key: cord-0684527-fudgk5yq authors: Rahmati, Masoud; Shamsi, Mahdieh Molanouri; Khoramipour, Kayvan; Malakoutinia, Fatemeh; Woo, Wongi; Park, Seoyeon; Yon, Dong Keon; Lee, Seung Won; Shin, Jae Il; Smith, Lee title: Baseline physical activity is associated with reduced mortality and disease outcomes in COVID‐19: A systematic review and meta‐analysis date: 2022-04-13 journal: Rev Med Virol DOI: 10.1002/rmv.2349 sha: 2477d95698428bb50e35699573fed0ec285a786e doc_id: 684527 cord_uid: fudgk5yq Among coronavirus disease 2019 (COVID‐19) patients, physically active individuals may be at lower risk of fatal outcomes. However, to date, no meta‐analysis has been carried out to investigate the relationship between physical activity (PA) and fatal outcomes in patients with COVID‐19. Therefore, this meta‐analysis aims to explore the hospitalisation, intensive care unit (ICU) admissions, and mortality rates of COVID‐19 patients with a history of PA participation before the onset of the pandemic, and to evaluate the reliability of the evidence. A systematic search of MEDLINE/PubMed, Cumulative Index to Nursing and Allied Health Literature, Scopus, and medRxiv was conducted for articles published up to January 2022. A random‐effects meta‐analysis was performed to compare disease severity and mortality rates of COVID‐19 patients in physically active and inactive cases. Twelve studies involving 1,256,609 patients (991,268 physically active and 265,341 inactive cases) with COVID‐19, were included in the pooled analysis. The overall meta‐analysis compared with inactive controls showed significant associations between PA with reduction in COVID‐19 hospitalisation (risk ratio (RR) = 0.58, 95% confidence intervals (CI) 0.46–0.73, P = 0.001), ICU admissions (RR = 0.65, 95% CI 0.52–0.81, P = 0.001) and mortality (RR = 0.47, 95% CI 0.38–0.59, P = 0.001). The protective effect of PA on COVID‐19 hospitalisation and mortality could be attributable to the types of exercise such as resistance exercise (RR = 0.27, 95% CI 0.15–0.49, P = 0.001) and endurance exercise (RR = 0.41, 95% CI 0.23–0.74, P = 0.003), respectively. Physical activity is associated with decreased hospitalisation, ICU admissions, and mortality rates of patients with COVID‐19. Moreover, COVID‐19 patients with a history of resistance and endurance exercises experience a lower rate of hospitalisation and mortality, respectively. Further studies are warranted to determine the biological mechanisms underlying these findings. The rapid spread of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus two (SARS-CoV-2) has led to 282 million confirmed cases and 5.4 million deaths. 1 A high rate of transmission of SARS-CoV-2 and mortality owing to COVID-19 is mainly due to emerging new variants, which make efforts less effective in the fight against the virus. 2 However, a variety of public health interventions such as government policy, mask-wearing, and vaccination have been implemented worldwide to mitigate and control the spread of the outbreak of COVID-19 disease. 3 Restrictive measures to prevent the spread have resulted in difficulties for the population to maintain healthy lifestyles such as the engagement in recommended levels of physical activity (PA). 4 Meyer et al. 5 reported 30% reduction in PA during COVID-19 quarantine independent of sex and age. Specific home-based PA recommendations have been recently published in an attempt to take advantage of both quarantine and staying physically active. 6, 7 Adherence to government PA guidelines during the COVID-19 pandemic has been strongly recommended. Studies have shown that potential outcomes from leading an unhealthy lifestyle, such as hypertension, diabetes, obesity, and cardiovascular disease (CVD) increase the risk of SARS-CoV-2 infection as well as the severity and mortality rate. 8 Importantly, obesity and hypertension were the most prevalent disorders reported in hospitalised and deceased patients due to COVID-19. [9] [10] [11] Several studies have shown that a baseline sedentary lifestyle increases the mortality of hospitalised patients with COVID-19. [12] [13] [14] [15] [16] [17] [18] [19] Moreover, engaging in healthy lifestyle behaviours may protect against the most severe consequences of COVID-19 disease including systemic inflammation, and reduced quality of life. 12, 20, 21 Importantly, an unhealthy lifestyle has been considered a risk factor for COVID-19 hospital admission. 15 Different mechanisms may explain the protective effect of PA on COVID-19 outcomes and disease severity. 14 Regular PA improves immune function, and regularly active individuals have a lower incidence, intensity of symptoms, and mortality from COVID-19 and other various viral infections. [22] [23] [24] [25] Moreover, regular PA reduces the risk of systemic inflammation, which is considered the primary contributor to lung damage in COVID-19 patients. 26 Additionally, it has a protective impact on COVID-19 risk factors such as obesity and hypertension. 9 ,14 Furthermore, we previously reported that a sedentary lifestyles increase the risk of COVID-19 severity and mortality. 16 Further, high hospitalisation rates have been reported in patients with less cardiorespiratory fitness. 27 Given this mortality risk in physically inactive COVID-19 patients, this meta-analysis aims to explore the hospitalisation, intensive care unit (ICU) admissions, and mortality rates of COVID-19 patients with a history of PA participation before the onset of the pandemic. The present study was carried out in accordance with methodological guidelines from the Cochrane Handbook for Systematic Reviews. 28 The present study's findings were reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses statement (Supplementary Material S1). 29 Relevant studies were systematically searched in electronic databases including MEDLINE/PubMed, Cumulative Index to Nursing and Allied Health Literature, Scopus, and medRxiv by two researchers (MA and FM) up to January 2022. The search strategy was as follows: ("severe acute respiratory syndrome coronavirus 2" or "novel coronavirus" or "COVID-19" or "2019-nCoV" or "SARS-CoV-2") and ("survival" or "fatal outcome" or "mortality" or "death" or "hospitalisation" or "intensive care") and ("physical activity," or "exercise training," or "physical training," or "exercise activity"; Supplementary Material S2). Furthermore, we searched all reference lists of included studies for any other eligible articles. Language restriction was not considered. The Eligibility criteria followed the PICOs question. 30 In prospective and cross-sectional studies, we included studies that examine the relationship between PA and COVID-19 clinical outcomes and have reported at least one of the following outcomes: COVID-19 related mortality, hospitalisation, and ICU admission. Furthermore, editorials, letters, commentaries, and abstracts with insufficient data were excluded from the present meta-analysis. First, titles and abstracts of all retrieved articles were screened by two investigators (M.A., F.M.) for relevance. Second, the relevant fulltext articles were reviewed for inclusion and the following data were extracted from eligible studies, where available: study design, country, PA documentation, age and gender, relative outcomes, and comorbidity factors. In all stages, discrepancies were resolved through discussion before conducting meta-analysis. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of studies. The NOS for cohort studies includes 3 domains (quality of selection, comparability, quality of outcome, and adequacy of followup), with a maximum score of nine points. 31 Studies with NOS scores of 0-3, 4-6, and 7-9 were considered low, moderate, and high quality, respectively. 32 We also performed a subgroup analysis to determine the effect of PA levels on our study outcomes based on Metabolic Equivalent of Task (MET) minutes per week. Low and moderate-vigorous PA levels were classed as achieving less than or equal to 500 and higher than 500 MET-min per week, respectively. 13, 16, 33 Additionally, we performed another subgroup analysis to determine the effect of PA inducedadaptation on our study outcomes based on types of exercise related to endurance exercise, resistance exercise, and combined training adaptations. All meta-analyses were conducted using Review manager (Version 5.4, The Nordic Cochrane Centre, Copenhagen, The Cochrane Collaboration, 2014). Dichotomous outcomes were pooled and expressed as risk ratios (RRs) with 95% confidence intervals (CI). 34 The pooled analysis results were classified based on study types into two categories, prospective cohorts and cross-sectional and the pooled RRs were estimated using the random-effect model. Heterogeneity was calculated using Cochran's Q statistics and I 2 . I 2 from zero to 24%, 25%-49%, 50%-74% and 75%-100% were interpreted as low, moderate, substantial and considerable heterogeneity. 34 Funnel plots with Egger weighted regression test were used for assessing publication bias using STATA version 16. Finally, the overall pooled prevalence of the respective outcomes was re-estimated by the one study removed methods to perform sensitivity analysis. A total of 1956 potentially relevant articles were identified in our literature search. Four hundred and 60 studies remained after removing duplicates. After screening titles and abstracts, 1397 research articles were excluded. Of 33 obtained research articles, another 21 articles were excluded (no sufficient data (n = 8); editorial or news (n = 2) and reviews (n = 11); Supplementary Table S2 ). 35 Finally, 12 articles met the eligibility criteria and were included in the meta-analysis ( Figure 1 ). [16] [17] [18] [19] and are listed in Table 2 . All included studies were of high quality with NOS scores equal to or greater than 7 ( Table 3 ). The designs of the included studies were as follows: cohort (n = 6) and cross-sectional (n = 6) and we performed a subgroup analysis based on different study types. Cohort study Comparability ( stratifying studies based on different PA levels decreased heterogeneity to I 2 = 0% (P = 0.80, Figure 3c ). In total, nine studies involving 867,978 cases ( In sensitivity analyses, the overall pooled estimates of the respective outcomes obtained in each analysis closely resembled the preliminary associations. Further, funnel plots were checked for the included studies, which suggested no noticeable bias in the present meta-analysis ( Figure 5) . Additionally, Begg's correlation rank and Egger's regression did not show significant publication bias (Table 4 ). In this study, we performed pooled analyses to estimate the hospi- Previous studies have demonstrated that PA reduces the incidence of non-communicable and chronic diseases and the mortality in infectious diseases. 39, 40 The beneficial effects of regular PA on the immune system have been considered one of the main underlying mechanisms in reducing severe outcomes in both chronic and infectious diseases and their subsequent hospitalisation. [41] [42] [43] Additionally, regular PA has been shown to boost innate immune system responses, including the production of macrophages, natural killer cells, and neutrophils. 25, 44 More importantly, there is an improvement in acquired immune system function including T cells and antibody responses following regular PA. 45, 46 In addition to the direct effects of PA on the immune system, the metabolic regulation as a result of participating in regular PA can also improve the innate immune system's response to pathogens. 47 Taken together, these mechanisms partly explain the relationship between PA and COVID-19 severe outcomes in the present meta-analysis. 10 of 16 -RAHMATI ET AL. In addition to the beneficial effects on the immune system, PA also brings cardiorespiratory and musculoskeletal adaptations. 48 According to the present results, increased muscle strength was associated with a reduced risk of COVID-19 hospitalisation. Considering the effects of age on increasing hospitalisation 49 can promote muscle strength while maintaining muscle mass, which effectively prevents the occurrence of severe cases of disease. 50, 51 Interaction between exercised skeletal muscle and the immune system may be owing to the production of anti-inflammatory cytokines such as IL-6. 52 Moreover, in some progressive diseases such as some types of cancer, the maintenance of muscle mass has been associated with more effective immune responses to fight against the severe outcomes of the disease. 53, 54 Taken together, the present findings and discussed mechanisms indicate that improved muscle strength may be protective from hospitalisation in COVID-19 disease. However, more studies are needed to investigate this issue. In the present meta-analysis, PA was associated with reducing the risk of ICU admission and mortality in COVID-19 patients. Moreover, the risk of mortality was associated with a lower baseline physical fitness. It has been suggested that preexisting health conditions are a major cause of mortality in COVID-19. 55 In this meta-analysis, we showed that PA decreases the hospitalization, ICU admission, and mortality rates of COVID-19 patients. Additionally, COVID-19 patients with a history of resistance and endurance exercises experience a lower rate of hospitalization and mortality, respectively. The findings of this meta-analysis suggest that public health authorities should continue to encourage people to participate in recommended levels of PA during the COVID-19 pandemic while following public health safety guidelines. Coronavirus disease (COVID-19)-Statistics and research. 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Front Physiology Effects of exercise training and supplementation with selenium nanoparticle on T-helper 1 and 2 and cytokine levels in tumor tissue of mice bearing the 4 T1 mammary carcinoma Combined effect of aerobic interval training and selenium nanoparticles on expression of IL-15 and IL-10/TNF-α ratio in skeletal muscle of 4T1 breast cancer mice with cachexia Causes of death and comorbidities in hospitalized patients with COVID-19 The association of estimated cardiorespiratory fitness with COVID-19 incidence and mortality: a cohort study European Guidelines on cardiovascular disease prevention in clinical practice Excessive exercise and immunity: the J-shaped curve The Active Female Worldwide effect of COVID-19 on physical activity: a descriptive study This research was supported by the Lorestan University, Khorramabad, Iran. The authors declare that there are no conflict of interests. Masoud Rahmati and Jae Il Shin developed the idea and designed the study and had full access to all data in the study and take re- All data relevant to the study are included in the article or uploaded as supplementary information. The data are available by accessing the published studies listed in Table 1 . https://orcid.org/0000-0003-4792-027XWongi Woo https://orcid.org/0000-0002-0053-4470Jae Il Shin https://orcid.org/0000-0003-2326-1820 Additional supporting information can be found online in the Supporting Information section at the end of this article.