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

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.