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COVID-19 infection and long COVID affect multiple organ systems, including the respiratory, cardiovascular, renal, digestive, neuroendocrine, musculoskeletal systems, and sensory organs. Exerkines, released during exercise, have a potent crosstalk effect between multiple body systems. This review describes the evidence of how exerkines can mitigate the effects of COVID-19 in each organ system that the virus affects. The evidence presented in the review suggests that exercise should be considered a first-line strategy in the prevention and treatment of COVID-19 infection and long COVID disease.
Exercise is the Most Important Medicine
for COVID-19
Georgia Torres, PhD;
Demitri Constantinou, MBChB, FACSM;
Philippe Gradidge, PhD;
Deepak Patel, MD;
and Jon Patricios, MBBCh, MMedSci
COVID-19 infection and long COVID affect multiple organ systems,
including the respiratory, cardiovascular, renal, digestive, neuroendocrine,
musculoskeletal systems, and sensory organs. Exerkines, released during
exercise, have a potent crosstalk effect between multiple body systems.
This review describes the evidence of how exerkines can mitigate the effects
of COVID-19 in each organ system that the virus affects. The evidence
presented in the review suggests that exercise should be considered a
first-line strategy in the prevention and treatment of COVID-19 infection
The worldwide presence of COVID-19 infections continues
with sporadic spikes in infection numbers (1). The virus af-
fects multipleorgan systems, including the respiratory, cardio-
vascular, renal, digestive, neuroendocrine, musculoskeletal
systems, and sensory organs (2). In addition, long COVID
(postacute sequelae of COVID-19 [PASC]) has been identified
as a post COVID-19 infection condition that affects at least
65 million individuals worldwide (3). This chronic disease im-
pacts heart, lung, pancreas, kidney, spleen, liver, blood vessels,
and the neurological, gastrointestinal, immune, and reproduc-
tive systems with a wide variety of pathology (3). Furthermore,
COVID-19 infection and long COVID increases the risk of med-
ical conditions, including cardiac arrest, heart failure, stroke,
pulmonary embolism, diabetes, myalgic encephalomyelitis, and
dysautonomia with breakthrough afflictions of coagulation, he-
matological, pulmonary, and neurological conditions (3). There
are currently no validated effective treat-
ments for long COVID (3).
Consistently meeting physical activity
guidelines has been associated with re-
duced risk of severe COVID-19 infection
outcomes, i.e., hospitalization (22% to
42% reduction), ICU admission (34%
to 38% reduction), deterioration, and
death (43% to 83% reduction) (47),
across demographic and clinical charac-
teristics (8). Furthermore, those engaged
in regular physical activity have an 11%
to 22% lower risk of infection (6,911). The greatest benefit is
provided by achieving at least 500 metabolic equivalent of task
(MET)-min per week of physical activity, which is equivalent
to 150 min of moderate-intensity or 75 min of vigorous-intensity
physical activity per w eek (6). Studies also have found that car-
diorespiratory fitness (CRF) is a predictor of COVID-19 disease
progression and mortality (5,12,13).
Exerkines are signaling moieties that are released during ex-
ercise and affect multiple organ systems via endocrine, para-
crine, and/or autocrine pathways (14). They are released from
skeletal muscle (myokines), brown adipose tissue (baptokines),
white adipose tissue (adipokines), neurons (neurokines), heart
(cardiokines), and liver (hepatokines). This review explores
how exerkines, via molecular signals and pathways, may ame-
liorate and/or attenuate the effects of COVID-19 and long
COVID on organ systems. This will highlight how and why ex-
ercise is the most important medicine and an effective treatment
for COVID-19, and especially for long COVID.
Organ Systems Affected by COVID-19/Long COVID and
the Effect of Exercise
The Cardiovascular System, COVID-19, Long COVID, and
the Effect of Exercise
Dysregulation of the renin-angiotensin-aldosterone system
(RAAS) has been a characteristic feature in COVID-19 (2).
This system is involved in the maintenance of electrolyte bal-
ance, vascular resistance, and thus maintenance of systemic
blood pressure and cardiovascular health (15). The dysregula-
tion may cause increased incidences of thromboembolism and
hypertensive episodes. The inflammation caused in the coro-
nary arteries during COVID-19 infection may speed up the
Department of Exercise Science and Sports Medicine, Faculty of Health
Sciences, University of the Witwatersrand, Johannesburg, South Africa;
Division of Sports & Exercise Medicine, Department of Family Medicine &
Primary Care, School of Clinical Medicine, Faculty of Health Sciences,
University of the Witwatersrand, Johannesburg, South Africa; and
Sport and Health (WiSH), School of Clinical Medicine, Faculty of Health
Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Address for correspondence: Georgia Torres, PhD, Department of Exercise
Science and Sports Medicine, Faculty of Health Sciences, University of the
Witwatersrand, Johannesburg, South Africa; E-mail:
Current Sports Medicine Reports
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284 Vol u m e 22 Number 8 Augu st 2 02 3 Exercise Medicine for COVID-19
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formation of plaques and thus cause ischemic changes in the
heart (16). Electrolyte imbalance induced by the RAAS dysreg-
ulation also may lead to heart ailments seen with COVID-19
(e.g., hypokalemia can cause hyperpolarization of the cardiac
myocytes leading to arrhythmia) (17). The hypokalemia in
COVID-19 may also be caused by direct viral-mediated myo-
cardial injury leading to decreased cardiac output (18). In long
COVID, the immune-mediated inflammatory response is as-
sociated with endothelial dysfunction and thus increased risk
of deep vein thrombosis, pulmonary embolism, and bleeding
events (19). A reduction in vascular density also has been
found in patients with long COVID (20).
It is well established that exercise reduces the risk of cardio-
metabolic disease and mortality (21,22). The beneficial effects
of exercise on cardiovascular risk factors alone however, do
not account for the effects of exercise on cardiometabolic health
(14). The effect of exerkines on the cardiovascular system could
further explain how exercise is a medicine for this body system.
The exerkines, angiopoietin 1(myokine), fractalkine (myokine);
12,13 dihydroxy-9Z-octadecenoic acid (12,13 diHOME)
(baptokine), fibroblast growth factor 21 (FGF21) (hepatokine
and adipokine), IL-6 (myokine), IL-8 (myokine), musclin
(myokine and neurokine), myonectin (myokine), nitric oxide,
and vascular endothelial growth factor (VEGF) (myokines),
enhance vascularization, angiogenesis, endothelial function,
and myocardial energy utilization, thus mitigating the effects
of COVID-19 on the cardiovascular system (14). Exercise
has an anti-inflammatory effect (as is described in section 5),
which also may oppose the systemic inflammation that occurs
with COVID-19 and injures heart tissue.
In addition, the release of the muscle-derived mesenchymal stem
cells during exercise has been purported to repair cardiomyocytes
(23).This mechanism may be important when heart tissue has
been damaged with COVID-19 infection or long COVID.
The Respiratory System, COVID-19, and the Effect
of Exercise
COVID-19 can result in chronic health issues, such as im-
paired lung function, reduced exercise performance, and di-
minished quality of life. Pulmonary rehabilitation (PR) pro-
grams, including telerehabilitation programs, can be safe and
effective in improving respiratory symptoms and exercise ca-
pacity in patients with COVID-19, both during the acute
phase and in the postacute phase. Studies on the longer-term
implications of COVID-19 have emerged, and data suggest
that patients may experience prolonged symptom profiles, with
recovery only 29% at 5 months posthospitalization (24,25). At
6 months, impaired reduced pulmonary diffusing capacity per-
sists in 30% to 55% of patients, with evidence of evolving fi-
brosis (26). Studies have shown that PR can improve outcomes
in both acute and chronic COVID-19 patients, with significant
improvements in dyspnea, exercise capacity, and lung function.
A review highlighted the potential benefits of PR for patients
with preexisting pulmonary conditions and are recovering from
COVID-19 (27). Pulmonary rehabilitation should be consid-
ered as a key component of the management of COVID-19-
related respiratory symptoms. Energy conservation techniques
may play a pragmatic role in PR in mild to moderately severe
cases to counter post-COVID-19 fatigue (27).
While the COVID-19 virus primarily enters the body
through the upper respiratory tract, it is still not completely
clear which cells and tissues are initially targeted by the virus.
However, there is evidence to suggest that the virus can infect
and replicate in cells throughout the respiratory tract, includ-
ing in the upper and lower airways.
The mucosal immune system in the upper respiratory tract
plays an important role in defending against viral infections like
COVID-19. Increasing aerobic capacity can enhance immunity
through immune cells and immunoglobulins advancement and
regulating CRP levels (28). It could act as an antibiotic and anti-
oxidant, restoring normal lung tissue elasticity and strength (28).
Exercise has been shown to increase the levels and function
of immune cells like T-lymphocytes, neutrophils, macro-
phages, and monocytes, as well as increase the levels of immu-
noglobulins like IgA, which play a vital role in fighting lung in-
fections (29,30). Secretory IgA, in particular, is an antibody
that helps to neutralize viruses and prevent them from entering
cells. Further, exercise can potentially enhance the production
of secretory IgA in the respiratory tract (31). Exercise duration
may play a protective role in the respiratory tract through dis-
criminatory change in mucosal immunity through the cellular-
ity, antiviral activity, and gene expression (32).
A study that assessed whether exercise-induced myokines
would mitigate the COVID-19 infectivity of the bronchial ep-
ithelium through angiotensin-converting enzyme 2 -ACE2 in-
tonation demonstrated evidence suggesting exercise has a pro-
tective effect against COVID-19 (33).
The role of extracellular superoxide dismutase (EcSOD)
(myokine) in protecting against oxidative stress-related diseases
such as acute lung injury/acute respiratory distress syndrome
(ALI/ARDS) has been demonstrated (34). The dysregulation
and recruitment of activated neutrophils in the lung microvascu-
lature, interstitial, and alveolar space is a key step in ALI/ARDS,
leading to increased reactive oxygen species (ROS) and pro-
inflammatory mediators. EcSOD plays a critical role in the
first line of defense against superoxide generation in the lung
tissue. Studies have shown that reduced levels of EcSOD are
associated with disease development, while enhanced EcSOD
expression is protective against ROS and oxidative damage in
various pathological processes. Exercise-induced EcSOD has
been suggested as an effective therapeutic intervention for pre-
vention and treatment of numerous oxidative stress-related
diseases, including ALI/ARDS (34). The evidence supports that
exercise enhances immunity, antioxidative effects, function,
and overall benefits for the respiratory system in COVID-19.
The Neuroendocrine, Nervous System, COVID-19, Long
COVID, and the Effect of Exercise
The neurological consequences of COVID-19 infection in-
clude mild symptoms like headache, nausea, vomiting, dizziness,
loss of senses (smell and taste), and severe symptoms like ataxia,
convulsions, altered consciousness, ischemic or hemorrhagic
stroke, meningitis, encephalitis, rarely Guillain-Barré syndrome
variants, and new onset of psychotic symptoms (2). Autopsy
studies in COVID-19 deceased also have shown widespread
brain lesions (2). The impact of long COVID on the neurologi-
cal system includes tinnitus, hearing loss, vertigo, dysautonomia,
chronic fatigue syndrome, neuroinflammation, reduced cere-
bral blood flow, and small fiber neuropathy (3). It is suggested
that neurological symptoms arise due to the direct neuropathic
effect of the virus or the indirect effect of cytokine-induced
neuroinflammation (2). Current Sports Medicine Reports 285
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The exerkines apelin (adipokine and myokine), cathepsin B
(myokine), FGF21 (hepatokine and adipokine), irisin (myokine),
IL-6 (myokine), lactate (myokine), adiponectin (adipokine), and
GPLD1 (myokine) released during an exercise session increase
production of brain-derived neurotropic factor that enhances
neurogenesis, improve cognition and mood and increases syn-
aptic plasticity (14). These exerkines may thus be part of the
medicine needed for COVID-19 as they oppose the effects of
the virus. Furthermore, IL-6 increases both basal glucose up-
take and glucose transporter (GLUT4) translocation. In addi-
tion, IL-6 increases insulin-stimulated glucose uptake (23).
Thus, this exerkine may mitigate the detrimental effects of
COVID-19 on glycemic control.
A recent review on neuroendocrine symptoms of COVID-19
hypothesized that exercise attenuates β-cell dysfunction and the
long-term neuroendocrine effects of COVID-19 by moderating
the inflammatory response, supporting brain homeostasis, and
promoting insulin sensitivity (35). Long COVID also has been
associated with increased stress levels, anxiety, and depression
(35). Regular exercise has been shown to alleviate stress and
anxiety (36) and has been associated with lower odds of inci-
dent depression or an increase in subclinical symptoms (37).
The evidence indicates that exercise is an important medicine
for treating these symptoms of long COVID. In summary, exer-
cise remains a type of polypill that helps to ameliorate the harm-
ful effects of COVID-19 on the neuroendocrine system (23).
Organ Damage, COVID-19, and the Effect of Exercise
Multiorgan damage (to heart, lungs, liver, kidneys, pan-
creas, and spleen) has been associated with COVID-19 (3).
Mesenchymal stem cells released during exercise can repair
damaged myocardium and skeletal muscle tissue (23). In addi-
tion, circulating angiogenic cells released during exercise from
bone marrow mediate endothelial repair and angiogenesis.
These mechanisms may help repair the tissue damage that
the COVID-19 virus produces. Exercise also has been shown
to generate new cardiomyocytes, which would be beneficial
in the healing of damaged myocardium (38).
It also is important for damaged/nonfunctioning cells/organelles
(as can occur with COVID-19 infection) to be removed so that
body systems may function optimally. Exercise may help this
process since autophagy occurs with every exercise session,
within the heart (39), pancreas, liver, adipose tissue, brain,
and skeletal muscle (23). Noteworthy for COVID-19 rehabil-
itation is that research has identified that mitochondria are
damaged with COVID-19 infection and are involved in symp-
toms (such as fatigue) of long COVID (40). Exercise has been
found to clean-upnonfunctioning, damaged mitochondria,
and thus ensure that energy production is optimized and skel-
etal muscle health is maintained (41).
In addition, CD8+ and CD4+ T cells infiltrate injured skeletal
muscle tissue. Regulatory T cells migrate toward IL-33 and aid in
muscle regeneration by producing factors, such as amphiregulin,
that promote muscle stem cell proliferation (42).
Immunity, COVID-19, Long COVID Response, and the Role
of Exercise, Including Exercise as an Immune Adjuvant
A subthreshold and delayed protective T cell-mediated adap-
tive immune response in symptomatic patients is pronounced
in patients with severe COVID-19 in the initial period (2).
Figure: COVID-19 infection versus exercise effects.
286 Vol u m e 22 Number 8 Augu st 2 02 3 Exercise Medicine for COVID-19
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Immune dysregulation has been reported in individuals with
long COVID. This involved exhausted T cells, reduced or ab-
sent CD4
and CD8
T-cell numbers (43) and a lack of naïve
T and B cells (44,45). In addition, T-cell senescence becomes
an issue in the elderly, and this is a population that is at risk
of severe outcomes with COVID-19 infection. With increasing
age, decreased numbers of new, naïve T cells are released from
the thymus, and the ability of the adaptive immune system to
respond to novel pathogens (like COVID-19) declines (42).
Exercise has been shownto release the myokines IL-6, IL-7,
and IL-15 that specifically increase recent thymic emigrant
T-cell output from the Thymus, and promote the survival
and increase the proliferation of naïve T cells (46,47). This
may protect T cells from the effects of COVID-19 infection
and outputs. In addition, T cells and B cells are mobilized into
the blood circulation by the increase in catecholamines during
exercise and at exercise cessation the myokines are proposed
to affect immune cell redistribution and activation (48). The
immune dysregulation and lack of response that occurs with
long COVID infection, may thus be attenuated by effects of
exercise on immunity.
Furthermore, the frequent redistribution of natural killer
(NK) cells and viral-specific T (VST) cells with each exercise
bout increases immune surveillance and reduces the accumu-
lation of senescent/exhausted T cells, while maintaining the
number and diversity of naïve T cells. In turn, this reduces in-
fection risk, increases the manufacture of therapeutic VST
cells specific to latent and nonlatent viruses and increases pro-
tection provided from vaccines (46,49).
Lastly, aerobic exercise has been shown to preferentially
mobilize lymphocytes with effector functions (i.e., NK cells,
CD8+, CD4+ T cells, and γδ T cells) (50). As previously men-
tioned, these are the same Tcells that have a reduced or absent
response during COVID-19 infection. Could exercise be a
medicine for counteracting this negative effect of COVID-19?
Initial inflammation during COVID-19 infection causes the
release of pro-inflammatory cytokines (IL-6, TNF-a) (2,51)
and recruitment of peripheral immune cells. This induces more
tissue injury and in severe cases, leads to cytokine storm that con-
sequently kills T cells and delayed/or suppressed B cell-mediated
humoral response (2). Exercise can reduce this inflammation via
the action of IL-6, which when released as a myokine during ex-
ercise, has anti-inflammatory actions via the induction of IL-10
and IL-1RA by monocyte/macrophages (46). IL-6 released
during exercise also inhibits the action of pro-inflammatory cyto-
even in the elderly (42). Exercise may help reduce chronic in-
flammation (that occurs with long COVID), as a result of IL-6
(myokine) enhancing lipolysis and fat oxidation (reducing vis-
ceral fat), via a mechanism that involves AMPK activation (52).
Reducing adiposity may be beneficial to attenuating the ef-
fects of COVID-19, as circulating adipokine levels have been
associated with COVID-19 hospitalization, but not mortality
(53). Although vigorous exercise may induce short-term in-
flammatory effects, the overall effect of a moderate intensity ex-
ercise bout, is anti-inflammatory (42). Lastly, a review found
that increasing the aerobic capacity (CRF) could produce im-
provements in the function of immune and respiratory systems,
particularly specific to COVID-19 infections (28). Therefore,
exercise is an important medicine for the immune system during
COVID-19 and for long COVID as it maintains/improves
immune function, prevents immune senescence, reduces in-
flammation, mobilizes, and redistributes virus-specific T cells,
and reduces stress.
As a species, our origins as hunter-gatherers necessitated
covering large distances using multiple muscle groups daily in
the pursuit of food and water to survive (54). Challenging nat-
ural environments, the accompanying physical demands and
resultant natural selection forged our modern-day genome
(55). Being physically active was necessary for survival. In a
modern-day context, the benefits of regular physical activity
in promoting cardiovascular health (and with it survival) has
been widespread for some time (56,57). The effects of physical
activity on the immune system have more recently been well de-
scribed (58) and brought to the forefront by recent research re-
lated to COVID-19 outcomes (4,7,9) and vaccine efficacy (59).
In a recent systematic review and meta-analysis, Chastin et al.
(60) quantified the reduction in community-acquired infections
associated with habitual physical activity as 31% with a 37%
reduction in mortality. Physical activity resulted in increased
counts, greater concentrations of salivary IgA and de-
creased neutrophil counts compared with controls. Physical ac-
tivity also was associated with higher antibody responses to
vaccination (60).
Interest in the potential impact of physical activity on vaccine ef-
fectiveness also was piqued by the COVID-19 epidemic as it be-
came apparent that vaccines were a powerful tool in lowering
morbidity and mortality (61). Previous cross-sectional studies
and randomized controlled trials have demonstrated increased
postvaccination antibody titer levels in adults who engage in
regular physical activity (62,63). This effect appears tobe par-
ticularly beneficial in the elderly (64). In the first study that
used objectively-measured physical activity data, Collie et al.,
showed enhanced effectiveness of vaccination with Ad26.COV2.S
(Janssen/J&J) against COVID-19 hospital admission (59). The
study also suggested a possible dose-response.
The Figure compares the effects of COVID-19 versus the
opposingeffects of exercise to this virus. The evidence pre-
sented in this review adds to the Nieman et al. (65) viewpoint,
that it is time to include treatment for and reduced risk of
COVID-19 and long COVIDto the Exercise is Medicine list
of physical activity-related health benefits.The potent,
multi-organ effects of exerkines position exercise as the most
important medicine for COVID-19 and long COVID. How-
ever, it should be noted that the evidence exists for non-
COVID-19 patients and needs to be verified in COVID-19
and long COVID patients.
Future research needs to investigate the suggested molecu-
lar pathways and mechanisms within clinical trials of exercise
interventions for long COVID. This will allow for the map-
ping of molecular transducers and signaling pathways that
occur during exercise with individuals post COVID-19, with
long COVID.
The authorsdeclare no conflict of interest and do not have
any financial disclosures.
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Introduction Physical activity before COVID-19 infection is associated with less severe outcomes. The study determined whether a dose‒response association was observed and whether the associations were consistent across demographic subgroups and chronic conditions. Methods A retrospective cohort study of Kaiser Permanente Southern California adult patients who had a positive COVID-19 diagnosis between January 1, 2020 and May 31, 2021 was created. The exposure was the median of at least 3 physical activity self-reports before diagnosis. Patients were categorized as follows: always inactive, all assessments at 10 minutes/week or less; mostly inactive, median of 0–60 minutes per week; some activity, median of 60–150 minutes per week; consistently active, median>150 minutes per week; and always active, all assessments>150 minutes per week. Outcomes were hospitalization, deterioration event, or death 90 days after a COVID-19 diagnosis. Data were analyzed in 2022. Results Of 194,191 adults with COVID-19 infection, 6.3% were hospitalized, 3.1% experienced a deterioration event, and 2.8% died within 90 days. Dose‒response effects were strong; for example, patients in the some activity category had higher odds of hospitalization (OR=1.43; 95% CI=1.26, 1.63), deterioration (OR=1.83; 95% CI=1.49, 2.25), and death (OR=1.92; 95% CI=1.48, 2.49) than those in the always active category. Results were generally consistent across sex, race and ethnicity, age, and BMI categories and for patients with cardiovascular disease or hypertension. Conclusions There were protective associations of physical activity for adverse COVID-19 outcomes across demographic and clinical characteristics. Public health leaders should add physical activity to pandemic control strategies.
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Background Obesity is a risk factor for adverse outcomes in COVID-19, potentially driven by chronic inflammatory state due to dysregulated secretion of adipokines and cytokines. We investigated the association between plasma adipokines and COVID-19 severity, systemic inflammation, clinical parameters, and outcome of COVID-19 patients. Methods In this multi-centre prospective cross-sectional study, we collected blood samples and clinical data from COVID-19 patients. The severity of COVID-19 was classified as mild (no hospital admission), severe (ward admission), and critical (ICU admission). ICU non-COVID-19 patients were also included and plasma from healthy age, sex, and BMI-matched individuals obtained from Lifelines. Multi-analyte profiling of plasma adipokines (Leptin, Adiponectin, Resistin, Visfatin) and inflammatory markers (IL-6, TNFα, IL-10) were determined using Luminex multiplex assays. Results Between March and December 2020, 260 SARS-CoV-2 infected individuals (age: 65 [56–74] BMI 27.0 [24.4–30.6]) were included: 30 mild, 159 severe, and 71 critical patients. Circulating leptin levels were reduced in critically ill patients with a high BMI yet this decrease was absent in patients that were administered dexamethasone. Visfatin levels were higher in critical COVID-19 patients compared to non-COVID-ICU, mild and severe patients (4.7 vs 3.4, 3.0, and 3.72 ng/mL respectively, p < 0.05). Lower Adiponectin levels, but higher Resistin levels were found in severe and critical patients, compared to those that did not require hospitalization (3.65, 2.7 vs 7.9 µg/mL, p < 0.001, and 18.2, 22.0 vs 11.0 ng/mL p < 0.001). Conclusion Circulating adipokine levels are associated with COVID-19 hospitalization, i.e., the need for oxygen support (general ward), or the need for mechanical ventilation and other organ support in the ICU, but not mortality.
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Background: Both vaccination and physical activity have been shown to independently decrease the likelihood of severe COVID-19 infection. Objective: To assess the association between regular physical activity and vaccination against COVID-19 among healthcare workers. Methods: A test negative case-control study design was used to estimate the risk of having an associated COVID-19-related hospital admission, among individuals who were unvaccinated compared with those who were fully vaccinated with Ad26.COV2.S (>28 days after a single dose). 196 444 participant tests were stratified into three measured physical activity subgroups with low, moderate and high activity, to test the hypothesis that physical activity is an effect modifier on the relationship between vaccination and hospitalisation. Results: Vaccine effectiveness against a COVID-19-related admission among vaccinated individuals within the low activity group was 60.0% (95% CI 39.0 to 73.8), 72.1% (95% CI 55.2 to 82.6) for the moderate activity group, and 85.8% (95% CI 74.1 to 92.2) for the high activity group. Compared with individuals with low activity levels, vaccinated individuals with moderate and high activity levels had a 1.4 (95% CI 1.36 to 1.51) and 2.8 (95% CI 2.35 to 3.35) times lower risk of COVID-19 admission, respectively (p value <0.001 for both groups). Conclusions: Regular physical activity was associated with improved vaccine effectiveness against COVID-19 hospitalisation, with higher levels of physical activity associated with greater vaccine effectiveness. Physical activity enhances vaccine effectiveness against severe COVID-19 outcomes and should be encouraged by greater public health messaging.
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Objective To quantify the association between physical activity and risk of SARS-CoV-2 infection, COVID-19-associated hospitalisation, severe illness and death due to COVID-19 in adults. Design A systematic review and meta-analysis. Data sources Three databases were systematically searched through March 2022. Eligibility criteria for selecting studies Peer-reviewed articles reporting the association between regular physical activity and at least one COVID-19 outcome in adults were included. Risk estimates (ORs, relative risk (RR) ratios or HRs) were extracted and pooled using a random-effects inverse-variance model. Results Sixteen studies were included (n=1 853 610). Overall, those who engaged in regular physical activity had a lower risk of infection (RR=0.89; 95% CI 0.84 to 0.95; I ² =0%), hospitalisation (RR=0.64; 95% CI 0.54 to 0.76; I ² =48.01%), severe COVID-19 illness (RR=0.66; 95% CI 0.58 to 0.77; I ² =50.93%) and COVID-19-related death (RR=0.57; 95% CI 0.46 to 0.71; I ² =26.63%) as compared with their inactive peers. The results indicated a non-linear dose–response relationship between physical activity presented in metabolic equivalent of task (MET)-min per week and severe COVID-19 illness and death (p for non-linearity <0.001) with a flattening of the dose–response curve at around 500 MET-min per week. Conclusions Regular physical activity seems to be related to a lower likelihood of adverse COVID-19 outcomes. Our findings highlight the protective effects of engaging in sufficient physical activity as a public health strategy, with potential benefits to reduce the risk of severe COVID-19. Given the heterogeneity and risk of publication bias, further studies with standardised methodology and outcome reporting are now needed. PROSPERO registration number CRD42022313629.
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Physical inactivity is a well-established risk factor for chronic diseases, such as cardiovascular disease, cancer, and diabetes mellitus. There is a growing awareness that physical inactivity should also be regarded as a risk factor for acute respiratory infections (ARIs). ARIs, such as the common cold, influenza, pneumonia, and coronavirus disease 2019 (COVID-19), are among the most pervasive diseases on earth and cause widespread morbidity and mortality. Evidence in support of the linkage between ARI and physical inactivity has been strengthened during the COVID-19 pandemic because of increased scientific scrutiny. Large-scale studies have consistently reported that the risk for severe COVID-19 outcomes is elevated in cohorts with low physical activity and/or physical fitness, even after adjusting for other risk factors. The lowered risk for severe COVID-19 and other ARIs in physically active groups is attributed to exercise-induced immunoprotective effects, including enhanced surveillance of key immune cells and reduced chronic inflammation. Scientific consensus groups, including those who submitted the Physical Activity Guidelines for Americans, have not yet given this area of research the respect that is due. It is time to add “reduced risk for ARIs” to the “exercise is medicine” list of physical activity-related health benefits.
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Background Recent studies have highlighted Coronavirus disease 2019 (COVID-19) as a multisystemic vascular disease. Up to 60% of the patients suffer from long-term sequelae and persistent symptoms even 6 months after the initial infection. Methods This prospective, observational study included 58 participants, 27 of whom were long COVID patients with persistent symptoms > 12 weeks after recovery from PCR-confirmed SARS-CoV-2 infection. Fifteen healthy volunteers and a historical cohort of critically ill COVID-19 patients ( n = 16) served as controls. All participants underwent sublingual videomicroscopy using sidestream dark field imaging. A newly developed version of Glycocheck™ software was used to quantify vascular density, perfused boundary region (PBR-an inverse variable of endothelial glycocalyx dimensions), red blood cell velocity (VRBC) and the microvascular health score (MVHS™) in sublingual microvessels with diameters 4–25 µm. Measurements and main results Although dimensions of the glycocalyx were comparable to those of healthy controls, a µm-precise analysis showed a significant decrease of vascular density, that exclusively affected very small capillaries (D5: − 45.16%; D6: − 35.60%; D7: − 22.79%). Plotting VRBC of capillaries and feed vessels showed that the number of capillaries perfused in long COVID patients was comparable to that of critically ill COVID-19 patients and did not respond adequately to local variations of tissue metabolic demand. MVHS was markedly reduced in the long COVID cohort (healthy 3.87 vs. long COVID 2.72 points; p = 0.002). Conclusions Our current data strongly suggest that COVID-19 leaves a persistent capillary rarefication even 18 months after infection. Whether, to what extent, and when the observed damage might be reversible remains unclear.
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Background The Covid-19 pandemic has emerged as the leading public health challenge of our time (20th century). While vaccinations have finally blunted the death rate, concern has remained about more virulent forms highlighting the need for alternative approaches. Epidemiological studies indicate that physical activity has been shown to decrease the risk of infection of some respiratory viruses. Part of the salutary effects of exercise is believed to be through the elaboration of cytokines by contracting skeletal muscles (termed myokines). The objective of this study was to investigate whether exercise-induced myokines would mitigate the SARS-CoV-2 infectivity of the bronchial epithelium through modulating the SARS-CoV-2 Covid-19 receptor (angiotensin-converting enzyme 2 -ACE2) its priming enzyme, transmembrane serine protease 2 (TMPRSS2).Methods We utilized a cell culture model of exercise to generate myokines by differentiating C2C12 cells into myotubules and inducing them to contract via low-frequency electric pulse stimulation. Condition media was concentrated via centrifugation and applied to human immortalized human bronchial epithelium cell line (6HBE14o) along with conditioned media from unstimulated myotubules as controls. Following exposure to myokines, the 16HBE14o cells were harvested and subjected to quantitative RT-PCR and Enzyme-Linked Immunosorbent Assay (ELISA) for assessment of mRNA and protein levels of ACE2 and TMPRSS2, respectively. Pilot proteomic data was performed with isotope barcoding and mass spectroscopy.ResultsQuantitative Real-Time PCR of 16HBE14o with 48 h treated unstimulated vs. stimulated myokine treatment revealed a reduction of ACE2 and TMPRSS2 mRNA by 32% (p
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Background No effective pharmacological or non-pharmacological interventions exist for patients with long COVID. We aimed to describe recovery 1 year after hospital discharge for COVID-19, identify factors associated with patient-perceived recovery, and identify potential therapeutic targets by describing the underlying inflammatory profiles of the previously described recovery clusters at 5 months after hospital discharge. Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study recruiting adults (aged ≥18 years) discharged from hospital with COVID-19 across the UK. Recovery was assessed using patient-reported outcome measures, physical performance, and organ function at 5 months and 1 year after hospital discharge, and stratified by both patient-perceived recovery and recovery cluster. Hierarchical logistic regression modelling was performed for patient-perceived recovery at 1 year. Cluster analysis was done using the clustering large applications k-medoids approach using clinical outcomes at 5 months. Inflammatory protein profiling was analysed from plasma at the 5-month visit. This study is registered on the ISRCTN Registry, ISRCTN10980107, and recruitment is ongoing. Findings 2320 participants discharged from hospital between March 7, 2020, and April 18, 2021, were assessed at 5 months after discharge and 807 (32·7%) participants completed both the 5-month and 1-year visits. 279 (35·6%) of these 807 patients were women and 505 (64·4%) were men, with a mean age of 58·7 (SD 12·5) years, and 224 (27·8%) had received invasive mechanical ventilation (WHO class 7–9). The proportion of patients reporting full recovery was unchanged between 5 months (501 [25·5%] of 1965) and 1 year (232 [28·9%] of 804). Factors associated with being less likely to report full recovery at 1 year were female sex (odds ratio 0·68 [95% CI 0·46–0·99]), obesity (0·50 [0·34–0·74]) and invasive mechanical ventilation (0·42 [0·23–0·76]). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate with cognitive impairment, and mild, relating to the severity of physical health, mental health, and cognitive impairment at 5 months. We found increased inflammatory mediators of tissue damage and repair in both the very severe and the moderate with cognitive impairment clusters compared with the mild cluster, including IL-6 concentration, which was increased in both comparisons (n=626 participants). We found a substantial deficit in median EQ-5D-5L utility index from before COVID-19 (retrospective assessment; 0·88 [IQR 0·74–1·00]), at 5 months (0·74 [0·64–0·88]) to 1 year (0·75 [0·62–0·88]), with minimal improvements across all outcome measures at 1 year after discharge in the whole cohort and within each of the four clusters. Interpretation The sequelae of a hospital admission with COVID-19 were substantial 1 year after discharge across a range of health domains, with the minority in our cohort feeling fully recovered. Patient-perceived health-related quality of life was reduced at 1 year compared with before hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials. Funding UK Research and Innovation and National Institute for Health Research.
Frailty and a failing immune system lead to significant morbidities in the final years of life and bring along a significant burden on healthcare systems. The good news is that regular exercise provides an effective countermeasure for losing muscle tissue when we age while supporting proper immune system functioning. For a long time, it was assumed that exercise-induced immune responses are predominantly mediated by myeloid cells, but it has become evident that they receive important help from T lymphocytes. Skeletal muscles and T cells interact, not only in muscle pathology but also during exercise. In this review article, we provide an overview of the most important aspects of T cell senescence and discuss how these are modulated by exercise. In addition, we describe how T cells are involved in muscle regeneration and growth. A better understanding of the complex interactions between myocytes and T cells throughout all stages of life provides important insights needed to design strategies that effectively combat the wave of age-related diseases the world is currently faced with.
Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field. In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations. Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process. Long COVID is an often debilitating illness of severe symptoms that can develop during or following COVID-19. In this Review, Davis, McCorkell, Vogel and Topol explore our knowledge of long COVID and highlight key findings, including potential mechanisms, the overlap with other conditions and potential treatments. They also discuss challenges and recommendations for long COVID research and care.