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

项目摘要/摘要 随着低收入和中等收入国家越来越多的艾滋病毒携带者存活到青春期， 慢性肺病(CLD)已成为一种重要但知之甚少的并发症 青少年和青年艾滋病毒携带者(ALWH)。在正在进行的纵向呼吸II研究中(K23 在肯尼亚内罗毕，162名ALWH患者中有19%的人肺活量异常，而162名ALWH患者中这一比例为11% 未感染的参与者；59%的ALWH在高分辨率胸部CT扫描上有≥1异常，并有马赛克 衰减是最常见的。慢性呼吸道症状在62%的人中也非常普遍 ALWH和49%的未感染参与者。艾滋病毒与肺功能受损独立相关，并且 ALWH中肺活量测定受损的危险因素包括吸入暴露，如二手烟和 环境中的细颗粒物，以及生长缺陷。K23研究的目标包括：审查 慢性阻塞性肺疾病进展的危险因素和机制随时间的差异；确定艾滋病毒感染的作用 关于肺功能随时间的变化，考虑到与其他危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有关 功能随时间增长。然而，鉴于新冠肺炎疫情，这些纵向研究一直在进行 出于安全原因停了下来。由于这些研究现在可以恢复，并增加了预防措施，行政当局 本K23的补充将为以下目标提供必要的资源：1)完整的纵向肺 功能和临床数据收集，按照母公司K23中的建议进行计划分析；2)添加测试 对于新冠肺炎来说，既可以通过肺活量测定(快速聚合酶链式反应检测)来缓解SARS-CoV-2潜在传播的风险，也可以 探讨新冠肺炎感染对肺功能生长发育的影响(血清学抗体检测)。 本补编的不可或缺的支持将保持呼吸II这一独特和创新的队列 了解慢性肝病进展的资源，特别是围产期感染艾滋病毒的人， 与来自同一地理集水区的人口统计相似的未受感染的参与者相比 新冠肺炎的背景。这一队列包括的胸部CT数据集比任何已发表的文献都要大 到目前为止。用于生物标记物分析的血清(目前正在进行中)有可能告知机制途径 CLD.研究基础设施已经在支持实施子研究，以获得量化 空气污染暴露的测量方法，并将呼吸II中的CLD与高收入人群的ALWH队列进行比较 环境，是一个很好的平台，支持未来的分项研究。这项研究的结果将提供 为R01水平研究提供信息的关键数据，以调查对病理生理的新见解 在资源有限的环境下ALWH中CLD进展的机制，揭示了危险因素和 预防和治疗干预措施可以针对的机制，以减轻慢性阻塞性肺病的负担。

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.