Mechanisms & risk factors of chronic lung disease in HIV+ adolescents in Nairobi

项目总结/摘要 随着越来越多的低收入和中等收入国家感染艾滋病毒的儿童活到青春期， 慢性肺病（CLD）已成为一种重要但知之甚少的并发症， 艾滋病毒感染者青少年和年轻成年人协会。在正在进行的纵向BREATHE II研究（K23 HL 129888，PI Attia），162名ALWH中有19%的人肺功能异常，而162名ALWH中有11%的人肺功能异常。 未感染受试者; 59%的ALWH在高分辨率胸部CT扫描中有≥1处异常，有马赛克 其中衰减最为常见。慢性呼吸道症状在62%的人中也非常普遍， ALWH和49%的未感染者。HIV与肺功能受损独立相关， ALWH中肺功能受损的风险因素包括吸入暴露，如二手烟， 环境细颗粒物，以及生长缺陷。K23研究的目标包括： CLD进展的风险因素和机制随时间的差异;确定HIV感染的作用 肺功能随时间的变化，考虑与其他风险因素的复杂相互作用;以及，评估 慢性免疫激活和炎症的生物标志物是否与肺功能减退相关 随着时间的推移功能增长。然而，鉴于COVID-19大流行，这些纵向研究已被 出于安全原因停止。由于这些研究现在可以在增加预防措施的情况下恢复， 对K23的补充将为以下目的提供必要的资源：1）完整的纵向肺 功能和临床数据收集，以进行母K23中提出的计划分析; 2）添加测试 对于COVID-19，通过肺量测定（快速PCR检测）降低SARS-CoV-2潜在传播的风险， 检测COVID-19感染对肺功能生长发育的作用（血清学抗体检测）。 这一补充的不可或缺的支持将保持呼吸二组，一个独特的和创新的 了解ALWH中CLD进展的资源，特别是那些围产期HIV感染者， 与来自同一地理集水区的人口统计学上相似的未感染参与者相比， COVID-19的背景。该队列包括的胸部CT数据集大于任何已发表的文献 迄今用于生物标志物分析的血清（目前正在进行中）有可能为以下疾病的机制途径提供信息 CLD。研究基础设施已经支持子研究的实施，以获得定量的 空气污染暴露的措施，并将BREATHE II中的CLD与高收入人群中的ALWH队列进行比较。 设置，是一个定位良好的平台，以支持未来的子研究。这项研究的结果将提供 为R 01级研究提供信息的关键数据，以研究对病理生理学的新见解 在资源有限的情况下，ALWH中CLD进展的机制，揭示了风险因素， 这些机制可以通过预防和治疗干预措施来减轻CLD的负担。

PROJECT SUMMARY/ABSTRACT As increasing numbers of children with HIV are surviving to adolescence in low- and middle-income countries, chronic lung disease (CLD) has emerged as an important but poorly understood complication amongst adolescents and young adults living with HIV (ALWH). In the ongoing, longitudinal BREATHE II Study (K23 HL129888, PI Attia) in Nairobi, Kenya, 19% of 162 ALWH have abnormal spirometry compared to 11% of 162 uninfected participants; 59% of ALWH have ≥1 abnormality on high-resolution chest CT scan, with mosaic attenuation among the most common. Chronic respiratory symptoms are also highly prevalent among 62% of ALWH and 49% of uninfected participants. HIV is independently associated with impaired lung function, and risk factors for impaired spirometry among ALWH include inhaled exposures, such as secondhand smoke and ambient fine particulate matter, as well as growth deficits. Objectives of the K23 research include: examining differences in risk factors and mechanisms of CLD progression over time; determining the role of HIV infection on change in lung function over time, considering the complex interplay with other risk factors; and, evaluating whether biomarkers of chronic immune activation and inflammation are associated with diminished lung function growth over time. However, in light of the COVID-19 pandemic, these longitudinal studies have been halted for safety reasons. As these studies can now resume with added precautions, an Administrative Supplement to this K23 will provide essential resources for the following Aims: 1) complete longitudinal lung function and clinical data collection to conduct planned analyses as proposed in the parent K23; 2) add testing for COVID-19 both to mitigate risk of potential spread of SARS-CoV-2 through spirometry (rapid PCR test) and to examine the role of COVID-19 infection on lung function growth and development (serologic antibody test). The indispensable support of this Supplement will maintain the BREATHE II cohort, a unique and innovative resource for understanding CLD progression among ALWH, especially those with perinatal HIV acquisition, compared to demographically similar uninfected participants from the same geographic catchment area in the context of COVID-19. This cohort includes a dataset of chest CTs that is larger than in any published literature to date. Serum for biomarker analysis (currently underway) has the potential to inform mechanistic pathways of CLD. The study infrastructure is already supporting implementation of sub-studies to obtain quantitative measures of air pollution exposure and to compare CLD in BREATHE II to a cohort of ALWH in a high-income setting, and is a well-positioned platform to support future sub-studies. Findings of this research will provide critical data for informing R01-level research to investigate novel insights into the pathophysiologic mechanisms of CLD progression in ALWH in resource-limited settings, shedding light on risk factors and mechanisms that can be targeted by preventative and therapeutic interventions to mitigate the burden of CLD.