 和大规模给药 (MDA) 试验的数据 还提出了治疗 LMI 的好处。然而，这些推定治疗策略也可以促进药物治疗 电阻，并且在低传输设置中不实用。更灵敏的检测方法包括 分子方法越来越多，但有证据表明它们可以有效减轻疾病负担 缺乏。为了为政策和实践提供信息，迫切需要有关其影响和安全性的证据 检测和治疗儿童 LMI。拟议项目的目标是确定长期 检测和治疗儿童 LMI 对健康和社会经济的影响。我们假设与 疟疾检测是被动的并且基于标准诊断 (PCD)、检测和 通过主动病例检测（ACDm）和被动病例中的分子检测方法治疗 LMI 儿童的检测（PCDm）将改善全因发病率，并具有认知和社会经济效益。 为了检验这一假设，我们建议对 6 个月大的儿童进行开放标签随机对照试验 在坦桑尼亚巴加莫约的一个既定试验地点，到 10 岁，那里的传播率很低，我们已经 发现很大一部分感染是低密度的。治疗恶性疟原虫 LMI 的效果 通过主动或被动病例检测可能会有所不同。因此，我们将把这些作为单独的干预措施进行研究 将每个与护理标准进行比较。将招募总共 600 名儿童作为人口代表性样本 （每组 n=200，包括 15% 的随访损失）使至少 85% 的功效（两侧 a=0.05）能够检测到 与对照相比，每种干预措施的效果大小为 20%。孩子们将被随机分配到三组之一 研究组：1) 标准护理 PCD（对照），发烧的儿童将接受蒿甲醚治疗 基于阳性快速诊断测试 (RDT) 结果的 lumefantrine (AL)，2) ACDm（第 2 组），儿童将 每年接受 3 次疟疾检测（使用 RDT 和 qPCR），并进行 AL 进行 RDT 或 qPCR 阳性，以及 3) PCDm（第 3 组），其中儿童发烧时将接受疟疾检测 （使用 RDT 和 qPCR）并给予 AL 以检测 RDT 或 qPCR 阳性。标准 PCD 将在 第 2 组将不进行 ACD，第 3 组将不进行 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 仅靠儿童的长期健康。我们假设添加 ACDm 会降低全因病的发生率 访问。次要结局包括贫血、生长、安全性、疟疾、抗生素使用、临床症状、发烧 发作、发烧发作后的临床失败、免疫反应、认知和社会经济影响。 (2) 至 评估 PCDm 与标准 PCD 对长期儿童健康的影响。我们假设 PCDm 与 标准 PCD 将降低全因病就诊的发生率。次要结果如目标 1 中所述。(3) 评估 ACDm 和 PCDm 的成本效益。为了告知干预措施的潜在可扩展性， 我们将使用目标 1 和 2 的社会经济成本数据来比较每种干预措施以进行控制和计算 成果包括：避免每次就诊的成本、每个残疾调整生命年 (DALY) 以及每个经济 美元节省了。我们从全因发病率和 社会经济影响具有创新性，因为现状是考虑它们与疟疾的相关性。 具体结果和传播；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 儿童 LMI 及其相关发病率；儿童健康对全球健康、社会和人类的重要性 经济;以及此类首次试验有可能导致政策和实践发生变化。