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Figure.  Macroscopic and Microscopic Findings in the Lung
Macroscopic and Microscopic Findings in the Lung

Macroscopic (A and B) and histologic (C) images of organizing and end-stage diffuse alveolar damage (hematoxylin-eosin staining) with hyaline membranes (D, arrowheads, ×100), multinucleated giant cells (E, arrowheads, ×400), and squamous/osseous metaplasia (F and G, arrowheads, ×200) in a patient with a fatal course of coronavirus disease 2019.

Table.  Clinical Characteristics and Lung Pathology
Clinical Characteristics and Lung Pathology
1.
Huang  C, Wang  Y, Li  X,  et al.  Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.   Lancet. 2020;395(10223):497-506. doi:10.1016/S0140-6736(20)30183-5PubMedGoogle ScholarCrossref
2.
Wang  D, Hu  B, Hu  C,  et al.  Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.   JAMA. Published online February 7, 2020. doi:10.1001/jama.2020.1585PubMedGoogle Scholar
3.
Hanley  B, Lucas  SB, Youd  E, Swift  B, Osborn  M.  Autopsy in suspected COVID-19 cases.   J Clin Pathol. 2020;73(5):239-242. doi:10.1136/jclinpath-2020-206522PubMedGoogle ScholarCrossref
4.
Gu  J, Korteweg  C.  Pathology and pathogenesis of severe acute respiratory syndrome.   Am J Pathol. 2007;170(4):1136-1147. doi:10.2353/ajpath.2007.061088PubMedGoogle ScholarCrossref
5.
van den Brand  JM, Smits  SL, Haagmans  BL.  Pathogenesis of Middle East respiratory syndrome coronavirus.   J Pathol. 2015;235(2):175-184. doi:10.1002/path.4458PubMedGoogle ScholarCrossref
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    7 Comments for this article
    EXPAND ALL
    Viral PCR in Pleural Fluid
    Anand Sundaralingam, MBBS, BSc, MRCP | Oxford University Hospitals
    Could the authors comment further on what proportion of the patients were found to be viral PCR positive in pleural fluid? Though pleural effusion appears to not be a prominent respiratory manifestation of Covid-19, the presence of viral PCR in pleural fluid may well represent a hazard to clinicians performing pleural procedures and may need to guide infection control policies.
    CONFLICT OF INTEREST: None Reported
    COVID-19 Post-Mortem Findings
    Arturo Tozzi, Pediatrician | University of Noth Texas
    In this intriguing paper, the Authors report acute and organizing diffuse alveolar damage as the predominant histopathologic finding in postmortem evaluation of 10 patients with COVID-19.  These data run counter to the not yet reviewed series of 38 cases described by Carsana et al. on MedRxiv (https://doi.org/10.1101/2020.04.19.20054262), who emphasize how the main relevant finding in COVID-19 deceased patients is the presence of platelet-fibrin thrombi in small arterial vessels.

    Arturo Tozzi
    Center for Nonlinear Science, University of North Texas, Denton, Texas, USA
    tozziarturo@libero.it
    Arturo.Tozzi@unt.edu

    Carlo Venditti
    Rheumatology
    Ospedale Rummo, Benevento, Italy
    carlo.venditti@alice.it
    CONFLICT OF INTEREST: None Reported
    Re: Viral PCR in Pleural Fluid
    Rainer Claus, MD | Hematology and Oncology, Medical Faculty, University of Augsburg, Germany
    Thank you for your interesting and relevant comment. In the meantime, we have extended our cohort to 19 patients. Of those, 10 patients had clinically relevant pleural effusion and 5 patients were indeed found to be positive for SARS-CoV-2 by RT-PCR in the pleural fluid. Thus, pleural procedures might possibly be associated with an increased risk of infection.
    CONFLICT OF INTEREST: None Reported
    Thanks!
    Daniel Goyal, MRCP, PhD | Gibraltar Health Authority
    The lack of autopsies in this new infection has been somewhat frustrating. These findings are very welcomed. And thanks for the concise descriptions. Emboli not seen! Not sure viral load was checked - which would be useful. And should we be reconsidering steroids?
    CONFLICT OF INTEREST: None Reported
    Postmortem examination on COVID-19, virus existance and note for preventive practice
    Viroj Wiwanitkit, MD | Dr DY Patil University, Pune, India
    The results from this report by Schaller on postmortem examination of patients with COVID-19 [1] hints at the possibility that SARS-CoV-2 might still exist in body after death, which could account for some unexplained deaths. Safety in postmortem examinations is an important clinical issue to be kept in mind for all practitioners [2 - 3]; it is unclear if we have sufficient protective practices at present.

    References
    1. Schaller T, Hirschbühl K, Burkhardt K, et al Georg Postmortem Examination of Patients With COVID-19. JAMA. Published online May 21, 2020. doi:10.1001/jama.2020.8907
    2. Sriwijitalai W, Wiwanikit V. Corrigendum
    to "COVID-19 in Forensic Medicine Unit Personnel: Observation From Thailand" [J Forensic Legal Med 72 May 2020, 101964]
    J Forensic Leg Med . 2020 May;72:101967. doi: 10.1016/j.jflm.2020.101967.
    3. Sriwijitalai W, Wiwanikit V. COVID-19 in Forensic Medicine Unit Personnel: Observation From Thailand. J Forensic Leg Med. 2020 May;72:101964. doi: 10.1016/j.jflm.2020.101964
    CONFLICT OF INTEREST: No declared COIs
    READ MORE
    Why No Testing of GI Specimens?
    Giovanni Ghirga, Pediatrician, Italy |
    Xiao showed that ACE2 protein, which has been proven to be a cell receptor for SARS-CoV-2, is abundantly expressed in the glandular cells of gastric, duodenal, and rectal epithelia, supporting the entry of SARS-CoV-2 into the host cells (1). Furthermore, in more than 20% of patients with SARS-CoV-2, it was observed that the test result for viral RNA remained positive in feces, even after test results for viral RNA in the respiratory tract converted to negative, indicating that the viral gastrointestinal infection and potential fecal-oral transmission can last even after viral clearance in the respiratory tract (1).

    In this
    paper specimens from lung, heart, liver, spleen, kidney, brain, pleural effusion, and cerebrospinal fluid (CSF) were assessed and we hoped specimens from gastric and intestinal epithelia would have been assessed.

    References

    1) Hiao F, et al. Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology. May 2020. Volume 158, Issue 6, Pages 1831–1833.e3
    Giovanni Ghirga, Pediatrician, Italy
    CONFLICT OF INTEREST: None Reported
    READ MORE
    No Thromboembolic Events
    Vedat Aslan, MD | Antalya Education and Research Hospital
    No thrombosis in autopsy. So why are d-dimer levels so high in Covid-19 patients?

    I think fibrosis is the cause. In primary idıopathic pulmonary fibrosis (IPF) patients, D-dimer elevation is an important sign of prognosis. In Covid-19 patients, after extravasation of plasma into the interstitial space (capillary leak), fibrinogen in plasma interacts with fibronectin to cause fibrosis. Tissue plasminogen also starts to degrade this fibrosis and then D-dimer levels start to elevate. Autopsy findings also show this.
    Thrombosis can be the very late complication of Covid-19.
    CONFLICT OF INTEREST: None Reported
    Views 155,276
    Citations 0
    Research Letter
    May 21, 2020

    Postmortem Examination of Patients With COVID-19

    Author Affiliations
    • 1Institute of Pathology and Molecular Diagnostics, University Medical Center Augsburg, Augsburg, Germany
    • 2Department of Hematology and Clinical Oncology, University Medical Center Augsburg, Augsburg, Germany
    • 3Institute of Laboratory Medicine and Microbiology, University Medical Center Augsburg, Augsburg, Germany
    • 4Department of Gastroenterology, University Medical Center Augsburg, Augsburg, Germany
    JAMA. Published online May 21, 2020. doi:10.1001/jama.2020.8907

    Approximately 15% of individuals affected by coronavirus disease 2019 (COVID-19) develop severe disease, and 5% to 6% are critically ill (respiratory failure and/or multiple organ dysfunction or failure).1,2 Severely ill and critically ill patients have a high mortality rate, especially with older age and coexisting medical conditions. Because there are still insufficient data on cause of death, we describe postmortem examinations in a case series of patients with COVID-19.

    Methods

    Between April 4 and April 19, 2020, we conducted serial postmortem examinations in patients with proven severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who died at the University Medical Center Augsburg (Germany). Autopsies were conducted according to published best practice.3 Specimens from lung, heart, liver, spleen, kidney, brain, pleural effusion, and cerebrospinal fluid (CSF) were assessed. Postmortem nasopharyngeal, tracheal, bronchial swabs, pleural effusion, and CSF were tested for SARS-CoV-2 by reverse transcriptase–polymerase chain reaction. This study was approved by the local institutional review board, and written informed consent was obtained from next of kin.

    Results

    Of 12 consecutive patients with COVID-19 who died, postmortem examinations were conducted in 10. The median age was 79 years (range, 64-90 years); 7 patients were male. All cases tested positive for SARS-CoV-2 by nasopharyngeal swab at time of hospital admission. The median duration from admission to death was 7.5 days (range, 1-26 days). The most frequent initial symptoms included fever, cough, and dyspnea. In 9 patients, infiltrations with ground-glass opacity predominantly in middle and lower lung fields were detected by chest x-ray. Patients had a median of 4 known preexisting comorbidities (range, 0-6), with cardiovascular disease being most frequent (Table). Preexisting structural lung damage (eg, emphysema) was found in 2 patients. None of the patients had thromboembolic events in central vessels at autopsy or prior to death.

    In all cases, including 6 patients who did not receive invasive ventilation, disseminated diffuse alveolar damage at different stages (the histopathological correlate of acute respiratory distress syndrome) was the major histologic finding. Diffuse alveolar damage was detectable in all lobes but appeared unevenly distributed with pronounced manifestation in middle and lower lung fields (Figure, A-B). Signs of exudative early-phase acute diffuse alveolar damage with hyaline membrane formation, intra-alveolar edema, and thickened alveolar septa with perivascular lymphocyte-plasmocytic infiltration were consistently found. Organizing-stage diffuse alveolar damage with pronounced fibroblastic proliferation, partial fibrosis, pneumocyte hyperplasia leading to interstitial thickening and collapsed alveoles, and patchy lymphocyte infiltration was the predominant finding. In areas of organizing diffuse alveolar damage, reactive osseous and squamous metaplasia were observed (Figure, C-G). Fully established fibrosis was most prominent in patient 1, ultimately leading to almost complete destruction of pulmonary parenchyma. In 5 patients, minor neutrophil infiltration was indicative of secondary infection and/or aspiration.

    Mild lymphocytic myocarditis and signs of epicarditis were detectable in 4 and 2 cases, respectively. Liver histology showed minimal periportal lymphoplasmacellular infiltration and signs of fibrosis. There was no morphologically detectable pathology in other organs. Specifically, no signs of encephalitis or central nervous system vasculitis were found.

    At time of autopsy, SARS-CoV-2 was still detectable in the respiratory tracts of all patients. Polymerase chain reaction testing was positive in pleural effusion but negative in all CSF samples.

    Discussion

    In this postmortem evaluation of 10 patients with COVID-19, acute and organizing diffuse alveolar damage and SARS-CoV-2 persistence in the respiratory tract were the predominant histopathologic findings and constituted the leading cause of death in patients with and without invasive ventilation. Periportal liver lymphocyte infiltration was considered unspecific inflammation. Whether myoepicardial alterations represented systemic inflammation or early myocarditis is unclear; criteria for true myocarditis were not met. Central nervous system involvement by COVID-19 could not be detected.

    This study has limitations, including the small number of cases from a single center and missing proof of direct viral organ infection.

    The pulmonary histologic characteristics of COVID-19 resembled those observed in diseases caused by other Betacoronavirus infections such as severe acute respiratory syndrome4 and Middle East respiratory syndrome.5

    Section Editor: Jody W. Zylke, MD, Deputy Editor.
    Back to top
    Article Information

    Accepted for Publication: May 11, 2020.

    Corresponding Author: Rainer Claus, MD, Department of Hematology and Clinical Oncology, University Medical Center Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany (rainer.claus@uk-augsburg.de).

    Published Online: May 21, 2020. doi:10.1001/jama.2020.8907

    Author Contributions: Drs Schaller and Claus had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Schaller and Hirschbühl contributed equally as first authors. Drs Märkl and Claus contributed equally as senior authors.

    Concept and design: Schaller, Hirschbühl, Braun, Trepel, Märkl, Claus.

    Acquisition, analysis, or interpretation of data: Schaller, Hirschbühl, Burkhardt, Märkl, Claus.

    Drafting of the manuscript: Schaller, Hirschbühl, Braun, Trepel, Märkl, Claus.

    Critical revision of the manuscript for important intellectual content: Schaller, Hirschbühl, Burkhardt, Trepel, Märkl, Claus.

    Statistical analysis: Claus.

    Obtained funding: Braun.

    Administrative, technical, or material support: Schaller, Hirschbühl, Burkhardt, Trepel, Märkl.

    Supervision: Claus.

    Conflict of Interest Disclosures: None reported.

    Additional Contributions: We thank the physicians from the intensive care unit (Michael Wittmann, MD, and Ulrich Jaschinski, MD), and the Department of Radiology (Thomas Kröncke, MD) of the University Medical Center Augsburg. We thank Jürgen Schlegel, MD, from the Department of Neuropathology, School of Medicine, Institute of Pathology, Technical University Munich, for sampling brain tissue. Technical support was provided by Alexandra Martin, AMLT, Christian Beul, AMLT, and Elfriede Schwarz, AMLT, from the Institute of Pathology and Molecular Diagnostics, University Medical Center Augsburg. No compensation was received for their roles in the study.

    References
    1.
    Huang  C, Wang  Y, Li  X,  et al.  Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.   Lancet. 2020;395(10223):497-506. doi:10.1016/S0140-6736(20)30183-5PubMedGoogle ScholarCrossref
    2.
    Wang  D, Hu  B, Hu  C,  et al.  Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.   JAMA. Published online February 7, 2020. doi:10.1001/jama.2020.1585PubMedGoogle Scholar
    3.
    Hanley  B, Lucas  SB, Youd  E, Swift  B, Osborn  M.  Autopsy in suspected COVID-19 cases.   J Clin Pathol. 2020;73(5):239-242. doi:10.1136/jclinpath-2020-206522PubMedGoogle ScholarCrossref
    4.
    Gu  J, Korteweg  C.  Pathology and pathogenesis of severe acute respiratory syndrome.   Am J Pathol. 2007;170(4):1136-1147. doi:10.2353/ajpath.2007.061088PubMedGoogle ScholarCrossref
    5.
    van den Brand  JM, Smits  SL, Haagmans  BL.  Pathogenesis of Middle East respiratory syndrome coronavirus.   J Pathol. 2015;235(2):175-184. doi:10.1002/path.4458PubMedGoogle ScholarCrossref
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