Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes
the novel coronavirus disease 2019 (COVID-19), has been responsible for a large global
outbreak. The latest number of confirmed cases of COVID-19 is >4.6 million globally,
including >315,000 confirmed deaths, and obliging >4 billion people to stay confined
to their homes . Most people with COVID-19 experience mild to moderate illness,
but around 15% progress to severe pneumonia, and about 5% progress to acute respiratory
distress syndrome. The maintenance of social distancing, frequent hand-washing, and
avoiding touching the eyes, nose and mouth have been strongly advised by the WHO.
Reports from health authorities worldwide have converged for placing cities in lockdown,
with no outdoor activities permitted including physical exercise. However, it is important
to consider the benefits of regular exercise-induced immunomodulation as a potential
means of taking precautions and also in clinical management. Indeed, sedentary behaviors
such as watching TV, long periods of sitting, and the use of smartphones are associated
with an increased risk of obesity, hypertension, and type 2 diabetes mellitus. This
is an important topic for discussion, considering that, upon admission to hospital,
most of the patients have presented with comorbidities like diabetes (10–20%), hypertension
(16.9%), and other metabolic diseases including obesity and chronic inflammation (53.7%)
The immunopathology of the SARS-CoV-2 infection involves both the innate and adaptive
immune system. After infection by the virus, there is an increase of neutrophil count
and a decrease in the number of natural killer (NK) cells, and the advent of leukopenia
based on the reduced percentage of monocytes, eosinophils, and basophils . Regarding
the adaptive immune response, a reduction in TCD4+ and TCD8+ lymphocytes has been
observed. The upregulation of B lymphocytes induces the detection of high levels of
IgG in the plasma 7–10 days after SARS-CoV-2 infection. In addition, there is an elevated
production of proinflammatory cytokines including tumor-necrosis factor (TNF)-α, interleukin
(IL)-6, IL-1β, IL-8, IL-17, and IL-2 . The abnormal elevated concentrations of
these cytokines leads to crosstalk activation of the neuroendocrine-immune system,
with a consequent release of glucocorticoids which can impair the immune response
. The abnormally elevated release of cytokines can induce multiple organ failure,
involving the heart, liver, kidney, and lungs. Particularly in the lungs, the cytokine-induced
infiltration of neutrophils and macrophages can provoke the formation of hyaline membranes
and fracture of the alveolar wall .
Exercise-induced immunomodulation has been recognized for >3 decades, with around
5,000 peer-reviewed original and review papers available in the MEDLINE and PubMed
databases. Exercise-induced immunomodulation seems to be dependent on the interplay
of the intensity, duration, and frequency of exercise . In both human and animal
models, exercise of long duration and/or intense exercise (>2 h and/or >80% of maximal
oxygen uptake, VO2max) is associated with markers of immunosuppression such as: (1)
increased production of proinflammatory cytokines (IL-6, IL-8, TNF-α, and IL-1) ;
(2) an increase in lower respiratory tract infections ; (3) reduced activity of
NK cells, T and B lymphocytes, and neutrophils; (4) reduced production of salivary
IgA and plasma IgM and IgG; and (5) a low expression of major histocompatibility complex
II (MHC II) in macrophages [9, 10]. These changes can be detected hours to days after
the end of a prolonged and/or intense bout of endurance exercise. In addition, the
hormones of the hypothalamic-pituitary-adrenal axis, glucocorticoid receptors, and
intracellular NF-κB signaling seem to be involved in chronic inflammatory airway disease;
all of these are increased after prolonged/intense exercise . Thus, long-duration
and/or intense exercise may make humans more susceptible to infection (mainly upper
respiratory tract infections) which can increase the risk of infection and aggravation
Conversely, clinical and translational studies on humans have demonstrated that regular
bouts of short-lasting (i.e., 45–60 min), moderate-intensity exercise (50–70% VO2max),
performed at least 3 times a week is beneficial for the host immune defense, particularly
in older adults and people with chronic diseases . Moderate-intensity exercise
seems to be associated with increased leukocyte function in humans , and has been
found to enhance chemotaxis, degranulation, cytotoxic activity, phagocytosis, and
the oxidative activity of neutrophils and macrophages in rats . Increased cytolytic
activity of NK cells and NK cell-activating lymphokine (LAK) during a 60-min of moderate-intensity
exercise by healthy cyclists was also reported . Thus, contrary to long-duration/intense
exercise, moderate-intensity exercise may contribute to increased immune protection.
Whether or not individuals habituated to practicing moderate-intensity exercise experience
less serious complications associated with COVID-19 deserves further investigation.
COVID-19 cases have been reported in certain populations like elderly people, children/adolescents,
and pregnant women. The older population is more susceptible to infection in general
and has also been identified as being particularly vulnerable during the current outbreak.
It has been demonstrated that regular, moderate exercise by older adults reduces concentrations
of proinflammatory cytokines (IL-6, TNF-α, and IL-1β), increases NK cell and TCD8+
cell cytotoxic activity, and enhances neutrophil function and B lymphocyte proliferation
. Although the reported number of cases of COVID-19 in children/adolescents is
relatively low, it is important to note that chronic moderate/intense exercise and/or
exercise training in healthy children and adolescents are associated with a reduction
in the incidence of infection and a faster recovery of the immune system . In pregnant
women with COVID-19, fetal distress and preterm delivery have been seen in some cases,
but no evidence of in utero transmission has been observed .
Physical exercise concurrent with exercise training (aerobic-resistance training)
seems to enhance macrophage phagocytosis and oxidative burst, neutrophil oxidative
burst, increase the percentage of TCD4 lymphocytes, and reduce circulating TNF-α and
IL-6, followed by an increase in IL-1β . Whether such exercise-induced alterations
in the immune system would be protective against SARS-CoV-2 infection in these populations
is unknown and further studies will be necessary. However, it is interesting to consider
that exercise could play a role in counteracting the negative effects of isolation
and confinement stress on immune competency in this population.
Clinically, the first phase of immune response induced by SARS-CoV-2 infection is
a specific adaptive immune response to eliminate the virus and prevent disease progression.
Patients with severe complications derived from COVID-19 infection present with lymphocytopenia
and a cytokine release syndrome mediated by leukocytes other than T cells. This is
important because the reduction of IL-6 and TNF-α increases the release of anti-inflammatory
cytokines. Anti-inflammatory cytokines can suppress a hyperactive immune response,
promoting tissue repair, especially for lung damage . Interestingly, there is an
increase in the expression of proinflammatory cytokines in skeletal muscle (TNF-α
and IL-1β) during moderate-intensity exercise, but there is no alteration in the circulating
of these cytokines . In contrast, there is a noticeable increase in the circulating
concentrations of the anti-inflammatory cytokines IL-1 receptor antagonist (IL-1ra)
and IL-10 . Low-to-moderate intensity exercise (30–60% VO2max) also increases
the production of anti-inflammatory cytokines (IL-4 and IL-10) by T cells. Thus, regular
moderate-intensity exercise may be effective in enhancing an anti-inflammatory response,
which could help to revert lymphocytopenia in COVID-19 patients. Further experimental
studies will be necessary to confirm or refute this hypothesis.
In conclusion, the pandemic of COVID-19 has become a clinical threat worldwide, for
physicians, researchers, nurses, healthcare workers, and mostly the general population.
There is consensus that the way to reduce the rate of contamination and spread of
SARS-CoV-2 via human-to-human transmission is social distancing. However, the practice
of moderate-intensity exercise at home is recommended. Low-to-moderate exercise-induced
immunomodulation might be an important tool to improve immune responses against the
progression of SARS-CoV-2 infection.
The authors have nothing to disclose.
There was no funding.
All authors contributed equally.