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Human Nutrition Research Unit, Department of Agricultural, Food, & Nutritional Science, University of Alberta, 113 Street and 87 Avenue NW, 2-004 Li Ka Shing Center for Health Research Innovation, Edmonton, Alberta, Canada
Human Nutrition Research Unit, Department of Agricultural, Food, & Nutritional Science, University of Alberta, 113 Street and 87 Avenue NW, 2-004 Li Ka Shing Center for Health Research Innovation, Edmonton, Alberta, Canada
Human Nutrition Research Unit, Department of Agricultural, Food, & Nutritional Science, University of Alberta, 113 Street and 87 Avenue NW, 2-004 Li Ka Shing Center for Health Research Innovation, Edmonton, Alberta, Canada
Department of Geriatrics, Neurosciences and Orthopaedics, Catholic University of the Sacred Heart, Rome, ItalyGeriatric Department, Fondazione Policlinico Universitario Agostino Gemelli’ IRCCS, Rome, ItalyDepartment of Translational and Precision Medicine, Sapienza University of Rome, Rome, ItalyCenter for Geriatric Medicine (Ce.M.I.), Università Cattolica del Sacro Cuore, L.go F. Vito 1, Rome 00168, Italy
Center for Geriatric Medicine (Ce.M.I.), Università Cattolica del Sacro Cuore, L.go F. Vito 1, Rome 00168, ItalyDepartment of Geriatrics and Orthopedics, Università Cattolica del Sacro Cuore, Rome, ItalyOrthogeriatric Unit, Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, Italy
Human Nutrition Research Unit, Department of Agricultural, Food, & Nutritional Science, University of Alberta, 113 Street and 87 Avenue NW, 2-004 Li Ka Shing Center for Health Research Innovation, Edmonton, Alberta, Canada
Long COVID negatively impacts muscle mass, function, and quality of life.
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Longitudinal studies, including long-term assessment of muscle mass and function, can help identify the impact of long COVID on muscle health.
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Respiratory muscle dysfunction may be a marker of muscle wasting and recovery outcome during long COVID.
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Age differences should be explored in future studies to better understand how long COVID affects muscle health across the life course.
Introduction
The World Health Organization (WHO) has recently created a clinical case definition to frame a condition of symptom persistence following a coronavirus disease 2019 (COVID-19).
World Health Organization. (2021). A clinical case definition of post COVID-19 condition by a Delphi consensus, 6 October 2021. World Health Organization.
The condition, known as post-COVID-19, postacute sequelae of COVID-19, or long COVID, develops in individuals with a history of probable or confirmed SARS-CoV-2 infection in the past 3 months and encompasses a wide range of signs and symptoms that persists for weeks or months and cannot be explained by an alternative diagnosis. Long COVID symptoms can develop de novo after acute COVID-19 or persist from the initial illness. Common symptoms include, but are not limited to shortness of breath, fatigue, weakness, cognitive dysfunction, body aches, sore throat, cough, diarrhea, anosmia, and dysgeusia.
Interestingly, a high prevalence of skeletal muscle weakness and low physical performance has been reported in COVID-19 survivors without prior musculoskeletal problems.
Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study.
possibly because of the combined effect of viral infection and preexisting age-related declines in muscle mass and function.
The purpose of this narrative review is to describe the potential long-term effects of COVID-19 on muscle health in adults. We used the term muscle health to describe muscle mass and function (ie, strength and performance). Here, we describe muscle health outcomes in people with long COVID presenting with different degrees of disease severity and assessed by different body composition and physical function methods. In addition, we report the impact of long COVID on quality of life (QoL) related to muscle health.
Mechanisms of muscle damage in long COVID
After entering the human body, the spike protein of SARS-CoV-2 binds to the cell membrane receptor angiotensin converter enzyme 2 (ACE2) using the transmembrane protease, serine 2 (TMPRSS2) to deliver its genetic material.
Because ACE2 and TMPRSS2 are expressed in most tissues and organs, SARS-CoV-2 can invade and cause damage to almost all body systems, including the skeletal muscle.
In addition to direct virus-mediated injury, other factors contributing to muscle damage during a COVID-19 episode include systemic inflammation, electrolyte disturbances, critical ill myopathy, drugs (eg, corticosteroids), and hypoxia.
Systemic inflammation sustained by increased blood levels of interferon gamma, C-reactive protein, interleukin (IL) 6, IL-2, IL-10, and tumor necrosis factor α has been described in people with long COVID.
These proinflammatory cytokines are well known for their ability to negatively impact muscle protein metabolism through triggering catabolic pathways and suppressing anabolism.
The mechanisms underlying the transition from acute to chronic inflammation after a COVID-19 episode are largely unknown. Anomalous microclots enriched in acute-phase inflammatory molecules and resistant to fibrinolysis have been found in blood samples of individuals with long COVID.
Hence, it is plausible that inflammatory cytokines trapped within microclots may leak into the circulation, thereby maintaining a state of chronic inflammation. SARS-CoV-2 infection was also shown to cause long-term proinflammatory reprogramming of macrophages, possibly via epigenetic modifications.
In older COVID-19 survivors, SARS-CoV-2–induced long-term inflammation may superimpose to the age-dependent chronic inflammation (inflamm-aging), leading to more severe disruption of muscle metabolic homeostasis.
Over time, proinflammatory cytokines lead to muscle fiber proteolysis, decreased protein synthesis, hindered capacity of satellite cells to proliferate and differentiate, and eventually fibrosis.
The long tail of Covid-19' - the detection of a prolonged inflammatory response after a SARS-CoV-2 infection in asymptomatic and mildly affected patients.
observed an increase in proinflammatory biomarkers and disruption of muscle metabolic homeostasis 40 to 60 days after initial diagnosis in individuals who had mild and asymptomatic COVID-19.
Physical inactivity potentially exacerbated by quarantine and hospitalization has also a major impact on muscle mass and function.
Lastly, inadequate dietary intake and poor nutritional status, which are common during a COVID-19 episode, negatively impact skeletal muscle during recovery.
observed that ∼42% of hospitalized patients with COVID-19 were malnourished and the prevalence increased to ∼67% in those admitted to ICU. It has been hypothesized that reduced food intake caused by COVID-19 symptoms (ie, anorexia, diarrhea, vomiting, nausea, abdominal pain, anosmia, and dysgeusia) and increased nutritional needs are main factors leading to malnutrition.
Fig. 1 illustrates some of the mechanisms associated with muscle damage in individuals with long COVID.
Fig. 1Potential mechanisms of muscle damage in patients with long COVID-19. Systemic inflammatory state during the acute phase results in chronic release of proinflammatory cytokines, contributing to imbalances in muscle protein metabolism and impaired muscle health. In addition, physical inactivity due to hospitalization and quarantine as well as inadequate nutrition intake may also negatively impact muscle mass, quality, and function.
(From Servier Medical Art. Servier. Available at https://smart.servier.com/; under Creative Commons Attribution 3.0 Unported License)
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
Impact of COVID-19 in nutritional and functional status of survivors admitted in intensive care units during the first outbreak. Preliminary results of the NUTRICOVID study.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
assessed fat mass and fat-free mass (FFM) using BIA in people who recovered from mild (n = 25) and moderate (n = 23) disease severity. The 2 body compartments were not different between individuals who suffered mild or moderate disease, although a sex-specific comparison was not presented.
In a prospective cohort study, 46 patients who were admitted to the ICU and received mechanical ventilation were assessed 3 months after hospital discharge.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
Thoracic CT scans at the 12th vertebra were used to quantify skeletal muscle area, skeletal muscle radiation attenuation (an index of muscle quality), and intermuscular adipose tissue (IMAT).
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
Patients were categorized based on their performance on the 6-min walk distance (6MWD) test as having normal (n = 24) or low physical performance (<80% of predicted, n = 22).
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
Both skeletal muscle area and skeletal muscle radiation did not differ between patient subgroups; however, IMAT was higher in those with low physical performance.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
Physical performance remained significantly associated with IMAT after adjusting for age, sex, handgrip strength, and diffusing capacity for carbon monoxide.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
US images of the diaphragm muscle were assessed in 21 patients admitted to rehabilitation after severe COVID-19 and compared with 11 non–COVID-19 controls who needed ventilator support during hospitalization.
Diaphragm muscle thickness was not different between cases and controls, but the thickening ratio (ie, maximal inspiration/end-expiration) was reduced in patients who had been diagnosed with COVID-19, suggesting reduced diaphragm function.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
compared handgrip strength of 52 patients with type 2 diabetes (T2D) who had mild to moderate COVID-19 and T2D patients who did not have COVID-19 (n = 56). Although no difference in strength was found between groups, handgrip strength was significantly reduced when patients with COVID-19 were categorized into high and low fatigue scores.
These findings indicate that neither patient group had significant dynapenia, but patients with T2D who had COVID-19 had higher fatigue and lower muscle strength than those who did not have COVID-19.
Handgrip strength and quadriceps muscle strength were assessed in a cross-sectional study including patients recovering from mild (n = 25) and moderate (n = 23) interstitial pneumonia after at least 12 weeks from COVID-19 diagnosis.
The prevalence of impaired physical performance in long COVID was evaluated in 4 studies including participants with different degrees of disease severity.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
In a prospective observational study of mild to critical COVID-19 cases (n = 124), 22% of patients presented with low performance on the 6MWD test (ie, <80% of predicted) at 10 weeks after hospital discharge.
Although the prevalence of low 6MWD performance was numerically greater in individuals with moderate (28%) and severe (32%) compared with mild (12%) and critical (5%) disease, no statistical difference was found among groups, possibly due to the small sample size.
Using the same criteria to define impaired physical performance, another study observed that 48% of patients who survived critical COVID-19 had low performance on the 6MWD test at 3 months after hospital discharge.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
Notably, the greater proportion of functional impairment observed in the latter study was likely driven by patients who required mechanical ventilation during ICU stay. Tanrivedi and colleagues
compared physical performance between groups of disease severity, and found that survivors of mild (n = 25) and moderate (n = 23) COVID-19 had similar 4-m gait speed.
The longest study evaluating physical performance in long COVID assessed 238 and 198 individuals after 4 and 12 months postdischarge, respectively.
Using a cutoff of 10 on the SPPB, low physical performance was found in 22.3% and 18.7% of patients at 4 and 12 months of follow-up, respectively. Highly functioning individuals (ie, those who scored 10 or more on the SPPB) also performed a 2-min walk test at both time points; 31.5% and 7.1% of patients had a poor physical function at 4 months and 12 months follow-up, respectively. Furthermore, the proportion of patients with low performance on either the SPPB or the 2-min walk test) was smaller at 12 months (25.8%) than at 4 months (52.8%).
This finding suggests that although some patients improved their physical function as they recovered, a significant proportion of individuals was still experiencing detrimental effects of COVID-19 after 12 months of hospital discharge.
Quality of Life Related to Muscle Health
QoL is related to several factors, and not only muscle health or physical performance. However, in this article, we focused only on studies assessing QoL related to muscle health. QoL of patients diagnosed with long COVID has been reported in 4 studies that assessed muscle function.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
Impact of COVID-19 in nutritional and functional status of survivors admitted in intensive care units during the first outbreak. Preliminary results of the NUTRICOVID study.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
Impact of COVID-19 in nutritional and functional status of survivors admitted in intensive care units during the first outbreak. Preliminary results of the NUTRICOVID study.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
assessed the QoL of 46 patients 3 months after hospital discharge using the EQ-5D. Health-related QoL was lower in people with low performance on the 6MWD test (n = 22) compared with those presenting with a normal test result (n = 24). The second study is an ongoing multicenter observational study including 176 COVID-19 survivors.
Impact of COVID-19 in nutritional and functional status of survivors admitted in intensive care units during the first outbreak. Preliminary results of the NUTRICOVID study.
Preliminary results showed that 71.2% of participants were unable to move or presented with moderate impairment and 75.5% reported problems to perform daily activities.
Impact of COVID-19 in nutritional and functional status of survivors admitted in intensive care units during the first outbreak. Preliminary results of the NUTRICOVID study.
QoL of 239 patients with long COVID was assessed 3 and 6 months after the onset of COVID-19-related symptoms using the 5-level EuroQol-5 Dimensions version (EQ-5D-5 L).
; 61.9% of the patients reported they were receiving physiotherapy and 11.7% rehabilitation between 3 and 6 months of follow-up. However, 62% of the patients still presented with moderate-to-extreme problems performing daily activities, and 49% experienced moderate-to-severe pain/discomfort.
Lastly, QoL was assessed using the Nijmegen Clinical Screening Instrument in 124 patients with symptoms persisting for more than 6 weeks who attended a COVID-19 aftercare facility.
Patients were divided into 4 groups (mild: n = 27; moderate: n = 51; severe: n = 26; and critical: n = 20). Functional impairment was observed in 64% of the patients, fatigue in 69%, and reduced QoL in 72%.
Long COVID has recently only been recognized; therefore, available evidence on the impact of this condition on muscle health is limited. Overall, studies suggest that long COVID negatively impacts body composition, muscle function, and QoL.
Body composition in individuals with long COVID was not found to differ based on disease severity.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
However, this finding may be attributed to limitations of the body composition techniques used and small sample size, among others. Furthermore, the lack of body composition assessments during the acute phase and at hospital discharge hinders our understanding of whether people did experience changes in body composition, and at which disease phase. In one study, IMAT was found to be greater in patients with low physical performance.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
In fact, 4 ongoing clinical trials are investigating how abnormal diaphragm muscle thickening ratio, which is related to muscle contractility, can impact QoL of individuals with long COVID.
some studies hereby included reported worse physical performance in patients who recovered from severe COVID-19, when compared with those who had suffered a mild or moderate disease.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
observed that critically ill patients with low muscle mass who were recovering from sepsis experienced worse physical function 6 months after hospital discharge, when compared with critically ill patients with normal muscle mass. The presence of other comorbidities, such as obesity and pulmonary disease, has also been associated with symptoms of long COVID, including poor muscle function,
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
Impact of COVID-19 in nutritional and functional status of survivors admitted in intensive care units during the first outbreak. Preliminary results of the NUTRICOVID study.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
Evolution of the nutritional status of COVID-19 critically-ill patients: a prospective observational study from ICU admission to three months after ICU discharge.
malnutrition is a possible contributor to low QoL during long COVID. The relationship between QoL and nutritional status has been previously investigated in other conditions and is associated with impaired functional status and delayed recovery.
Although older adults are at greater risk for the detrimental effects of long COVID on muscle health, little is known regarding age-related differences, and whether the sequelae are worse in older compared with younger adults. Age differences should be explored in future studies to better understand how long COVID affects muscle health across the lifespan.
Finally, despite the limited literature, long COVID directly or indirectly impacts muscle health. Muscle mass and function assessments can contribute toward the identification, diagnosis, and management of poor muscle health resulting from long COVID, consequently informing the design of targeted interventions.
Early approaches to optimize muscle health throughout disease trajectory and the recovery period are essential and should involve a multidisciplinary team of health professionals.
Summary
Despite the relatively low number of studies and the presence of methodological limitations, available evidence suggests long COVID negatively impacts muscle health and QoL. These sequelae may be amplified in older adults due to preexisting age-related declines in muscle health. Acute and long-term assessments of these parameters are needed to optimize patient care. The mechanisms by which long COVID impacts muscle health are multifactorial and involve a combination of systemic inflammation, physical inactivity, poor nutritional status, and inadequate dietary intake. Other factors such as age, comorbidities, and degree of disease severity may also contribute to negative musculoskeletal outcomes during long COVID.
Overall, the evidence to date suggests long COVID negatively impacts body composition, muscle function, and QoL. Recovery and rehabilitation services with adequate nutrition, mental and social support should be explored as potential multimodal interventions to improve muscle health of these patients.
Clinics care points
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Clinicians should be aware of the prevalence and deleterious impact of poor muscle health in individuals with long COVID.
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People with long COVID can present with skeletal muscle symptoms 1 year after diagnosis.
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Muscle health in long COVID is related to low quality of life
Disclosure
The authors have nothing to disclose.
References
World Health Organization. (2021). A clinical case definition of post COVID-19 condition by a Delphi consensus, 6 October 2021. World Health Organization.
Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study.
The long tail of Covid-19' - the detection of a prolonged inflammatory response after a SARS-CoV-2 infection in asymptomatic and mildly affected patients.
Functional outcomes and their association with physical performance in mechanically ventilated Coronavirus disease 2019 survivors at 3 Months following hospital discharge: a cohort study.
Impact of COVID-19 in nutritional and functional status of survivors admitted in intensive care units during the first outbreak. Preliminary results of the NUTRICOVID study.
Evolution of the nutritional status of COVID-19 critically-ill patients: a prospective observational study from ICU admission to three months after ICU discharge.
C.M. Prado has received honoraria and/or paid consultancy from Abbott Nutrition, Nutricia, Nestlé Health Science, Fresenius Kabi, and Pfizer. The other authors declare that they have no known conflicts of interest.
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