Assessment of Musculoskeletal Pain, Fatigue and Grip Strength in Hospitalized Patients with COVID-19

IMPORTANCE Coronavirus disease 2019 (COVID-19) is an emerging disease that was declared as a pandemic by WHO. Although there are many retrospective studies to present clinical aspects of the COVID-19, still the involvement of the musculoskeletal system has not been deeply investigated. OBJECTIVE To classify the symptoms of musculoskeletal system in COVID-19 patients, to evaluate myalgia, arthralgia and physical/mental fatigue, to assess handgrip muscle strength, and to examine the relationship of these parameters with the severity and laboratory values of the disease. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study was performed at the IUC-Cerrahpaşa Pandemic Clinic. Hospitalized 150 adults with laboratory and radiological conrmation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) according to WHO interim guidance were included in the study. Data were recorded from May 15,2020, to June 30, 2020. MAIN OUTCOMES AND MEASURES Demographic data, comorbidities, musculoskeletal symptoms, laboratory ndings and CT scans were recorded. To determine the disease severity 2007 idsa/ats guidelines for community acquired pneumonia was used. Myalgia severity was calculated by numerical rating scale (NRS). Visual analog scale and Chalder Fatigue Scale (CFS) were used for fatigue severity determination. Handgrip strength (HGS) was measured by Jamar hand dynamometer. RESULTS 103 patients (68.7%) were nonsevere and 47 patients (31.3%) were severe. The most common musculoskeletal symptom was fatigue (133 [85.3%]), followed by myalgia (102 [68.0%]), arthralgia (65 [43.3%]) and back pain (33 [22.0%]). Arthralgia, which was mostly notable at wrist (25 [16.7%]), ankle (24 [16.0%]) and knee (23 [15.3%]) joints, showed signicant correlation with disease severity. There was severe myalgia according to NRS regardless of disease severity. The physical fatigue severity score was signicantly higher in severe cases, whereas no relationship was found with mental fatigue score. Female patients with severe infection had lower grip strength with a mean value of 18.26 kg (P= .010) in dominant hand, whereas no relationship was found between disease severity and grip strength in male patients, but the mean values in both genders and in decades appears below the specied normative values. Lactate dehydrogenase (LDH) level and lymphocyte count were signicantly correlated with lower grip strength. LDH, C-reactive protein (CRP) and D-dimer levels were above the normal range in patients with myalgia, arthralgia and fatigue.


Introduction
COVID-19 is an emerging disease that was declared as a pandemic by the World Health Organization (WHO) on 12 March. Up to date, 225.173 cases have been diagnosed as COVID-19 in Turkey, and 15.581.009 cases globally [1,2].
Musculoskeletal symptoms are quite common in patients with COVID-19 aside from other symptoms like fever, sore throat, dry cough, and dyspnea. Myalgia, arthralgia, and fatigue are the most common musculoskeletal symptoms; those have been reported with a peak ratio of 40%, 15%, and 85% respectively [3,4,5]. Although they are totally different, myalgia and arthralgia was usually taken into account together in majority of studies [6]. There are many retrospective studies to present clinical aspects of the COVID-19 disease, still the involvement of the musculoskeletal system has not been deeply investigated, and there is lack of terminological clarity in terms of these symptoms. Myalgia is the most frequently used term to explain all of these musculoskeletal symptoms, and this can lead to some misunderstanding results in assessing clinical presentation of the disease [7]. Perhaps, the question should be asked here, "Is myalgia good enough to explain musculoskeletal involvement in patients with COVID-19?". Recent evidence is emerging on the musculoskeletal involvement [8], and our clinical experience at the University Pandemic Clinic also supported that those symptoms were considerably common and could be quite serious during the period of disease.
To date, the most concrete rational of this rheumatologic connection is a common in ammatory environment, in other words "a cytokine storm" caused by also infectious pathway of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). IL-6 is the predominantly produced cytokine, as in response to exercise-induced destruction of muscle, and as part of the cytokine storm it can also induce muscle dysfunction [9]. Handgrip strength (HGS) is considered to be a non-invasive, simple, objective and reliable method for assessing muscle function [10].
The aim of the present study is to classify the symptoms of musculoskeletal system in COVID-19 patients, to evaluate myalgia, arthralgia and physical/mental fatigue with validated clinical scales, to assess handgrip muscle strength, and to examine the relationship of these parameters with the severity and laboratory ndings of the disease. To our knowledge, this is the rst study revealing a structured prospective musculoskeletal approach in COVID-19 patients.

Study design and participants
This cross-sectional study was performed at IUC -Cerrahpaşa Pandemic Clinic which was assigned by the government to manage patients with COVID-19.
In 133 patients who a rmed fatigue as a symptom; Chalder Fatigue Scale and physical and mental state VAS-F were performed (table 4). 120 of them have been con rmed by CFS. The mean value of physical fatigue severity score was signi cantly higher (7.  Handgrip strength values of patients were compared with normative data according to age and gender, grouped as normal and lower [16]. Laboratory correlations with normal and lower grip strength related to gender were shown in table 8.

Discussion
Coronaviruses are a large family of viruses that are known to cause mild to moderate respiratory tract infection. A novel Coronavirus was identi ed in this century and called SARS-CoV-2, and the name of the disease caused by this virus announced as COVID-19. Although some cases may be asymptomatic or present with diarrhea or anorexia, the majority of them present with the complaint of fever, cough and generalized weakness and myalgia [17]. However, in these patients, especially the musculoskeletal system complaints have not been adequately investigated, besides, our clinical experience with COVID-19 patients supported that those symptoms were considerably common and could be quite serious during the period of disease. Therefore, the purposes of this study were to reveal musculoskeletal complaints, examine the handgrip strengths and also to look into the relation between the severity and laboratory ndings of the disease with all these parameters.
Arthralgia is a quite common symptom in our study, involving mostly wrist, ankle and knee joints in patients with COVID-19. On the other hand, prevalence of arthralgia has been reported relatively low in patients with COVID-19 [5]. However, this prevalence data based on retrospective studies, and there is usually an overlap with myalgia [6]. In the present study, arthralgia is directly correlated to the disease severity. According to our data, it was related to plasma CRP, which is a proin ammatory marker, and a valuable tool in the current COVID-19 pandemic.
Myalgia is one of the most frequent symptoms in our cases with a 7.20 symptom severity score indicating "severe myalgia".
The term "muscle damage" or even "muscle injury" has been widely used to explain muscle involvement in COVID-19 patients although there is no enough data to support this statement [18]. None of our patients, even in cases with severe myalgia and fatigue, had ndings of rhabdomyolysis indicating the rapid breakdown of skeletal muscle. Moreover, there is only one case report addressing rhabdomyolysis as a potential late complication of COVID-9 [19].
LDH, which releases from cells or organs in response to tissue injury in the absence of overt cell death [20], was the most related marker in terms of myalgia and fatigue in our study. This nding supported by a new theory asserting that COVID-19 can cause musculoskeletal pain with completely different mechanisms rather than other viral infections. Increased LDH and anaerobic glycolysis lead to an increase in lactate level in muscles, and this can cause hypoxia and ischemic muscle pain. That is why, as the virus load decreases; the oxygenation of erythrocytes increases, muscle lactate level decreases, and pain relievers [21,22]. Increased expression of endothelial cell adhesion molecules, which is related to coagulopathy in COVID-19 patients [23], cause hypoxia and expressed by increased D-dimer level, which was also related with myalgia and fatigue in our study. In brief, it is possible to state that patients with COVID-19 clinically present ischemic myalgia.
CK, which is a mitochondrial protein, is thought to increase in case of injury with absence of cell death. However, pathologic con rmation was not demonstrated and additively, electron microscopic examination of ischemic area showed cells were severely damaged and necrotic [24]. This can also explain why there was no relationship between myalgia and CK indicating muscle damage in our cases. Therefore, our results indicate that muscle involvement in COVID-19 disease is mostly related to a functional impairment rather than a real tissue damage.
Some of the patients, even those who appear to have only mild symptoms initially, also end up struggle with fatigue or muscle pain that linger for weeks or months [25]. Fatigue was the most frequent nding among all of the symptoms in our cases. However, the correlation with disease activity was found only for the physical fatigue rather than mental fatigue, and this made think us that, there was a relevance between fatigue and the pathogenesis of SARS-CoV-2 infection. Patients mostly experience muscle loss, which can result in direct physical fatigue.
There are some possible causal relationships between SARS-CoV-2 and muscle wasting. First of all, increased proin ammatory cytokines in COVID-19 disease, especially elevated IL-6 levels can induce muscle atrophy by acting through the Jak/Stat3 pathway [26]. Also observations from other researches mention that, high levels of IL-6 are associated with the age-related decline in muscle function due to sarcopenia [27].
On second thought, the ubiquitin proteasome system (UPS) has been shown to play an important role in mediating muscle wasting. There is also a link Normative data for HGS values has been studied in the literature and expected normal values according to the age ranges and gender are speci ed [16]. When compared with the current normative data, the average HGS values of the patients in our study, the mean values in both genders and in decades appears below the speci ed normative values. This indicates that all patients develop a dysfunction in muscle function. When the HGS values of the patients were compared with the disease activity, the average HGS values of women decrease signi cantly with the disease activity. Likewise, Crp and ferritin values, which are in ammatory markers that show disease activity, are found to be correlated with lower grip strength in women. According to our current ndings, although there is a loss of muscle function in both sexes and all age groups, this loss of muscle function was correlated with the disease activity especially in women.
Considering current clinical musculoskeletal symptoms of COVID-19 disease, and the possible relationship between the virus and muscle metabolism, a functional impairment can be expected in patients during the disease.
Presumed limitations of this study include, having a relatively small sample in order to study the data in each age group in more detail. More studies with a larger and more diverse sample are needed to support our results.

Conclusions
Musculoskeletal symptoms are quite common aside from other multi-systemic symptoms in patients with COVID-19. Arthralgia is related to disease severity, and should be considered apart from myalgia. COVID-19 patients have severe myalgia regardless of the disease activity. Muscle involvement in COVID-19 disease seems to be related to hypoxia leading to severe ischemic myalgia and physical fatigue. Although there is a muscle weakness in all patients, the loss of muscle function is related with the disease activity especially in women. Muscular involvement in corona disease is a triangle of myalgia, physical fatigue, and functional loss.

Declarations
Author Disclosures: There was no external funding in the preparation of this manuscript.
Each author certi es that he or she, or a member of his or her immediate family, has no commercial association (i.e., consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a con ict of interest in connection with the submitted manuscript.
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