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Association Between SARS-CoV-2 Infection and Immune-Mediated Myopathy in Patients Who Have Died

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Key Points

Question  Is there a COVID-19–associated myopathy, and is it a viral or postviral phenomenon?

Findings  In this case-control autopsy study, 26 of 43 individuals (60%) who had died with a diagnosis of COVID-19 showed signs of muscle inflammation, ranging from mild to severe inflammatory myopathy. Inflammation was more pronounced in patients who were chronically ill and those who had seroconverted to SARS-CoV-2 than those who died after acute or subacute courses of COVID-19 and those who died of other illnesses, and no evidence was found for a direct infection of muscle tissue.

Meaning  In this study, SARS-CoV-2 was associated with an immune-mediated myopathy.

Abstract

Importance  Myalgia, increased levels of creatine kinase, and persistent muscle weakness have been reported in patients with COVID-19.

Objective  To study skeletal muscle and myocardial inflammation in patients with COVID-19 who had died.

Design, Setting, and Participants  This case-control autopsy series was conducted in a university hospital as a multidisciplinary postmortem investigation. Patients with COVID-19 or other critical illnesses who had died between March 2020 and February 2021 and on whom an autopsy was performed were included. Individuals for whom informed consent to autopsy was available and the postmortem interval was less than 6 days were randomly selected. Individuals who were infected with SARS-CoV-2 per polymerase chain reaction test results and had clinical features suggestive of COVID-19 were compared with individuals with negative SARS-CoV-2 polymerase chain reaction test results and an absence of clinical features suggestive of COVID-19.

Main Outcomes and Measures  Inflammation of skeletal muscle tissue was assessed by quantification of immune cell infiltrates, expression of major histocompatibility complex (MHC) class I and class II antigens on the sarcolemma, and a blinded evaluation on a visual analog scale ranging from absence of pathology to the most pronounced pathology. Inflammation of cardiac muscles was assessed by quantification of immune cell infiltrates.

Results  Forty-three patients with COVID-19 (median [interquartile range] age, 72 [16] years; 31 men [72%]) and 11 patients with diseases other than COVID-19 (median [interquartile range] age, 71 [5] years; 7 men [64%]) were included. Skeletal muscle samples from the patients who died with COVID-19 showed a higher overall pathology score (mean [SD], 3.4 [1.8] vs 1.5 [1.0]; 95% CI, 0-3; P < .001) and a higher inflammation score (mean [SD], 3.5 [2.1] vs 1.0 [0.6]; 95% CI, 0-4; P < .001). Relevant expression of MHC class I antigens on the sarcolemma was present in 23 of 42 specimens from patients with COVID-19 (55%) and upregulation of MHC class II antigens in 7 of 42 specimens from patients with COVID-19 (17%), but neither were found in any of the controls. Increased numbers of natural killer cells (median [interquartile range], 8 [8] vs 3 [4] cells per 10 high-power fields; 95% CI, 1-10 cells per 10 high-power fields; P < .001) were found. Skeletal muscles showed more inflammatory features than cardiac muscles, and inflammation was most pronounced in patients with COVID-19 with chronic courses. In some muscle specimens, SARS-CoV-2 RNA was detected by reverse transcription–polymerase chain reaction, but no evidence for a direct viral infection of myofibers was found by immunohistochemistry and electron microscopy.

Conclusions and Relevance  In this case-control study of patients who had died with and without COVID-19, most individuals with severe COVID-19 showed signs of myositis ranging from mild to severe. Inflammation of skeletal muscles was associated with the duration of illness and was more pronounced than cardiac inflammation. Detection of viral load was low or negative in most skeletal and cardiac muscles and probably attributable to circulating viral RNA rather than genuine infection of myocytes. This suggests that SARS-CoV-2 may be associated with a postinfectious, immune-mediated myopathy.

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Article Information

Accepted for Publication: May 9, 2021.

Published Online: June 11, 2021. doi:10.1001/jamaneurol.2021.2004

Corresponding Authors: Tom Aschman, MD (tom.aschman@charite.de), and Werner Stenzel, MD (werner.stenzel@charite.de), Department of Neuropathology, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany.

Correction: This article was corrected on August 12, 2021, to fix an error in Figure 1.

Author Contributions: Drs Stenzel and Aschman 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.

Concept and design: Aschman, Heppner, Stenzel.

Acquisition, analysis, or interpretation of data: Aschman, Schneider, Greuel, Meinhardt, Streit, Goebel, Büttnerova, Elezkurtaj, Scheibe, Radke, Meisel, Drosten, Radbruch, Corman, Stenzel.

Drafting of the manuscript: Aschman, Stenzel.

Critical revision of the manuscript for important intellectual content: Schneider, Greuel, Meinhardt, Streit, Goebel, Büttnerova, Elezkurtaj, Scheibe, Radke, Drosten, Radbruch, Heppner, Corman, Stenzel.

Statistical analysis: Aschman.

Obtained funding: Drosten, Corman.

Administrative, technical, or material support: Schneider, Greuel, Meinhardt, Streit, Büttnerova, Elezkurtaj, Scheibe, Radke, Drosten, Radbruch, Heppner, Corman, Meisel, Stenzel.

Supervision: Goebel, Radke, Heppner, Corman, Stenzel.

Conflict of Interest Disclosures: Dr Corman reported grants from the German Ministry of Health, German Federal Ministry of Education and Research, and European Union's Horizon 2020 research during the conduct of the study; in addition, Dr Corman is named together with Euroimmun on a patent application filed recently regarding the diagnostic of SARS-CoV-2 by antibody testing. Dr Drosten reported grants from Horizon 2020 (RECOVER; grant GA101003589), the German Ministry of Health, and the German Federal Ministry of Education and Research (NaFoUniMedCovid19-PROVID, grant FKZ:01KX2021) during the conduct of the study. Dr Radbruch reported grants from the German Research Foundation (grant CRC 130 TP17) and the German Federal Ministry of Education and Research (Organostrat/Defeat Pandemics Netzwerk Universitätsmedizin) during the conduct of the study; and grants from Sanofi Foundation and Novartis Foundation and personal fees from Novartis and Sanofi outside the submitted work. Dr Heppner reported grants from the German Federal Ministry of Education and Research during the conduct of the study. No other disclosures were reported.

Funding/Support: The virological part of this work was funded by European Union's Horizon 2020 research and innovation program through RECOVER (grant GA101003589 [Dr Drosten]), the German Ministry of Health (Konsiliarlabor für Coronaviren and SeCoV [Drs Drosten and Corman]), and the German Federal Ministry of Education and Research (NaFoUniMedCovid19-PROVID; grant FKZ:01KX2021 [Drs Drosten and Corman]) and project VARIPath (grant 01KI2021 [Dr Corman]).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Francisca Egelhofer, Petra Matylewski, Cordula zum Bruch, Silvia Stefaniak, Department of Neuropathology, Charité Universitätsmedizin, and Anistan Sebastiampillai, Department of Pathology, Charité Universitätsmedizin, for their excellent technical assistance. They were not compensated for their contributions.

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