COVID-19 Lung Injury, ARDS, and Thrombosis: Acute Disease and Long-Term Subphenotypes

Overview of Proposed Research Project: COVID-19, the disease caused by the novel coronavirus SARS-CoV-2, has impacted governments, economies, and healthcare systems worldwide. The virus spreads efficiently, affecting people of all ages. Although most individuals are asymptomatic or have a self-limiting illness, others develop severe disease and die. This proposal focuses on characterizing severely ill COVID-19 patients hospitalized at New York Presbyterian (NYP) Hospital Columbia University Medical Center (CUMC) and Weill Cornell Medical Center (WCMC) in New York City, which has become an infection epicenter in the United States. Preliminary data suggests that severely ill COVID-19 patients do not resemble 'typical' patients with acute respiratory distress syndrome (ARDS). First, there appears to be at least two different subtypes of severely ill COVID patients requiring mechanical ventilation. Second, some patients have a significant burden of blood clots in their lungs that impair oxygen transfer. Third, some patients exhibit signs of lung stiffening and scarring during the transition from acute illness to convalescence. Taken together, these observations suggest that the identification of different subtypes of severely ill COVID-19 patients will affect their prognosis and treatment.

Description of the Critical Problem: The death rate of COVID-19 patients who are severely ill, especially those needing a ventilator or extracorporeal membrane oxygenation (ECMO), is unacceptably high. In order to save more lives, there needs to be better treatment of the sickest patients. This application uses real-world data from thousands of severely ill COVID-19 patients hospitalized in New York City to identify subgroups that may benefit from targeted interventions or medications. For example, if we were able to recognize the patient with the greatest likelihood of developing worsening disease from the time they were admitted to the hospital, the medical staff could immediately triage them to higher levels of observation. They could be recruited to participate in clinical trials designed to test drugs aimed at preventing worsening. Additionally, it appears that severely ill COVID-19 patients are more likely to develop blood clots and lung scarring. It is currently not standard practice to screen patients for blood clots or lung scarring, even though U.S. Food and Drug Administration-approved treatments exist for treating these conditions. We surmise that identifying blood clots or lung fibrosis in COVID survivors will lead to optimization of targeted treatments that will improve their long-term lung health and physical function.

Applicability of the Research: Initial reports of COVID-19 described clusters of patients with respiratory compromise, which often progressed to respiratory failure. Other organs, beside the lung, were less involved. Patients admitted to the intensive care unit (ICU) and those needing ventilator or extracorporeal membrane oxygenation (ECMO) are more likely to die, with their death related to ARDS. Based on current reports and our experience in the management of severely ill COVID-19 patients, we find that there are pertinent differences between these patients and 'usual' ARDS. These differences may lead to different treatments for certain patients, both during the acute phase of their illness and after discharge from the hospital. Thus, this study focuses on identifying subgroups of patients in order to speed treatment, improve survival, and preserve physical function.

Impact of Research: Accurate diagnosis of severe COVID-19 subphenotypes will provide short-term benefits of improving clinical care during hospitalization and the immediate convalescent period. Long-term benefits of this study may include identification of better biomarkers of severe disease, deeper understanding of risk factors for severe illness, and improved treatment strategies during hospitalization and after discharge. This proposal focuses on characterizing severe COVID-19 to identify subclassifications of patients that will allow for improved methods of treatment to mitigate death and disability. Thus, the proposed research is relevant to active duty Service Members, Veterans, military beneficiaries, and the American public.

Relevance of the Project to FY20 PRMRP Topic Areas of Emerging Viral Diseases and/or Respiratory Health: The project addresses two of the focus areas: (1) Research to understand novel molecular and biological mechanisms of COVID-19 health impacts and identification/validation of biochemical, physiological, or combined biomarkers for evaluating short- and long-term health impacts from COVID-19 and (2) Development of improved methods for assessing and treating lung injury due to coronaviruses, particularly COVID-19.