Document text
Principal Investigator: Homer L Twigg
Organization: INDIANA UNIVERSITY INDIANAPOLIS
Fiscal Year: 2024
Award: $752,410
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><7S Gamma Globulin><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Active Follow-up><Acute><Address><Alveolar><Antibodies><Automobile Driving><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Benign><Blood><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Reticuloendothelial System><Body System><Bronchioalveolar Lavage><Bronchoalveolar Lavage><Bronchoalveolar Lavage Fluid><Bronchopulmonary Lavage><Bronchoscopy><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 S protein><COVID-19 infected patient><COVID-19 infection><COVID-19 patient><COVID-19 positive patient><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 virus><CV-19><Characteristics><Chemotactic Cytokines><Chest imaging><Chronic><Chronic lung disease><Clinical><CoV-2><CoV2><Coronavirus Infectious Disease 2019><Data><Development><Diagnosis><Disease><Disorder><Failure><Fibrosis><Fibrotic lesions in lung><Future><Glass><Goals><Grippe><HIV><Homologous Chemotactic Cytokines><Hospital Admission><Hospitalization><Human Immunodeficiency Viruses><IgA><IgG><Immune><Immune response><Immunes><Immunity><Immunochemical Immunologic><Immunoglobulin A><Immunoglobulin G><Immunologic><Immunologic Stimulation><Immunological><Immunological Stimulation><Immunological response><Immunologically><Immunologics><Immunostimulation><Indiana><Infection><Inflammation><Inflammation Mediators><Inflammatory><Inflammatory Response><Influenza><Innate Immunity><Intercrines><LAV-HTLV-III><Laboratories><Link><Lung><Lung Diseases><Lung Inflammation><Lung Lavage><Lung Respiratory System><Lung Tissue Fibrosis><Lung immune response><Lung scar><Lung tissue scar><Lymphadenopathy-Associated Virus><Lymphatic cell><Lymphocyte><Lymphocytic><Marrow Neutrophil><Modeling><Morbidity><Morbidity - disease rate><Native Immunity><Natural Immunity><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Non-Polyadenylated RNA><Non-Specific Immunity><Nonspecific Immunity><Nucleocapsid Proteins><Organ System><PASC><Pathogenesis><Patient Recruitments><Patients><Pattern><Phenotype><Pneumonia><Pneumonitis><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Post Acute Sequelae of COVID19><Post Acute Sequelae of SARS-CoV-2><Post Acute Sequelae of SARS-CoV2><Post Acute Sequelae of severe acute respiratory syndrome coronavirus 2><Post-Acute Sequelae of SARS-CoV-2 Infection><Process><Proteins><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Fibrosis><Pulmonary Inflammation><Pulmonary Scar><Pulmonary Tissue fibrosis><RNA><RNA Gene Products><Radiography><Reporting><Residual><Residual state><Respiratory Signs and Symptoms><Ribonucleic Acid><Risk><Roentgenography><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SIS cytokines><Sampling><Scarring at the lung><Scarring in the lung><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><T cell response><T-Cells><T-Lymphocyte><Thoracic imaging><United States><Universities><Viral><Viral Antigens><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Virus Diseases><Virus-HIV><Work><Wuhan coronavirus><active followup><acute COVID-19><acute SARS-CoV-2 infection><acute infection><acute phase of COVID-19><acute phase of SARS-CoV-2 infection><adverse sequelae of COVID><adverse sequelae of COVID-19><adverse sequelae of coronavirus disease><adverse sequelae of coronavirus disease 2019><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after infection by SARS-CoV-2><after severe acute respiratory distress syndrome CoV-2 infection><airway symptom><bronchopulmonary lavage therapy><chemoattractant cytokine><chemokine><chronic COVID-19 sequelae><chronic pulmonary disease><clinical diagnosis><cohort><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cytokine><developmental><disease of the lung><disorder of the lung><driving><fibrosis in the lung><fibrotic lung><follow up><follow-up><followed up><following COVID-19 infection><following SARS-CoV-2 infection><following SARS-CoV2 infection><following infection by SARS-CoV-2><following severe acute respiratory distress syndrome CoV-2 infection><followup><hCoV19><host response><immune senescence><immune system response><immunoresponse><immunosenescence><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><inflammation marker><inflammatory environment><inflammatory marker><inflammatory mediator><inflammatory milieu><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><long haul sequelae of COVID-19><long haul sequelae of coronavirus disease 2019><long-term sequelae of COVID-19><long-term sequelae of SARS-CoV-2><long-term sequelae of coronavirus disease 2019><long-term sequelae of severe acute respiratory syndrome coronavirus 2><lung disorder><lung fibrosis><lymph cell><mortality><nCoV2><neutralizing antibody><neutrophil><participant enrollment><participant recruitment><patient enrollment><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><peripheral blood><post COVID-19 sequelae><post SARS-CoV-2 infection><post acute sequelae following COVID-19><post-COVID><post-COVID-19><post-acute sequelae following SARS-CoV-2 infection><post-acute sequelae of COVID-19><post-acute sequelae of acute COVID infection><post-acute sequelae of coronavirus disease 2019><post-coronavirus disease 2019><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><pulmonary><pulmonary immune response><radiologic imaging><radiological imaging><respiratory symptom><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><spike proteins on SARS-CoV-2><thymus derived lymphocyte><viral RNA><viral infection><virus RNA><virus antigen><virus infection><virus protein><virus-induced disease>