Sars-Cov-2 Associated Myopathy

An association between SARS-CoV-2 infection and myopathy was suspected early in the pandemic: patients with severe COVID-19 showed increased levels of creatine kinase that could not be solely explained by cardiac affection. On the other hand, myalgia and muscle weakness are frequent symptoms in patients with mild or moderate COVID-19 - as with many other viral infections -and subsets of infected patients report persistent muscular weakness and fatigue even months after the initial infection. We performed a case-control autopsy comparing patients with severe COVID-19 to patients with other critical illnesses and assessed inflammation of skeletal muscle tissue by quantification of immune cell infiltrates, expression of major histocompatibility complex (MHC) class I and class II antigens on the sarcolemma. 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. In a subset of patients, MHC class I and MHC class II expression showed a clear perifascicular pattern. Signs of degenerating and necrotic fibers could also be found, however there was no statistically significant difference in the frequency of occurrence when compared to non-COVID-19 critically ill patients. We interpreted this as non-specific signs of muscular damage in critically ill patients. Numbers of macrophages, lymphocytes and natural killer cells were found to be increased in muscles from patients with COVID-19. Interestingly, no relevant expression of MxA on myofibers could be found by immunohistochemistry, but in some cases, expression of MxA was found on capillaries. Ultrastructural analysis of selected muscles with perifascicular MHC-expression did not show tubuloreticular inclusions. However, capillaries of the analyzed samples showed basement membrane alterations and signs of ongoing regenerative processes. In addition, we evaluated inflammation of cardiac muscles by quantification of immune cell infiltrates in the same patients, and found that skeletal muscles showed more inflammatory features than cardiac muscles. Moreover, 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 or electron microscopy. This suggests that SARS-CoV-2 may be associated with a postinfectious, immune-mediated myopathy.

Olfactory transmucosal SARSCoV-2 invasion as port of central nervous system entry in COVID-19

Introduction: Coronavirus disease 2019 (COVID-19) is a pandemic respiratory disease which is accompanied by a broad spectrum of neurological manifestations in more than one-third of COVID-19 cases. For the latter, olfactory and gustatory disturbances such as anosmia and ageusia, are often leading symptoms of SARS-CoV-2 infection. Given the close proximity of neuronal and supporting cells the olfactory mucosa as a neural-mucosal interface may represent a potential port of CNS entry for SARS-CoV-2. Objectives: Identifying potential sites of SARS-COV-2 CNS entry and morphological changes associated with SARS-CoV-2 infection. Methods: We systematically investigated postmortem tissue of the CNS and nasopharynx from 75 individuals with COVID-19. Based on the correlation of clinical data and (neuro-) pathological examinations, SARSCoV- 2-specific morphological changes were determined. Using quantitative real-time PCR, RNAscope in situ hybridization, immunohistochemistry and electron microscopy, we characterized the CNS tropism of SARSCoV- 2 and the consequences thereof. Results: Acute thromboembolic ischemic infarcts (n = 10/64) and a strong innate immune response, mediated by HLA-DR+ microglia with a linked increase in proinflammatory mediators in the cerebrospinal fluid, are leading alterations in the CNS. Besides, a distinct immunoreactivity for SARSCoV Spike protein was found in the olfactory epithelium - here co-localizing with neural/neuronal cells - and cerebral endothelial cells. We were also able to illustrate intact coronavirus particles in the olfactory mucosa ultrastructurally. Conclusion: SARSCoV- 2 can enter the nervous system by crossing the neural-mucosal interface in the olfactory mucosa. SARSCoV- 2 infection results in an innate immune response with activation of HLA-DR+ microglia and increased levels of inflammatory mediators in the CNS.