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

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 PARTICIPANTSThis 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 RELEVANCEIn 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. Det...

Acute Myocardial Injury and Rhabdomyolysis in COVID-19 Patients: Incidence and Mortality

“…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 post-infectious, immune-mediated myopathy [13]. There may be various direct and indirect mechanisms of acute myocardial injury in COVID-19 including ischemic injury, hypoxic injury (MI type 2), direct viral myocarditis, stress cardiomyopathy and systemic cytokine storm.…”

Myopathy in acute and long-term COVID-19

“…In a recent study, Agergaard and colleagues showed that in patients with long-term muscular complains or fatigue after mild or moderate SARS-CoV-2 infection, myopathy was a common finding ( Agergaard et al, 2021 ). Their study could not provide definite evidence for a causal link between acute infection and long-term myalgia, fatigue and myopathy but it supports the findings from the two recent autopsy studies ( Aschman et al, 2021 , Suh et al, 2021 ).…”

“…Two recent studies investigated skeletal muscle in autopsy specimens from patients with COVID-19 ( Aschman et al, 2021 , Suh et al, 2021 ). Aschman and colleagues showed signs of muscle inflammation, ranging from mild to severe inflammatory myopathy in 60% of the patients who died with severe COVID-19, and the inflammation was more pronounced in skeletal muscle compared to cardiac muscle.…”

Post-COVID symptoms of potential peripheral nervous and muscular origin

“…Twenty-three patients (55%) presented overexpression of MHC-I antigens, and seven (17%) presented MHC-II overexpression; neither of these findings were observed in the autopsies performed in any of the 11 controls. 22 …”

“…Therefore, it is possible that in patients with acute and severe forms of COVID-19, muscle involvement may be explained by an exaggerated immune response (e.g., type 1 interferon overexpression or cytokine storm), or immune-mediated. 21 , 22 However, further research is needed to clarify the precise pathophysiology of the signs and symptoms suggestive of muscle damage in patients with PACS.…”