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Fatal COVID-19 is Characterized by Distinct Vasculopathic Features and Increased Congestion of the Alveolar Capillary-Bed
29 Pages Posted: 22 Jun 2021
More...Abstract
Background: Clinical and radiologic studies investigating Coronavirus disease 2019 (COVID-19) indicate that a possible cause of severe hypoxia is marked ventilation-perfusion (VA/Q) mismatch. Published histopathology reports diffuse alveolar damage (DAD) in fatal COVID-19 is indistinguishable from other causes of DAD. We compared lung parenchymal and vascular alterations between COVID-19 and DAD of other etiologies using a multidimensional approach.
Methods: This autopsy cohort consisted of consecutive COVID-19 patients (n=20) and patients with clinical acute respiratory distress syndrome and histologic DAD (n=21; non-COVID-19 viral and non-viral etiologies). Premortem chest CTs were evaluated for mosaic attenuation and vascular changes. Postmortem lung tissues were compared using histopathological, immunohistochemical, transcriptomics and computational analyses. Machine-learning-derived morphometric analysis of microvasculature was performed, with a random forest classifier quantifying vascular congestion (VSCong), in different microscopic compartments.
Findings: On premortem CT, COVID-19 patients showed more mosaic attenuation (p<0·020), and subsegmental dilated vasculature (p=0·003) compared to controls. Histopathology revealed vasculopathic changes including: capillary-congestion and hemangiomatosis-like changes (p=0·043), microthrombi (p=0·026), thromboemboli (p=0·0036), infarcts (p=0·048), and perivascular inflammation(p <0·001). Immunohistochemistry revealed increased CD4+ T-cells(p=0·023), TIM3+ lymphocytes/macrophages (p=0·037/0·019), and PD-1+ cells(p=0·008). Morphometric analysis in COVID-19 revealed significantly higher bronchiolar VS Cong (p <0·0001) and alveolar-septal VSCong (p<0·0001), with larger overall VSCong range (p=0·002). Septal-congestion was associated with a significantly shorter time-to-death from symptom onset (p=0·02).
Interpretation: Severe COVID-19 is characterized by significant vasculopathy and aberrant alveolar septal-congestion, which may be associated with shorter time-to-death. Dilated sublobar vessels and heterogeneously increased septal-congestion may translate to VA/Q mismatch in COVID-19. These findings warrant further investigation in larger multi-institutional autopsy cohorts.
Funding Information: Supported by Internal Sundry, and Vickery-Colvin Award from the Department of Pathology, Massachusetts General Hospital.
Declaration of Interests: LPH reports grants from Boehringer Ingelheim and has received personal consulting fees from Boehringer Ingelheim, Pliant Therapeutics, and Biogen Idec, all of which are not related to this study. SET have received CDC funding for other COVID-related work which are not related to this study. JAB has received grant support from Zeus Scientific, bioMerieux, Immunetics, the Bay Area Lyme Foundation and the Lyme Disease Biobank Foundation for work not related to this study, and has been a consultant for T2 Biosystems, DiaSorin and Roche Diagnostics, not related to this study. BPL reports royalties from Elsevier, Inc. for his work as an associate textbook editor, not related to this study. MMK has served as a compensated consultant for H3 Biomedicine and AstraZeneca and has received research (institutional) funding from Novartis and loyalty from Elsevier, all of which are not related to this study. The other authors declare no competing interests.
Ethics Approval Statement: Analysis of patient autopsy material was reviewed and approved by the Partners Human Research IRB (Protocol #: 2020P001146).
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