Association Between Inflammatory Pathways and Phenotypes of Pulmonary Dysfunction Using Cluster Analysis in Persons Living With HIV and HIV-Uninfected Individuals.

Background: Persons living with HIV (PLWH) are at risk of developing different phenotypes of chronic lung disease, including chronic obstructive pulmonary disease. Mechanisms underlying these phenotypes are unclear. Objective: To identify clusters of peripheral inflammatory mediators associated with pulmonary function to determine inflammatory pathways and phenotypes of chronic obstructive pulmonary disease in PLWH and HIV-uninfected individuals. Methods: Study participants were PLWH and HIV-uninfected individuals enrolled in the Pittsburgh HIV Lung Cohort. Pulmonary function tests were performed for all participants. Chest computed tomographic scans were performed in a subset of PLWH. Plasma levels of 19 inflammatory mediators were measured by Luminex or ELISA. Clusters were identified based on the expression pattern of inflammatory mediators in PLWH and HIV-uninfected individuals, and the relationships among clinical parameters were evaluated within clusters by using cluster and network analyses. Results: In PLWH, we identified a distinct cluster with higher levels of Th1, Th2, and Th17 inflammatory mediators with increased complexity of these mediators and inferred presence of pathogenic Th17 cell types. Individuals in this cluster had worse airway obstruction and more radiographic emphysema. In HIV-uninfected individuals, a cluster with high-grade systemic inflammation also had worse diffusing capacity for carbon monoxide. Conclusions: Inflammatory pathways associated with pulmonary dysfunction in PLWH suggest multifaceted immune dysregulation involved in different phenotypes of pulmonary dysfunction with a potential specific contribution of the Th17 pathway to airway obstruction in PLWH. Identification of these associations may help in development of treatments that could alter the course of the disease.