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      Covid-19 and Exercise-Induced Immunomodulation


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          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 references13

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          COVID-19: consider cytokine storm syndromes and immunosuppression

          As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).
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            Comorbidity and its impact on 1590 patients with Covid-19 in China: A Nationwide Analysis

            Background The coronavirus disease 2019 (Covid-19) outbreak is evolving rapidly worldwide. Objective To evaluate the risk of serious adverse outcomes in patients with coronavirus disease 2019 (Covid-19) by stratifying the comorbidity status. Methods We analysed the data from 1590 laboratory-confirmed hospitalised patients 575 hospitals in 31 province/autonomous regions/provincial municipalities across mainland China between December 11th, 2019 and January 31st, 2020. We analyse the composite endpoints, which consisted of admission to intensive care unit, or invasive ventilation, or death. The risk of reaching to the composite endpoints was compared according to the presence and number of comorbidities. Results The mean age was 48.9 years. 686 patients (42.7%) were females. Severe cases accounted for 16.0% of the study population. 131 (8.2%) patients reached to the composite endpoints. 399 (25.1%) reported having at least one comorbidity. The most prevalent comorbidity was hypertension (16.9%), followed by diabetes (8.2%). 130 (8.2%) patients reported having two or more comorbidities. After adjusting for age and smoking status, COPD [hazards ratio (HR) 2.681, 95% confidence interval (95%CI) 1.424–5.048], diabetes (HR 1.59, 95%CI 1.03–2.45), hypertension (HR 1.58, 95%CI 1.07–2.32) and malignancy (HR 3.50, 95%CI 1.60–7.64) were risk factors of reaching to the composite endpoints. The HR was 1.79 (95%CI 1.16–2.77) among patients with at least one comorbidity and 2.59 (95%CI 1.61–4.17) among patients with two or more comorbidities. Conclusion Among laboratory-confirmed cases of Covid-19, patients with any comorbidity yielded poorer clinical outcomes than those without. A greater number of comorbidities also correlated with poorer clinical outcomes.
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              COVID-19: immunopathology and its implications for therapy

              Xuetao Cao (2020)
              Severe coronavirus disease 2019 (COVID-19) is characterized by pneumonia, lymphopenia, exhausted lymphocytes and a cytokine storm. Significant antibody production is observed; however, whether this is protective or pathogenic remains to be determined. Defining the immunopathological changes in patients with COVID-19 provides potential targets for drug discovery and is important for clinical management.

                Author and article information

                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 )
                5 June 2020
                : 1-3
                [1] aLaboratory of Physiology of Exercise − CAV − Federal University of Pernambuco, Recife, Brazil
                [2] 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
                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.

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                References: 15, Pages: 3


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