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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 6  |  Issue : 3  |  Page : 443-447

The association of serum creatine phosphokinase levels with severity of lung involvement and hypoxia in patients with COVID-19


1 Chronic Respiratory Disease Research Center, National Research Institute of Tuberculosis and Lung Diseases, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Department of Preventive Medicine, Research Institute of Internal Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
3 Department of Pulmonary Medicine, Clinical Research and Development Center, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
4 Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Disease, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Date of Submission24-May-2022
Date of Decision24-Jul-2022
Date of Acceptance08-Aug-2022
Date of Web Publication17-Sep-2022

Correspondence Address:
Atefeh Abedini
Chronic Respiratory Disease Research Center, National Research Institute of Tuberculosis and Lung Diseases, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_193_22

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  Abstract 


Background: An increase in the serum levels of creatine phosphokinase (CPK) could be associated with an unfavorable clinical outcome in coronavirus disease (COVID-19) patients; however, detailed information on this association is scarce. The aim of this study was to investigate upon admission CPK serum level and its relationship with the degree of involvement in chest computed tomography (CT) scans and hypoxia in patients with COVID-19. Methods: This cross-sectional survey was conducted on 191 COVID-19 patients who were referred to a major respiratory referral center in Tehran, Iran, in 2019. CPK serum level, oxygen saturation, blood pressure, temperature, and severity of lung involvement (based on lung CT scan) were measured. The severity of lung involvement in cuts of CT imaging was reported with a score between 1 and 4. The descriptive and relational statistics were conducted using Pearson's correlation coefficient and one-way analysis of variance. Results: The average age of the patients was 55.22 ± 15.39 years, and the male was predominant in gender (65.4%). There was a statistically significant relationship between CPK serum level and the severity of lung involvement in patients with COVID-19 (P = 0.04). Furthermore, a significant and reverse correlation was observed between CPK serum level and oxygen saturation in the patients (r = –0.160, P = 0.04). Conclusion: The results of this study showed that COVID-19 patients with elevated CPK levels upon admission are prone to more severe lung involvement, worsening oxygenation, and respiratory failure. Hence, considering the initial critical care strategies for such patients could be of the essence.

Keywords: Chest computed tomography scan, COVID-19, creatine phosphokinase, hypoxia, lung involvement


How to cite this article:
Kiani A, Rahimi F, Afaghi S, Mehrparvar M, Tavana S, Varharam M, Abedini A. The association of serum creatine phosphokinase levels with severity of lung involvement and hypoxia in patients with COVID-19. Biomed Biotechnol Res J 2022;6:443-7

How to cite this URL:
Kiani A, Rahimi F, Afaghi S, Mehrparvar M, Tavana S, Varharam M, Abedini A. The association of serum creatine phosphokinase levels with severity of lung involvement and hypoxia in patients with COVID-19. Biomed Biotechnol Res J [serial online] 2022 [cited 2022 Dec 8];6:443-7. Available from: https://www.bmbtrj.org/text.asp?2022/6/3/443/356153




  Introduction Top


Over 2 years is passed since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was initially announced in China,[1] and more than 560 million people were afflicted with the disease during the coronavirus disease (COVID-19) pandemic until July 2022.[2],[3] The clinical manifestation of patients could be varied from subclinical to progressive acute respiratory syndrome.[4],[5] Other organs could also be involved through the infection, leading to cardiac failure, liver and kidney injury, and coagulation system activation.[3] As COVID-19 triggers the immune system's inflammatory and cytokine response,[6],[7],[8] various inflammatory markers including D-dimer, erythrocyte sedimentation rate, C-reactive protein, ferritin, and procalcitonin were evaluated as predictors of clinical outcomes in afflicted patients.[9] Creatine phosphokinase (CPK) as an indicator of cardiac and skeleton muscle injury had been previously revealed to be at higher levels during sepsis, organ infections, and critical care patients.[10] Therefore, levels of CPK could potentially be utilized as predictors of severity and poor progression in patients with COVID-19. Notwithstanding, studies about this indicator of muscle damage with the severity of SARS-CoV-2 infection have been shortly evaluated[11] as well as the pathophysiological etiology of this relation, if any, is yet to be revealed. Moreover, it is not well recognized that the correlation of CPK with disease severity revealed in previous observational studies is accurate or was only due to other sociodemographic or clinical characteristics. Hence, the aim of our study was to elucidate whether the CPK levels upon admission could be correlated with the severity of lung involvement and oxygenation status.


  Methods Top


Study design and participants

This present study was a descriptive–analytical and cross-sectional study conducted on 191 patients with COVID-19 patients referred to Masih Daneshvari Hospital as a major respiratory referral center in Tehran, Iran, in 2019. The patients with COVID-19 who had the age over 15 years with consent to participate in the study were included in this survey. Based on the real-time polymerase chain reaction test and relevant clinical symptoms determined by National Research Institute of Tuberculosis and Lung Diseases (NRITLDs) protocols,[12] a definitive diagnosis of COVID-19 was given to the patients. The exclusion criteria were as follows: (1) recipients of organ transplants, (2) those who have previously taken steroid drugs or long-term broad-spectrum antibiotics, (3) pregnant or lactating women, (4) patients with chronic diseases, (5) history of recent trauma, (6) recent intramuscular injection, and (7) patients who have taken drugs in the last 3 months cause myositis (e.g., statins). Before the beginning of the study, written informed consent was obtained from all the patients. Eventually, 191 COVID-19 patients with mild-to-moderate and severe lung involvement were included in the study.

Data collection

After registering the sociodemographic and clinical information of the patients, including age, gender, and history of various diseases, blood sampling was done from the patients. To perform blood tests, a blood sample of 10 cc was taken from the brachial vein under sterile conditions by an experienced nurse and laboratory technician. A centrifuge with a speed of 3500 rpm for 10 min was used to separate the serum at a temperature of 4 degrees. Then, the separated serum for each individual blood sample was transferred into sterile microtubes next to the flame. The microtubes were kept in an −80°C freezer until the experiment. CPK serum level was measured using the ELISA kits. Furthermore, the arterial blood oxygen saturation percentage was measured using a pulse oximeter. Eventually, a chest CT scan was performed on the patients, and according to NRITLD protocols of the diagnosis of COVID-19, the severity of the lung involvement was scored as follows:[12],[13] without lung involvement = 0 score, <25% lung involvement = 1 score, 25%≤ lung involvement <50% = 2 scores, 50%≤ lung involvement <75% = 3 score, and 75%≤ lung involvement = 4 scores. The data collection tool was a researcher-made checklist containing demographic, vital signs, blood oxygen saturation percentage, lung involvement score by the chest-CT scan, type of lung involvement, and laboratory findings of upon admission CPK was recorded. The extracted data were double-checked by two independent clinical researchers, and the scoring system of lung involvement was conducted by experienced pulmonologists.

Study sample size

Based on the previous studies (56) that showed the prevalence of COVID-19 patients with elevated CPK at about 14%, and taking into account that the confidence level of analysis was 95% and P value was deemed as significant in lower than 0.05%, the sample size was calculated using the following formula in the online software of MedCalc using the following formula (The computed number = 185):



Statistical analysis

The Shapiro–Wilk test was used to check the normality of the data. All data were analyzed to be confirmed as being normally distributed. Categorical and continuous variables were presented as case number (percentage) and mean ± standard deviation, respectively. To compare the categorical variables, Chi-squared or Fisher's exact test was utilized as appropriate. Independent t-tests or Mann–Whitney U tests were used for comparison of the mean between continuous variables as necessitated. One-way analysis of variance and Pearson's correlation coefficient were used to analyze the correlation of severity levels of lung involvement with levels of CPK. The statistical significance level was considered less than 0.05. All statistics of this study were done using SPSS version 22 software (SPSS, Chicago, IL, USA).

Ethical consideration

The study was approved by the Ethical Committee of the Shahid Beheshti University of Medical Sciences in Tehran, Iran (ethical number: IR.SBMU.MSP.REC.1401.436). All the procedures of this study were performed based on the ethical guidelines of the 1975-Helsinki declaration.

Patients' consent form

A consent letter consists of a fully consenting declaration of the patients regarding cooperation in the study and using patient medical record information in this study was conducted. Patients without consent were excluded from this study.


  Results Top


The average age of the patients was 55.22 ± 15.39 years with a range of 15 to 98 years and 65.4% of the patients (n = 125) were men. In terms of the severity of lung involvement in chest CT scans, the majority of patients (44.5%) had a score of greater than 2 (26% to 50% lung involvement). About 20.4% of admitted patients had less than 25% lung involvement [Table 1]. The results of the one-way variance test showed that there was a statistically significant relationship between the CPK serum level in patients with COVID-19 and the severity of lung involvement (P = 0.042). As the mean CPK serum level increased, the severity of lung involvement in patients increased significantly. Comparatively, the finding shows that more than 60% of patients with 1 and 2 severity scores had normal CPK serum levels; while, in 61.1% of patients with 4 severity scores had CPK serum levels higher than normal. Moreover, in the evaluation of CPK findings in normal (CPK ≤200 U/L) and abnormal (CPK >200 U/L) groups, it was also observed that CPK serum level has a significant relationship with the severity of lung involvement (P = 0.013) [Table 2]. Furthermore, a significant and reverse correlation was observed between CPK serum levels and oxygen saturation in patients with COVID-19 (r = –0.160, P = 0.041). In other words, the increase in CPK level in patients was remarkably associated with a decrease in blood oxygen saturation in patients [Table 2]. Finally, the results showed a significant statistical relationship between the severity of lung involvement and blood oxygen saturation (P < 0.001). As the severity of lung involvement in the patients increased, their blood oxygen saturation decreased significantly [Table 2]. No significant relationship was observed between the variables of temperature and systolic and diastolic blood pressure with the severity of lung involvement (P > 0.05) [Table 2].
Table 1: Clinical characteristics of patients with coronavirus disease 2019 (n=191)

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Table 2: Levels of clinical variables and creatine phosphokinase categorized by lung involvement severity score

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  Discussion Top


Primary identifying of high-risk COVID-19 patients could help to sooner initiation of the critical care strategies and lead to improvement in clinical outcomes.[14],[15] Therefore, in this study, we aimed to investigate the association of upon admission CPK serum levels with the severity of lung involvement and hypoxia in such patients. As a result, we found a significant correlation between CPK with more pulmonary lobes infection and hypoxia. Hence, COVID-19 patients with elevated CPK could be at higher risk of worsening in respiratory function and acute respiratory distress syndrome. The association of CPK with lung infection disease had been previously evaluated in diseases even before the COVID-19 pandemic.[10],[16] Of instance, Zhao et al.[17] reported that the mean CPK serum level during hospitalization was higher in patients with community-acquired pneumonia compared to those who had no radiological evidence of pneumonia. Furthermore, previous evaluations indicated that CPK levels were remarkably higher in those who were died due to influenza virus subtypes pneumonia, although CPK was not found as an independent risk factor of fatality when multivariate regression models were conducted.[18],[19],[20] To support the findings of this study, several studies have showed that elevated CPK serum has been related to an increase in the severity of COVID-19, although detailed information on the relationship of CPK with the level of lung involvement and hypoxia were not indicated.[10],[21] CPK upon admission has been reported to be significantly higher in patients who experienced raised length of hospital stay,[10],[22],[23] required more of critical care support,[24] and had an increment in the fatality rate.[22],[25] The supporting hypothesis is that raised CPK following muscle injury could be occurred due to direct invasion of virus (e.g., in cardia)[26] or following indirect injury (e.g., in skeletal muscle)[27] as a response of the immune system leading cytokine storm and inflammatory state. The latter could be presented as rhabdomyolysis in some severe cases.[27] Interestingly, it was shown that the increase in the serum level of CPK and rhabdomyolysis could be the merely symptoms in some cases afflicted with SARS-CoV-2 invasion.[28] Furthermore, prior studies have also shown that muscle mass wasting could potentially worsen the disease outcome and increase the chance of ICU admission due to a variety of infectious diseases.[29] This condition mostly could be presented with elevated CPK during the disease progression and had been reported more in geriatric who were admitted to intensive care units following both viral and bacterial pneumonia comparing to younger patients.[30] Notably, exceed of 40% of our study patients were over 60 years old and the potential risk of muscle loss (and raised CPK as an indicator) could emphasize once more time that the elderly is at greater risk of poor outcome during SARS-CoV-2 infection.

Limitations

Our study had some limitations that are mentioned as follows: first, the outcome of the patients (mortality, recovery, and hospital length of stay) was not evaluated in this study; second, the sample size of this study was not remarkable in which limited the evaluation for accessing to predictive value of CPK cutoff points; moreover, third, majority of the study patients were men and about 40% were over 60 years old; therefore, to ensure the generalization of the results to the entire general population for both gender and variety of ages, more studies with greater sample size consistent with gender and age homogeneity are required.


  Conclusion Top


The results of this study supported that patients with SARS-CoV-2 infection and increased levels of CPK are at higher risk of severe lung involvement, worsening oxygenation, and subsequent respiratory failure. Accordingly, we suggest that in hospitalized patients diagnosed with COVID-19, CPK level testing due to better judgment for the plausible early critical care management be conducted.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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