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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

See all articles by Julian A. Villalba

Julian A. Villalba

Massachusetts General Hospital - Department of Pathology; Harvard Medical School - Department of Pathology

Caroline F. Hilburn

Harvard University - Massachusetts General Hospital

Michelle A. Garlin

Harvard University - Massachusetts General Hospital

Grant A. Elliot

Unboxed Systems LLC.

Yijia Li

Harvard University - Harvard Medical School; University of Pittsburgh - Division of Infectious Diseases

Emilio Madrigal

Harvard University - Massachusetts General Hospital

Manuel Taso

Harvard University - Beth Israel Deaconess Medical Center

Keiko Kunitoki

Harvard University - Massachusetts General Hospital

Alexis J. Aviles

Harvard University - Massachusetts General Hospital

Milagros P. Araujo-Medina

Harvard University - Massachusetts General Hospital

Liana Bonnano

Harvard University - Massachusetts General Hospital

Baris Boyraz

Harvard University - Massachusetts General Hospital

Samantha N. Champion

Harvard University - Massachusetts General Hospital

Cynthia K. Harris

Harvard University - Massachusetts General Hospital

T. Leif Helland

Harvard University - Massachusetts General Hospital

Bailey Hutchison

Harvard University - Massachusetts General Hospital

Soma Jobbagy

Harvard University - Massachusetts General Hospital

Michael S. Marshall

Harvard University - Massachusetts General Hospital

Daniel S. Shepherd

Harvard University - Massachusetts General Hospital

Jaimie L. Barth

Harvard University - Massachusetts General Hospital

Yin P. Hung

Harvard University - Massachusetts General Hospital

Amy Ly

Harvard University - Massachusetts General Hospital

Lida P. Hariri

Harvard University - Massachusetts General Hospital

Sarah E. Turbett

Harvard University - Massachusetts General Hospital

Virginia M. Pierce

Harvard University - Massachusetts General Hospital

Ivan O. Rosas

Baylor College of Medicine

Lindsey Baden

Harvard University - Brigham and Women’s Hospital; Harvard University - Department of Medicine

John A. Branda

Harvard University - Clinical Microbiology Laboratory; Harvard University - Harvard Medical School

Eric S. Rosenberg

Harvard University - Massachusetts General Hospital

Miles A. Miller

Harvard University - Massachusetts General Hospital

Javier E. Mendez-Pena

Harvard University - Massachusetts General Hospital

Ivan Chebib

Harvard University - Massachusetts General Hospital

Ivy A. Rosales

Harvard University - Massachusetts General Hospital

Rex N. Smith

Harvard University - Massachusetts General Hospital

Robert B. Colvin

Harvard University - Massachusetts General Hospital

Brent P. Little

Harvard University - Massachusetts General Hospital

James R. Stone

Harvard University - Massachusetts General Hospital

Mari Mino-Kenudson

Massachusetts General Hospital - James Homer Wright Pathology Laboratories; Harvard University - Department of Pathology

Angela R. Shih

Harvard University - Massachusetts General Hospital

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).

Suggested Citation

Villalba, Julian A. and Hilburn, Caroline F. and Garlin, Michelle A. and Elliot, Grant A. and Li, Yijia and Madrigal, Emilio and Taso, Manuel and Kunitoki, Keiko and Aviles, Alexis J. and Araujo-Medina, Milagros P. and Bonnano, Liana and Boyraz, Baris and Champion, Samantha N. and Harris, Cynthia K. and Helland, T. Leif and Hutchison, Bailey and Jobbagy, Soma and Marshall, Michael S. and Shepherd, Daniel S. and Barth, Jaimie L. and Hung, Yin P. and Ly, Amy and Hariri, Lida P. and Turbett, Sarah E. and Pierce, Virginia M. and Rosas, Ivan O. and Baden, Lindsey and Branda, John A. and Rosenberg, Eric S. and Miller, Miles A. and Mendez-Pena, Javier E. and Chebib, Ivan and Rosales, Ivy A. and Smith, Rex N. and Colvin, Robert B. and Little, Brent P. and Stone, James R. and Mino-Kenudson, Mari and Shih, Angela R., Fatal COVID-19 is Characterized by Distinct Vasculopathic Features and Increased Congestion of the Alveolar Capillary-Bed. Available at SSRN: https://ssrn.com/abstract=3871725 or http://dx.doi.org/10.2139/ssrn.3871725

Julian A. Villalba

Massachusetts General Hospital - Department of Pathology

55 Fruit St, GRJ-5-514B
Boston, MA 02114
United States
(617)-643-4393 (Phone)
(617)-726-5957 (Fax)

Harvard Medical School - Department of Pathology

55 Fruit St, GRJ-5-514B
Boston, MA 02114
United States
(617)-643-4393 (Phone)
(617)-726-5957 (Fax)

Caroline F. Hilburn

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Michelle A. Garlin

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Grant A. Elliot

Unboxed Systems LLC. ( email )

Boston, MA
United States

Yijia Li

Harvard University - Harvard Medical School ( email )

25 Shattuck St
Boston, MA 02115
United States

University of Pittsburgh - Division of Infectious Diseases ( email )

Emilio Madrigal

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Manuel Taso

Harvard University - Beth Israel Deaconess Medical Center ( email )

330 Brookline Avenue
Boston, MA 02115
United States

Keiko Kunitoki

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Alexis J. Aviles

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Milagros P. Araujo-Medina

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Liana Bonnano

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Baris Boyraz

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Samantha N. Champion

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Cynthia K. Harris

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

T. Leif Helland

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Bailey Hutchison

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Soma Jobbagy

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Michael S. Marshall

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Daniel S. Shepherd

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Jaimie L. Barth

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Yin P. Hung

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Amy Ly

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Lida P. Hariri

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Sarah E. Turbett

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Virginia M. Pierce

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Ivan O. Rosas

Baylor College of Medicine ( email )

Lindsey Baden

Harvard University - Brigham and Women’s Hospital ( email )

Harvard University - Department of Medicine ( email )

Boston, MA 02115
United States

John A. Branda

Harvard University - Clinical Microbiology Laboratory ( email )

Boston, MA
United States

Harvard University - Harvard Medical School ( email )

25 Shattuck St
Boston, MA 02115
United States

Eric S. Rosenberg

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Miles A. Miller

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Javier E. Mendez-Pena

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Ivan Chebib

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Ivy A. Rosales

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Rex N. Smith

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Robert B. Colvin

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Brent P. Little

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

James R. Stone

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States

Mari Mino-Kenudson (Contact Author)

Massachusetts General Hospital - James Homer Wright Pathology Laboratories ( email )

55 Fruit St, Warren 122
Boston, MA 02114
United States
(617)-726-8026 (Phone)
(617)-726-7474 (Fax)

Harvard University - Department of Pathology

Boston, MA
United States

Angela R. Shih

Harvard University - Massachusetts General Hospital ( email )

55 Fruit Street Boston
Boston, MA 02114
United States