Vasculopathy and Increased Vascular Congestion in Fatal COVID-19 and Acute Respiratory Distress Syndrome
Julian A. Villalba, Caroline F. Hilburn, Michelle A. Garlin, Grant A. Elliott, Yijia Li, Keiko Kunitoki, Sergio Poli, George A. Alba, Emilio Madrigal, Manuel Taso, Melissa C. Price, Alexis J. Aviles, Milagros Araujo-Medina, Liana Bonanno, Bariş Boyraz, Samantha N. Champion, Cynthia K. Harris, T. Leif Helland, Bailey Hutchison, Soma Jobbagy, Michael S. Marshall, Daniel Shepherd, Jaimie L. Barth, Yin P. Hung, Amy Ly, Lida P. Hariri, Sarah E. Turbett, Virginia Pierce, John A. Branda, Eric Rosenberg, Javier E. Mendez-Pena, Ivan Chebib, Ivy A. Rosales, R. Neal Smith, Miles A. Miller, Iván O. Rosas, C. Corey Hardin, Lindsey R. Baden, Benjamin D. Medoff, Robert B. Colvin, Brent P. Little, James R. Stone, Mari Mino–Kenudson, Angela Shih
Abstract
Abstract Rationale The leading cause of death in coronavirus disease 2019 (COVID-19) is severe pneumonia, with many patients developing acute respiratory distress syndrome (ARDS) and diffuse alveolar damage (DAD). Whether DAD in fatal COVID-19 is distinct from other causes of DAD remains unknown. Objective To compare lung parenchymal and vascular alterations between patients with fatal COVID-19 pneumonia and other DAD-causing etiologies using a multidimensional approach. Methods This autopsy cohort consisted of consecutive patients with COVID-19 pneumonia (n = 20) and with respiratory failure and histologic DAD (n = 21; non–COVID-19 viral and nonviral etiologies). Premortem chest computed tomography (CT) scans were evaluated for vascular changes. Postmortem lung tissues were compared using histopathological and computational analyses. Machine-learning-derived morphometric analysis of the microvasculature was performed, with a random forest classifier quantifying vascular congestion (CVasc) in different microscopic compartments. Respiratory mechanics and gas-exchange parameters were evaluated longitudinally in patients with ARDS. Measurements and Main Results In premortem CT, patients with COVID-19 showed more dilated vasculature when all lung segments were evaluated (P = 0.001) compared with controls with DAD. Histopathology revealed vasculopathic changes, including hemangiomatosis-like changes (P = 0.043), thromboemboli (P = 0.0038), pulmonary infarcts (P = 0.047), and perivascular inflammation (P < 0.001). Generalized estimating equations revealed significant regional differences in the lung microarchitecture among all DAD-causing entities. COVID-19 showed a larger overall CVasc range (P = 0.002). Alveolar-septal congestion was associated with a significantly shorter time to death from symptom onset (P = 0.03), length of hospital stay (P = 0.02), and increased ventilatory ratio [an estimate for pulmonary dead space fraction (Vd); p = 0.043] in all cases of ARDS. Conclusions Severe COVID-19 pneumonia is characterized by significant vasculopathy and aberrant alveolar-septal congestion. Our findings also highlight the role that vascular alterations may play in Vd and clinical outcomes in ARDS in general.