Analysis of immunologic mechanisms in patients with chronic lung disease after acute COVID infection - Project Summary/Abstract As of February 8, 2023 more than 102.7 million cases of SARS-CoV-2 infection leading to COVID-19 disease have occurred in the United States. Besides the acute morbidity and mortality associated with hospitalization, many patients with COVID-19 develop prolonged complications in the lung characterized by long term respiratory symptoms and radiographic changes due to pulmonary fibrotic and inflammatory processes. Some reports suggest 60-70% of patients who had severe COVID-19 infection will have residual pulmonary disease with fibrosis and/or ground glass opacities on chest imaging consistent with persistent lung inflammation. What drives the chronic immune and inflammatory response is unclear, but persistent viral antigen stimulation well after acute infection has resolved has been described in many viral infections. Persistent immune stimulation can lead to chronic inflammation through multiple mechanisms, including induction of innate immunity, chronic B and T cell responses, and immunosenescence, a highly pro-inflammatory process due to repeated T cell stimulation. In preliminary data we have extensively characterized the alveolar milieu in patients presenting with post COVID- lung disease up to 2 years after being diagnosed with acute infection. We have identified three patterns based on bronchoalveolar lavage (BAL) characteristics: a benign BAL pattern associated with stable lung scaring, a neutrophilic BAL pattern associated with increased cytokine concentrations and pulmonary fibrotic changes, and a lymphocytic pattern associated with increased chemokine concentrations and ground glass opacities on chest imaging. Importantly, we describe persistence in BAL of SARS-CoV-2 RNA in 85% of subjects and spike protein in half the subjects we have studies do far. In this project we hypothesize that chronic lung disease after COVID-19 infection is due to persistent viral proteins in the lung and a poor pulmonary immune response to SARS-COV-2. To address this hypothesis we propose the following specific aims. (1) To obtain bronchoalveolar lavage and peripheral blood for mechanistic studies on a cohort of patients who have persistent lung disease after acute COVID infection, including repeat follow up bronchoscopies on a subset of patients. (2) To further characterize BAL cellular and inflammatory patterns in patients with post COVID lung disease and link them with clinical diagnoses. (3) To assess COVID specific pulmonary humoral and cellular immune responses in patients with post COVID lung disease to determine linkages between COVID specific immunity, failure to clear viral RNA and proteins, and subsequent pulmonary disease. We have the capacity to recruit patients with post COVID lung disease who have BAL available for study and perform detailed cellular, inflammatory mediator, and SARS-CoV-2 specific immune analysis to explore potential mechanisms for the different pulmonary phenotypes seen. We feel the approaches utilized in this study will provide valuable information on post COVID lung disease, suggest approaches to management and treatment, and may be even be applicable to future studies on lung diseases after other viral infections.
