Abstract The proposed experiments will test the hypothesis: Extensive longitudinal and immunometabolic phenotyping will advance our understanding of the heterogeneous mechanisms for SA and inform future therapeutic development and clinical management strategies. Specifically, comprehensive phenotyping will reveal distinct biological mechanisms and clinical outcomes for SA patients with persistent type 2 inflammation, non-type 2 disease, and defective resolution. Severe asthma (SA) is characterized by persistent airway inflammation, airway hyper-responsiveness, and decreased lung function despite glucocorticoids. Here, we are proposing to extend the NHLBI Severe Asthma Research Program (SARP) for a translational, longitudinal mechanistic study of SA. This longitudinal study design represents an essential “next step” to provide information on the stability of SA endophenotypes and their relationship to disease severity and progression. Investigation into SA airway inflammation has uncovered heterogeneous pathobiology. Approximately 50% of patients are characterized by increased type 2 (T2) inflammation; discoveries that led recently to new T2 targeted therapies. There remains a continuing and critical need to further elucidate mechanisms underlying the distinct pathobiology in subpopulations of SA to provide molecular phenotyping for risk stratification, new therapeutic development, especially for non-T2 inflammation, and precision clinical management. Over the last 6 years, SARP has recruited a large US cohort of SA patients. Subjects were comprehensively characterized at baseline and then monitored over three years of longitudinal follow up, leading to significant new insights into clinical, structural, functional and immunometabolic disturbances in SA. In work in progress, analyses of 3-year longitudinal follow-up has established 3 principal immunophenotypes: (1) persistent T2 inflammation, (2) intermittent T2 inflammation, and (3) persistent non-T2 inflammation. The immunophenotypes had both similarities and differences at presentation with differences evolving further over 3 years of longitudinal follow up (e.g., changes in bronchodilator responsiveness, risk for exacerbations; vide infra). In addition to lung specific inflammation, many SA patients have systemic inflammation, metabolic dysfunction and defects in resolution mechanisms. To address our main hypothesis, we propose a national, multicenter collaborative study with a mechanistic translational approach with 4 specific aims to rigorously and comprehensively investigate the molecular and cellular origin of SA immunometabolic phenotypes and their relationship to disease progression.

Project Narrative Patients with severe asthma do not respond to current asthma therapies, resulting in substantial excess morbidity at great personal and societal costs. The pathobiology of severe asthma is heterogeneous, so there is a continuing and critical need to understand the disease’s biological mechanisms to provide molecular phenotyping for risk stratification and inform future therapeutic development and clinical management strategies. Here, we are proposing a multicenter longitudinal mechanistic study of patients with severe asthma.