Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19<br /><br /> Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the disease, relatively little is known about the associated morphologic and molecular changes in the peripheral lung of patients who die from Covid-19.<br /> Seven lungs are obtained during autopsy from patients who died from Covid-19 and compared them with seven lungs obtained during autopsy from patients who died from acute respiratory distress syndrome (ARDS) secondary to influenza A(H1N1) infection and 10 age-matched, uninfected control lungs. The lungs were studied with the use of seven-color immunohistochemical analysis, micro–computed tomographic imaging, scanning electron microscopy, corrosion casting, and direct multiplexed measurement of gene expression.<br />RESULTS<br /> In patients who died from Covid-19–associated or influenza-associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar damage with perivascular T-cell infiltration. The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels in patients with Covid-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (P<0.001). In lungs from patients with Covid-19, the amount of new vessel growth — predominantly through a mechanism of intussusceptive angiogenesis — was 2.7 times as high as that in the lungs from patients with influenza (P<0.001).<br />CONCLUSIONS<br /> Vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection. The universality and clinical implications of our observations require further research to define. (Funded by the National Institutes of Health and others.)<br /> Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans is associated with a broad spectrum of clinical respiratory syndromes, ranging from mild upper airway symptoms to progressive life-threatening viral pneumonia. Clinically, patients with severe coronavirus disease 2019 (Covid-19) have labored breathing and progressive hypoxemia and often receive mechanical ventilatory support. Radiographically, peripheral lung ground-glass opacities on computed tomographic (CT) imaging of the chest fulfill the Berlin criteria for acute respiratory distress syndrome (ARDS). <br /> Histologically, the hallmark of the early phase of ARDS is diffuse alveolar damage with edema, hemorrhage, and intra alveolar fibrin deposition.<br /> Diffuse alveolar damage is a nonspecific finding, since it may have noninfectious or infectious causes, including Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV, SARS-CoV-2, and influenza viruses. <br /> Among the distinctive features of Covid-19 are the vascular changes associated with the disease. With respect to diffuse alveolar damage in SARS-CoV7 and SARS-CoV-2 infection, the formation of fibrin thrombi has been observed anecdotally but not studied systematically. Clinically, many patients have elevated D-dimer levels, as well as cutaneous changes in their extremities suggesting thrombotic microangiopathy.<br /> Diffuse intravascular coagulation and large-vessel thrombosis have been linked to multisystem organ failure. Peripheral pulmonary vascular changes are less well characterized; however, vasculopathy in the gas-exchange networks, depending on its effect on the matching of ventilation and perfusion that results, could potentially contribute to hypoxemia and the effects of posture (e.g., prone positioning) on oxygenation. <br /> Despite previous experience with SARS-CoV18 and early experience with SARS-CoV-2, the morphologic and molecular changes associated with these infections in the peripheral lung are not well documented. <br />