Muscle manifestations and CK levels in COVID infection: results of a large cohort of patients inside a Pandemic COVID-19 Area

doi:10.21203/rs.3.rs-98470/v1

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Muscle manifestations and CK levels in COVID infection: results of a large cohort of patients inside a Pandemic COVID-19 Area

https://doi.org/10.21203/rs.3.rs-98470/v1

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Objective: to investigate both muscular manifestations and CK levels of a large cohort of patients with COVID-19 infection and to determine whether hyperckemia is associated with morbidity and mortality.

Methods: Data of 615 patients discharged from ASST Ovest Milanese (Milan, Lombardy, Italy) with final diagnosis of COVID-19 infection were retrospectively extracted from electronical medical records from 21 February to 1 May 2020. Patients were descriptively analyzed with respect to the following variables: sex, age, muscular manifestations (including myalgia/arthralgia and fatigue), respiratory involvement (SARS pneumonia or respiratory failure) and history of falls. Association between patients’ characteristics and CK levels was investigated. In addition, the proportion of patients who died following access to the ER was calculated. Finally, the effect of CK levels and other patients’ features on mortality was estimated using a logistic regression model.

Results: 176 (28.6%) patients had raised serum CK levels. 88 (14.3%) had muscular manifestations, of which 81 (13.2%) complained fatigue and 17 (2.8%) had myalgia and/or arthralgia. CK levels were significantly associated with respiratory involvement and fatal outcome.

Conclusions: Our study provides preliminary evidence that hyperckemia is a predictor of respiratory involvement and fatal outcome in patients with COVID-19 infection. For patients with muscle damage symptoms, screening for COVID-19 infection is recommended together with the dosage of CK level.

Neurology

COVID-19

myalgia

Coronavirus

As of April 15, 2020, Lombardy region accounted for 37% of cases of COVID-19 infection and had 112.9 deaths per 100 000 population, almost six times higher than in the rest of Italy [1].

Although COVID-19 involves pulmonary system in the first place, in more than one-third of patients it causes neurological manifestations [2]. Literature data report various symptoms affecting the central nervous system, the peripheral nervous system and the skeletal muscle. In particular, skeletal muscle injury was defined by muscle pain or fatigue associated with elevated serum creatine kinase (CK) level above 200 U/L [3][4].

During the ongoing pandemics of COVID-19 infection, descriptions of muscle involvement have been recently reported [5][3][6]. However, the correlation between serum CK levels and muscle injury was poorly investigated [3][7].

Evidence of possible muscle involvement by coronaviruses dates back to 2003. During Severe Acute Respiratory Syndrome (Sars)-Cov outbreak in March 2003 muscle weakness and raised serum CK levels occurred in more than 30% of the SARS-infected patients [8]. In 2005 Leung et al. described a spectrum of myopathic changes associated with a SARS infection. Nevertheless, viral particle was identified in the muscle [9]. SARS-COV-2 is structurally similar to SARS-COV, and both bind to the angiotensin-converting enzyme 2 (ACE2) receptor to enter human cells. ACE2 is expressed in various human tissues in addition to the lungs, including muscle, although to a lesser extent [10]. These premises suggest a possible tropism of COVID-19 for muscle.

The primary aim of our study was to investigate both muscular manifestations and CK levels of a large cohort of patients with COVID infection in order to find a possible correlation among them. The secondary aim was to identify the association between CK levels and in-hospital death.

Data of 615 patients discharged from ASST Ovest Milanese (Milan, Lombardy, Italy) with final diagnosis of COVID-19 infection were collected from 21 February to 1 May 2020.

Clinical data were retrospectively extracted from electronical medical records including laboratory findings and they were checked by two neurologists (ADR and EPV).

The institutional ethics board of ASST Grande Ospedale Metropolitano Niguarda, Milan, approved this study and due to the nature of retrospective chart review, waived the need for informed consent from individual patients (Approval number: 411-21072020).

The recorded data included the following: age, sex, muscle symptoms (including myalgia/arthralgia and fatigue), history of falls, respiratory involvement (SARS pneumonia or respiratory failure) and CK level. Any occurrence of in-hospital death was also recorded. CK levels were evaluated at the time of Emergency Room (ER) arrival. Patients with elevated CK levels (≥ 200 U/L) were stratified in three groups as a previous paper [11]: CK 200-554 U/L (group 1), CK 555-1038 U/L (group 2), CK ≥1039 U/L (group 3).

Statistical analysis

Given the low number of people affected by myalgia and/or arthralgia, this condition was considered jointly with fatigue in the following analyzes.

Patients were descriptively analyzed with respect to the following variables: sex, age, muscular manifestations, respiratory involvement and history of falls, according to the CK level. In addition, the proportion of patients who died following access to the ER was calculated. The association between patient characteristics, considered individually, and CK level was studied using proportional odds logistic regressions, one for each variable, and estimating the odds ratio and its 95% confidence interval (CI). The proportional odds model has the same structure as the binary logistic regression model but uses an ordinal outcome variable (such as CK level) with more than two possible levels. It estimates a common odds ratio over all possible cut-offs of the outcome scale.

The association between clinical features and CK levels was also investigated through a multiple regression model. In this way, it was possible to identify the effect of each variable on the CK level accounting for the value of the other variables.

Finally, a logistic regression model was fitted to identify the predictors of in-hospital death. CK level was included in the model as a categorical variable. Adjustments were made for the above-mentioned variables.

The Statistical Analysis System Software (version 9.4; SAS Institute, Cary, North Carolina, USA) was used for the analyses. For all hypotheses tested, two-tailed P values less than 0.05 were considered to be significant.

Patients

A total of 615 hospitalized patients (mean age: 66.2 (±17.4); males: 386 (62.8%)) with confirmed COVID-19 infection were included in the analysis. Of these patients, 88 (14.3%) had muscular manifestations, of which 81 (13.2%) complained fatigue and 17 (2.8%) had myalgia and/or arthralgia. Nobody reported cramps.

CK levels were dosed in all patients (11-12328): 439 (71.4%) patients had normal values of CPK (≤ 199 U/L). Among patients with elevated levels of CPK, 127 patients (20.7%) were included in group 1, 31 patients (5.0%) in group 2 and 18 patients (2.9%) in group 3. The mean value of CPK was 262 U/L. The demographic, clinical and laboratory characteristics are shown in Table 1.

Variables associated with CK levels

Bivariate association analysis results are reported in Table 1. Muscular manifestations and age were not significantly associated with CK level.

Conversely, sex (men), respiratory involvement and history of falls were related with hyperckemia. Men prevalence was 58.1% among patients with normal CK level and 83.3% among those with CK level ≥1039 U/L.

Among patients with normal CK levels 25.3% had respiratory failure, whereas this figure was greater than 50% among those with CK levels higher than 554 U/L. On the opposite side, the prevalence of SARS pneumonia was higher among patients who had CK levels lower than 555 U/L.

Patients who fell had CK levels significantly higher than others. In particular, the percentages of those who fell were 2.3% and 22.2% among patients with CK <200 and ≥1039, respectively.

Multivariate analysis confirmed these results. Table 2 shows the adjusted estimates of association between CK levels and the other variables. Respiratory failure was the most associated feature with higher CK level (OR: 3.71, 95% CI 1.88 to 7.29), followed by history of falls (OR: 3.56), SARS pneumonia (OR: 2.04) and male sex (OR: 1.90).

CK level and death

One hundred and three patients (16.7%) died. Table 3 shows adjusted estimates of the risk of death according to the characteristics shown in Table 1. CK levels were significantly associated with death. Compared with the normal level group, an increased risk of 51%, 179% and 226% was observed among patients with CK 200-554 U/L, 555-1038 U/L and ≥1039 U/L, respectively (p-value=0.010). When patients with elevated CK levels (≥ 200 U/L) were combined into one group, the risk of death was increased by 89% (95% CI, 7%-233%).

Sex, age and respiratory involvement were also associated with mortality risk.

In this study we evaluated the CK levels of a very large cohort of patients focusing on muscle symptoms and clinical outcome.

To our knowledge, only two studies analysed the correlation between CK levels and muscle injury [3][7].

Mao et al. studied the neurological manifestations of 214 patients with Coronavirus disease showing that patients with muscle injury had significantly higher levels of CK (median: 400 U/L [range 203.0-12216.0] vs median: 58.5 U/L [range 8.8-212.0]; p < .001).Therefore, they speculated that muscle symptoms were owing to skeletal muscle injury and significantly elevated proinflammatory cytokines in serum may cause skeletal muscle damage [3]. Conversely, Vacchiano et al. found in 108 Covid-19 patients that muscle pain was not associated with CK high levels, supporting the notion that this symptom was not directly accounted for by muscle injury and making a direct viral mechanism unlikely [7]. As Italian colleagues, we did not find significant correlation among muscle symptomatology and CK levels.

Regarding the clinical aspects, in literature the rate of cases presented myalgia and fatigue varies from 35.8% (11) to 44% [6]. In our population only 15.8% of patients complained muscular symptoms. A reason could be that, because of the extreme circumstances in our hospitals at the peak of this pandemic, ER clinicians reported only the prevalent symptoms of the patients. Moreover, a proportion of patients were unconscious at the time of arrival in the hospital or suffered of previous severe cognitive impairment so it was hard to access if neuromuscular symptoms were present or not. Furthermore, electrophysiological studies that could have been done to evaluate myopathy were infeasible during the COVID-19 epidemic.

In our cohort the mortality rate was 16.7% in line with previous studies [12]. Interestingly, we found that CK levels in patients with respiratory failure were much higher than those of patients with non-severe infection, in accordance with literature reports [3]. We also found that CK levels were significantly correlated to fatal outcome. Previous studies confirmed that CK is an important predictor of oxygenation failure and death in patients with Severe Acute Respiratory Syndrome (SARS) [13][14]. In 2007 Chan et al. made a retrospective analysis of 1312 patients affected with SARS showing that CK is one of the predictive elements of oxygenation failure and poor outcome in these patients [15]. The most recent literature regarding Sars-COV-2 infection reported raised serum CK levels in 33% of patients, reaching 46% for Intensive care unit patients [6]. A Chinese retrospective study confirmed that median CK levels (normal values < 190) were higher in deceased patients (189 U/L) than in the other patients (84 U/L) [16]. Recently, Bonetti et al. found that CK represents one of the laboratory predictors of death from Covid-19 [17]. There are currently a few published case reports of rhabdomyolysis with myalgia and fatigue associated with severe SAR-COV-2 infection [18] also with potential implications on renal function [19]. We, thus, can conclude that CK levels are correlated with the severity of COVID infection.

Our study provides evidence that hyperckemia is a predictor of respiratory failure and fatal outcome. Muscle manifestations are not associated with the raise of CK levels; however, because of the extreme hospital circumstances, they can be easily misdiagnosed. For patients with muscle damage symptoms, screening for COVID-19 infection is recommended together with the dosage of CK level. Further prospective studies to document the frequency of COVID-associated muscle damage are warranted.

CK: creatine kinase; Sars: Severe Acute Respiratory Syndrome; CI: confidence interval; OR: odds ratios; Ref.: reference interval

Funding

None.

Conflicts of interest/Competing interests

Authors have no conflict of interest to declare.

Ethics approval

Consent to participate

Not applicable.

Acknowledgements

None.

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Table 1. Characteristics of cohort members according to the creatine kinase (CK) levels.

	CK level (U/L)				OR (95% CI)
	0-199 (N=439)	200-554 (N=127)	555-1038 (N=31)	≥1039 (N=18)	OR (95% CI)
Sex
Female	184 (41.9%)	34 (26.8%)	8 (25.8%)	3 (16.7%)	1.00 (Ref.)
Male	255 (58.1%)	93 (73.2%)	23 (74.2%)	15 (83.3%)	2.11 (1.44 to 3.10)
Age (years)
0-49	69 (15.7%)	18 (14.2%)	2 (6.5%)	3 (16.7%)	1.00 (Ref.)
50-64	115 (26.2%)	29 (22.8%)	9 (29.0%)	3 (16.7%)	1.09 (0.60 to 1.96)
65-74	92 (21.0%)	34 (26.8%)	3 (9.7%)	5 (27.8%)	1.34 (0.74 to 2.42)
≥75	163 (37.1%)	46 (36.2%)	17 (54.8%)	7 (38.9%)	1.33 (0.77 to 2.30)
Muscular manifestations
No	371 (84.5%)	112 (88.2%)	29 (93.6%)	15 (83.3%)	1.00 (Ref.)
Yes	68 (15.5%)	15 (11.8%)	2 (6.5%)	3 (16.7%)	0.70 (0.41 to 1.19)
Respiratory involvement
No	78 (17.8%)	9 (7.1%)	3 (9.7%)	1 (5.6%)	1.00 (Ref.)
SARS pneumonia	250 (57.0%)	79 (62.2%)	8 (25.8%)	7 (38.9%)	2.15 (1.15 to 4.04)
Respiratory failure	111 (25.3%)	39 (30.7%)	20 (64.5%)	10 (55.6%)	4.00 (2.08 to 7.67)
History of falls
No	429 (97.7%)	120 (94.5%)	30 (96.8%)	14 (77.8%)	1.00 (Ref.)
Yes	10 (2.3%)	7 (5.5%)	1 (3.2%)	4 (22.2%)	3.54 (1.60 to 7.85)

Abbreviations: CK: creatine kinase; OR: odds ratios; CI: confidence interval; Ref.: reference interval

Table 2. Association among CK levels, muscular manifestations and other features

	OR (95% CI)
Sex
Female	1.00 (Ref.)
Male	1.90 (1.28 to 2.82)
Age (years)
0-49	1.00 (Ref.)
50-64	0.87 (0.47 to 1.59)
65-74	0.98 (0.53 to 1.81)
≥75	0.99 (0.56 to 1.75)
Muscular Manifestations
No	1.00 (Ref.)
Yes	0.73 (0.43 to 1.26)
Respiratory involvement
No	1.00 (Ref.)
SARS pneumonia	2.04 (1.07 to 3.88)
Respiratory failure	3.71 (1.88 to 7.29)
History of falls
No	1.00 (Ref.)
Yes	3.56 (1.57 to 8.09)

Abbreviations: CK: creatine kinase; OR: odds ratios; CI: confidence interval; Ref.: reference interval

Table 3. Association among in-hospital death, CK levels, muscular manifestations and other features

	OR (95% CI)
Sex
Female	1.00 (Ref.)
Male	1.97 (1.09 to 3.56)
Age (years)	1.17 (1.13 to 1.22)
Muscular Manifestations
No	1.00 (Ref.)
Yes	0.84 (0.37 to 1.92)
Respiratory involvement
No	1.00 (Ref.)
SARS pneumonia	0.38 (0.16 to 0.92)
Respiratory failure	2.48 (1.07 to 5.77)
History of falls
No	1.00 (Ref.)
Yes	0.77 (0.24 to 2.48)
CK level (U/L)
0-199	1.00 (Ref.)
200-554	1.51 (0.78 to 2.91)
555-1038	2.79 (1.04 to 7.51)
≥1039	3.26 (0.84 to 12.69)
p-value trend	0.010

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Muscle manifestations and CK levels in COVID infection: results of a large cohort of patients inside a Pandemic COVID-19 Area

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