Vasculopathy and Increased Vascular Congestion in Fatal COVID-19 and Acute Respiratory Distress Syndrome

Abstract

<b>Rationale:</b> 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. <b>Objective:</b> To compare lung parenchymal and vascular alterations between patients with fatal COVID-19 pneumonia and other DAD-causing etiologies using a multidimensional approach. <b>Methods:</b> This autopsy cohort consisted of consecutive patients with COVID-19 pneumonia (<i>n</i> = 20) and with respiratory failure and histologic DAD (<i>n</i> = 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 (C_Vasc) in different microscopic compartments. Respiratory mechanics and gas-exchange parameters were evaluated longitudinally in patients with ARDS. <b>Measurements and Main Results:</b> In premortem CT, patients with COVID-19 showed more dilated vasculature when all lung segments were evaluated (<i>P</i> = 0.001) compared with controls with DAD. Histopathology revealed vasculopathic changes, including hemangiomatosis-like changes (<i>P</i> = 0.043), thromboemboli (<i>P</i> = 0.0038), pulmonary infarcts (<i>P</i> = 0.047), and perivascular inflammation (<i>P</i> < 0.001). Generalized estimating equations revealed significant regional differences in the lung microarchitecture among all DAD-causing entities. COVID-19 showed a larger overall C_Vasc range (<i>P</i> = 0.002). Alveolar-septal congestion was associated with a significantly shorter time to death from symptom onset (<i>P</i> = 0.03), length of hospital stay (<i>P</i> = 0.02), and increased ventilatory ratio [an estimate for pulmonary dead space fraction (<i>V_d</i>); <i>p </i>= 0.043] in all cases of ARDS. <b>Conclusions:</b> 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 <i>V_d</i> and clinical outcomes in ARDS in general.