Cardiopulmonary Inflammation and Multi-System Imaging During the Clinical Course of COVID-19 Infection in Asymptomatic and Symptomatic Persons

Clinical Center

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Abstract

There is little sequential, methodically collected data on patients with COVID-19 that can be correlated with the severity of disease or the long-term sequelae. Such information is necessary to understand how to most logically intervene with directly acting antiviral agents and immunologic response modifiers. This protocol will enroll patients to the Clinical Center in a longitudinal study (NIH 20-CC-0113). The goal is to link a) inflammatory responses present in blood, bronchoalveolar lavage, urine and spinal fluid with b) viral RNA levels in blood and body fluids and c) innovative imaging of COVID-19 target organs (lungs, heart, brain and kidneys) from the earliest stages of infection and at later time points as the infection and host responses evolve, through recovery and convalescence. We believe that this approach will provide novel insights into mechanisms associated with the initiation, progression and resolution of lung, cardiac and systemic inflammation. These mechanisms are presumed to be essential in the pathogenesis and survival from this infection. This information will help guide diagnostic and therapeutic innovation and assess long-term consequences of this infection. We plan to conduct a comprehensive analysis of host inflammatory responses to COVID-19 infection linked to clinical variables, levels of viral RNA in blood, body fluids (lavage, urine, spinal fluid) and sequential imaging modalities performed at 3 5 time points during the course of infection. We will obtain sequential sampling of blood and urine and perform serial bronchoalveolar lavages in asymptomatic, minimally symptomatic (i.e. fever, myalgias, anosmia, cough but without significant respiratory symptoms) and symptomatic patients (i.e. those who require hospitalization for their infection). The current protocol will study two cohorts of patients. The first cohort (n=75) will be composed of acutely diagnosed persons with either no or limited symptoms (e.g. fever, myalgias, fatigue, anosmia) and organ dysfunction to those persons requiring hospitalization for respiratory disease or other organ dysfunction. They will be cared for in the CC and undergo a comprehensive approach of sequential body fluid sampling (i.e. bronchoalveolar lavage, blood, urine and spinal fluid) and radiographic imaging (high resolution CT scan, MRI of brain, heart and lung, renal ultrasound and echocardiography) during their acute illness. These studies will be repeated during the recovery phase (approximately 4 to 12 weeks after onset of illness) and during convalescence (12 weeks to 12 months after the acute illness). A second cohort of patients (n=75) will be recruited after their treatment at regional hospitals. Both cohorts will be evaluated with an identical series of tests in their recovery and convalescent phases. These studies will allow a comprehensive evaluation of host inflammatory responses with viral loads in target organs (blood, lung, urine and spinal fluid), complemented by innovative imaging using high resolution CT scan, MRI imaging of the brain, heart and lung, renal ultrasound and echocardiography. Understanding COVID-19 pathophysiology is vital to developing new strategies for therapy and prevention. The current proposal provides a longitudinal study from the onset of infection, through recovery and convalescence in a spectrum of patients with a focus on major target organs (i.e. heart, lung, brain, kidney) where associated dysfunction has been associated with increased mortality. We will simultaneously study the inflammatory and viral responses in the blood and pulmonary compartments which will provide insight into how one site mirrors or differs from the other. In addition to immunophenotyping, we will apply single cell RNA sequencing in order to use transcriptional signatures to identify cell populations in the lung and blood with the goal to identify novel distinct immune cells subsets during the course of infection. Soluble mediators in the collected body fluids will be measured including inflammatory mediators, procoagulant factors and specialized proresolving molecules. Lastly, functional studies will be conducted in vitro to assess responses of immune cells to specific SARSCoV-2 peptides and proteins. In aggregate, this study will provide a systematic cross section analysis of host immunity and virus RNA that will help elucidate pathogenesis, progression and recovery in host cellular and humoral immunity from the acute infection to convalescence.