What’s known
- It is known that myalgia and fatigue are most common complaints in
COVID-19.
- However, the characters of these symptoms has not been systematically
evaluated.
- In addition to this, there is no sufficient data evaluating its
relationship with laboratory findings and emotional stateWhat’s new
- Arthralgia and myalgia are very common and spreads locally to
sensitive surrounding tissues, particularly in the back.
- Severity and frequency of pain are higher in patients with more
disease anxiety.
- Muscle pain is associated with low levels of lymphocytes and high
levels of creatine kinase.
INTRODUCTION
The novel SARS-CoV-2 (COVID-19) virus infection was recognized as a
pandemic by the World Health Organization (WHO) in March 2020. The
disease can present with very different symptoms. These symptoms include
fever, cough, dyspnea, headache, diarrhea, arthralgia, myalgia, fatigue,
and rarely arthritis.1 The type and severity of these
symptoms may vary from patient to patient. Some patients may be
asymptomatic or have mild prodromal symptoms, while others may present
with severe acute respiratory syndrome (SARS) and multiorgan
failure.2,3
Musculoskeletal symptoms (particularly fatigue, muscle, and joint pains)
are very common at the onset and course of COVID-19. Although, the
prevalence of these symptoms has not been systematically established.
Studies are often single-center and retrospective in
natüre.4,5 The presence and severity of these symptoms
can negatively affect daily life activities, It prevents them from
maintaining a good quality of life.6,7 In the long
term, symptoms can progress into muscle atrophy and contractures. Thus,
revealing these symptoms and their associated factors is crucial.
Musculoskeletal symptoms are closely related to many clinical symptoms,
disease severity, and respiratory distress in particular. Also, symptoms
appear to be associated with certain blood parameters like interleukin-6
(IL-6) and tumor necrosis factor-alpha (TNF-α).4,8
Here, we examined musculoskeletal symptoms, along with their
localization and severity in COVID-19 patients. Besides, we investigated
the presence-severity of these symptoms and their correlation with
disease anxiety and blood parameters.
METHODS
Patient population
Data were prospectively collected (between July 2020 and November 2020).
Patients who applied to the COVID-19 outpatient clinic, who had a thorax
computed tomography (CT) compatible with COVID-19 pneumonia, and who had
a positive Polymerase Chain Reaction (PCR) test were included. Some
diseases that were considered to influence the data and results were
excluded (Table 1). Age, sex, smoking/alcohol use, and symptoms at
admission (fever, cough, dyspnea, fatigue, anorexia, weakness) were
inquired.
Questionnaires
The impact of events scale-revised (IES-R)
The scale consists of 22 questions that reveal the psychogenic effect of
COVID-19 and the pandemic on patients. Each question is scored from 0 to
4. Increasing scores indicate that higher disease anxiety. Questions
included the following examples:
Things like viruses, germs, or diseases remind me of the COVID-19
quarantine and related feelings. I can see images related to COVID-19
like photographs. Total scores range from 0 to 88. Higher scores
indicate a greater impact by the disease. The cut-off point was set at
33. The scale consists of 3 subscales. These are intrusion at questions
1, 2, 3, 6, 9, 14, 20; avoidance at questions 5, 7, 8, 11, 12, 13, 17,
22, and hyperarousal at questions 4, 10, 15, 18, 19,
21.9
The pain quality assessment scale (PQAS)
This scale evaluates muscle joint pain and the quality of pain.
Patients’ symptoms are examined to cover the last 1 week. Pain
localization (neck, shoulder, elbow, hand-wrist, waist, hip-thigh, knee,
foot-ankle) is determined. They are asked to choose one of the 3 main
headings to define their pain. 1) Temporary pain, sometimes there but
other times not. 2) Unstable and constant pain. From time to time, it
suddenly becomes severe. 3) Stable and constant pain. The scale consists
of 20 questions. Each question is scored between 0-10, Each question is
evaluating a different domain and quality of pain. 0 describes no pain,
whereas 10 defines the most severe pain felt. Total scores range from 0
to 200. Higher scores indicate worse pain
quality.10,11
Blood tests
Blood samples were taken from the antebrachial vein. A separator tube
with a separator gel was used for serum tests and potassium-EDTA tubes
were used for blood counts. The blood samples were centrifuged at 5000
rpm for 10 minutes and separated into the serums. The samples were
evaluated on an Automated Blood Cell Analyzer (Pentra 120 Retic
Hematology Analysis Device, ABX, Montpellier, France), Hitachi 7600
chemistry analyzer (Hitachi, Tokyo, Japan) using an immunoturbidimetric
method (WakoChemicals, Osaka, Japan) by spectrophotometric measurements
(on a c702 modular analyzer, Cobas 8000 series) From the samples,
D-dimer, white blood cell (WBC), neutrophil, lymphocyte, thrombocyte,
creatine kinase (CK), alanine aminotransferase (ALT), aspartate
aminotransferase (AST), blood urea nitrogen (BUN), creatinine, amylase,
lipase, lactate dehydrogenase, ferritin, fibrinogen, and C-reactive
protein parameters were analyzed. For blood CK, the cut-off point was
set at 200 U/L. The patients were divided into 2 groups as CK over or
below 200 U/L.
Statistical analysis
Data analysis was performed using the SPSS® version
17.0 statistical package software (SPSS Inc., Chicago, IL, United
States). Numerical data are given as mean±standard deviation and median
(minimum-maximum). Categorical data are presented as number (n) and
percentage (%). Categorical data were compared using either the
Chi-Squared test or Fisher’s exact test. Data distribution was evaluated
using Kolmogorov-Smirnov and Shapiro-Wilk tests. Numerical differences
between the two groups were analyzed using Student’s t-test or the
Mann-Whitney U test (depending on data distribution). The cut-off point
was calculated based on a receiver operator characteristic (ROC) curve
analysis. Cut-off points were then determined according to sensitivity
and specificity. The area under the curve (AUC) was calculated. The
confidence interval (CI) was determined. Spearman’s Correlation test was
used to assess the correlations between numerical data. Correlation
coefficients between 0-0.25 were considered weak, 0.25-0.50 were
considered weak-moderate, 0.50-0.75 were considered strong, and
0.75-1.00 were considered very strong. The level of statistical
significance was set at 0.05.
RESULTS
A total of 163 patients were included, 70 of whom (42.9%) were female
and 93 (57.1%) were male. The patients had an age average of 56.81 ±
16.32. The most common symptom of admission was fatigue (n = 114,
69.9%). It was followed by anorexia, dyspnea, weakness, cough, and
fever (Table 2). 31 of the patients (19%) were smokers and 5 (3.1%)
were alcohol users.
The prevalence of muscle-joint pain was 63.2% (n = 103). The
most common pain locations were the back (n = 52, 50.5%),
foot-ankle (n = 51, 49.5%), and the knees (n = 49,
47.6%). Temporary pain was the most common type of pain reported
(n = 69, 67.0%). It was followed by unstable-constant pain
(n = 30, 29.1%) and stable-constant pain (n = 4, 3.9%).
Patients’ demographic characteristics, symptoms on admission, and muscle
and joint pains are summarized in Table 2. The mean total PQAS score was
found to be 57.82 ± 40.38 (2.0-156.0). Pain characteristics according to
PQAS are given in Table 3.
Muscle-Joint pain and related factors
Age and sex were similar between patients with and without muscle-joint
pain (p = 0.570; 0.278). Muscle-joint pain was higher in patients
presenting with fever, fatigue, loss of appetite, and weakness (p
<0.001). Those with muscle-joint pain also had a higher
prevalence and severity of disease anxiety (p = 0.008; 0.043).
These patients had higher intrusion, avoidance, and hyperarousal
subscale scores. There was a weak-moderate positive correlation between
PQAS and IES-R scores (p <0.001, r = 0.366). Also, there was a
weak-moderate negative correlation between PQAS scores and lymphocyte
levels (p = 0.012, r = -0.347).
The number of patients with a CK blood level above 200 U/L was 14.9%.
This rate was higher at 23.3% in patients with muscle-joint pain.
Patients with muscle-joint pain had higher CK and lower lymphocyte
levels (p = 0.016; 0.040). Table 4 shows the blood parameters of
patients with and without muscle-joint pain.
According to the ROC curve analysis, the CK cut-off value was 71.5, with
a sensitivity of 55% and a specificity of 50% (p = 0.016, AUC =
0.614, CI = 0.527-0.701) (Fig. 1). Fig. 2 presents the frequencies of
patients with and without muscle-joint pain at a cut-off value of 71.5.
The impact of events scale-revised and related factors
The mean total IES-R score was 36.89 ± 17.76 (3-86). IES-R scores were
mild in 85 patients (52.1%) and severe in 78 (47.9%). However, age and
sex were similar between patients with mild and severe scores. There was
no difference between their complaints at clinical presentation. The
group with severe impact had a higher frequency of muscle and joint pain
(p = 0.043). For these patients, the pain was more frequent in
the shoulder, the back, elbows, and hand-wrist (p = 0.001; 0.039;
0.018; 0.047, respectively).
Regarding blood parameters, the group with severe impact had lower WBC
and lymphocyte levels and higher CK levels (p = 0.06; 0.010;
0.009, respectively). Patient groups and blood parameters are summarized
in Table 5.
DISCUSSION
The clinical picture for COVID-19 ranges from asymptomatic presentation
to severe pneumonia. Fever, cough, fatigue, and muscle-joint pains are
among the most common symptoms.4,12,13 When the
literature is reviewed, it is seen that most of the studies on
COVID-19-related muscle-joint pain are retrospective. Many of the
studies have also been reported from China. Hence, it is unclear whether
the musculoskeletal symptoms at the onset are affected by
socio-geographic factors.14 Studies have reported
different frequencies of fatigue and muscle-joint pain. In a study on 51
patients by Xu and his co-workers, the frequencies of fatigue and
muscle-joint pain were 4% and 16%, respectively.15In a study by Mo et al. on 155 patients, fatigue was present in 73.2%
of the sample, while myalgia/arthralgia was present in
61%.16 Research conducted in Europe report higher
frequencies of musculoskeletal symptoms. For example, Lechien et al.
examined the data of 417 COVID-19 patients from 12 European hospitals
and reported myalgia in 246 (59%) and arthralgia in 129
(31%).17 In our study, 103 (63.2%) of our patients
were found to have muscle-joint pain. This rate is similar to those in
the literature, particularly to those reported in Europe. However, there
is no study that systematically evaluates pain localization and
characteristics. In the current study, patients with muscle-joint pain
often reported intense and dull pain. The pain spread locally to
sensitive surrounding areas. The most common locations were the back,
foot-ankle, the knees, and the waist.
The mechanism of muscle-joint pain in viral diseases is yet to be
clearly revealed. This mechanism is believed to be based on increased
proinflammatory cytokines on muscle tissue during viral infection.
Muscle-joint pain is accompanied by high levels of IL-6 and TNF-α. It is
thought that muscle pains in COVID-19 may reflect the overall
inflammatory state and cytokine response.18 The
correlation between musculoskeletal symptoms and the parameters
associated with infection and inflammation (white blood cell, leukocyte,
lymphocyte, CRP, etc.) has not yet been studied in detail. To date,
there is still no information regarding the presence of COVID-19 in
skeletal muscles, joints, or bones. Musculoskeletal symptoms are based
on the secondary effects of the inflammatory and/or immune response. The
presence of muscle-joint pain has been associated with disease severity.
Also, low lymphocyte levels are associated with disease severity,
central nervous system involvement, and muscular symptom
severity.19 In our study, lymphocyte levels were lower
in patients with muscle-joint pain. Besides, there was a negative
correlation between PQAS scores and lymphocyte levels.
Careful monitoring of kidney functions and muscle enzymes is crucial in
SARS-CoV-2 infection. One study in China reported high CK levels
(>200 U/L) in 19% of hospitalized
patients.19 In our study, 14.9% of our patients had
CK levels over 200 U/L. This rate was found to be at 23.3% in patients
with muscle-joint pain. Lee et al. determined that the severity of
COVID-19 was associated with CK levels, and disease severity increased
in parallel to CK levels.20 Another study found that
patients with muscle pain symptoms had higher CK and lactate
dehydrogenase blood levels. This is believed to be associated with the
angiotensin-converting enzyme 2 (ACE-2) receptors in skeletal muscles
and increased proinflammatory process.21-23 In the
present study, there was a statistically significant correlation between
the presence of muscle-joint pain and high CK levels. Although, pain
intensity and CK levels were not significantly correlated.
It has long been known that epidemics have psychological effects on
patients. One study on the presence of anxiety and depression in
COVID-19 patients reported frequencies of 18.6% for anxiety 13.4% for
depression.22 Patients with anxiety and depression are
at high risk for chronic pain and muscle joint pain. Both the
psychogenic effect of COVID-19 and the social isolation caused by the
pandemic are thought to facilitate the development of symptoms of
anxiety and depression.24,25 In our study, disease
anxiety was found to be very high in patients with muscle and joint
pain. This patient group also had higher intrusion, avoidance, and
arousal subscale scores. Besides, patients with high disease anxiety had
high PQAS scores and blood CK levels.
LIMITATIONS OF THE STUDY
One limitation of this research was not revealing the patients’ lung
findings and the severity of their clinical conditions, and not
analyzing the correlation between muscle joint pain and laboratory
parameters. Although patients with a history of psychiatric disease were
excluded, muscle-joint pain is still a subjective clinical symptom,
Therefore not easy to assess. Also, since joint fluid and muscle biopsy
were not taken from patients, correlation with local inflammation could
not be examined.
CONCLUSION
The frequency of muscle-joint pain is quite high in COVID-19. Pain
spreads locally to sensitive surrounding tissues, particularly in the
back. The severity and frequency of pain are higher in patients with
more disease anxiety. The presence of muscle pain is associated with low
levels of lymphocytes and high levels of CK.
STATEMENT OF ETHICS
Permission to conduct the research was obtained from the Ministry of
Health of the Republic of Turkey on 07.07.2020. Approval was obtained
from the Clinical Research Ethics Committee at Karatay University (No:
2020/053, Date: 17.07.2020, Number of Meetings: 5,). The Declaration of
Helsinki and good clinical practice guidelines were adhered to
throughout the research. Consent was obtained from the included patients
to use their data.
FUNDING SOURCES
No grants from any public and/or commercial funding organizations were
received for the conduct of this research.
DISCLOSURE STATEMENT
All authors declare that they have no conflicts of interest to disclose.
AUTHOR CONTRIBUTIONS
Conception and design of the work, acquisition, analysis, and
interpretation of data: Eren F, Demir A. Drafting the manuscript and
critical revision for intellectual content: Eren F, Bakdik B. Final
perusal and approval of the manuscript: Eren F, Demir A, Bakdik B.