MATERIALS AND METHODS
Here a systematic review of systematic reviews and meta-analyses was conducted (Figure 1). We also cited high-quality articles in Reference Citation Analysis (https://www.referencecitationanalysis.com).
Figure 1 Flow diagram of the study.
PICOS model: (1) Studies that considered patients with long-term COVID-19 symptoms at least > 4 wk of COVID-19 infections (population); (2) Studies where the primary aim was to evaluate long-term COVID-19 symptoms in mild, moderate, severe, and critical patients that have a follow-up of at least 14 d (interventions); (3) Studies with or without a control group (comparisons); (4) Studies that reported the long COVID-19 symptoms (outcomes); and (5) Systematic review and meta-analyses (study designs). From January 2020 to mid-July 2022, any relevant studies that followed the above mentioned PICOS model and that reported musculoskeletal complications in long COVID-19 were eligible for inclusion.
The search was carried out by two independent researchers in all electronic databases, mainly MEDLINE, EMBASE, Web of Science, and Google Scholar with this time period. We combined search terms and key words related to the population (e.g., “COVID-19”, “SARS-CoV-2”, “long Covid-19”, “long Covid”, “long haulers”) and outcomes (e.g., “fatigue”, “pain”, “musculoskeletal”, “myalgia”, “myopathy”, “arthralgia”, “arthritis”, “rheumatic”, “joint”). We additionally filtered study designs “systemic review” and “meta-analyses” in humans.
Inclusion and exclusion
All the systematic reviews and meta-analyses on long COVID-19 following our above-mentioned PICOS model were included. After the preliminary search, we extracted the musculoskeletal complications that were reported in long COVID-19 studies or in post COVID-19 studies (at least 4 wk after COVID-19 active infection). We excluded any musculoskeletal issues that occurred after any neurological sequelae of long COVID-19 and excluded any myocarditis or issues related to smooth muscle dysfunction.
Study selection and data extraction
Titles and abstracts were screened for potentially eligible studies. Following an initial screening, full texts of potentially eligible studies were acquired for detailed evaluation eliminating all duplicates. Manual scanning of key articles and review papers was conducted to identify additional articles missed by the search strategy. Two reviewers assessed the articles independently and in case of any disagreements, the opinion of the third reviewer was consulted.
We performed a descriptive analysis of the included reviews.
According to the National Institute of Health and Care Excellence guidelines, post-acute COVID-19 and post-COVID-19 syndrome are included in long COVID. Post-acute-COVID-19 means ongoing symptomatic COVID-19 for people who still have symptoms 4 wk and 12 wk after acute COVID-19. On the other hand, post-COVID-19 syndrome means that patients are having persisting symptoms for > 12 wk after acute symptoms. According to the World Health Organization, post-COVID-19 conditions generally occur 3 mo from the onset of COVID-19 with symptoms lasting for at least 2 mo and should be unexplained by any alternative diagnosis.
Another definition consists of “not recovering several weeks or months following the start of symptoms that were suggestive of COVID-19, regardless individuals were tested or not”. Common symptoms reported are fatigue, shortness of breath, cognitive dysfunction/attention disorder, hair loss, and dyspnea[29,30]. Musculoskeletal symptoms of skeletal muscle, neurological, bone, and joint disorders have also been reported. The proinflammatory responses can impact nearly every organ system, including the musculoskeletal system. Myalgias, arthralgias, fatigue, exercise, and intolerance are some of the common musculoskeletal sequelae.
Why musculoskeletal system affected?
SARS-CoV-2 has three structural proteins (membrane protein, spike protein, and envelope protein). Spike glycoprotein through its subunits S1 and S2 helps in entering the host cells. The angiotensin-converting enzyme 2 (ACE2) receptor acts as the entry receptor using the serine protease trans-membrane protease, serine 2 (TMPRSS2) for spike protein priming. Following the binding of the receptor, viral spike protein is broken down by TMPRSS2 proteolytically, which exposes a fusion peptide signal that helps in the fusion of viral and human membranes. It leads to the cytoplasmic release of viral RNA. Interestingly, ACE2 is found in the lung, heart, kidney, liver, gastrointestinal, and musculoskeletal systems.
In humans, endothelial cells, smooth muscle cells, pericytes, muscle stem cells, macrophages, B cells, T cells, natural killer cells, and myonuclei express TMPRSS2. Furthermore, several cells in the synovium including fibroblasts, monocytes, B cells, and T cells express ACE2 and TMPRSS2. However, only smooth muscle cells and pericytes express ACE2. Articular cartilage (proliferative, hypertrophic, and effector chondrocytes) express ACE2, and only homeostatic chondrocytes (which control circadian rhythm in cartilage) express TMPRSS2. In the meniscus, a few cartilage progenitors and regulatory fibrochondrocytes express ACE2 (no TMPRSS2 is detected). ACE2 is also found to be present in composite unenriched cortical and trabecular bone and osteoblast enriched tissues. TMPRSS2 was almost absent in composite bone tissue, and TMPRSS2 was detected in all osteoblast-enriched samples.
The presence of these receptors implies that skeletal muscle, synovium, and cortical bone may serve as potential areas of direct SARS-CoV-2 infection and its probable long-term sequelae. The cytokines and signaling molecules are induced by the infection [C-X-C motif chemokine 10, interferon-gamma, interleukin (IL)-1β, IL-6, IL-8, IL-17, and tumor necrosis factor-alpha (TNF-α)]. They play a crucial role in the pathogenesis of clinical signs and symptoms and long-term sequelae of COVID-19. Interferon-gamma, IL-1β, IL-6, IL-17, and TNF-α show a negative impact on skeletal muscle (fiber proteolysis and decreasing protein synthesis). IL-1β and IL-6 may lead to fibrosis after inducing increased muscle fibroblast activity. IL-1β and TNF-α induce muscle fiber growth by inhibiting the differentiation and proliferation of satellite cells, the progenitor cells.
COVID-19 therapy sequelae in the musculoskeletal system
Corticosteroids, a lifesaving medication in the management of COVID-19, has been overused in many cases. Additionally, long-term corticosteroid use has been known to cause a variety of effects on the bone, including osteonecrosis, reduced bone mineral density (BMD), avascular necrosis of the hip joint, and osteoporosis with or without fracture. It implies that steroids might be an important cause of multiple musculoskeletal complications.
Skeletal muscle and fatigue
Many studies have reported fatigue myalgia and generalized weakness as some of the common persisting complaints in symptomatic infections of the disease. In the previous epidemics of SARS, extensive myalgias and muscle dysfunction were also reported. Direct viral infection and/or the cytokine storm could lead to pathological changes in skeletal muscle tissue in addition to deconditioning due to prolonged disuse during the hospitalization or disease period.
Mayer et al showed that a long intensive care unit stay is linked with a rapid and significant reduction in the volume of the rectus femoris muscle (average: 18.5%), until the 7th d of hospitalization. Carfì et al, in a study to follow up the post-COVID-19 patients in a hospital in Italy, found that in recovered patients, 87.4% responded with at least one persistent symptom, especially fatigue. Paneroni et al evaluated the muscle strength of the quadriceps and biceps femoris of patients in post-discharge recovered COVID-19 cases. They found that 86% of cases had quadriceps weakness and 73% had biceps femoris weakness. These findings proved muscle dysfunction in individuals with long COVID-19. Jacobs et al in their study to assess the persistence of symptoms and quality of life at 35 d after hospitalization of COVID-19 infection found fatigue as the most common persisting symptom.
Fatigue was found to be the most common symptom followed by shortness of breath (31%), loss of smell (22%), and muscle ache (21%) by the Office for the National Statistics, census 2021, in the estimates of the prevalence of self-reported long COVID-19 and associated activity limitation using United Kingdom Coronavirus (COVID-19) Infection Survey data. Compared with age-matched healthy controls, approximately 2-3 mo after discharge, moderate to severe cases had a 32% reduction in grip strength and a 13% reduction in the distance walked in 6 min.
Aiyegbusi et al did a review on symptoms, complications, and management of long COVID-19 and found that 47% reporting fatigue as the most common, myalgia (muscle pain) in 25%, and joint pain in 20%. Varghese et al found that 54% of the patients reported fatigue as one of the persisting symptoms. Huang et al did a follow-up study from June 16, 2020 to September 3, 2020 to assess 6 mo consequences of COVID-19 in patients discharged from the hospital, and they reported fatigue (63%) and sleep difficulties (26%) as the most common symptoms. Miyazato et al also reported fatigue as one of the prolonged and late-onset symptoms conducted in patients admitted for COVID-19 to the Disease Control and Prevention Center and National Center for Global Health and Medicine from February to June 2020. Daher et al conducted a follow-up study on 33 confirmed COVID-19 positive patients 6 wk post-discharge to assess the pulmonary and extrapulmonary disease sequelae and found a significant tendency among the patients to suffer from fatigue symptoms with significant limitations of their mobility, which was reflected by reduced 6-min walking test distance among the extrapulmonary sequelae. In their study, characterizing long COVID-19 in an international cohort over 7 mo of symptoms and their impact, Davis et al also reported the patients who have had or were suspicious of COVID-19 reported fatigue as the most common persisting symptom even after 6 mo.
Multiple etiologies of fatigue (physical, mental, emotional) could be present. Therefore, fatigue should be researched according to the accompanying symptoms or more specific features. Another sequelae is intolerance to physical activities associated with a chronic fatigue condition and difficulty in returning to normal daily life. Eighteen people living with long COVID-19 in the United Kingdom were interviewed with a semi-structured questionnaire in a qualitative study by Humphrey et al showing people faced reduced physical function, compounded by the cognitive and psychological effects of long COVID-19.
Arthralgia and myalgia
Arthralgia is pain localized to the joints, while myalgia is pain localized to muscle. They are typically present in the early course of the disease and in patients experiencing long-term effects of COVID-19 or a prolonged disease course. Studies have described how SARS-CoV-2 infection induces systemic elevations of cytokines and signaling molecules. This ‘cytokine storm’ is thought to be implicated in musculoskeletal manifestations, among many others. Myalgia and arthralgia are reported as one of the most common persistent symptoms in patients with post-acute sequelae of COVID-19 and are more notable in patients who were prone to being positioned during intensive care unit admission.
In a study of 294 patients hospitalized with COVID-19, Hoong et al observed that 30% of patients reported musculoskeletal complaints; 37.5% had myalgia, 5.7% had arthralgia, 6.8% had new-onset backache, and 50% had generalized body aches. Elhiny et al reported that physical decline was the most common symptom reported in musculoskeletal complications. Patients who also had mild to moderate forms of the infection can experience exacerbated muscle and joint pain. Petersen et al in their study of long COVID-19 in a longitudinal study in the Faroe Islands found out arthralgia is one of the most persistent symptoms following fatigue and loss of smell and taste.
Follow-up of adults with non-critical COVID-19 after symptom onset in a study by Carvalho-Schneider et al found that 13% of the patients who never had arthralgia at the onset of the disease reported arthralgia 30 d after discharge and 21% after 60 d. The study by Chopra et al on clinical predictors of long COVID-19 symptoms in patients with mild COVID-19 at 30 d post-discharge (long COVID-19) found myalgia as one of the most common persistent symptoms following fatigue and cough. Stavem et al also reported myalgia as one of the most common persisting symptoms 1.5-6.0 mo after infection in non-hospitalized patients. Ghosn et al in a large prospective cohort study in France among the post-discharge patients at 3 mo and 6 mo observed mostly fatigue, dyspnea, joint pain, and myalgia. COVID-19 has also been found to cause reactive arthritis and new-onset inflammatory arthritis typically occurring within a month after its diagnosis.
There were reported cases of reactive arthritis post discharge from COVID-19. Derksen et al in a Dutch study of 5 patients who presented with inflammatory arthritis 6.6 wk post COVID-19 infection, found that 2 patients had strongly positive and another patient had weakly positive anti-CCP antibodies, suggesting post-COVID-19 rheumatoid arthritis development.
C-X-C motif chemokine 10, IL-17, and TNF-α induce osteoclastogenesis and inhibit osteoblast proliferation and differentiation causing increased bone fragility. Berktaş et al assessed the BMD of hospitalized COVID-19 patients at diagnosis and follow-up visits using chest computed tomography. BMD was retrospectively measured by quantitative computed tomography. BMD decreased by a mean of 8.6% (± 10.5%) from diagnosis to follow-up. The osteoporosis ratio increased two-fold after hospitalization for COVID-19 because of this substantial bone loss.
An animal experimental study characterized the effects of SARS-CoV-2 infections on bone metabolism in an established golden Syrian hamster model for COVID-19. SARS-CoV-2 caused significant multifocal loss of bone trabeculae in the long bones and lumbar vertebrae of all infected hamsters implicating the same could happen in humans post-COVID-19. A multicenter study by Kottlor et al showed that COVID-19 patients requiring intensive care had significantly lower BMD than those who were managed in non-intensive care settings.
Researchers at Indiana University School of Medicine discovered that the mouse models infected with the novel coronavirus lost nearly 25% of their bone mass within 2 wk of infection. They also found mouse models with a 63% increase in osteoclasts, the cells that cause the bone to break down.
Musculoskeletal manifestations can be a result of underlying neurological disturbances. The central and peripheral nervous systems control our movements via the spinal motor neurons, which act as the final common pathway to the muscles. Many studies have reported peripheral neuropathy, most commonly Guillain-Barre and related symptoms. Guillain-Barre syndrome and critical illness-induced polyneuropathy/myopathy are two important peripheral neuropathies seen in COVID-19.
A follow-up study conducted for 8 mo in Denmark performed electromyography and conventional nerve conduction study of 20 patients with persistent fatigue. They found that all patients with myopathic electromyography reported physical fatigue; 8 patients reported about myalgia while 3 patients without myopathic changes complained about physical fatigue. Long-term COVID-19 does not cause large fiber neuropathy, but myopathic changes were seen. Acute myopathies are reported in acute COVID-19 infection, which may have a detrimental effect in the muscle in the post infective stages.
COVID-19 has multisystem effects including physical as well as psychological effects. The wholesome evaluation and rehabilitation of such patients require a multifaceted and interdisciplinary approach to cover all aspects properly. Identification of the pre-existing disabling conditions contributing to the cumulative effect of long COVID-19 is also an important aspect. Reinfection, post-viral bacterial and fungal infections, baseline routine investigations along with C-reactive protein, fibrinogen, D-dimer, troponin, and ferritin can also be considered if clinically indicated. Cardiac function tests (echocardiography) should be done to check cardiopulmonary status before framing the exercise program.
Rehabilitation should be addressed holistically following the domains of the International Classification of Functioning, Disability, and Health. Studies have shown that early mobilization helps in the reduction of the harmful effects of the disease, especially on muscle and cardiopulmonary function, mobility, and function, implying rehabilitation of long COVID-19 should start from the beginning. Physical exercise should be individualized specifying intensity, frequency, duration, and type of exercise. Exercise should be gradually increased according to one’s capacity. The patient should be educated with an emphasis on self-management. The patient should respect the pain and their own capabilities. Energy conservation techniques such as simplifying tasks, pacing the activities over time, and taking breaks should be followed. Repeated practice of functional activities and a set of specific actions according to the patient’s priorities, needs, and goals may improve the functional aspects. All such activities need to be evaluated regularly to determine whether they should be continued, changed, or stopped.
However, no studies on rehabilitation intervention have been investigated in long COVID-19 for musculoskeletal complications in particular. In our systematic reviews, we did only descriptive analysis. We did not address the individual cases or case series study or any cohort or trials, which may miss the characteristics of the individual cases in particular. However, performing a systematic review of all systematic reviews and meta-analyses provided a stronger evidence-based study.