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      Covid-19 and Exercise-Induced Immunomodulation

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          Abstract

          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 [1]. 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%) [2]. 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 [3]. 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 [4]. 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 [5]. 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 [4]. 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 [6]. 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) [7]; (2) an increase in lower respiratory tract infections [8]; (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 [6]. 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 by COVID-19. 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 [6]. Moderate-intensity exercise seems to be associated with increased leukocyte function in humans [11], and has been found to enhance chemotaxis, degranulation, cytotoxic activity, phagocytosis, and the oxidative activity of neutrophils and macrophages in rats [12]. 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 [11]. 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 [13]. 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 [6]. 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 [14]. 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 [6]. 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 [3]. 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 [15]. 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 [15]. 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. Disclosure Statement The authors have nothing to disclose. Funding Sources There was no funding. Author Contributions All authors contributed equally.

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          Most cited references 9

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          COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome?

          A severe outbreak of coronavirus disease 2019 (COVID-19) emerged in China in December 2019, and spread so rapidly that more than 200,000 cases have so far been reported worldwide; on January 30, 2020, the WHO declared it the sixth public health emergency of international concern. The two previously reported coronavirus epidemics (severe acute respiratory syndrome [SARS] and Middle East respiratory syndrome [MERS]) share similar pathogenetic, epidemiological and clinical features as COVID-19. As little is currently known about SARS-CoV-2, it is likely that lessons learned from these major epidemics can be applied to the new pandemic, including the use of novel immunosuppressive drugs.
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            Cytokine expression and secretion by skeletal muscle cells: regulatory mechanisms and exercise effects.

            Cytokines are important mediators of various aspects of health and disease, including appetite, glucose and lipid metabolism, insulin sensitivity, skeletal muscle hypertrophy and atrophy. Over the past decade or so, considerable attention has focused on the potential for regular exercise to counteract a range of disease states by modulating cytokine production. Exercise stimulates moderate to large increases in the circulating concentrations of interleukin (IL)-6, IL-8, IL- 10, IL-1 receptor antagonist, granulocyte-colony stimulating factor, and smaller increases in tumor necrosis factor-α, monocyte chemotactic protein-1, IL-1β, brain-derived neurotrophic factor, IL-12p35/p40 and IL-15. Although many of these cytokines are also expressed in skeletal muscle, not all are released from skeletal muscle into the circulation during exercise. Conversely, some cytokines that are present in the circulation are not expressed in skeletal muscle after exercise. The reasons for these discrepant cytokine responses to exercise are unclear. In this review, we address these uncertainties by summarizing the capacity of skeletal muscle cells to produce cytokines, analyzing other potential cellular sources of circulating cytokines during exercise, and discussing the soluble factors and intracellular signaling pathways that regulate cytokine synthesis (e.g., RNA-binding proteins, microRNAs, suppressor of cytokine signaling proteins, soluble receptors).
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              Can exercise affect immune function to increase susceptibility to infection?

              Multiple studies in humans and animals have demonstrated the profound impact that exercise can have on the immune system. There is a general consensus that regular bouts of short-lasting (i.e. up to 45 minutes) moderate intensity exercise is beneficial for host immune defense, particularly in older adults and people with chronic diseases. In contrast, infection burden is reported to be high among high performance athletes and second only to injury for the number of training days lost during preparation for major sporting events. This has shaped the common view that arduous exercise (i.e. those activities practiced by high performance athletes/ military personnel that greatly exceed recommended physical activity guidelines) can suppress immunity and increase infection risk. However, the idea that exercise per se can suppress immunity and increase infection risk independently of the many other factors (e.g. anxiety, sleep disruption, travel, exposure, nutritional deficits, environmental extremes, etc.) experienced by these populations has recently been challenged. The purpose of this debate article was to solicit opposing arguments centered around this fundamental question in the exercise immunology field: can exercise affect immune function to increase susceptibility to infection. Issues that were contested between the debating groups include: (i) whether or not athletes are more susceptible to infection (mainly of the upper respiratory tract) than the general population; (ii) whether exercise per se is capable of altering immunity to increase infection risk independently of the multiple factors that activate shared immune pathways and are unique to the study populations involved; (iii) the usefulness of certain biomarkers and the interpretation of in vitro and in vivo data to monitor immune health in those who perform arduous exercise; and (iv) the quality of scientific evidence that has been used to substantiate claims for and against the potential negative effects of arduous exercise on immunity and infection risk. A key point of agreement between the groups is that infection susceptibility has a multifactorial underpinning. An issue that remains to be resolved is whether exercise per se is a causative factor of increased infection risk in athletes. This article should provide impetus for more empirical research to unravel the complex questions that surround this contentious issue in the field of exercise immunology.
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                Author and article information

                Journal
                Neuroimmunomodulation
                Neuroimmunomodulation
                NIM
                Neuroimmunomodulation
                S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com )
                1021-7401
                1423-0216
                5 June 2020
                : 1-3
                Affiliations
                aLaboratory of Physiology of Exercise − CAV − Federal University of Pernambuco, Recife, Brazil
                bHuman Performance Research Group, Federal University of Technology, Parana, Brazil
                Author notes
                *Carol Góis Leandro, Universidade Federal de Pernambuco, Centro Acadêmico de Vitória − CAV, Recife (Brazil), carol.leandro@ 123456ufpe.br
                Article
                nim-0001
                10.1159/000508951
                7316658
                32506067
                Copyright © 2020 by S. Karger AG, Basel

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

                Page count
                References: 15, Pages: 3
                Categories
                Letter

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