The Relevance of a Physical Active Lifestyle and Physical Fitness on Immune Defense: Mitigating Disease Burden, With Focus on COVID-19 Consequences

Abstract

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a fast spreading virus leading to the development of Coronavirus Disease-2019 (COVID-19). Severe and critical cases are characterized by damage to the respiratory system, endothelial inflammation, and multiple organ failure triggered by an excessive production of proinflammatory cytokines, culminating in the high number of deaths all over the world. Sedentarism induces worse, continuous, and progressive consequences to health. On the other hand, physical activity provides benefits to health and improves low-grade systemic inflammation. The aim of this review is to elucidate the effects of physical activity in physical fitness, immune defense, and its contribution to mitigate the severe inflammatory response mediated by SARS-CoV-2. Physical exercise is an effective therapeutic strategy to mitigate the consequences of SARS-CoV-2 infection. In this sense, studies have shown that acute physical exercise induces the production of myokines that are secreted in tissues and into the bloodstream, supporting its systemic modulatory effect. Therefore, maintaining physical activity influence balance the immune system and increases immune vigilance, and also might promote potent effects against the consequences of infectious diseases and chronic diseases associated with the development of severe forms of COVID-19. Protocols to maintain exercise practice are suggested and have been strongly established, such as home-based exercise (HBE) and outdoor-based exercise (OBE). In this regard, HBE might help to reduce levels of physical inactivity, bed rest, and sitting time, impacting on adherence to physical activity, promoting all the benefits related to exercise, and attracting patients in different stages of treatment for COVID-19. In parallel, OBE must improve health, but also prevent and mitigate COVID-19 severe outcomes in all populations. In conclusion, HBE or OBE models can be a potent strategy to mitigate the progress of infection, and a coadjutant therapy for COVID-19 at all ages and different chronic conditions.

Full text

The Relevance of a Physical Active
Lifestyle and Physical Fitness on
Immune Defense: Mitigating
Disease Burden, With Focus on
COVID-19 Consequences
Tayrine Ordonio Filgueira
1
, Angela Castoldi
1
, Lucas Eduardo R. Santos
2,3
,
Geraldo Jose
´de Amorim
1,4
, Matheus Santos de Sousa Fernandes
2,3
,
Weydyson de Lima do Nascimento Anasta
´cio
2
, Eduardo Zapaterra Campos
2
,
Tony Meireles Santos
2
*
†
and Fabrı
´cio Oliveira Souto
1,5
*
†
1
Keizo Asami Immunopathology Laboratory, Universidade Federal de Pernambuco, Recife, Brazil,
2
Pós Graduação em
Educação Física, Universidade Federal de Pernambuco, Recife, Brazil,
3
Pós Graduação em Neuropsiquiatria e Ciências do
Comportamento, Universidade Federal de Pernambuco, Recife, Brazil,
4
Serviço de Nefrologia do Hospital das Clínicas,
Universidade Federal de Pernambuco, Recife, Brazil,
5
Núcleo de Ciências da Vida, Centro Acadêmico do Agreste,
Universidade Federal de Pernambuco, Caruaru, Brazil
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a fast spreading
virus leading to the development of Coronavirus Disease-2019 (COVID-19). Severe and
critical cases are characterized by damage to the respiratory system, endothelial
inflammation, and multiple organ failure triggered by an excessive production of
proinflammatory cytokines, culminating in the high number of deaths all over the world.
Sedentarism induces worse, continuous, and progressive consequences to health. On
the other hand, physical activity provides benefits to health and improves low-grade
systemic inflammation. The aim of this review is to elucidate the effects of physical activity
in physical fitness, immune defense, and its contribution to mitigate the severe
inflammatory response mediated by SARS-CoV-2. Physical exercise is an effective
therapeutic strategy to mitigate the consequences of SARS-CoV-2 infection. In this
sense, studies have shown that acute physical exercise induces the production of
myokines that are secreted in tissues and into the bloodstream, supporting its systemic
modulatory effect. Therefore, maintaining physical activity influence balance the immune
system and increases immune vigilance, and also might promote potent effects against
the consequences of infectious diseases and chronic diseases associated with the
development of severe forms of COVID-19. Protocols to maintain exercise practice are
suggested and have been strongly established, such as home-based exercise (HBE) and
outdoor-based exercise (OBE). In this regard, HBE might help to reduce levels of physical
inactivity, bed rest, and sitting time, impacting on adherence to physical activity,
promoting all the benefits related to exercise, and attracting patients in different stages
of treatment for COVID-19. In parallel, OBE must improve health, but also prevent and
mitigate COVID-19 severe outcomes in all populations. In conclusion, HBE or OBE
Frontiers in Immunology | www.frontiersin.org February 2021 | Volume 12 | Article 5871461
Edited by:
Pietro Ghezzi,
Brighton and Sussex Medical School,
United Kingdom
Reviewed by:
Juerg Hamacher,
Lindenhofspital, Switzerland
Alejandra Pera,
University of Cordoba, Spain
*Correspondence:
Tony Meireles Santos
tony.meireles@ufpe.br
Fabricio Oliveira Souto
fabricio.souto@ufpe.br
†
These authors have contributed
equally to this work
Specialty section:
This article was submitted to
Inflammation,
a section of the journal
Frontiers in Immunology
Received: 24 July 2020
Accepted: 13 January 2021
Published: 05 February 2021
Citation:
Filgueira TO, Castoldi A,
Santos LER, de Amorim GJ,
de Sousa Fernandes MS,
Anasta
´cio WLN, Campos EZ,
Santos TM and Souto FO (2021)
The Relevance of a Physical Active
Lifestyle and Physical Fitness
on Immune Defense: Mitigating
Disease Burden, With Focus
on COVID-19 Consequences.
Front. Immunol. 12:587146.
doi: 10.3389/fimmu.2021.587146
REVIEW
published: 05 February 2021
doi: 10.3389/fimmu.2021.587146

models can be a potent strategy to mitigate the progress of infection, and a coadjutant
therapy for COVID-19 at all ages and different chronic conditions.
Keywords: COVID-19, social isolation, sedentarism, home-based exercise, immune system
INTRODUCTION
After decades of qualified research to understand the effects of
physical inactivity and sedentarism on human health, this topic
continues to be discussed and is still a challenge to achieve
satisfactory levels of physical activity (1). The consequences of
sedentary timeline evolution are continuous, progressive,
unforgiving, and almost silent. A cyclic pattern is established,
with no precise beginning, but includes: a reduction of corporeal
capacity; an increase in physical and emotional discomfort when
exposed to higher levels of physical demand; and a sedentarism
behavioral pattern associated with any kind of exercise
avoidance, which is often associated with others dangerous
behaviors to health (2). The entrance to this vicious cycle
might be promoted by social, economic, clinical, age, gender,
schooling, race, civil status, and others factors (3). Despite these
aspects, it is outside the scope of this review to explore
these determinants.
The original silent aspect of sedentarism becomes abruptly
relevant in suddenly adverse conditions such in war, public
calamities, and pandemics, as that caused by the Severe Acute
Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) which
resulted in Coronavirus Disease-2019 (COVID-19) (4,5).
Regardless of sedentarism, in calamity conditions, humans are
exposed to mentally, physically, and nutritionally unusual
situations, with a direct impact on health, mediated by, among
other factors, the immune system (6).
SARS-CoV-2 infection compromises the immune system
affecting individuals with underlying conditions or risk factors,
such as cardiovascular and metabolic diseases on which a
sedentary lifestyle can be a risk factor for morbidity and
mortality (7,8). Hypertension, type 2 diabetes, obesity, asthma,
hematologic diseases, chronic obstructive pulmonary disease,
chronic kidney disease, immunosuppression, and advanced age
are associated with critical COVID-19 disease and higher
hospitalization rates (9,10). This raises interesting questions
about the complex interaction between sedentarism and
comorbidities, and how these impact COVID-19 outcomes,
with special attention to the role of the immune system.
In order to discuss the close relationship between the patterns
of physical activity and the consequent levels of physical fitness
and the immune system, this review aims to outline objective
considerations on the maintenance of physical activity that can
balance the immune system and increase immune surveillance. In
fact, many types of exercise, such as aerobic, strength, or combined
training, and sports in indoor or outdoor environments can
impact the immune response (11). Therefore, to promote potent
effects against the consequences ofchronic diseases associated with
the development of severe forms of COVID-19. The present
review discusses the benefits of physical activity, and special
attention was given to home-based exercise (HBE) (exercise at
home) and outdoor-based exercise (OBE) benefits as a powerful
strategy to mitigate the progress of infection and adjunctive
therapy for COVID-19 at all ages and different chronic
conditions. HBE could be a potent strategy to maintain exercise
levels regarding social distancing during quarantine periods, but
also OBE can be a formidable strategy to reinforce the
maintenance of physical activity for those who are comfortable
to go out or who are transitioning to habitual exercise practice.
PHYSICAL HEALTH AND THE IMPACT OF
ASSOCIATED COMORBIDITIES ON
COVID-19 SEVERITY
Clinical manifestations of COVID-19 arise after an incubation
period of about 5.2 days, depending mainly on age (> 70 years),
comorbidities, and on the efficiency of the immune response (12,
13). In summary, patient symptoms are reported as fever, cough,
sore throat, respiratory dysfunction, SpO2 less than 95%, and
fatigue, while other symptoms include sputum production,
headache, hemoptysis, diarrhea, vomiting, dyspnea, acute
myocardial injury, chronic cardiovascular damage, and
lymphopenia (10,14–16). These manifestations impact on
physical health, which can provide a rapid evolution of the
clinical picture. This dramatically increases the risk of
mortality from associated comorbidities (17).
The clinical spectrum of SARS-CoV-2 infection ranges from
asymptomatic to critical illness. From the documented cases of
COVID-19, 80% of individuals are asymptomatic or experience
mild symptoms to moderate disease (18). Approximately 10-15%
of the cases progress to severe disease and about 5% become
critically ill (18,19). The estimation of susceptibility to infection in
individuals under 20 years of age is approximately half that of
adults over20 years old, and clinical symptoms manifest in 21% of
infections in 10 to 19-year-olds and rise to 69% of infections in
people over 70 years old (20). In fact, the mortality rate is also
higher in elderly individuals. A systematic review, which included
113 studies, observed an exponential relationship between age and
the infection fatality rate for COVID-19. The estimated age-
specific fatality for this rate is very low for children and younger
adults (0.002% at age 10 and 0.01% at age 25), but increases
progressively to 0.4% at age 55, 1.4% at age 65, 4.6% at age 75, and
15% at age 85 (21). This reinforces the need for public health
measures to mitigate severe infection in older adults that could
substantially decrease the hospitalization and mortality rates.
Confinement reduces the level of physical activity, muscle
mass, and function, increasing the risk of metabolic and health
complications, especially in the elderly (22–24). This scenario
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can anticipate a clinical picture of sarcopenia, the condition
already demonstrated to be related to increased fragility and risk
of falls, which provide a higher incidence of negative health
outcomes, including cardiovascular and respiratory disorders,
chronic obstructive pulmonary disease, and a high mortality rate
(24–26). Pre-sarcopenia, sarcopenia, and reduced muscle
strength are associated with acute respiratory distress
syndrome (ARDS) and death (27), which can be related to the
impaired immune response in COVID-19 patients (28).
However, more studies are necessary to understand the
mechanisms behind the relationship between sarcopenia,
fragility, social isolation, and hospitalization.
Increased COVID-19 severity in hypertensive individuals is
possibly associated with the involvement of the renin-
angiotensin-aldosterone system, which has a role in the
pathology of COVID-19 infection (29). In diabetic patients,
uncontrolled glycemia is a major risk factor for the severity
and mortality of COVID-19 (30). Hyperglycemia directly
induces SARS-CoV-2 replication and proinflammatory
cytokine production (31). SARS-CoV-2-infected monocytes
present higher glycolytic activity with increased mitochondrial
ROS production, which induces stabilization of hypoxia-
inducible factor-1a(HIF-1a) and consequently promotes
glycolysis. This was shown to be necessary for viral replication.
These changes induced by HIF-1ain monocytes upon SARS-
CoV-2 infection directly inhibit T cell response and reduce
epithelial cell survival (31). Increased blood glucose is a risk
factor for COVID-19 severity, however, a better comprehension
of the impact of diabetes and insulin treatment will provide more
information about the mechanisms behind the severity of
COVID-19 patients, and in diabetic nephropathy where
angiotensin-converting enzyme 2 (ACE2) circulating activity
seems to be higher in both the early and late stages of the
disease (32). In addition, most of these patients are under
treatment for their previous comorbidity and it might account
for the COVID-19 outcomes. Many of these drugs are
immunomodulatory compounds and it impacts on the
immune response.
There is a dose-response relationship between physical
activity and health outcomes that provides a reduction in the
risk of mortality related to the aforementioned aggravating
factors (33,34), raising the hypothesis of better outcomes and
decreasing hospitalization rates related to COVID-19 disease
in physically active patients. Below, we discuss in more detail
the effects of physical activity on immune response and
chronic diseases.
COVID-19: IMMUNE RESPONSE
COVID-19 disease was highlighted as a new beta-coronavirus
pandemic, with a high risk of mortality and contagion presented
in its mild, severe, or critical form. Phylogenetic analysis shows
that SARS-CoV-2 is part of the Coronaviridae family, such as
SARS-CoV and MERS-CoV, similar pathogens previously
reported to cause severe respiratory disease in humans (35).
The genomic correlation between SARS-CoV-2 to SARS-CoV
and to MERS-CoV is 82% and 50% of genetic similarity,
respectively (36). The morphology of SARS-CoV-2 consists of
single-stranded positive RNA and the transmembrane spike
glycoprotein (S protein).
The S protein has been shown to promote the virus
connection with the ACE2 of the host with ten to twentyfold
greater affinity than SARS-CoV or MERS-CoV (37). This
enzyme is found mainly in the epithelial cells of the respiratory
tract, such as alveolar type 2 (AT2)-epithelial cells. The infection
is first established in pneumocytes and enterocytes of the small
intestine and also infects the airway club and ciliated cells of the
upper respiratory tract (38). Although, there is evidence of
SARS-CoV-2 infection in tongue keratinocytes (39). Moreover,
ACE2 is observed in the kidney and heart tissue, gastrointestinal
tract, and blood vessels, which can induce critical complications
as well (40,41).
SARS-CoV-2 infection of AT2 epithelial cells also depends on
type II transmembrane serine protease (TMPRSS2) activity (42).
The virus attaches to the ACE2 receptor, and the spike protein is
cleaved by the TMPRSS2 resulting in viral replication (42).
SARS-CoV-2 then infects AT2 epithelial cells leading to cell
death (43–46). The death of infected cells releases viral RNA (45)
and damage-associated molecular patterns (DAMPs) such as
ATP and DNA (47,48) which will result in the activation of
alveolar macrophages (49) and neighboring epithelial cells,
culminating in the secretion of the proinflammatory cytokines
interleukin (IL)-1b, tumor necrosis factor (TNF), IL-6 (46,50),
and the chemokines monocyte chemoattractant protein (MCP)-
1, macrophage inflammatory protein (MIP)1-a, MIP1-b, and
human interferon-inducible protein 10 (IP-10) (19)(Figure 1).
This initial inflammation attracts monocytes, macrophages,
and virus-specific T cells and natural killer (NK) cells to the site
of infection, where they eliminate the infected cells before the
virus spreads (49,51). Neutralizing antibodies can block viral
infection (52), and alveolar macrophages recognize neutralized
viruses in dying cells and clear them by phagocytosis (53).
Altogether, these lead to the clearance of the virus and
minimallungdamage,resultinginrecovery(Figure 1).
However, in cases of an impaired immune response, the
infection spreads preferentially to the lower respiratory tract
(54,55), leading to the severe outcomes of the COVID-19 disease
(Figure 1).
In parallel, monocytes, macrophages, and adaptive immune
cells such as CD8 T cells and CD4 T cells, are mobilized to the
respiratory tract which contributes to IFN-gsecretion, promoting
further inflammation and establishing a proinflammatory
response (54,56). Upon reaching the bloodstream, it takes
seven days for the viral load to increase due to the reduction
of systemic immune cells, mainly NK and CD8 T cells (51).
The decreased number of NK cells and CD8 T cells in the
peripheral blood in addition to marked cell exhaustion
was associated with increased expression of CD94/NK group
2 member A (NKG2A). NKG2A levels have been shown to
induce NK and CD8 T cell exhaustion in chronic viral
infections. The increased expression of NKG2A in COVID-19
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patients was associated with a decreased secretion of IFN-g, IL-2,
and granzyme B from both NK and CD8 T cells (51), suggesting
that the impaired immune response during SARS-CoV-2 is due at
least in part to exhausted NK and CD8 T cells. Moreover, the
amount of key antiviral mediators, type I and III IFN, is
diminished during SARS-CoV-2 infection, which is in contrast
with what is seen in other viral infections (50,57). This suggests
an immunomodulatory effect to SARS-CoV-2 infection, which
leads to increased systemic viral load.
The factors that trigger severe illness in individuals infected
with SARS-CoV-2 are not completely understood. However, the
development of severe disease does not seem to be only related to
A
B
FIGURE 1 |Inflammatory responses during SARS-CoV-2 infection. (A) Virus entry –nasal epithelial cells and alveolar type II epithelial cells: (1) when SARS-CoV-2
infects cells expressing the surface receptors ACE2 and TMPRSS2, (2) the active replication and (3) release of the virus induces (4) the death of host cells. (5) These
cells will then release DAMPs, including ATP and viral RNA which will be (6) recognized by neighboring epithelial cells, endothelial cells, and alveolar macrophages. (7)
Proinflammatory cytokines and chemokines (including IL-6, TNF, IL-1b, IP-10, MIP1a, MIP1b, and MCP1), will be generated by those cells. (8) These proteins attract
monocytes, macrophages, T cells, and NK cells (which will secrete IFNg) to the site of infection, promoting further inflammation. (B) Lung/alveolar immune response:
in a healthy immune response (left side), alveolar macrophages recognize neutralized viruses and apoptotic cells and clear them by phagocytosis. The initial
inflammation attracts virus-specific T and NK cells to the site of infection, where they can eliminate the infected cells before the virus spreads. In addition, neutralizing
antibodies can block viral infection and CD4 T cells mediate efficient immune response. Altogether, these processes lead to clearance of the virus and minimal lung
damage, resulting in recovery and maintaining vascular integrity. In a dysfunctional immune response (right side), this may lead to further accumulation of immune
cells (massive infiltration of monocytes, T cells, NK cells macrophages, and neutrophils in the lungs) causing overproduction of proinflammatory cytokines, which
eventually damages the lung structure leading to pulmonary edema and pneumonia. Moreover, the NLRP3 inflammasome is induced by SARS-CoV-2 in monocytes
and epithelial cells, which will result in cell death and the release of IL-18, IL-1b, and Casp1p20. The resulting cytokine storm circulates to other organs, leading to
multi-organ damage and defective systemic immune response, with decreases CD8 T cells and NK cells as well as decreases cytotoxic capacity. Moreover, SARS-
CoV-2 affects vascular epithelial cells leading to endotheliitis development, and consequent dysfunction and death of endothelial cells. In addition, accumulation of
immune cells and inflammatory cytokines might lead to loss of inter-endothelial junctions which contribute to increased vascular permeability and vascular leakage.
The increased vascular leakage leads to pulmonary edema. Moreover, activation of the coagulation pathway with the accumulation of D-dimers and secretion of
inflammatory cytokines by both epithelial cells and immune cells contribute to the systemic inflammatory response observed in severe/critical COVID-19 patients.
ACE2, angiotensin-converting enzyme 2; DAMPs, damage-associated molecular patterns; IL, interleukin; G-CSF, granulocyte colony-stimulating factor; GM-CSF,
granulocyte-macrophage colony stimulating factor; IP-10, interferon gamma-induced protein-10; MIP1, macrophage inflammatory protein 1; TNF, tumor necrosis
factor; NLRP3, NLR family pyrin domain containing 3; NK, natural killer cell; Casp1p20, Caspase-1 subunit p20.
Filgueira et al. Physical Activity, Immune System, and COVID-19
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viral load and can be associated with the defect in the type I IFN
response by T cells (19). Furthermore, during the course of
COVID-19, severe inflammation is established through the
aggressive production of proinflammatory cytokines, known as
cytokine release syndrome (58). Due to the cytokine storm, high
levels of proinflammatory cytokines circulate to other tissues,
establishing multi-organ damage, with severe and critical
COVID-19 exhibiting considerably increased serum levels of
proinflammatory cytokines including IL-6, IL-1b, IL-10, IL-2,
IL-8,IL-17,granulocytecolony-stimulating factor (G-CSF),
granulocyte-macrophage colony-stimulating factor (GM-CSF),
IP10, MCP-1, MIP1-a, IFN-g, and TNF, which is thought to be
the major cause of disease severity and death in COVID-19
patients (56)(Figure 1).
NLR family pyrin domain containing 3 (NLRP3)
inflammasome activation was also shown to contribute to the
exacerbated inflammatory response in COVID-19 patients.
Active NLRP3 was found in PBMCs and postmortem tissues
from moderate and severe COVID-19 patients. Inflammasome-
derived products such as Casp1p20 and IL-18 in the sera were
correlated with the markers of COVID-19 severity, including IL-
6 and LDH. Higher levels of IL-18 and Casp1p20 are associated
with disease severity and poor clinical outcome (59). These,
associated with increased levels of other proinflammatory
proteins lead to shock and tissue damage in several organs
such as the heart, liver, and kidney, and the development of
respiratory or multiple organ failures (19,60,61)(Figure 1).
The inflammatory events observed during COVID-19 disease
reinforces the crucial role of an effective immune response
during SARS-CoV-2 infection that depends on the release of
inflammatory molecules during the disease and shows the
importance of immune cells, especially T cell response to
control SARS-CoV-2 infection and the consequent
development of severe COVID-19.
Given that the morbidity and mortality seen in COVID-19
are mainly associated with excessive inflammation, failure in
the adaptive immune response leading to an increased viral
load, and organ failure, a better comprehension of what drives
these events upon SARS-CoV-2 infection is necessary to better
identify therapeutic targets and the best time to start the
treatment. Moreover, associated comorbidities are often related
to severe COVID-19, and it is not clear whether the impaired
immune response is a result of associated diseases or if it is a
characteristic of the SARS-CoV-2 infection that might evade the
immune system.
COVID-19: PHYSIOPATHOLOGY
Due mainly to an impaired immune response, approximately
15% of COVID-19 cases become severe/critical and progress to
severe pneumonia and about 5% develop ARDS, septic shock,
and/or multiple organ failure (19) which are often associated
with the presence of comorbidities/risk factors described before.
The disease progression associated with an excessive and
dysregulated inflammatory response may cause harmful tissue
damage at the site of virus entry and at the systemic level. This
excessive proinflammatory response has been described to
induce an immune pathology presented as complications in
bilateral pulmonary parenchyma and pulmonary opacities (62),
severe pneumonia resulting in acute lung injury, and ARDS in
severe COVID-19 patients (60) and requires artificial ventilation
(19). Clinical and laboratory findings in patients with COVID-19
pneumonia include micro-hematuria, proteinuria, and acute
kidney injury (AKI). The presence of AKI has been shown as
an important systemic complication in severe cases of COVID-
19 worldwide and was associated with higher mortality (63).
Mechanisms in which SARS-CoV-2 affects the kidneys are
multifactorial, and case series and retrospective studies
reported mechanical ventilation and hypotension requiring
vasopressors as risk factors for AKI (63). Cheng and Luo (64)
have reported an increase in serum creatinine and blood urea
nitrogen, and a decrease of estimated glomerular filtration.
Hence, these complications were associated with the hospital-
death of COVID-19 patients (64).
Besides that, SARS-CoV-2 has a high tropism for the kidney
where it has been shown to replicate in almost 30% of COVID-19
patients (65) once renal parenchyma is rich in ACE2 receptors
expression (66). Postmortem series cases were described as direct
proximal tubular cells and podocytes infection (65,67). Severe
acute tubular necrosis with lymphocyte and macrophage
infiltration, prominent acute proximal tubular injury, and
peritubular erythrocyte aggregation and glomerular fibrin
thrombi with ischemic collapse were also observed in these
patients (65,68). Thrombophilia might be associated with the
evolution of acute tubular necrosis to cortical necrosis, and
hence, nonreversible kidney injury (69). However, some studies
have reported that most hemodialysis patients might be likely to
experience mild disease which does not develop into full-blown
pneumonia, probably due to the reduced function of the immune
system and decreased cytokine storms (70).
Immune hyper-response and hyperinflammation, besides
that previously mentioned, induce generalized endothelial
damage, contributing to increased coagulation, endotheliitis,
and systemic microangiopathy (71). In fact, coagulation
abnormalities, lower platelet counts, and increased levels of
fibrin degradation products such as D-dimers have been shown
to be associated with poor prognosis and could represent the
main cause of organ failure and death in patients with severe
COVID-19 (72,73). As coagulation imbalance is a characteristic
of sepsis, mediated by proinflammatory cytokines (74), it is
possibly the trigger for the same events in COVID-19 patients.
Besides the effects on organ failure, deregulated blood
coagulation functionality is associated with the cardiovascular
and nervous systems (75,76). In this sense, microvascular
thrombosis was found in patients with COVID-19 (77). This
condition is often associated with heart dysfunction, including
tachycardia, bradyarrhythmia, and acute myocardial infarction
(77,78). Although the neurological impacts have not been
properly studied, patients with COVID-19 may present
symptoms at the neurological level, whether nonspecific,
such as headaches and confusion, or specific, such as seizure
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or cerebrovascular problems (79). They have been justified
because SARS-CoV-2 is not only restricted to the respiratory
tract but also invades the central nervous system (80). In the
circulatory structure of the nervous system, COVID-19-induced
inflammatory response must provide devastating effects through
hypercoagulability, induced by sepsis, which can cause
imbalances in proinflammatory and vasoconstricting effects in
a large proportion, resulting in irreversible brain damage,
including stroke (76,81). However, anticoagulant therapy
appears to be associated with a better prognosis in severe
COVID‐19 patients (82).
In fact, COVID-19 disturbs several systems leading to severe
outcomes in a considerable portion of the affected population.
However, the growing incidence of long-term effects of COVID-
19 opens a discussion about the consequences of this disease and
suggests that longer-ranging longitudinal observational studies
will be critical to elucidate the durability and complexity of the
health consequences of COVID-19 (83).
COVID-19: SKELETAL MUSCLE
MANIFESTATIONS
Clinical manifestations of skeletal muscle involvement have also
been described during SARS-CoV-2 infection, not only in
currently infected or recovering patients but also in uninfected
individuals during quarantine and lockdown recommendations
(84,85). Mild muscle symptoms like myalgia and muscle
weakness were reported in one-quarter to one-half of COVID-
19 patients (19,86), and more severe symptoms, such as
myocardial injury, with an elevation in cardiac damage
biomarkers (troponin I and creatine kinase-MB (CK-MB) (87)
and rhabdomyolysis have also been described (88). Moreover, it
is known that the deleterious effect of hypomobility caused by
isolation with restriction to daily activities that require
commuting and rest is associated with COVID-19 symptoms.
Evidence has shown a significant decline in cardiorespiratory
fitness, induction of insulin resistance, vein thrombosis, and
muscle atrophy due to prolonged bed rest (89,90). Therefore,
this scenario, the reduction of physical stimuli due to
hospitalization or lockdown, might boost the side effects of
COVID-19.
The skeletal muscle system is a major organ in human body
and represents almost 40% of the corporal mass in adults. It is
responsible for the force generation that allows for corporal
movement execution and daily activities (91). Skeletal muscle is a
highly organized tissue formed by bundles of myofibers (muscle
fiber) that contains several myofibrils. Each muscle fiber has a
functional unit called sarcomere which is responsible for
muscular contraction (92).
The maintenance of skeletal muscle mass depends on the
balancebetweenthemechanismsthatpromoteincreased
synthesis and/or the degradation of proteins in the myocyte
(93). Factors capable of altering this equilibrium can cause
muscle mass loss and sarcopenia (94). The regulation of protein
synthesis in muscle is attributed mainly to the insulin-like
growth factor 1-Akt/mammalian target of the rapamycin
(IGF1-Akt/mTOR) pathway and to satellite cells. First, when
stimulatedbyfactorssuchasdiet,exercise,andanabolic
hormones such as IGF-1 and testosterone, is able to promote
increased synthesis and the inhibition of muscle protein
catabolism pathways (95). Second, because there are stem cells
present in the sarcolemma of the muscle fiber, they are activated
by the injury of the cell, caused by both physical exercise and
trauma, and participate in the repair processes of muscle
tissue (96).
The activation of intracellular pathways of ubiquitin-
proteasome and myostatin (92,97), by factors such as
inflammation, angiotensin 2, and glucocorticoids disuse,
induces the regulation of atrogen expression, muscle ring finger
1 (MuRF-1) and atrogin-1, responsible for the breakdown of
muscle proteins (98).
Several mechanisms have been proposed to explain the
occurrence of wasting and muscular dysfunction in infected
SARS-CoV-2 patients. A proposed mechanism is attributed to
the direct viral infection, given that ACE receptors are widely
expressed in skeletal muscle, especially in satellite cells,
mesenchymal stem cells, endothelial cells, and lymphocytes
(99). Besides that, it was proposed that SARS-CoV-2 could
promote dysregulation in the renin-angiotensin-system with
elevation in angiotensin II (Ag-II) and a decrease in
angiotensin 1-7. Elevation in Ag-II and its interaction with the
angiotensin-1 receptor leads to augmented inflammation, and
pro-fibrotic and pro-apoptotic events in skeletal muscle (85). The
mechanisms by which SARS-CoV-2 promotes muscle wasting
and sarcopenia are described in Figure 2.
The hyper inflammation and cytokine storm, common in
COVID-19 patients, with an elevation in IFN-g, IL-1b, IL-6, IL-
17, and TNF, promotes muscular proteolysis, decreased protein
synthesis, and satellite cells dysfunction, possibly another
mechanism of muscle wasting in these individuals (100,101).
Likewise, corticosteroids therapy (102) and mechanical
ventilation, commonly used in intensive care unit (ICU)
patients (85), and physical inactivity, due to public health
recommendations for quarantine (5,103), are other factors
associated with the occurrence of skeletal muscle wasting and
sarcopenia during the COVID-19 pandemic.
Special regard is given to populations with a high prevalence
of myopathies like the elderly and dystrophic muscle carriers,
like Duchenne dystrophy, where SARS-CoV-2 infection could
promote worsening of muscle wasting, sarcopenia, and frailty
(100,104,105). After SARS infection, patients could present with
altered muscle tests and disability for a long period, and low
strength, muscle mass loss, and worsening in physical
performance have been described as long as three months after
hospital discharge (106). These findings suggest that physical and
nutritional support are fundamental for COVID-19 patient
rehabilitation, especially for the elderly.
COVID-19 has been established as a systemic disease with
mild, severe, or critical respiratory illness associated with an
important increase in inflammatory cytokines serum levels and
commitment of the immune system that plays an essential role in
Filgueira et al. Physical Activity, Immune System, and COVID-19
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SARS-CoV-2 infection. In this context, a traditional active
lifestyle might promote a complex set of benefits to mitigate
the deleterious effects of SARS-CoV-2 infection on the immune
system and, therefore, it must improve the outcome of COVID-
19 in individuals affected by comorbidities.
ACUTE AND CHRONIC EFFECTS OF
EXERCISE ON THE IMMUNE DEFENSE
A sedentary lifestyle and a low level of physical fitness are
associated with increased plasma levels of proinflammatory
cytokines, such as IL-1b,IL-6,IL-7,TNF,andC-reactive
protein (CRP) (107–109). Concomitantly, high chronic levels
of systemic proinflammatory cytokines have been associated
with a higher incidence of metabolic, cardiovascular, and
rheumatic diseases, in addition to type 2 diabetes (110–112).
In contrast, exercise is an effective therapeutic strategy to
mitigate a series of metabolic disorders (113). Besides the effect
on metabolic changes, exercise must take out potent effects
against the “cytokine storm syndrome”experienced in
COVID-19 patients. Indeed, studies have shown that an acute
stimulus of physical exercise induces myokines production, such
as myostatin, IL-6, IL-7, IL-8, IL-10, IL-15, and leukemia
inhibitory factor, which are secreted in the tissues and in the
plasma, supporting the systemic modulatory effect of physical
exercise (11). In this context, physical exercise was found to
improve cell-mediated and humoral immunity, promoting
enhanced immunosurveillance with latent therapeutic value to
the consequences of infections and chronic diseases (114). Other
studies have suggested that exercise can significantly increase
antibody responses to vaccination, mainly in patients with a low
immune defense (115,116). Besides, exercise can prevent the
incidence of viral infections, the time of the infection, and
mortalitybyviruses,suchasinfluenza, rhinovirus, and
herpesviruses (117,118).
The acute exercise-induced immune response depends on
exercise characteristics, such as type, intensity, duration (119),
and its interaction with the subject’sfitness level. Acute exercise
is viewed as an efficient stimulus to improve CD34
+
hematopoietic stem cells and mobilize cell-mediated immunity,
such as a two- to fivefold increase in the blood circulating
leukocytes (120). Exercise bouts have been reported to raise the
mobilization of NK cells, enhance neutrophil chemotaxis and
phagocytosis, and the modulation of inflammatory/alternative
activated macrophages in adipose tissue (121,122). Further, a
proportion of broad proliferation and migration of adaptive
immunity cells was found due to acute exercises, such as viral-
specific CD4 and CD8 T cells, and discrete responses in memory
T cells. High levels of effector cells reach the bloodstream, lung,
FIGURE 2 | Mechanisms by which SARS-CoV-2 promotes muscle wasting and sarcopenia. A proposed mechanism is attributed to the direct viral infection, given
that ACE receptors are widely expressed in skeletal muscle, especially in satellite cells. Another mechanism is attributed to the interaction between SARS-CoV-2 and
the ACE2 receptor in respiratory epithelial cells that diminishes the biodisponibility of the ACE2 receptor. This promotes a deregulation in the renin-angiotensin-
system with elevation in Ang II and decreasing in Ang 1-7. Ang II leads to increased levels of myostatin and IL-6 and decreased IGF-1 expression. Myostatin
modulates the intracellular signaling molecules SMAD2/SMAD3, leading to increased expression of atrogens, such as MuRF-1 and atrogin-1, and inhibits PI3K/Akt/
mTOR signaling. Moreover, increased IL-6 expression plays a role through SOCS3 which also inhibits the IGF1-R signaling pathway. Together, these activities
promote increased protein breakdown and decrease protein synthesis in muscle, which leads to muscle wasting and disability. Ang, angiotensin; MuRF-1, muscle
ring finger 1; IGF1, insulin-like growth factor 1; IGF1-R, insulin-like growth factor 1 receptor; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; mTOR,
mammalian target of rapamycin; SOCS, suppressor of cytokine signaling.
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intestine, and lymphoid tissues, which in this context are able to
defend the organism against external infectious agents, such as
SARS-CoV-2 (122). In addition, acute exercise may be related to
the improvement of humoral immunity due to the production of
myokine by muscle contraction due to muscle regeneration (11).
These findings suggest the importance of exercise since these
immune cell subtypes are closely linked to viral response, such as
the response to SARS-CoV-2.
Chronically, the effects of sessions of exercise will modulate
immune system plasticity and might result in decreased chronic
inflammation and inducing resistance against infections and
chronic diseases (123). In the infection scenario, the benefits
of chronic exercise on immune defense have been shown. In
this context, the myokines, IL-6, and IL-8 promote immune
effector cell traffic, such as leukocytes, monocytes, neutrophils,
and T cells by adhesion molecules and chemokine receptors
expression (124,125). Moreover, the myokines IL-7 and IL-15,
involved in T cell homeostasis, promote the maintenance of
immune defense in tissues, such as the lungs, against infectious
agents (11). In addition, physical exercise has been associated
with the improvement of immune defense by decreasing fat
tissue that promotes the enhancement of low-grade chronic
inflammation (126).
One of the proposed mechanisms is through the secretion
of myokines that improve glycolytic and lipolytic metabolism
(127). These metabolic effects were demonstrated by better
glycemic control and weight loss in diabetic and nondiabetic
patients (128,129). Besides that, weight loss which is
potentialized by chronic physical exercise decreases chronic
low-grade inflammation observed in obese individuals (130,
131). Furthermore, the practice of physical activity has been
associated with promoting immunity maintenance, potent
systemic anti-inflammatory action, contributing to prevent
cardiometabolic diseases (132).
Together, these studies have shown the beneficial effects of
exercise on several aspects of the immune response and suggest
that exercise training, which is associated with an efficient
immune defense and better glycemic control which is shown to
play a role in immune cell activation by SARS-CoV-2 (31) would
be an effective strategy against hospitalization rates induced by
viral respiratory diseases, such as COVID-19.
EFFECTS OF EXERCISE-MEDIATED
IMMUNE RESPONSE ON
RESPIRATORY DISEASES
Respiratory infections have been associated with acute and
chronic changes in cell-mediated immunity, promoting
increased systemic inflammation. In this sense, an impaired
immune system can be considered as a mechanism for
the development of the severe disease, and adjunctive
therapeutic strategies, such as physical exercise, would prevent
inflammation, balance the immune system, and increase
immune vigilance. In this context, studies have looked at the
effects of exercise on the modulation of the immune response
and decreasing rates of infections, such as in viral diseases (133).
Whereas few studies have shown that high-intense and
prolonged (strenuous) exercise causes the suppression of
immune defense and progressively increases the risk of
infections [“J-curve”,first reported by Nieman (134)], to
demonstrate a relationship between physical fitness and
immune function (135). Additionally, acute febrile infections
have been associated with low performance during exercise due
to muscular atrophy, circulatory disturbance, and impaired
motor coordination. Acute symptoms of infection, such as
COVID-19, warrant caution until the nature and severity of
the disease is known (136). Therefore, strenuous exercise during
viral infections and fever may be risky, but also should be
avoided until, at least, the symptoms have normalized and the
infection has ended. However, other factors were implicated in
the impairment of immune response by physical exercises, such
as age, infection history, mental stress, sleep disruption, and
nutrition (137). Together these findings reinforce the side effects
of extreme exercise before, during, or after viral infection
associated with immunosuppression and substantial morbidity
and mortality (138,139).
Generally, randomized controlled studies have reported the
impact of moderate regular exercise to decrease the incidence of
upper respiratory tract infection (URTI) (140). Other studies
have demonstrated a reduction of around 50% of the symptoms
of URTI as a result of chronic exercise. Besides the characteristics
of exercise, the incidence of URTI might be impacted by physical
fitness. In this regard, studies have related a decrease of around
28% in the incidence of URTI rates in people with high fitness
and physical activity levels. Moreover, these studies have
reported a decrease of symptoms and, mainly, a reduction in
the severity of URTI, decreasing the number of days of URTI in
43% and 46% in people who practice moderate and high fitness
capacity, respectively (135). Experimental research has shown
that higher cardiorespiratory fitness may improve lung function
and have anti-inflammatory properties (141). These effects may
be in part explained by the upregulation of ACE receptors
in the lungs, with augmented angiotensin 1-7 production.
The vasodilator, antiproliferative, and antifibrotic effects of
angiotensin 1-7 production could mitigate the deleterious
effects of COVID-19 in the lungs (141).
In parallel, the impact of exercise on influenza has already
been investigated. An experimental study reported regular
beneficial effects of moderate exercise on the inflammatory
response and reduced viral load (142). Investigational studies
have shown that physical exercise can inhibit lung inflammation
and pneumonia by bacterial colonization (143,144).
Furthermore, a clinical study with the elderly has shown that
moderate or intense training can be a modifying factor in
stronger and longer-lasting antibody responses to the influenza
vaccine (145). Moreover, the positive effects of both chronic and
acute exercise on vaccine-induced immunogenicity were
observed, and seroprotection against influenza A/H1N1 and A/
H3N2 (116,146)wassignificantly associated with chronic
exercise. Evidence has also been reported that people who
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practice exercise can have decreased respiratory tract infection
incidence, but also could reduce the breathlessness in the
postoperative patient (147).
During the COVID-19 course, an increasing number of
studies have shown mild or severe cytokine release syndrome,
characterized as a cytokine storm, in patients who develop a
severe disease (148). IL-6 is an important member of the cytokine
network and plays a central role in acute inflammation, and it
has been shown to be one target for treatment. However, it has
been known for a while that IL-6 is a pleiotropic molecule (149).
IL-6 is released into the blood during exercise and it exerts anti-
inflammatory effects in several disease models (150). However,
adaptation to exercise training must reduce IL-6 production
and counterbalance potential stimulation for IL-6 secretion
(151). It has been shown that voluntary running protects
aged mice against exacerbated sepsis-induced inflammatory
response in the lung. This effect was associated with decreased
IL-6 and neutrophil infiltration and increased endothelial
nitric oxide synthase protein in the lung after sepsis (152).
The opposite was observed during influenza infection, IL-6
knockout mice had increased mortality associated with reduced
macrophage infiltration in the lung, increased fibroblast
proliferation, decreased epithelial cell survival, and increased
collagen deposition, suggesting a role for IL-6 in regulating
fibrosis development (153,154). These findings suggest that
IL-6 is required for protection against fibrosis development
secondary to influenza infection, however, physically active
patients, adapted to regular exercise could be protected
from the severe outcome of COVID-19 by anti-inflammatory
effects of exercise adaptation, which is also associated with
decreased IL-6.
EFFECTS OF EXERCISE-MEDIATED
IMMUNE RESPONSE TO
CHRONIC DISEASES
Several studies have established the effect of physical exercise
to prevent chronic diseases, but mainly, as an efficient therapy to
treat chronic diseases (155). The immune system has been highly
recognized as the link between these areas. Chronic diseases
such as obesity, type 2 diabetes, cardiorespiratory diseases,
many cancer types, psychological disorders [e.g., depression
(156), anxiety (157), bipolar disorder (158), and post-traumatic
stress (159)], and neurodegenerative diseases [e.g., Alzheimer’s
(160) and Parkinson’s(161)] are characterized by high levels of
oxidative stress, serum systemic proinflammatory cytokines, and
immune dysfunction. The positive impact of regular exercise in
chronic degenerative diseases is summarized by its ability to
increase cell-mediated humoral immunity, systemic anti-
inflammatory myokine production, regulation of transcription
factors expression, and molecular changes in weight loss (162).
Moreover, exercise is associated with increased systemic levels
of antioxidant enzymes, including catalase (around 28%),
superoxide dismutase (74.5%), and glutathione peroxidase
(41%) (163). Along with that, low levels of these enzymes are
linked to several diseases, such as atherosclerosis, Parkinson’s
disease, and Alzheimer’s disease (164,165), suggesting that
regular physical exercise could be beneficial and improve
disease outcomes. Therefore, intensity-moderated exercise
appears to have a complete health-promoting effect involving
the regulation of redox and inflammatory homeostasis when
compared to physical inactivity groups (166).
The role of physical exercise was also shown to improve T cell
responses, increasing both NK and CD8+ T cell mobilization
into the blood, migration into the tissues, and TNF activation of
these cells (122,167,168), and this is known to be the
mechanism by which physical exercise confers protection
against cancer (169). In this regard, we would speculate that
regular physical activity might mitigate the development of
severe COVID-19 disease since increasing the activation of NK
and CD8 T cells would improve the immune response against
SARS-CoV-2.
The impact of physical exercise has also been strongly
reported as a regulatory mechanism for the immune system in
obesity (170). One way is through the reduction of adipose tissue
(171). It is well known that hypertrophy and hyperplasia of the
adipocytes generate a hypoxic environment which is the trigger
for the increased inflammation observed in the adipose tissue
during obesity. It begins with apoptosis of adipocytes and
secretion of inflammatory factors that will then recruit
monocytes that further differentiate into classical inflammatory
macrophages, increased secretion of proinflammatory cytokines
(such as TNF, IL-6, and IL-1b), and infiltration of other
immune cells, including the adaptive immune cells CD4 and
CD8 T cells (172). In this context, evidence has been reported
that moderate exercise decreases classical inflammatory markers
in blood monocytes and reduces proinflammatory chemokines
(such as C-C chemokine receptor (CCR)-5, Rantes, C-C motif
chemokine ligand (CCL)-2, and intracellular adhesion molecule
(ICAM)-1) (173). In addition, low-intensity exercise is associated
with an anti-inflammatory systemic profile characterized by
increased expression of genes related to alternative activation
of macrophages (174,175).
Moreover, physical exercise is shown to enhance insulin
sensitivity (127) and this effect is linked to IL-6 (176), which
together with IL-10 and IL-1Ra are able to reduce IL-1bsignaling
(177), and consequently decrease insulin resistance. Further,
high levels of muscle-derived IL-6 have been reported to
improve glucose uptake by AMP-activated protein kinase-
dependent pathways (127).
On the other hand, dysregulated continual production of IL-6
leads to the onset or development of various diseases. It induces
the synthesis of acute-phase proteins such as CRP, serum
amyloid A, fibrinogen, and hepcidin in hepatocytes, whereas it
inhibits the production of albumin (178). IL-6 also plays an
important role in the acquired immune response by stimulation
of antibody production and of effector CD4 T cell development
and inhibits TGF-b-induced regulatory T cell (Treg)
differentiation (179,180). During the severe stage of COVID-
19, the inhibition of the IL-6 receptor (IL-6R) is being tested in
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clinical trials, and it has shown promising results in decreasing
the cytokine release syndrome in COVID-19 patients (148). It
was shown recently (181) in a randomized controlled trial with
abdominally obese individuals who received an IL-6R blocking
antibody (tocilizumab) or placebo during a 12-week intervention
with either bicycle exercise or no exercise that the effect of
exercise in reducing visceral adipose tissue was abolished in the
presence of IL-6 signaling blockade. This suggests that IL-6
signaling is required for the beneficial effects of exercise.
Although the effects of exercise training-secreted IL-6 on
immune response modulation are well reported (148), more
data are needed in humans for a set of severe inflammatory
diseases in order to ensure the safe practice of exercise to mitigate
or to treat patients at risk of developing severe COVID-19.
A meta-analysis of randomized controlled trials established
the effectiveness of exercise in reducing the main clinic
conditions of type 2 diabetes, such as hemoglobin A1C and
insulin resistance (182,183). The beneficial effects of exercise to
treat obesity-related conditions were also associated with
decreased IL-6 and TNF observed in trained obese individuals.
Moreover, several studies have established the effect of regular
physical activity to prevent and contribute to the treatment of
cardiovascular diseases. Immunoregulation of chronic
inflammation is also one pathway by which exercise helps the
cardiovascular system, vessel tissues, and intima-media thickness
of arteries, such as the carotid (184). Another important benefit
of regular exercise is to improve the serum levels of antioxidant
molecules, promoting fibrinolytic activity, and preventing
thrombogenesis (185). Besides this evidence, future studies are
needed to confirm the effects of exercise in immunosurveillance
to viral infections in people with chronic diseases.
It is not known clearly yet if there is further chronic disease
development after COVID-19 infection. However, physical
exercise could be offered to patients recovering from COVID-
19 in order to prevent lung fibrosis complications. Studies
performed in SARS survivors showed that these patients had
mild impairment of their lung function three months to two
years after hospital discharge and most of the patients had
decreased physical exercise capacity (186,187). Another study
showed that a 6-week supervised exercise training program in
patients recovering from SARS was effective in improving both
cardiorespiratory (VO
2Max
(3.6 mL/kg/min vs 1 mL/kg/min, p=
0.04) and musculoskeletal fitness (188). This study suggests that
supervised exercise training could improve lung function in
patients recovering from SARS-CoV-2.
The studies mentioned here and in the previous sections are
detailed in Table 1.
EFFECTS OF EXERCISE ON
IMMUNOSENESCENCE AND POTENTIAL
IMPACT ON COVID-19 SEVERITY
Immunosenescence contributes substantially to decreased health
in the elderly as well as to increased systemic inflammation
during aging, termed inflammaging. Inflammaging has been
related to an increased risk of most chronic diseases in the
elderly (189). Indeed, the influence of an active lifestyle on health
in old age may lie in its impact on inflammaging, as regular
physical activity has been associated with reduced systemic
inflammation in older adults (190,191).
Advanced age is associated with remodeling of both the
innate and the adaptive immune response, which can lead
to compromised immunity and disease. The key changes
include decreased migration and antimicrobial function in
neutrophils (192) and monocytes (193), reduced quality and
quantity of antibody production by B cells (194), reduced
NK cell cytotoxicity (195), thymic atrophy (196), increased
frequency of T cells with senescent/exhausted phenotype
(197), and increased secretion of proinflammatory cytokines
and chemokines (198) by senescent cells. Moreover, increased
coagulation and fibrinolysis activity in the elderly (199) are
associated with a higher risk of age-related diseases, such as
cardiovascular disease (200).
The effects of physical activity on immunosenescence remain
unexplored. However, few studies approach this topic by
assessing immune cell phenotypes in physically active
individuals who have maintained physical activity during
adulthood. A study performing analysis on healthy males (18-
61 years old; n= 102), observed a positive correlation between
aerobic fitness (VO
2Max
) and the frequency of naïve T cells and
reduced levels of senescent/exhausted CD4 and CD8 T cells
(201). Moreover, increased frequency of naïve T cells and recent
thymic emigrants in cyclists compared with inactive older adults
was also observed by another study comparing immune profiles
in 125 adults (55-79 years) who had maintained a high level of
physical activity (cycling) during their adult lives; 75 age-
matched older adults and 55 young adults not involved in
regular exercise (202).Theactiveindividualsalsohad
significantly higher serum levels of IL-7, known to be thyme
protection, and lower IL-6, which promotes thymic atrophy,
compared to age-matched inactive older adults. Besides, cyclists
also showed additional evidence of reduced immunosenescence,
such as Th17 polarization, and higher B regulatory cell frequency
than inactive controls. However, this study did not observe
changes in the frequency of senescent/exhausted CD8 T cells
in physically active compared to inactive elderly people (202).
Taken together, these studies suggest that physical activity could
mitigate some features of immunosenescence, and consequently
improve the immune response. However, the effects of
immunosenescence on immune response against SARS-CoV-2
are not well explored. Lymphopenia occurs in over 80% of
COVID-19 patients with marked reductions in circulating levels
of CD4, CD8 T cells, and NK cells (51,203), which suggests that
immunosenescence would worsen this scenario. Associated with
that, decreased phagocytic capacity by senescent resident
macrophages may promote a proinflammatory state and impair
phagocytosis of infected epithelial cells, where an imbalanced aged
immune response is then exacerbated by COVID-19 (43–46).
Moreover, the effects of immunosenescence on the quality and
quantity of antibodies directly affect the immune response against
SARS-CoV-2, eventually leading to harmed virus neutralization,
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increased viral load, and severe COVID-19 (52). In addition to that,
the systemic low-grade inflammation in elderly individuals might
play a role in the cytokine storm observed in severe COVID-19
patients (55). Besides, coagulation defects observed in
immunosenescence might also increase COVID-19 severity, since
coagulation imbalance is a feature of severe COVID-19 (72),
impacting the mortality rate. In this scenario, the need for
physical activity becomes necessary in order to prevent the effects
of immunosenescence and to mitigate the evolution of COVID-19
disease as well as hospitalization rates.
Data constantly updated from Our World in Data (204) show
that the numbers of COVID-19 confirmed cases per one million
inhabitants in countries in which the percentage of older adults is
higher than 25% of the total population, such as in Japan
(1,339.61) and the European countries: Italy (29,277.13),
Greece (11,486.07), and Germany (14,971.34) are not as high
as in countries such as United States (46,484.71) and Brazil
(31,654.45). It is therefore suggested that the high rates of
confirmed cases do not appear to be associated with the high
prevalence of elderly people in these countries, however, the
incidence of death and hospitalization rate in the elderly is higher
compared to younger adults and a more active lifestyle by this
population might mitigate those consequences (21). It is possible
that other aspects influence the incidence of cases in the elderly
population, such as lifestyle, socioeconomic status, and public
policies to mitigate contamination (205,206).
In fact, physical inactivity is recognized as a major cause of
the development of chronic diseases (207), in which high levels
of inactivity can lead to greater damage to the immune system,
especially in the elderly. These statements seem to be in
agreement with the prevalence of physically inactive
individuals in the countries with the highest incidence of cases.
High-income Western, Asian Pacific, and Latin American
countries are among the most physically inactive worldwide
(208), according to Guthold and Stevens (208) which analyzed
1.9 million individuals from 168 countries and showed that
globally, more than a quarter of adults (27.5%, 95% UI 25.0–
32.2) were insufficiently physically active in 2016 (208). The
prevalence of insufficient physical activity ranged from 36.8%
(95% UI 34.6-38.4) in high-income Western countries, 35.7%
(95% UI 34.4-37.0) in high-income Asian Pacific, and 39.1%
(37.8–40.6) in Latin America and the Caribbean. Brazil was
found to be one of the countries with the highest prevalence of
inactivity at 47.0% (38.9–55.3) (208).
Together these data suggest that the prevalence of the elderly
population is not directly associatedwiththehighprevalenceof
COVID-19 positive cases, however, inactivity levels seem to play a role.
Corroborating, it was shown recently by an observational
study that the performance of at least 150 min per week of
moderate physical activity and/or 75 min per week of vigorous
physical activity reduces the prevalence of hospitalizations by
34.3% in a group of 938 Brazilian survivors and those completely
recovered from COVID-19 from all ages after adjustment for
age, sex, BMI, and preexisting diseases (209). This study shows
the importance of physical activity to mitigate the consequences
of COVID-19, however, the mechanisms behind this associative
effect still have to be clarified, although the beneficial effects of
physical activity on the immune system have a potential role in
the observed outcome.
PHYSICAL ACTIVITY
RECOMMENDATIONS TO IMPROVE THE
IMMUNE SYSTEM
In order to maintain physical fitness levels during social
distancing periods, protocols to maintain exercise practice are
suggested. The American College of Sports Medicine (ACSM)
has been consolidating the ideal recommendations, as type,
frequency, duration, and intensity to promote health benefits
by physical exercise to all age groups (210,211). The
recommendation based on exercise characteristics is known to
be associated with different immune responses and immune
surveillance, especially the intensity (212). Since exercise
became an important way to maintain a healthy immune
system and its benefits embrace individuals of all ages, it is
important to adapt the practice to each age group and existing
chronic conditions in order to avoid injuries and side effects.
Table 1 summarizes the effects of physical activity protocols
on the immune response. It is important to note that moderate
exercise improves several aspects of the immune system in both
young and elderly individuals (from 18 to 85 years old). As
described in previous sections, the beneficial effects of physical
activity are broad and range from a decreased inflammatory
profile, modulation of immune cells mobilization to decreased
URTI infections, and increased antibody levels. Both short and
longer physical exercise practice induced benefit effects.
However, there is evidence that long periods of high-intensity
exercise for long periods seem to induce immunosuppression
and may be associated with later increased proinflammatory
cytokines. Furthermore, a period of at least two weeks (Short-
term Chronic Exercise) of physical activity is sufficient to
positively stimulate the immune system, modulating cell
migration and cytokine secretion, and inducing long-term
effects. On the other hand, acute exercise sessions induce acute
effects on the immune system, which return to basal levels
shortly afterward. The observed long-term effects of physical
activity on the immune system are linked to improved quality of
life and decreased severity of several disease states, including
COVID-19. In general, the studies described in Table 1 reinforce
the potential benefits of physical activity in promoting
immune defense.
Accordingly, to the ACSM, a good way to promote health in
different clinical conditions is to adapt the exercises following
moderate intensity (40%-59% of reserve heart rate or oxygen
uptake, 12-13 of Ratings of Perceived Exertion, and 50%-69% of
one maximum repetition), no less than 30 min of duration and at
least five days a week with professional support (213). In
addition, 20 min of vigorous physical activity (60%-89% of
reserve heart rate or oxygen uptake, 14-17 of Ratings of
Perceived Exertion, and 70%-84% of one maximum repetition)
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TABLE 1 | Summary findings of the effects of acute and chronic exercise protocols in immune response.
Type of
study
Methods Findings
Sample Exercise protocol
Type Frequency Intensity Duration
Philips
et al. (113)
Cross-
sectional
study
396 adults
(ages 50–69
years)
General
physical
activities
7
consecutive
days
Moderate to
vigorous
physical
activity
–30 min of the physical activity was associated with higher
adiponectin and lower complement component C3, leptin, IL-
6 and white blood cells concentrations. In obese subjects,
moderate to vigorous physical activity was associated with
lower white blood cells concentrations.
Edwards
et al. (115)
Randomized
controlled trial
133 young
healthy
adults
Resistance
training
1 session Sets of 30
seconds of
exercise and
30 seconds
of rest
15 min per
session
Exercise increased antibody levels. Therefore, these results
indicate the effectiveness of exercise as a vaccine adjuvant.
Williams
(117)
Cohort study 109,352
runners and
40,798
walkers
Aerobic
training
–––Higher doses of running and walking have decreased the
respiratory disease mortality in 7.9% per MET-hour per day
and 7.3% for all respiratory disease-related deaths.
Pneumonia mortality decreased 13.1% per MET-hour per
day, but also 10.5% per MET-hour per day for all pneumonia-
related deaths.
Diment
et al. (119)
Experimental 64 healthy
and
recreationally
active males
Aerobic
training
1 session 60% V˙
O2peak
(30MI); 80%
V˙O2peak
(30HI); 60%
V˙O2peak
(30MI)
30 min per
session;
30 min per
session;
120 min per
session
Immune induction by DPCP was impaired just by 120 min
per session group.
Mobius-
Winkler
(120)
Experimental 18 healthy
young men
Aerobic
training
1 session 70% of their
individual
anaerobic
threshold.
240 min A significant increase in leukocytes, as a very early rise in
vascular endothelial growth factor and later increase in IL-6.
All observed changes were normalized 24 hours after
finishing the test.
Campbell
et al. (122)
Experimental 13 healthy
and
physically
active males
with age
20.9 ± 1.5
years old
Aerobic
training
–35%
Wattmax
(low intensity
exercise);
and 85%
Wattmax
(high
intensity
exercise)
20 min High intensity exercise induced strong differential mobilization
of CD8TL subsets that exhibit a high effector and tissue-
migrating potential (RAEM > EM > CM > naïve). Increased NK
cells mobilization attributed to increased CD56dim NK cells.
Nieman
et al. (135)
Observational
study
1002 adults
(ages 18–85
years,
60% female,
40% male)
Aerobic
training
–– 12 weeks The number of days with URTI was significantly reduced,
43% in subjects reporting daily aerobic exercise compared to
those who were largely sedentary and 46% when comparing
subjects with low fitness routine. The URTI severity and
symptomatology were also reduced 32% to 41% between
high and low aerobic activity routine.
Matthews
et al. (140)
Observational
study
547 healthy
adults (49%
women)
aged 20–70
years old
Moderate-
vigorous
activity
–––The risk of URTI event was reduced by about 20% in men
and women.
de Araujo
et al. (145)
Cross-
sectional
61 healthy
elderly men
with 65-85
years
Sports, and
Aerobic
running
(Volleyball,
Basketball or
Running)
≥5 days/
Week
Moderate,
and Intense
Maintenance
of active
lifestyle for 5
years
Subjects who practiced moderate or intense physical training
had long-standing antibody responses to the influenza
vaccine components, resulting in higher percentages of
seroprotection.
Bhatt et al.
(147)
Prospective
case control
study
30 cases
and 30 case
matched
controls
aged 18
years or
more
Aerobic
training
2 days
(Acute
exercise)
Moderate (≥
70% of max
heart rate)
10 minutes
per session
The practice of early aerobic activity with a pedaler halves the
rate of respiratory tract infection and postoperative
hospitalization after complex abdominal surgery. In addition,
in the subjective shortness of breath, there was also a
reduction with the use of a pedal exerciser, meaning the
potential to improve resistance to exercise in the
postoperative patient.
(Continued)
Filgueira et al. Physical Activity, Immune System, and COVID-19
Frontiers in Immunology | www.frontiersin.org February 2021 | Volume 12 | Article 58714612

at least three days a week, besides staying active throughout the
day with daily activities was recommended (213).
To attain the recommended target, an option is to combine
moderate and vigorous physical exercise corresponding to a
demand of ≥500 to 1000 metabolic equivalent of task (MET)-
minutes per week (considering that 1 MET corresponds to the
consumption of 3.5 mL of oxygen for each kilogram of body
mass per minute) which correspond to ≥5400–7900 steps/day or
approximately 4-6 km (213). The previous recommendations
characterized the individuals as ‘active’if they reached the
minimum of 10,000 steps/day, which corresponds to
approximately 7.5 km (214). However, more recently, it was
established that a number > 7500 steps/day (5.7 km) seems to be
enough for individuals to achieve the recommended daily energy
expenditure (215). As shown by Tudor-Locke and Craig (215), it
seems prudent to use the number of steps to identify the level of
sedentary physical activity and behavior. However, some
limitations need to be considered regarding the characteristics
of the investigated populations, the instruments used to quantify
the steps, and the variety of body movements that are not
characterized as steps, but have a fundamental role in the daily
energy expenditure (215).
The recommendations mentioned above are based on the
performance of aerobic activities, however, the ACSM also
suggests the implementation of routines to maintain or
increase muscular strength and endurance for at least two days
TABLE 1 | Continued
Type of
study
Methods Findings
Sample Exercise protocol
Type Frequency Intensity Duration
Tyml et al.
(152)
Animal study Male
C57BL/6
mice
Voluntary
running wheel
1-3 days
per Week
High levels of
voluntary
physical
activity
8 weeks Voluntary running has been able to protect against
exacerbated sepsis induced by inflammatory and pro
coagulant responses in aged mice. These were due to
increased eNOS protein after running exercise.
Bigley
et al. (168)
Randomized
Trial
Twelve male
and four
female
trained, and
non-
smoking
cyclists
Aerobic
training
1-3 Weeks Incremental
protocol with
power
variation 5%
to 15%
Continuous
cycling for 30
minutes
Physical exercise was able to promote a preferential
redistribution of subsets of NK cells with a highly
differentiating phenotype and increases cytotoxicity against
HLA expression target cells.
Baturcam
et al. (173)
Experimental
study
Adult male
and female
nondiabetic
subjects
Aerobic and
resistance
training
3 to 5 times
per Week
Moderate (50
- 60% of
max heart
rate)/
Vigorous (65
- 80% of
max heart
rate)
3 months Physical exercise significantly decreased expression of
RANTES and CCR5 in adipose tissue of obese patients with
concomitant reduction in TNF, IL-6, and p-JNK.
Yakeu
et al. (174)
Experimental
study
17 healthy
adults
Aerobic
training
3 times per
Week
Low intensity
(10.000
steps/week)
8 weeks Physical exercise was associated with the positive regulation
of markers linked to the function of M2 macrophages, PGC-
1aand PGC-1b. However, it negatively regulated the
functionality of the M1 macrophage markers. In addition,
plasma levels of Th2 cytokines increased after exercise, while
those of Th1 cytokines decreased.
Barry et al.
(175)
Randomized
controlled trial
37 inactive
obese 30–
65 years old
High Intense
Interval
Training (HIIT)
and Moderate
Intensity
Continuous
Training
(MICT)
5 times per
week
–2 weeks
(equivalent to
10 sessions)
Moderate-intensity continuous training decrease percentage
of monocytes positives for receptor C-C motif chemokine
receptor, reduced surfaced protein expression of C-X-C
chemokine receptor on monocyte, in addition high intensity
interval training increased protein expression and percentage
CCR5 positive monocytes, T cells and neutrophils.
Wedell-
Neergaard
et al. (181)
Randomized
controlled trial
53 patient
samples (27
exercise and
26 non-
exercise)
Aerobic
training
3 times per
Week
High intensity
interval
training (50 -
85% of
VO
2max
)
12 Weeks Physical exercise reduced visceral fat. The effect of exercise
was abolished in the presence of IL-6 blockade. Blocking IL-
6 increased cholesterol levels, an effect not reversed by
physical exercise. Therefore, IL-6 is necessary for exercise to
reduce visceral fat tissue mass and emphasizes a potentially
important metabolic consequence of IL-6 blockade
IL-6, Interleukin 6; MET, Metabolic equivalent of task; DPCP, Diphenylcyclopropenone; RAEM, CD45RA+ effector-memory; EM, Effector memory; CM, Central memory; NK, Natural Killer;
URTI, Upper respiratory tract infection; eNOS, Nitric oxide synthase 3; HLA, Human leukocyte antigen; CCR5, C-C chemokine receptor type 5; TNF, Tumor Necrosis Factor; p-JNK, c-Jun
N-terminal kinase; PGC-1a, Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha; PGC-1b, Peroxisome proliferator-activated receptor-gamma coactivator 1 beta;
CCR5, C-C chemokine receptor type 5.
Filgueira et al. Physical Activity, Immune System, and COVID-19
Frontiers in Immunology | www.frontiersin.org February 2021 | Volume 12 | Article 58714613

a week (213). Ideally, individuals should train each major muscle
group for a total of 2-4 sets with 8-12 repetitions and rest
intervals between sets of 2-3 min and between sessions of 48 h
(213). The recommended intensity to improve muscular strength
ranges from 60% - 70% of one maximum repetition (1-RM) in
moderate intensities and ≥80% of 1-RM in vigorous intensities
(213). In addition, the ACSM also recommended at least two
days a week for a series of flexibility exercises for each major
muscle-tendon group (holding static for 10-30 s) and
neuromotor activities to improve balance, agility, coordination,
and gait for 20-30 min per day (213).
Also, the following recommendations for preventing
undesirable effects of exercise in people with pulmonary and
respiratory diseases suggest that exercise should be a mandatory
component of pulmonary rehabilitation (213). Regarding the
individuals with asthma, volume and exercise type are similar to
the usual recommendations, but it is suggested that they make
progressive and slight increases in intensity, beginning with
moderate intensities and if well-tolerated progress to 60%-70%
of reserve heart rate (213). These recommendations could be
achieved in different facility contexts, including HBE with
appropriate adequacy and creativeness to build a viable
exercise program.
On the other hand, an excessive increase over a long period of
training load has been described as a variable that negatively
impacts immune cells. As previously discussed, the practice of
prolonged exhaustive exercise was associated with an increase in
the risk of common infectious diseases. Additionally, few studies
have related the practice of prolonged intensive exercise as the
cause of acute immunosuppression (201), like the
immunodeficiency “window”, increasing the odds of illness,
such as COVID-19 (132). Evidence has suggested that
increased levels of anti-inflammatory cytokines during intense
and prolonged exhaustive exercise, might lead to an increased
risk of the development of URTI (216). Therefore, practicing
exercise in closed environments and crowding might favor the
transmission of viruses and should be avoided (217). Future
studies and guidelines should explore this subject.
In parallel, a point to be considered is the season, especially
winter, which reverberates in the immune system, increasing the
risk of infectious diseases (135,216). As well as the temperature
change which affects energy supply to the immune system,
decreasing the immune surveillance, and consequently, greater
exposure to upper respiratory tract-related diseases (218,219).
HOME-BASED EXERCISE AND
OUTDOOR-BASED EXERCISE
The World Health Organization (WHO) guideline recommends
at least 150 to 300 min per week of moderate or 75 to 150 min of
vigorous-intensity exercise per week, besides a combination of
both, including aerobic resistance, and flexibility exercise
protocols to all adults, including the elderly and patients with
chronic health conditions or disability, but also recommends an
average of 60 min per day for children and youth to reduce levels
of physical inactivity and improve global health (220). During
the COVID-19 pandemic and the wide recommendation for the
temporary interruption of different service providers, including
health and fitness facilities, HBE has been shown as a possible
strategy for people to stay active and end sedentary behavior in
social isolation scenarios or with limited options. The need to
maintain the exercise routine can be supplied by HBE which
might help to reduce levels of physical inactivity and sitting time,
impacting on adherence to exercise and attracting patients in
different stages of treatment for chronic diseases (221–223) due
to its convenience. In addition, WHO highlights that HBE must
overcome environment limitations during all the stages of the
COVID-19 lockdown, providing a cheap, safe, and controllable
exercise protocol to the general population with all ages whether
they are affected by COVID-19 or not (224).
Moreover, few studies have shown improvements in
cardiorespiratory capacity, blood pressure control, and
improvements in the quality of life in practitioners of HBE
(225,226). A meta-analysis of randomized controlled trials
also showed improved cardiorespiratory capacity, decreased
fatigue, and reduced symptoms of adjuvant treatment in breast
cancer survivors (227). In a sedentary group, another study has
shown that after 24 weeks of HBE, subjects had better levels of
metabolic assets, such as reducing fasting blood glucose, glycated
hemoglobin, total cholesterol, and triglycerides, decreased fat
tissue, blood pressure, and proinflammatory hs-CRP serum
levels. In addition, it was observed that high levels of high-
density lipoprotein (HDL) cholesterol (228). In the elderly
population, a systematic review and meta-analysis reported the
effect of HBE to reduce falls, sarcopenia, delaying cognitive
health, and dementia, and also improve balance, mobility, and
muscle strength (229,230).
In addition to the benefits described, through the application
of HBE, studies have shown that this activity can significantly
improve the immune system. In the pneumonia scenario, HBE in
frail elderly people was reported to enhance peak cough flow
(p<0.01) and physical function (p<0.05), preventing aspiration
pneumonia (231). Moreover, in thyroid cancer patients, 12 weeks
of HBE promoted a significant enhancement in the levels of NK
cells (232). Other cancer randomized controlled trials have
observed a significant reduction of TNF serum levels after 12
weeks of HBE (233,234). In stage II-III colorectal cancer
survivors, HBE increased levels of insulin-like growth factor-1,
IGF binding protein (IGFBP)-3, and adiponectin (233). Lately,
some evidence has noted an enhancement of HDL levels after 12
weeks of HBE, but also these results were associated with
decreasing IFNgserum levels in postmenopausal women (235).
In this context, it is known that HBE with a self-selected
prescription template must be efficient to improve
cardiorespiratory capacity and peak oxygen consumption
(236). The characteristics of the self-selected model present
evidence that points to a direction for participants to
experience moderate exercise intensities (237). Thus, it is
possible that, if properly prescribed, this strategy would
become efficient in promoting the maintenance and/or
development of physical fitness in recovered COVID-19
Filgueira et al. Physical Activity, Immune System, and COVID-19
Frontiers in Immunology | www.frontiersin.org February 2021 | Volume 12 | Article 58714614

patients and individuals in quarantine, to the detriment of the
coronavirus. The self-selected activities model is also
characterized by prioritizing improvements in affective aspects
related to the participants’pleasure (237) and the importance of
affective responses in adhering to physical exercise has already
been demonstrated (238). Instructions could be obtained by
mobile applications, specifichornbooks,onlinevideos,or
preferably, by presential or remote supervision by a certified
professional (235).
Although highly recommended, especially in the context of
social isolation, the practice of HBE is not characterized as the
only way to avoid physical inactivity. Another option is the
practice of physical activity in places where it is possible to
maintain a safe distance from others, so called outdoor based
exercises (OBE). OBE is characterized by the number of physical
activities done in outdoor spaces, for example in green places,
green gyms, parks, squares, beaches, or neighborhood outdoor
spaces. The findings by Lahart and Darcy (239) do not suggest
better physical or wellbeing benefits in indoor vs. outdoor
activities. However, it is possible that the practice of activities
in open environments, with immersion in nature, such as parks,
fields, and streets can have a positive impact on the maintenance
and development of physical fitness and mental health (239).
Kim and Lee (240) have observed that six weeks of combined
exercise using outdoor exercise equipment was effective in
enhancing fitness capacities, such as reduction of retinoic acid
receptor responder protein 2 levels and insulin resistance in the
elderly. Moreover, a randomized controlled trial has remarked a
decrease of physiological stress by cortisol levels due to walking
in nature (241). In another study, it was found that in this
moment of isolation, individuals are more likely to travel long
distances to be in urban green spaces, where exercising and
relaxing seems to be the most desired activities (242). Therefore,
it is suggested that practicing exercise in compliance with
hygiene and safety standards is fundamental regardless of
the environment.
It is important to highlight that the social isolation caused by
the pandemic implies a series of negative consequences for
mental health. A recent systematic review by Vindegaard and
Benros (243) showed increased levels of post-traumatic stress
and depression after infection. In addition, indirect negative
effects were observed, such as increased symptoms of anxiety,
depression, and insomnia, both among patients and health care
workers (243). Another concern that must be considered by
public authorities is in vulnerable families who may be victims of
domestic violence and multiple types of aggressive and
depressive behavior (244), which in this moment of social
isolation can become more present, especially in groups more
vulnerable to psychosocial stressors (245).
In the context of depression, the symptoms seem to be
associated with lower amounts of muscle mass among adults
and the elderly, and this may be a consequence of levels of
physical activity, an association between muscle fitness,
functional limitations and disabilities, frailty, and health-
related quality of life (246). In fact, it is known that exercise is
crucial to reducing the deleterious effects related to muscle mass
loss caused by aging or a sedentary lifestyle (247). Muscle mass
loss naturally causes decreases in muscle strength, which in turn
can be associated with mental health, especially in people with
depressive symptoms. In a review by Marques and Gomez-Baya
(246), it was suggested that muscle fitness is inversely related to
depressive symptoms among adults and older adults. It is
possible that individuals with reduced muscle strength may feel
less comfortable and motivated to exercise, such as HBE or OBE.
Future studies should try to confirm the possible influences that
muscle mass loss and strength can exert in adherence to physical
exercise programs, and in future behavior.
Interventions focused on short term exercises with potential
for physical and psychological improvements should be used as
strategies to mitigate the effects of reduced muscle strength and
demotivation to exercise. One of the possibilities, with low cost
and few limitations, may be in the handgrip exercise. In a review
by Rijk and Roos (248), associations were described between
handgrip strength and cognitive, functional, and mobility status,
suggesting that low levels of handgrip strength can predict the
decline of these conditions. The effectiveness of handgrip
strength exercise as a predictor of mood responses, depression,
vigor, and sleep quality in elderly women has also been
demonstrated (249). Therefore, it is suggested that this type of
exercise may have viable potential to promote adequate physical
and psychological responses, especially in populations limited in
terms of possibilities to perform physical exercise and in terms of
health and physical fitness.
Together, all the consequences described need to be taken
into account and discussed, leading to a better prescription of
physical exercises. Each physical exercise proposal, whether HBE
or OBE, must be directed to mitigate the symptom presented by
the individual, whether due to muscle mass loss, strength
reduction, or depressive state. For example, being outdoors can
be a relief in an emotional state negatively impacted by
confinement measures. In fact, loneliness has already been
shown to have significant effects on moderate levels of
depression (250). And according to Torales and O’Higgins
(251), global health measures must be taken to meet the
demands that impact the psychosocial aspects related to
isolation. In summary, HBE and OBE can have important
differences that must be considered before practicing, since the
external environment can generate positive impacts on mental
health, in addition to improving the immune defense. It is
therefore suggested that physical exercise could be seen as a
way to promote physical and mental health, combining
individual needs, safety, and the search for better physical
fitness and psychological responses.
CONCLUSIONS
Achieving suggested physical activity standards have been
mentioned by a large body of evidence to improve immunity
and enhance the deleterious effects of COVID-19 disease.
Moreover, this achievement in exercise levels is especially
recommended during social isolation. Guidelines addressed to
Filgueira et al. Physical Activity, Immune System, and COVID-19
Frontiers in Immunology | www.frontiersin.org February 2021 | Volume 12 | Article 58714615

the general population on each chronic disease indexed by
ACSM, which recommends 150–300 min of moderate to
vigorous-intensity cardiorespiratory physical activity per week
and two sessions per week of muscle strength training (213) are
available, as well as several protocols of HBE considering the
same recommendations for the general population. Home-based
platforms or video classes with physical education professionals
can be useful to ensure the security and effectiveness of these
protocols. In the COVID-19 pandemic situation, WHO
guidelines have been recommending a similar protocol to
ACSM in order to improve global health and mitigate the
consequences of COVID-19. In this sense, these guidelines
have considered HBE as an alternative during lockdown
periods and OBE during the period that the population has
access to open places with social distancing (249).
Although, exceeding WHO recommended physical activity
levels during the lockdown might not be scientifically
sustainable, in order to avoid high intense and prolonged
exercise. Therefore, although exercise will not prevent us,
directly, from SARS-CoV-2 infection, it might prevent us from
developing a severe form of COVID-19, improve the immune
defense, and counteract the negative effect of this disease in our
immune system due to its anti-inflammatory properties shown
to improve the outcome of chronic and infectious diseases
(Figure 3). Besides, exercise is a strategy to balance the
symptoms of stress due to social isolation. Moreover, physical
exercise is also the most effective therapy for those who are
asymptomatic or experiencing only mild symptoms, mainly
vulnerable people such as the elderly and people with chronic
diseases. Therefore, maintaining physical exercise levels would
reduce the comorbidities of COVID-19, also minimize future
complications from this disease, and should be strongly
recommended to the population in this scenario.
Therefore, future studies should investigate the impact of
HBE and OBE with safe social distancing on the rehabilitation of
COVID-19-induced morbidities, treatment, hospitalization, and
other consequences of the disease. Thus, well-designed studies
are necessary to consolidate the real impact of HBE or OBE on
the immune system of COVID-19 patients.
AUTHOR CONTRIBUTIONS
TF, AC, FS, EC, and TS conceived the study and wrote the
manuscript. TF, MF, LS, WA, GA, and AC carried out the
literature review, and led the draft and audit of this
manuscript. TF, AC, TS, GA, LS, and FS contributed to the
final revision of the manuscript. TS and FS contributed equally.
In addition, the mutual and proportional commitment to
support the writing, technical, and idiomatic revision of the
authors is highlighted. All authors contributed to the article and
approved the submitted version.
FUNDING
This study was financed in part by the Coordenacão de
Aperfeicoamento de Pessoal de Nıvel Superior - Brasil
(CAPES) - Finance Code 001; the National Council for
Scientific and Technological Development (CNPq) and
FIGURE 3 | Effects of exercise and inactivity on physical health and the risk of severe disease upon viral infections. Inactivity is described as a risk factor for
sarcopenia, reduced muscle function and functionality, cardiovascular and metabolic diseases, impaired immune function and immunosenescence, but also it has
been associated with impairing energy expenditure, increasing total body and abdominal fat. On the other hand, physically active individuals have improved T cell
responses, decreased levels of lung inflammation and bacterial pneumonia, improved lung function, stronger and long-lasting antibody responses to the influenza
vaccine, decreased immunosenescence, increased anti-inflammatory capacity, and decreased upper respiratory tract infection (URTI) incidence and symptoms.
Filgueira et al. Physical Activity, Immune System, and COVID-19
Frontiers in Immunology | www.frontiersin.org February 2021 | Volume 12 | Article 58714616

Pernambuco Science and Technology Support Foundation
(FACEPE). AC is supported by FACEPE (BFP-0102-1.11/19)
and CNPq (159958/2019-9), LERS by FACEPE (IBPG-0555-
4.09/18), and TOF by CAPES (88887.470105/2019-00).
ACKNOWLEDGMENTS
The authors thank Micaelly Oliveira Rodrigues de Moraes for
the graphics.
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Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
Copyright © 2021 Filgueira, Castoldi, Santos, de Amorim, de Sousa Fernandes,
Anastacio, Campos, Santos and Souto. This is an open-access articledistributed under
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