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.

项目总结/摘要 随着疟疾传播的下降，越来越多的感染在体内持续存在，但感染程度较低。 低密度疟疾感染往往是慢性的，在疟疾患者中占很高比例。 社区中的儿童和发烧的儿童，但他们在很大程度上被忽视， 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， 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，大部分数据 来为高传输设置和结果是混合的。也可以从较低的传输设置中获取数据 会对健康产生负面影响有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的患者， 损伤间歇性预防性治疗（IPT）和大规模给药（MDA）试验的数据 也表明了治疗LMI的好处。然而，这些假定的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 分子治疗方法越来越多，但有证据表明，它们在减少疾病负担方面的有效性 缺乏。为了向政策和实践提供信息，迫切需要关于以下方面的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的健康和社会经济影响。我们假设， 疟疾检测是被动的，基于标准诊断， 采用主动病例检测（ACDm）和被动病例检测（PADm）的分子检测方法治疗LMI 在儿童中检测多氯二苯并对二恶英（PCDm）将改善全因发病率，并具有认知和社会经济效益。 为了验证这一假设，我们建议在6个月的儿童中进行一项开放标签随机对照试验， 到10岁，在坦桑尼亚巴加莫约的一个已建立的试验地点，那里的传播率很低， 发现高比例的感染是低密度的。治疗恶性疟原虫LMI的效果 通过主动或被动的情况检测可以不同。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名儿童的人口代表性样本 （每组n=200，包括15%的失访）至少有85%的把握度（双侧a=0.05）来检测 与对照组相比，每种干预措施的效应量为20%。儿童将被随机分为三组 研究组：1）PCD标准治疗（对照组），发热儿童接受蒿甲醚治疗 本芴醇（AL），基于阳性快速诊断试验（RDT）结果，2）ACDm（第2组），其中儿童将 每年接受三次疟疾检测（使用RDT和qPCR），使用AL进行RDT或 qPCR阳性，3）多氯二苯并呋喃（第3组），其中儿童在发烧时将接受疟疾检测 （使用RDT和qPCR），并针对RDT或qPCR阳性给予AL。标准PCD将在 第2组将不进行ACD，第3组将不进行ACD。为了捕获亚急性或慢性效应，将在以下时间进行随访： 2年具体目标是：（1）评估标准PCD + ACDm与标准PCD的影响 长期的儿童健康。我们假设添加ACDM将降低全因疾病的发生率 探访次要结局包括贫血、生长、安全性、疟疾、抗生素使用、临床症状、发热 发烧发作后的临床失败，免疫反应，认知和社会经济影响。(2)到 评估多氯二苯并对二恶英与标准多氯二苯并对二恶英对儿童健康的长期影响。我们假设PCDm与 标准PCD将降低全因病假的发生率。次要结局如目标1所述。（三） 评价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和目标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 结果包括：避免每次生病的成本，每个残疾调整生命年（DADs）和每个经济 美元节省。我们从全因发病率的角度应对LMI挑战的方法， 社会经济影响是创新性的，因为现状是考虑它们与疟疾的相关性- 具体的结果和传输;我们还将利用创新的新工具来评估认知评估， 长期的社会经济影响。我们研究的意义在于， 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;以及这种首次试验导致政策和实践变化的潜力。