Prevalence and Predictive Factors of Rhabdomyolysis in COVID-19 Patients: A Cross-sectional Study

Introduction

As we enter the third year of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SAR CoV 2) still poses major health problems worldwide. Considering the growing fully vaccinated population and the development of improved patient management protocols, researchers have shifted their attention from the management of the acute respiratory symptoms to other complications of the disease.^1-3 Recent studies indicate that these multiorgan and/or extrapulmonary complications are associated with a significantly higher risk of mortality.^4-6

Rhabdomyolysis is caused by muscle necrosis and the subsequent dissolution of intracellular components into the bloodstream.⁷ Although rhabdomyolysis is most often caused by direct injuries to the muscles, compartment syndrome, exertion or prolonged immobilization, the condition can also be the result of infections. Association of rhabdomyolysis with viral infections such as influenza A, influenza B, human immunodeficiency virus (HIV), and herpes has been previously demonstrated.^8,9 The severity of the condition varies from an asymptomatic illness to a severe condition involving life-threatening elevation in serum creatinine, disseminated intravascular coagulation, and renal failure.¹⁰

The SARS-CoV-2 that is responsible for COVID-19 has also been reported to cause rhabdomyolysis.¹¹ Although it was previously reported that rhabdomyolysis mostly occurred in severe cases of COVID-19 patients with older age and comorbidities (e.g., cardiovascular disease), there are recent reports of rhabdomyolysis developing in younger patients with less-severe forms of COVID-19.^12-14 Therefore, the present prospective observational study aimed to demonstrate the prevalence and predictive factors of rhabdomyolysis in COVID-19 patients.

Materials and Methods

The present observational study was performed on patients who were admitted to the emergency department (ED) of Shohadaye Tajrish Hospital in Tehran, Iran, between March 2020 and March 2021. The study was approved by the ethics committee of Shahid Beheshti University of Medical Sciences (ethics code: IR.SBMU.MSP.REC.1400.099), and the researchers adhered to the principles of the Helsinki Convention.

Patients confirmed with COIVD-19 and an established creatinine phosphokinase (CPK) level upon admission to the ED were included in this study. The diagnosis of COVID-19 was made with a positive reverse transcriptase-polymerase chain reaction (RT-PCR) for SAR-CoV-2 from a nasopharyngeal specimen and/or pulmonary complications identified by computed tomography scan. Patients without a CPK level, pregnant women, polytraumatic cases, and bedridden patients before the diagnosis of COVID-19 were all excluded.

Demographic data (age and gender), patients’ symptoms (cough, dyspnea, myalgia, headache, chest pain), vital signs, venous blood gas parameters, hematologic and blood biochemistry parameters, and data on urine analysis were collected from patients’ profile using a predesigned checklist. Peak CPK levels were used to define rhabdomyolysis. Like our previous study, a CPK level equal to or more than 1000 IU/L was defined as the presence of moderate to severe rhabdomyolysis. An emergency medicine resident under the direct supervision of an emergency medicine specialist was responsible for data gathering.

We examined normality assumption by checking kurtosis, skewness, box plot, and Q–Q plot. t-Test and Mann–Whitney U test were used for comparisons of continuous variables in alive and dead patients. Apart from evaluating the association between categorical variables, the Chi-square test and Fisher’s exact test were used. In addition, a multivariate logistic regression model was performed for investigating the independent predictive factors of COVID-19–related rhabdomyolysis. The findings were reported as odds ratio (OR) and 95% confidence interval (95% CI). P value less than 0.05 was considered statistically significant. We developed a prognostic rule using the independent predictors of rhabdomyolysis in COVID-19 patients. Accordingly, each independent variable received a score equal to 1. The receiver operating characteristic (ROC) curve, sensitivity, specificity, and likelihood ratio were calculated to assess the prognostic performance of the rule. All analyses were done using the STATA 14.0 statistical software.

Results

Five hundred and six confirmed COVID-19 patients with a mean age of 58.36 ± 17.83 years were studied (56.32% male). The demographic characteristics and laboratory findings of studied cases at baseline are presented in Tables 1 and 2, respectively. Rhabdomyolysis occurred in 44 (8.69%) cases throughout their hospitalization. The mean age of rhabdomyolysis cases was 58.58 ± 17.78 years compared to 56.11 ± 18.36 years of non-rhabdomyolysis cases (P = 0.3816). Patients with rhabdomyolysis were significantly more likely to be male (75.0% vs. 54.55%, P = 0.009).

Dyspnea was found to be significantly more prevalent in the rhabdomyolysis group (63.42% vs. 47.62%, P = 0.043). Additionally, patients with rhabdomyolysis had significantly lower mean systolic blood pressure than patients without rhabdomyolysis (112.88 ± 21.26 vs. 120.16 ± 18.04 mmHg, P = 0.013).

The analysis of laboratory data during hospitalization revealed that venous blood bicarbonate levels were higher in patients with rhabdomyolysis (28.44 ± 32.56 vs. 24.17 ± 4.78, P = 0.013), which was probably due to adding bicarbonate to the intravenous (IV) solutions for urine alkalization in rhabdomyolysis cases. Also, the mean platelet count was significantly lower in rhabdomyolysis cases (177.83 ± 65.75 vs. 208.86 ± 92.38, P = 0.036). A significant difference was also observed between the groups regarding blood urea nitrogen (BUN; P = 0.0002), aspartate transaminase (AST; P = 0.0001), alanine transaminase (ALT; P = 0.0009), Na (P = 0.013), and D-dimer (P = 0.033), which is presented in Table 2.

Independent predictors of rhabdomyolysis

Applying a multivariate logistic regression model and utilizing a univariate analysis revealed that male gender (OR = 2.78, 95% CI: 1.28, 6.00), hyponatremia (OR = 2.46, 95% CI: 1.08, 5.59), myalgia (OR = 3.04, 95% CI: 1.41, 6.61), D-dimer >1000 (OR = 2.84, 95% CI: 1.27, 6.37), and elevated AST level (three times higher than the normal range) (OR = 3.14, 95% CI: 1.52, 6.47) were the significant preliminary predictors of rhabdomyolysis [Table 3].

A prognostic rule was developed using the independent predictors of rhabdomyolysis in COVID-19 patients. The COVID-19–related Rhabdomyolysis Prognostic rule (CORP rule) score ranged from zero to 5, indicating the lowest risk to the highest risk of developing rhabdomyolysis following COVID-19 infection. The area under the curve of the CORP rule was 0.75 (95% CI: 0.69, 0.81), indicating its fair performance in the prognosis of rhabdomyolysis following COVID-19 infections [Figure 1]. The best cutoff of the CORP rule was 3, with a sensitivity of 72.9% and a specificity of 72.7% [Table 4]. In this cutoff, there were 336 true-negative, 35 true-positive, 126 false-positive, and 13 false-negative cases. The CORP rule is presented in Figure 2.

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Figure 1:

Area under the ROC curve of the CORP rule in the classification of high-risk COVID-19 patients for rhabdomyolysis CORP rule = coronavirus disease 2019-related Rhabdomyolysis Prognostic rule, COVID-19 = coronavirus disease 2019, ROC = receiver operating characteristic.

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Figure 2:

The COVID-19 related Rhabdomyolysis Prognostic rule (CORP rule). AST=aspartate transaminase.

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Discussion

We found evidence of rhabdomyolysis in 8.69% of patients following COVID-19 infection. Male gender, hyponatremia, myalgia, elevated D-dimer, and elevated AST levels were independent predictive factors of rhabdomyolysis.

Rhabdomyolysis is a condition in which there is injury or death to muscle cells, which results in the release of cellular components into the bloodstream.¹⁵ In addition to the symptoms caused by the general reaction of tissue death, muscle cells contain specific components like myoglobin which can lead to rhabdomyolysis. Myoglobulin is toxic to the kidneys and its association with acute kidney injury is well known.¹⁶ COVID-19 can injure the muscle cells by direct invasion in conjunction with a wide spectrum of pulmonary and extrapulmonary manifestations such as rhabdomyolysis with hypovolemia, fever, acidosis, bacterial superinfection, and so on.^17-19 For instance, COVID-19 can cause excessive fluid depletion due to fever, gastrointestinal loss, tachypnea, possible cardiovascular injuries, and decreased intake of fluids.^20,21 The following hypovolemia could be a cause of damage to the muscle tissue. Additionally, the drop in arterial oxygen saturation in severe forms of COVID-19 is also another contributing factor to muscle injury secondary to tissue hypoxia. Moreover, COVID-19 can cause coagulopathies with elevated D-dimer and alterations in other laboratory findings descriptive of the coagulopathic state. Coagulopathies are a well-known etiology of muscular tissue death, further contributing to the development of rhabdomyolysis.^22,23

For the first time, we tried to provide a prognostic rule for predicting developing rhabdomyolysis following COVID-19 infection. Male gender, hyponatremia, myalgia, elevated D-dimer, and elevated AST levels were included to calculate the rule. It appears that the CORP rule could correctly classify 72.8% of COVID-19 patients for their risk of developing rhabdomyolysis.

This study has a number of limitations. Since COVID-19 can cause myalgia and coagulopathies in the absence of rhabdomyolysis, the laboratory and clinical findings could be due to COVID-19 itself and are not specifically indicative of rhabdomyolysis. In addition, we included the admission time laboratory findings to develop the prognostic rule, and if the serial values of these variables were used in the decision rule, its predictive value might have increased. The CORP score was developed based on the available data of COVID-19 patients, and some variables such as inotropic requirement and serum phosphorus were not always available.

Conclusion

This prospective study showed that 8.69% of patients developed rhabdomyolysis following COVID-19 infection. Male gender, hyponatremia, myalgia, elevated D-dimer, and elevated AST levels were independent predictive factors of rhabdomyolysis. The CORP rule with optimal cutoff can correctly classify 72.8% of COVID-19 patients for their risk of developing rhabdomyolysis.