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: 10609863
• 负责人: Michelle Sang Hsiang
• 金额: $ 120.65万
• 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/10609863
• 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; 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; Toxic effect; Uganda; Visit; arm; artemether; benflumetol; burden of illness; co-infection; comparison control; comparison intervention; cost; cost effectiveness; cost-effectiveness evaluation; density; detection method; disability-adjusted life years; economic cost; economic impact; efficacy evaluation; follow-up; global health; health economics; 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.

项目摘要/摘要 随着疟疾的传播下降，体内越来越低的感染持续存在。 低密度疟疾感染（LMI）通常是慢性的，代表了高比例的感染。 社区中的孩子和出现发烧的孩子，但在很大程度上被忽略了，因为 标准护理点诊断对检测它们的敏感性有限，它们被认为是偶然的或 有益的是，它们可能会再次提供保护性免疫，未来疟疾疾病。但是，大部分数据 用于高传输设置，结果混合在一起。也来自较低传输设置的数据 提出负面的健康后果。越来越多的身体证据表明LMI是相关的 复发性疟疾，慢性贫血，生长不良，与侵入性细菌疾病的共同感染和认知 损害。来自间歇性预防疗法（IPT）和大众药物管理（MDA）试验的数据 还提出了治疗LMI的好处。但是，这些推定的治疗策略也可以促进药物 电阻，在低传输设置中不实用。更敏感的检测方法包括 分子方法越来越可用，但证据证明了它们减轻疾病负担的有效性 缺乏。为了告知政策和实践，迫切需要证明有关的影响和安全 检测和治疗儿童的LMI。拟议项目的目的是确定长期 检测和治疗儿童LMI的健康和社会经济效应。我们假设这与 疟疾检测是被动的，并基于标准诊断（PCD），检测和 通过使用分子检测方法在活性病例检测（ACDM）和被动病例中处理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益处。 为了检验这一假设，我们建议在6个月的儿童中进行开放标签的随机对照试验 在坦桑尼亚Bagamoyo的一个已建立的试用地点到10岁，那里的传输很低，我们有 发现高密度的高度感染是低密度。治疗恶性疟原虫LMI的影响 通过主动或被动病例检测可能会有所不同。因此，我们将研究它们作为单独的干预措施，并且 将每个人与护理标准进行比较。将招募600名儿童的人口代表样本 （n =每只手臂200，包括随访的15％损失）至少能力（双面A = 0.05）检测A 与对照相比，每个干预措施的效应大小为20％。孩子将被随机分为三个 研究臂：1）护理标准PCD（控制），在该标准中，出现发烧的儿童会接受囊状 基于阳性快速诊断测试（RDT）结果的Lumefantrine（AL），2）ACDM（ARM 2），儿童将 每年接受3次疟疾测试（使用RDT和QPCR），并为RDT或 QPCR积极性和3）PCDM（ARM 3），其中儿童发烧时会接受疟疾的测试 （使用RDT和QPCR）与AL用于RDT或QPCR阳性。标准PCD将在 手臂2，将在第3臂中进行无ACD。为了捕获亚急性或慢性效应，将发生随访 2年。具体目的是：（1）评估标准PCD加ACDM与标准PCD的影响 独自一人长期儿童健康。我们假设添加ACDM会降低全因病人的发生率 访问。次要结果包括贫血，生长，安全性，疟疾，抗生素使用，临床症状，发烧 发作发作后的发作，临床失败，免疫反应，认知和社会经济影响。 （2）至 评估PCDM与Standard PCD对长期儿童健康的影响。我们假设PCDM与 标准PCD将降低全因病态访问的发生率。次要结果如AIM 1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伸缩性 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控制和计算 结果在内，包括：每次病人的访问避免，每个残疾调整后的生活年（达利）和经济的费用 美元保存。我们从全因发病率的角度应对LMI挑战的方法 社会经济影响具有创新性，因为现状是为了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 长期社会经济影响。我们研究的意义在于全球范围内的相关性 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;以及这类第一次试验的潜力导致政策和实践变化。