Physical activity,COVID-19,and respiratory comorbidities:The good,the bad,and the ugly

Anh-Tuan Dinh-Xuan,Thông Hua-Huy,Sven Günther

Lung Function&Respiratory Physiology Units,Department of Respiratory Physiology and Sleep Medicine,Assistance Publique-H^opitaux de Paris,Cochin&George Pompidou Hospitals,University Paris Cité,Paris 75006,France

Almost 3 years after the outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the coronavirus disease 2019 (COVID-19) that has caused more than 6 million deaths worldwide,1the pandemic persists and hampers our daily lives.There are at least 2 main reasons explaining why we still struggle to terminate this pandemic. First, novel variants of concern of SARS-CoV-2 unceasingly emerge despite almost 12 billion doses of vaccine being administered to date.1,2Second,our lack of understanding of the underlying biological mechanisms leading to postacute sequelae of COVID-19, or long COVID, contributes to the lingering effects of the pandemic.3Due to the airborne nature of SARS-CoV-2,the respiratory system is the most frequently impacted as the viral spike protein readily binds to the ubiquitous angiotensin-converting enzyme 2 lung cell membrane receptors. As with all acute lung injuries, the question relating to long-term lung function arose for all COVID-19 patients irrespective of the initial severity of the disease. We recently published a systematic review identifying 1578 publications reporting pulmonary function tests after the acute phase of the disease.4Following initial screening, the main results from 39 studies that measured and discussed the possible underlying lung abnormalities at various time points,were included in a systematic analysis.4Based on the results of these studies, we identified 3 common features were when measuring pulmonary function tests at rest in COVID-19 survivors:the existence of(a)an obstructive pattern,(b)a restrictive pattern, and (c) a lung gas exchange impairment.5-7Integrative responses to physical exercise, e.g., measuring 6-min walking distance or performing cardiopulmonary exercise test,have also been performed,but unfortunately,only in a limited number of investigations that consistently showed a direct relationship between abnormal spirometry results and impaired cardiopulmonary exercise testing.8,9The main parameter used to define bronchial obstructive pattern was the ratio of forced expiratory volume in 1 s over forced vital capacity(FVC).4Restrictive patterns were diagnosed by either a reduction of total lung capacity or the combination of a low FVC with a high forced expiratory volume in 1 s/FVC ratio,in cases when total lung capacity could not be measured.In some studies, reduced residual volume was also considered as part of the restrictive pattern.4Lung gas exchange was mostly assessed using the single breath carbon monoxide lung diffusing capacity(DLCO)test.5-7The earliest time point of evaluation after the acute phase of the disease was 1 month, with most studies reporting pulmonary function tests between 6 weeks to 4 months, and few reporting results at 6 months after discharge or onset of the disease.4-9A common feature emerging from all studies was the relatively high prevalence of reduced DLCO reported in 40%to 65%of patients as compared with the medium to high prevalence of restrictive pattern and the exceptionally low prevalence of obstructive pattern.4-9The high prevalence of altered DLCO found at the onset of the disease,or 1 month after discharge,results from ongoing residual inflammation related to the initial lung injury. However,the persistent low values of DLCO at 3 and 6 months,even in patients with normalized chest computed tomography results,raise concern10as various pathophysiological mechanisms might account for the abnormal lung gas exchange in patients following exposure to COVID-19.11Unlike most pulmonary function parameters, e.g., forced expiratory volume in 1 s,FVC,and total lung capacity,which are directly measured during respiratory maneuvers,DLCO is calculated as a product of the accessible alveolar volume and the carbon monoxide transfer coefficient. As a result, altered DLCOs in patients following COVID-194-9can occur through a reduction of alveolar volume, or carbon monoxide transfer coefficient, or both.12Deciphering between alveolar volume and carbon monoxide transfer coefficient as the cause for the reduced DLCO is crucial for the determination of the underlying COVID-19-related structural and/or functional changes of the lung.11Several mechanisms can account for an impaired pulmonary gas exchange resulting in hypoxemia in patients with COVID-19,including pneumonia and acute respiratory distress syndrome(ARDS) during the acute phase, and pulmonary fibrosis as a long-term consequence of either pneumonia or COVID-19-related ARDS.13Patients with“classical”ARDS not related to COVID-19, consistently have severe clinical symptoms when lung mechanics are markedly impaired.In other words,ARDS patients with the lowest oxygenation level are also those who have the worst lung mechanics and the highest pulmonary shunt. By contrast, lung mechanics are relatively preserved in patients with COVID-19-related ARDS, even in cases of profound hypoxemia.14This difference in lung mechanics between ARDS and COVID-19-related ARDS patients suggests different mechanisms for pulmonary shunt in patients with COVID-1911,13with chaotic architecture of the lung capillary vascular bed characterizing the so-called intussusceptive angiogenesis, and the presence of multiple pulmonary microthrombotic lesions.15Such an association suggests a co-occurrence of abnormal lung extracellular matrix remodeling and pulmonary vascular dysfunction in severely ill COVID-19 patients, which is likely related to immunological failure to control and negate the viral infection by SARS-CoV-2.16Excessive inflammation in response to contiguous infection of alveolar epithelial and capillary endothelial cells, coagulation defects, and uncontrolled neutrophilic activation potentially contribute to structural and functional changes of the alveolarcapillary units leading to impaired gas exchange and hypoxemia. Among patients infected by SARS-CoV-2, complications are greater in elderly individuals, especially those with underlying chronic comorbidities including diabetes and obesity.17

One remarkable and common feature of the various types of impaired lung function above medical conditions is that they are frequently associated with, and aggravated by, physical inactivity.18There is a global trend toward an older, obese,and physically inactive demographics that will likely continue for the near future.As for other physiological functions,innate and adaptive immunity declines with age, a process termed immunosenescence.19The association of immunosenescence with inflammaging, an age-related low-grade inflammation seen in elderly people may aggravate, but also be aggravated by SARS-CoV-2 infection.20The mechanisms underlying obesity are complex and diverse but physical inactivity certainly contributes to its worsening over time, creating a vicious circle. Importantly, obesity and physical inactivity increase the risk for hypertension, type 2 diabetes, and cardiovascular disease, three of the most important risk factors for the development of severe COVID-19. Finally, obesity and associatedmetabolic syndrome, in conjunction with a lack of physical activity cause systemic inflammation and adversely affect immune function and host defense in a way that mimics immunosenescence.21The existing data suggest that physical activity is associated with decreased COVID-19 cases and deaths.22Furthermore, we suggest that moderate physical activity with low intensity exercise,that can be initiated at the level of 1-3 metabolic equivalent of tasks or equivalent,should be part of COVID-19 patients’rehabilitation programs.23This will allow monitoring of respiratory functional improvement over time and to understand better the mechanisms underlying post-acute sequelae of COVID-19.4We hope that the scientific community will eventually find the way to halt the COVID-19 pandemic.However,we are uncertain on how to prevent postacute sequelae of COVID-19 becoming another chronic disease that will be added to an already long list of debilitating conditions, e.g., hypertension, type 2 diabetes, obesity, and cardiopulmonary disease.Carefully designed muscular cardiopulmonary rehabilitation programs through physical activity must be part of the solution to prevent and combat these chronic conditions.

Authors’contributions

ATDX has conceptualized and written the manuscript;THH and SG have conceptualized the manuscript.All authors have read and approved the final version of this manuscript,and agree with the order of presentation of the authors.

Competing interests

The authors declare that they have no competing interests.