key: cord-0793477-096v6taj authors: Pitscheider, Lea; Karolyi, Mario; Burkert, Francesco R.; Helbok, Raimund; Wanschitz, Julia V.; Horlings, Corinne; Pawelka, Erich; Omid, Sara; Traugott, Marianna; Seitz, Tamara; Zoufaly, Alexander; Lindeck‐Pozza, Elisabeth; Wöll, Ewald; Beer, Ronny; Seiwald, Stefanie; Bellmann‐Weiler, Rosa; Hegen, Harald; Löscher, Wolfgang N. title: Muscle involvement in SARS‐CoV‐2 infection date: 2020-09-30 journal: Eur J Neurol DOI: 10.1111/ene.14564 sha: becc73b25a4ae690acb40c147b7176c2aed48813 doc_id: 793477 cord_uid: 096v6taj BACKGROUND: Since the outbreak of the SARS‐CoV‐2 pandemic several reports indicated neurological involvement in COVID‐19 disease. Muscle involvement has also been reported as evidenced by creatine kinase (CK) elevations and reports of myalgia. METHODS: CK, markers of inflammation, pre‐existing diseases and statin use were extracted from records of Austrian hospitalized COVID‐19 patients. Disease severity was classified as severe in case of intensive care unit (ICU) admission or mortality. COVID‐19 patients were additionally compared to a historical group of hospitalized influenza patients. RESULTS: 351 patients with SARS‐CoV‐2 and 258 with influenza were included in the final analysis. CK was elevated in 27% of COVID‐19 and in 28% of influenza patients. CK was higher in severe COVID‐19 as were markers of inflammation. CK correlated significantly with inflammation markers, which had an independent impact on CK when adjusted for demographic variables and disease severity. Compared to influenza patients, COVID‐19 patients were older, more frequent male, had more comorbidities and more frequently a severe disease course. Nevertheless, influenza patients had higher baseline CK than COVID‐19, and 35.7% of ICU admitted patients had CK levels > 1000 U/l compared to only 4.7% of ICU‐admitted COVID‐19 patients. CONCLUSIONS: HyperCKemia occurs in a similar frequency in COVID‐19 and influenza infection. CK levels were lower in COVID‐19 than in influenza in mild and severe disease. CK levels strongly correlate with disease severity and markers of inflammation. To date it remains unclear whether hyperCKemia is due to a virus‐triggered inflammatory response or direct muscle toxicity. In early December 2019 the first cases of atypical pneumonia of unknown origin were observed and reported in China. The novel causative virus was quickly identified and finally named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 disease quickly spread around the world and Northern Italy and some areas in Austria became early hotspots in Europe. Since the outbreak of the disease and the detection of the virus several reports indicated neurological involvement in SARS-CoV-2 infection [1] [2] [3] [4] [5] . Central nervous system manifestations ranged from impaired consciousness, acute cerebrovascular disease, and ataxia to headache seizures and dizziness. Severe Accepted Article affections of the neuromuscular system, such as cases of peri-and postinfectious Guillain-Barre Syndrome [6] [7] [8] [9] [10] [11] [12] and myasthenic crises [13] [14] [15] [16] were reported and even though milder symptoms in form of peripheral neuropathic pain and impairments of taste and smell [1, 17] were more frequent. Muscle pain and elevated creatine kinase (CK) levels as indications of muscle affection have been observed in several case series from China [1, 18, 19] . In addition, a few cases of rhabdomyolysis were reported [20, 21] and Dalakas [22] suggested that these patients suffered from COVID-19-triggered necrotizing autoimmune myositis. It has also been suggested that population specific characteristics exist which influence disease severity and presentation. The latter is e.g. supported by the higher prevalence of olfactory and gustatory dysfunction in European (85.6%; [17] than in Asian patients (5.1%; [1] ). HyperCKemia on the other hand seems to occur with a similar frequency of 13.7% and 9.2% in Asian [18] and European [2] patients, respectively. The present study aimed to investigate muscle involvement in an Austrian cohort of patients with SARS-CoV-2 infection by analysing CK values, their evolution over the first 2 weeks of the disease course, the relationship to general markers of inflammation and disease severity. Finally, these results were compared to those of an influenza cohort. Values for CK, C-reactive protein (CRP), white cell blood count (WBC), procalcitonin, interleukin-6 (IL6) and ferritin were obtained at the day of hospitalisation (baseline), day 7 (± 2 days) and day 14 (± 2 days) when available. Patients were included into the study when at least one CK value (i.e. at baseline, day 7 or day 14) was available. HyperCKemia was defined as CK exceeding the upper limit of normal (>190 U/l in males and >170 U/l in females). Known pre-existing factors affecting disease severity were recorded: diabetes mellitus (DM), coronary heart disease (CHD), arterial hypertension and chronic obstructive lung disease (COPD). Also, the use of statins was recorded as a possible confounder for CK elevations. Disease severity was classified based on Accepted Article admission to an intensive care unit and mortality, respectively. Various treatments have been used: hydrochloroquine in 44, favipiravir in 18, ropinavir/ritonavir in 15, and remdesivir in 1 patient. Muscle biopsies were no performed. For comparison, demographic information, comorbidities, CK and CRP values from patients diagnosed with influenza at the University Hospital Innsbruck were extracted from anonymized patient records [23] . Data on treatment were not available. Statistical analysis was performed using SPSS 26.0 (SPSS Inc., Chicago, IL, USA). Distribution of data was assessed by Kolmogorov-Smirnov test, and non-parametric data were displayed as median and interquartile range (IQR). Spearman coefficient was used for correlation analysis. For group comparisons, Mann-Whitney-U test and Pearson's chi-squared test were applied as appropriate. Paired samples were compared by Friedman test. Linear regression was employed to identify predictors for increased CK levels including age, sex, centre, admission to ICU, death and various inflammatory markers in peripheral blood, e.g. CRP. The dependent variable (CK) and the covariates CRP, WBC, IL-6, procalcitonin and ferritin were log-transformed to achieve normal distribution. A p-value <0.05 was considered statistically significant. At baseline, CK levels were significantly higher in males (p<0.001) and there was a weak negative correlation with age (r=-0.107, p=0.069) which became statistically significant in multivariate analyses. CK levels did neither differ depending on the presence of CAD, arterial hypertension, DM or COPD, nor on the usage of statins. In general, CK and inflammatory markers were significantly higher in severe than in mild disease (Fig 1A for ICU-admitted and Fig. 1B for deceased patients) . CK did not change over time in severe disease but decreased significantly from baseline to day 7 in mild disease (Fig. 1A) . In 27% of patients baseline CK was elevated with a median of 313 (283-541) U/l, and hyperCKemia was significantly more Accepted Article frequent in the ICU (40%) than in the non-ICU (23%) group. In the population with elevated baseline CK it was significantly higher in the ICU (406; 28-643 U/l) than in the non-ICU group (287; 224-488 U/l). CK correlated significantly with inflammatory markers (except the WBC count) at all time points (suppl. Tab. 1). Linear regression analysis revealed that various inflammatory markers had an independent impact on CK levels, adjusted for demographic variables and disease severity (suppl. Tab. 2). Baseline CK in the Influenza group was significantly higher than in COVID-19, although CRP was lower (Tab. 1). At follow-up, CK did not differ between disease groups, but in contrast to COVID-19, CK in influenza did not change significantly over time. Similar to COVID-19, hyperCKemia at baseline was observed in 28% of influenza patients with a median CK of 300 (251-676) U/l. CK correlated significantly with CRP at baseline (r=0,204), but not at follow up. Although hyperCKemia was more frequent in severe (47%) than in mild (26%) disease this difference did not reach statistical significance (p = 0.051). In the hyperCKemia population, CK was significantly higher in the influenza ICU (1611; 579 -1776 U/l) than in the COVID-19 ICU population (406; 28-643 U/l), while CRP did not differ between groups (COVID- The main findings of the present study are that hyperCKemia is frequent in Austrian patients and CK levels correlate with various markers of inflammation in COVID-19 disease. HyperCKemia is more frequent in severe disease although in general it is mild. Although the frequency of hyperCKemia is similar in influenza patients, CK levels are higher in influenza patients with severe disease. HyperCKemia has been consistently reported in COVID-19 disease [1, 2, 18, [24] [25] [26] , e.g. in 10.7% [1] and 13.7% [18] of Asian and in 9.2% in South European [2] COVID-19 patients. In contrast, we observed CK elevations in 27% in our population. Even if we apply the definition of hyperCKemia (CK > 200 U/l) used by other authors [1, 18] there would still be 24% of patients with elevated CK in our population. The higher percentage of hyperCKemia in the present study might be explained by differences in disease severity, as CRP was less in the study by Mao [1] , which is also supported by the strong correlation of CRP Accepted Article and other inflammatory markers with CK levels. On the other hand, differences between European and Asian patients might exist, as it has also been suggested for the prevalence of gustatory and olfactory dysfunction [17] . In 40% of severely affected patients, e.g. those admitted to the ICU, hyperCkemia was observed, while this was only the case in 24% of mild cases. Also, CK was higher in severely affected patients, which corresponds to findings by others [1, 2, 18, [24] [25] [26] . It has been reported that CK is higher in patients with abnormal findings on lung imaging [27] . However, factors associated with a poor prognosis, such as age, DM, CHD, hypertension and COPD [28] , were not associated with elevated CK levels. Taken together, these findings indicate that CK, in addition to traditional markers of inflammation, might serve as an additional maker of disease severity but not as a prognostic marker. The incidence of hyperCKemia was similar in COVID-19 as in influenza patients. However, baseline CK in ICU-admitted patients was higher in influenza than in COVID-19 patients, despite similar CRP levels. Furthermore, 5.4% of influenza patients, compared to 1.4% of COVID-19 patients, presented CK levels exceeding 1000. Such a preponderance of very high CK in influenza patients was even more frequent in the ICU population, although the absolute numbers of patients were small. However, others have also shown hyperCKemia is frequent in influenza [29, 30] . Why CK is higher in influence remains unclear. Studies in cultured human muscle cell indicated that influenza virus infects muscle directly and not via proinflammatory cytokines [31] . On the other hand, a biopsy study form a case of CIVID-19 associated myositis showed perivascular infiltration extending into the endomysium [32] . This suggests that the mechanisms of muscle damage differ between SARS-CoV-2 and influenza virus and that SARS-CoV-2 is less myotoxic than influenza virus. Unfortunately, we were unable to establish the prevalence of myalgia in our patients, but it can be assumed that it is more frequent than hyperCKemia [2, 19, 24, 26] . Despite this, CK is a more robust indicator of muscle damage than myalgia. The pathophysiology of COVID-19 hyperCKemia is not understood yet. Interaction via the ACE-2 receptor, the receptor that binds SARS-CoV-2, has been implicated [22] . This is supported by the apparent expression of the receptor on skeletal muscle [33] , however, the receptor was not detected in autopsy studies [34] . Also, the lesser muscle involvement than in influenza suggests that SARS-CoV-2 does not specifically target the muscle. Although we were unable to obtain clinical data on possible ICU acquired weakness, critical illness myopathy [35] as the cause of hyperCKemia seems unlikely as hyperCKemia was already observed in mild cases, CK was already elevated on the first day of ICU admission and CK typically is normal in critical illness myopathy [36] . As many viral This article is protected by copyright. All rights reserved infection can cause muscle damage [37] it therefore seems likely that a viral infection-triggered immune response causes muscle damage via T-cell expansion or macrophage and proinflammatory cytokine mediated muscle fibre destruction [22, 38] . An immune-mediated mechanism is supported by the observation that higher inflammatory biomarkers correlated with higher CK values. To date, three cases of rhabdomyolysis in COVID-19 disease have been reported with CK > 10.000 U/l [20, 21] or CK > 8.000 U/l [39] . Although rhabdomyolysis is, besides clinical criteria, defined by CK > 1.000, in cases with severe muscle injury it typically exceeds >10.000 U/l. In the present study CK>1.000 U/l was only observed in 4/287 (1.4%) COVID-19 but in 14/257 (5.4%) influenza patients, but none had CK values exceeding 7.000 U/l. This also supports the notion that the SARS-CoV-2 virus is less myotoxic than influenza virus. In conclusion, hyperCKemia is as frequent in COVID-19 as in influenza infection, but less severe. In both diseases CK is higher in severe than in mild disease. As morphological data are lacking, it remains unclear whether hyperCKemia is due to a virus-triggered inflammatory response or direct muscle toxicity. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease Neurologic manifestations in hospitalized patients with COVID-19: The ALBACOVID registry A systematic review of neurological manifestations of SARS-CoV-2 infection: the devil is hidden in the details Early neurological manifestations of hospitalized COVID-19 patients Neurological Manifestations of COVID-19: A systematic review and current update Guillain-Barré syndrome related to COVID-19 infection Guillain-Barré syndrome in the COVID-19 era: just an occasional cluster? Early Guillain-Barré syndrome in coronavirus disease 2019 (COVID-19): a case report from an Italian COVID-hospital Guillain-Barré syndrome during SARS-CoV-2 pandemic: A case report and review of recent literature Guillain-Barré Syndrome Associated with SARS-CoV-2 Accepted Article This article is protected by copyright. All rights reserved 11 Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence? Guillain-Barré syndrome in a patient with antibodies against SARS-COV-2 COVID-19 in patients with myasthenia gravis Myasthenic crisis in COVID-19 Management of patients with generalised myasthenia gravis and COVID-19: four case reports COVID-19 in MuSK Myasthenia Gravis: A Case Report Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study Clinical Characteristics of Coronavirus Disease 2019 in China Risk factors for disease severity, unimprovement, and mortality in COVID-19 patients in Wuhan, China Rhabdomyolysis as Potential Late Complication Associated with COVID-19 Rhabdomyolysis as a Presentation of 2019 Novel Coronavirus Disease Guillain-Barré syndrome: The first documented COVID-19-triggered autoimmune neurologic disease: More to come with myositis in the offing Prognostic impact of high sensitive Troponin T in patients with influenza virus infection: A retrospective analysis Accepted Article This article is protected by copyright. All rights reserved 24 Clinical features of patients infected with 2019 novel coronavirus in Wuhan Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Epidemiological, clinical characteristics of cases of SARS-CoV-2 infection with abnormal imaging findings COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis Laboratory findings in patients with avian-origin influenza A (H7N9) virus infections Is there a clinical difference between influenza A and B virus infections in hospitalized patients? : Results after routine polymerase chain reaction point-of-care testing in the emergency room from Productive infection of human skeletal muscle cells by pandemic and seasonal influenza A(H1N1) viruses COVID-19-associated myositis with severe proximal and bulbar weakness Renin-angiotensin system: an old player with novel functions in skeletal muscle Organ distribution of severe acute respiratory syndrome(SARS) associated coronavirus(SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways Toxic Myopathies Acquired weakness in the ICU: critical illness myopathy and polyneuropathy Secondary myopathy due to systemic diseases Inflammatory Muscle Diseases Rhabdomyolysis as an initial presentation in a patient diagnosed with COVID-19 Accepted Article This article is protected by copyright. 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