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Exercise modulates the immune system in cardiorespiratory disease patients: Implications for clinical practice during the COVID-19 pandemic

Published:September 28, 2022DOI:https://doi.org/10.1016/j.hrtlng.2022.09.019

      Highlights

      • Moderate intensity exercise helps in boosting the immune system in population with cardiorespiratory disease.
      • Exercise and nutrition are important aspect in cardiopulmonary rehabilitation.
      • Cardiopulmonary rehabilitation will be important for population with the disease undergoing rehabilitation during the pandemic due its immune boosting and anti-inflammatory effect.
      • Long term effect of cardiorespiratory program during the pandemic is yet not clear.

      Abstract

      Background

      Patients with cardiorespiratory problems often suffer from systemic inflammation. Stress due to the disease and continuous inflammation can undermine the success of the rehabilitation program.

      Objective

      This review has been undertaken primarily to understand the effectiveness of exercise training on the immune system in individuals undergoing cardiorespiratory rehabilitation and its implications for further management during the COVID-19 pandemic.

      Methods

      Assessors analyzed related studies identified in the MEDLINE, PROQUEST, PUBMED, Cochrane Library, CINAHL, EMBASE, Google Scholar, Physiotherapy Evidence, and Science Direct databases. The studies were divided into groups focused on the effect of exercise on blood leukocytes, the anti-inflammatory effect, and the role of nutrition and exercise in resolving inflammation.

      Results

      Twenty-eight studies were included in this review. The number of studies included in each section was as follows: the effects of exercise training on leukocytes in cardiorespiratory conditions (n = 8), anti-inflammatory effect (n = 6), and the role of nutrition and exercise in resolving inflammation (n = 14). The bias risk assessment showed poor internal validity; most included studies were assigned no and unclear descriptors.

      Conclusions

      Substantive evidence is presented that emphasizes the role of moderate-intensity exercise in boosting the immune system in patients with cardiorespiratory diseases. Exercise has anti-inflammatory effects that are vital for overall well-being and resolving longstanding inflammation. Individuals with an active lifestyle had a better pathogen immune response than more sedentary individuals. Our findings highlight the current need to investigate the long-term effects of cardiorespiratory rehabilitation programs.

      Keywords

      Introduction

      Cardiorespiratory diseases are often considered the primary causes of mortality and morbidity, diminishing patients’ quality of life.
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      Exercise's anti-inflammatory and antioxidative effects on the skeletal muscles, adipose tissue, cardiovascular system, and immune system have already been shown. It has also been postulated that exercise reduces redox-sensitive transcription factors, proinflammatory cytokine profiles, and activator protein-1.
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      In addition, some studies have reported that the degree of inflammation in cardiorespiratory-related problems is related to workout intensity. However, there remains uncertainty in these results.
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      In contrast, other studies have found that physical activity's amelioratory effects on cardiorespiratory problems
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      and interval training's positive effects are better than other types of training.
      Nutritional intervention is also essential to boost immune surveillance and the success of cardiorespiratory rehabilitation.
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      A systematic review reported that regular fruit and vegetable consumption over long periods positively affects lung function in COPD individuals. Some nutritional studies have also shown the effects of dietary interventions on health-related quality of life, systemic inflammation, and physical functions.
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      Effects of nutritional interventions in individuals with chronic obstructive lung disease: a systematic review of randomized controlled trials.
      While disparities in clinical trials remain, there continues to be a need to examine the long-term effects of dietary interventions.
      This integrative literature review primarily focuses on understanding the effectiveness of exercise in modulating the immune responses of individuals undergoing cardiorespiratory rehabilitation and its implications for patient management during the COVID-19 pandemic.

      Methods

      We performed a comprehensive and thorough search of the MEDLINE, PROQUEST, Cochrane Library, PUBMED, CINAHL, EMBASE, Physiotherapy Evidence (PEDro), Google Scholar, and Science Direct electronic databases. We used search strings combining keywords and medical subject headings terms related to exercise, nutrition, impact on the immune system, blood parameters, anti-inflammatory effects, and cardiorespiratory diseases. Studies explicitly discussing the antioxidative anti-inflammatory role of exercises and the effects of exercise on blood parameters, nutrition, and acute and chronic immune responses were included in this review. Evidence was retrieved on exercise's role, which was then used to devise a plan for its management and practice with cardiorespiratory diseases during the COVID-19 pandemic. A graphical abstract for the current review is presented in Fig. 1. Bias risk was assessed using Cochrane's risk of bias tool in Review Manager v.5.4.1 to rate the quality of articles included in this study (Fig. 2). The Risk of bias evaluation was divided into domain allocation concealment, random sequence generation, blinding of participants, blinding of outcome data, incomplete outcome data, selective reporting, and other biases. Yes, no, and unclear descriptors were used to report each domain.
      Fig. 1
      Fig. 1Summarizing the effect of exercise in cardiorespiratory disease.
      Fig. 2
      Fig. 2Risk of bias assessment for the included studies on exercise training in cardiorespiratory conditions (Descriptors - yes, - No, - Unclear).

      Results

      Twenty-eight studies were included in this review. This study is divided into four themes: the impact of exercise training on blood parameters, high and moderate-intensity exercise training in cardiorespiratory diseases and their immune responses (Tables 1 and 3), anti-inflammatory effects of exercise training in cardiorespiratory diseases (Table 3), and the role of nutritional interventions in cardiorespiratory rehabilitation (Table 2). The number of studies included in each section was as follows: the effects of exercise training on leukocytes in cardiorespiratory conditions (n = 8), anti-inflammatory effect (n = 6), and the role of nutrition and exercise in resolving inflammation (n = 14). Furthermore, facts supporting exercise's involvement in modulating the immune response were also examined.
      Table 1Effects of exercise training on Leukocytes in cardiorespiratory conditions.
      AuthorsDesignConditionGroupType of trainingDurationEvaluationOutcome measureReported ResultReported Adverse EventsNumber of ExacerbationsAdherence with Intervention
      Intervention (n=)Control (n=)PrePost
      1.Van Helvoort HA et a
      • van Helvoort H.A.C.
      • van de Pol M.H.J.
      • Heijdra Y.F.
      • Dekhuijzen P.N.R.
      Systemic inflammatory response to exhaustive exercise in patients with chronic obstructive pulmonary disease.
      Case-controlCOPDCOPD=7Nonsmoking healthy participants =10Maximal intensity exerciseTotal duration of 8–12 min with gradual increases in the workload till enervationPrePostTotal LeukocytesLeukocytosis observed at the initial phase, especially neutrophils raise with drop in lymphocyte count at later stagesNot reportedNot reportedUnclear
      2.Van Helvoort HA, et al
      • Van Helvoort H.A.C.
      • Heijdra Y.F.
      • Thijs H.M.H.
      • Viña J.
      • Wanten G.J.A.
      • Dekhuijzen P.N.R.
      Exercise-induced systemic effects in muscle-wasted patients with COPD.
      Case-controlCOPDCOPD=16Healthy=

      11
      Maximal intensity exercise followed by submaximal intensity exercise after a weekSingle session bicycle ergometer

      With initial 3 min without loading later gradual increments in the load till

      exhaustion
      PrepostTotal LeukocytesThe observed leukocytosis not related to the intensity of exercise (maximal and submaximal exercise)Not reportedNot reportedUnclear
      3.Davidson WJ, et al
      • Davidson W.J.
      • Verity W.S.
      • Traves S.L.
      • Leigh R.
      • Ford G.T.
      • Eves N.D.
      Effect of incremental exercise on airway and systemic inflammation in patients with COPD.
      Pre-postCOPDCOPD=20Incremental exerciseSingle session bicycle ergometer

      With initial2 min without loading later gradual increments in the load till

      exhaustion
      PrePost

      Post 2 h

      Post 24 h
      Neutrophils,%

      Eosinophils,%

      Macrophages,%
      Short term session of incremental exercise, causes increased eosinophils, phlegm in patients with COPD, with no noteworthy variations in other inflammatory cellsNo adverse eventsNot reportedUnclear
      4.Jenkins AR, et al
      • Jenkins A.R.
      • Holden N.S.
      • Jones A.W.
      Inflammatory responses to acute exercise during pulmonary rehabilitation in patients with COPD.
      Pre-PostCOPDCOPD=40Cardiorespiratory fitness and strengthening exercisesSingle session consists of exercise and education for 2 h, 2 sessions per week for 8 weeksPrepostTotal / differential cell counts and neutrophil activation markers, maturity markers, suppressive, immature,

      progenitor,
      Leukocytosis observed at the initial phase, especially rise in the neutrophils countUnclearDue to aggravations of symptoms three participants discontinuedUnclear
      5.Nguyen T, et al
      • Nguyen T.
      • Obeid J.
      • Ploeger H.E.
      • Takken T.
      • Pedder L.
      • Timmons B.W.
      Inflammatory and growth factor response to continuous and intermittent exercise in youth with cystic fibrosis.
      Case-controlCystic fibrosisCystic fibrosis= 12Healthy=

      12
      Moderate intensity exercises

      followed by high intensity exercises, providing 30 min interval between two modes of exercise
      Single session of moderate-intensity exercise characterized by 2 sessions of exercises done at 50% of maximal power with 6 min of rest period between each session. Whereas high intensity exercise comprises of 6 short sessions done at 100% of maximal power with 1 min of rest between each sessionPrepostLeukocytes

      Neutrophils

      Lymphocytes

      Monocytes
      The prescribed exercise pattern couldn't notice any changes in leukocytes but, reported increase in growth hormonesNot reportedNot reportedUnclear
      van de Weert-van, et al.(
      • van de Weert-van Leeuwen P.B.
      • Hulzebos H.J.
      • Werkman M.S.
      • Michel S.
      • Vijftigschild L.A.W.
      • van Meegen M.A.
      • et al.
      Chronic inflammation and infection associate with a lower exercise training response in cystic fibrosis adolescents.
      )
      Longitudinal studyCystic fibrosisCystic fibrosis=13Callisthenic and aerobic exercisesPatient advised to perform 11 min of five Callisthenic exercise and aerobic exercises for 12 weeks at homePrepostLeukocytesIn addition to leucocytosis large amount of inflammatory cytokines production causes adverse effects on musclesUnclearUnclearUnclear
      6.Boas SR, et al
      • Boas S.R.
      • Danduran M.J.
      • McColley S.A.
      • Beaman K.
      • O'Gorman M.R.G
      Immune modulation following aerobic exercise in children with cystic fibrosis.
      Case-controlCystic fibrosisCystic fibrosis=15Healthy=

      15
      Aerobic activityExercise load progressed gradually considering the participant's anthropometricsPrepostTotal Leukocytes

      Granulocytes

      Lymphocytes

      Monocytes
      The immediate cellular response to exercise is normalNot reportedNot reportedUnclear
      7.Boas SR, et al
      • BOAS S.R.
      • DANDURAN M.J.
      • McBRIDE A.L.
      • McCOLLEY S.A.
      O???GORMAN and MRG
      Postexercise immune correlates in children with and without cystic fibrosis.
      Case-controlCystic fibrosisCystic fibrosis=12Healthy=

      12
      Aerobic activityExercise load progressed gradually considering the participant's anthropometricsPrepostTotal Leukocytes

      Granulocytes

      Lymphocytes

      Monocytes
      The observed post-exercise leukocytosis was indistinct in cystic fibrosisNot reportedNot reportedUnclear
      8.Van Helvoort HA, et al
      • van Helvoort H.A.C.
      • Heijdra Y.F.
      • de Boer R.C.C.
      • Swinkels A.
      • Thijs H.M.H.
      • Dekhuijzen P.N.R.
      Six-minute walking-induced systemic inflammation and oxidative stress in muscle-wasted COPD patients.
      Pre-postCOPD, ex-smoking patients with muscle wastedCOPD=106-min walking test (6MWT)

      Maximal cardiorespiratory exercises testing (CPET)
      As per ATS (American Thoracic Society) guidelinesPrepostLeukocytes

      Neutrophils

      Lymphocytes

      Monocytes
      6MWT showed less initiation of circulating inflammatory cells to

      CPET
      Not reportedNot reportedUnclear
      COPD- Chronic obstructive Pulmonary disease, n-number.
      Table 2Effect of nutrition and exercise on inflammatory markers post cardiorespiratory rehabilitation.
      AuthorsDesignGroupType of nutritional interventionType of physical activityEvaluationOutcome measureReported resultReported Adverse EventsNumber of ExacerbationsAdherence with Intervention
      Intervention (n=)Control (n=)PrePost
      1.Ford et al
      • Ford E.S.
      Does exercise reduce inflammation? Physical activity and C-reactive protein among U.S. adults.
      Cross-sectional13,748Vegetables and fruit intake (times per month)Self-reportedC-reactive protein in cardiovascular diseasePositive role in subsiding inflammation
      2.Sugawara et al
      • Sugawara K.
      • Takahashi H.
      • Kashiwagura T.
      • Yamada K.
      • Yanagida S.
      • Homma M.
      • et al.
      Effect of anti-inflammatory supplementation with whey peptide and exercise therapy in patients with COPD.
      RCT1714Nutrition supplementationHome-based low-intensity PR program0 wk.12 wk.CRQ, IL-6,8, TNF-ἀ, MRC, PI max, 6MWD, quadriceps muscle forceExercise combined with anti-inflammatory nutritional supplement shows an resolutory effect in elderly with stable COPDNot reportedUnclearUnclear
      3.Roca-Rodríguez et al
      • Roca-Rodríguez M del M.
      • Garrido-Sánchez L.
      • García-Almeida J.M.
      • Ruiz-Nava J.
      • Alcaide-Torres J.
      • Gómez-González A.
      • et al.
      Efectos del ejercicio sobre la inflamaciÓn en rehabilitaciÓn cardÍaca.
      Prospective cohort26Mediterranean dietOutpatient Cardiac rehabilitation08 wk.IPAQ, biochemical variables like IL-1, IL6, Lipid profile, Leptin and adiponectinNo changes in the inflammatory statusNot reportedUnclearUnclear
      4.Tung LF et al
      • Tung L.F.
      • Shen S.Y.
      • Shih H.H.
      • Chen Y.T.
      • Te Yen C
      • Ho S.C.
      Effect of high-flow nasal therapy during early pulmonary rehabilitation in patients with severe AECOPD: a randomized controlled study.
      RCT2727Nutritional educationHigh Flow nasal therapy + Exercise Limb strength training, and ergometer bicycle trainingPulmonary functions, Arterial blood gas analysis, WBC and CRPIncreases exercise tolerance and reduces systemic inflammation in1 eventNo change in number of Exacerbations Post InterventionsNot reported
      5.Beckie et al
      • Beckie T.M.
      • Beckstead J.W.
      • Groer M.W.
      The influence of cardiac rehabilitation on inflammation and metabolic syndrome in women with coronary heart disease.
      RCT4843Dietary Counselling and ModificationsCombined aerobic exercise and upper body resistance training. Aerobic exercise consisted of (treadmill walking, cycling, or rowing) with intensity 60–85% of maximal heart rate0 wk.12 wk.CRP, Intercellular adhesion molecule-1 (ICAM-1), (IL-6), and TNF-αGender based-CR and Traditional CR were effective in reducing inflammatory biomarkersUnclearUnclear
      6. Caulin-Glaser et- al
      • Caulin-Glaser T.
      • Falko J.
      • Hindman L.
      • La Londe M.
      • Snow R
      Cardiac rehabilitation is associated with an improvement in C-reactive protein levels in both men and women with cardiovascular disease.
      Retrospective cohort analysis172Nutritional EducationCardiac Rehabilitation0 wk.7–8 wk.Fasting blood sample for lipid profile, CRP, and glucoseDecrease the level of CRP regardless of gender, age, or presence of metabolic syndromeUnclearUnclearUnclear
      The bias risk assessment showed poor internal validity; most included studies were assigned no and unclear descriptors in most domains. The details of the bias risk assessment are shown in Fig. 2.

      Impact of exercise training on blood parameters

      While moderate-intensity exercises enhance the immune system, vigorous exercises can suppress the immune system.
      • Pendersen B.K.
      • Toft A.D.
      Effects of exercise on lymphocytes and cytokines.
      Acute training leads to increased neutrophil concentration during and after exercise. Similarly, moderate exercise can increase lymphocyte counts. Intense exercise did not affect lymphocyte count.
      • Pendersen B.K.
      • Toft A.D.
      Effects of exercise on lymphocytes and cytokines.
      Physical activity induces neutrophilia under cortisol's influence. Neutrophil chemotaxis is substantially decreased without a reduction in bactericidal activity during the post-exercise period (nearly 24 h) .
      • da Silveira M.P.
      • da Silva Fagundes K.K.
      • Bizuti M.R.
      • Starck É.
      • Rossi R.C.
      • de Resende e Silva D.T.
      Physical exercise as a tool to help the immune system against COVID-19: an integrative review of the current literature.
      This decrease in neutrophil chemotaxis reverses within 48 h post-exercise. However, it should be noted that infectious microorganism activity can increase during this period.
      • da Silveira M.P.
      • da Silva Fagundes K.K.
      • Bizuti M.R.
      • Starck É.
      • Rossi R.C.
      • de Resende e Silva D.T.
      Physical exercise as a tool to help the immune system against COVID-19: an integrative review of the current literature.
      It is believed that six-week moderate-intensity exercise can also increase erythropoiesis, increasing the red blood cell and plasma volumes.
      • Bizjak D.A.
      • Tomschi F.
      • Bales G.
      • Nader E.
      • Romana M.
      • Connes P.
      • et al.
      Does endurance training improve red blood cell aging and hemorheology in moderate-trained healthy individuals?.
      Finally, an eight-week structured exercise program resulted in a temporary increase in circulating plasma volume and plasma erythropoietin concentration and a gradual increase in red blood cell volume.
      • Montero D.
      • Breenfeldt-Andersen A.
      • Oberholzer L.
      • Haider T.
      • Goetze J.P.
      • Meinild-Lundby A.-.K.
      • et al.
      Erythropoiesis with endurance training: dynamics and mechanisms.

      The innate and adaptive immune system

      The body's defense is a multifaceted organization of organs, tissues, and cells.
      • Scudiero O.
      • Lombardo B.
      • Brancaccio M.
      • Mennitti C.
      • Cesaro A.
      • Fimiani F.
      • et al.
      Exercise, immune system, nutrition, respiratory and cardiovascular diseases during COVID-19: a complex combination.
      This multidimensional system acts on unrecognized foreign bodies or molecules (e.g., parasites, bacteria, viruses, fungi, and infected cells) to eliminate them from the body.
      • Scudiero O.
      • Lombardo B.
      • Brancaccio M.
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      • Cesaro A.
      • Fimiani F.
      • et al.
      Exercise, immune system, nutrition, respiratory and cardiovascular diseases during COVID-19: a complex combination.
      The body's defense or immune system can be divided into innate and adaptive immunity.

      Innate immunity

      This immune system is typically the primary defense mechanism against foreign pathogens. It typically comprises immune cell-like monocytes, macrophages, granulocytes, and NK cells.
      • Schultze J.L.
      • Aschenbrenner A.C.
      COVID-19 and the human innate immune system.

      Acquired immunity

      The primary purpose of adaptive immune responses is to recognize specific antigens by differentiating antigens.
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      • Watson W.
      • Kim H.L.
      An introduction to immunology and immunopathology.
      The adaptive immune system mainly comprises T and B cells, which produce antibodies against unrecognized foreign bodies.
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      • Kim H.L.
      An introduction to immunology and immunopathology.

      High and moderate-intensity exercise training in cardiorespiratory diseases and their immune responses

      Effect of exercise on the innate and adaptive systems

      Ample evidence suggests that regular moderate-intensity exercise enhances innate immune function.
      • Malaguarnera L.
      • Cristaldi E.
      • Vinci M.
      • Malaguarnera M.
      The role of exercise on the innate immunity of the elderly.
      In contrast, acute high-intensity or regular, intense exercise can disrupt the defense mechanism, increasing the risk of upper respiratory tract infection.
      • Malaguarnera L.
      • Cristaldi E.
      • Vinci M.
      • Malaguarnera M.
      The role of exercise on the innate immunity of the elderly.
      Evidence suggests that intense training sessions increase the likelihood of infection, relapse, and myocarditis. Macrophages, NK cells, and neutrophils are relatively responsive to acute exercise sessions. With chronic exercise training, the NK cells show increased inactivity. In contrast, opposite or suppression inactivity is observed in neutrophil functions with intense sessions. Evidence suggests that acute moderate exercise sessions with a duration <60 min and intensity <60% of VO2 max (oxygen uptake) are associated with reduced immune system stress.
      • Malaguarnera L.
      • Cristaldi E.
      • Vinci M.
      • Malaguarnera M.
      The role of exercise on the innate immunity of the elderly.
      Intermittent training is an aerobic training strategy that uses either rest or low-intensity-exercise periods between high-intensity periods. The primary concept behind this strategy is to allow more rigorous exercise periods than continuous high-intensity exercise.
      • Souza D.
      • Vale A.F.
      • Silva A.
      • et al.
      Acute and chronic effects of interval training on the immune system: a systematic review with meta-analysis.
      Acute high-intensity interval training usually destabilizes the immune system, but chronic functional bouts may lead to immune system adaptations without altering leukocyte count.
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      • et al.
      Acute and chronic effects of interval training on the immune system: a systematic review with meta-analysis.
      An acute exercise period may induce distinctive temporary biphasic variations in circulating lymphocyte numbers.
      • Walsh N.P.
      • Gleeson M.
      • Shephard R.J.
      • Gleeson M.
      • Woods J.A.
      • Bishop N.C.
      • et al.
      Position statement. Part one: immune function and exercise.
      Classically, high lymphocyte counts are observed throughout continuous training and immediately afterward, with fewer cells post-workout during the early recovery phase. This typical cell orchestration is commonly observed for T cells and, to a lesser extent, B cells.
      • Walsh N.P.
      • Gleeson M.
      • Shephard R.J.
      • Gleeson M.
      • Woods J.A.
      • Bishop N.C.
      • et al.
      Position statement. Part one: immune function and exercise.
      Studies have found that acute maximal exercise may lead to leucocytosis in younger (∼22 years) and older (∼65 years) adults.
      • Sellami M.
      • Gasmi M.
      • Denham J.
      • Hayes L.D.
      • Stratton D.
      • Padulo J.
      • et al.
      Effects of acute and chronic exercise on immunological parameters in the elderly aged: can physical activity counteract the effects of aging?.
      An increase in both CD4+ and CD8+ lymphocytes is observed post-exercise. Despite high CD3+ cell accumulation, lymphocyte production is often reduced in the aged. Therefore, exercise-induced leucocytosis is observed in younger and older individuals but less often in the aged.
      • Sellami M.
      • Gasmi M.
      • Denham J.
      • Hayes L.D.
      • Stratton D.
      • Padulo J.
      • et al.
      Effects of acute and chronic exercise on immunological parameters in the elderly aged: can physical activity counteract the effects of aging?.
      Additionally, training intensity tends to be related to the telomere length for CD4+ and CD8+ T cells.
      • Sellami M.
      • Gasmi M.
      • Denham J.
      • Hayes L.D.
      • Stratton D.
      • Padulo J.
      • et al.
      Effects of acute and chronic exercise on immunological parameters in the elderly aged: can physical activity counteract the effects of aging?.
      Table 1 discusses the exercise training results on leucocytes in cardiorespiratory conditions.

      Exercise-related immunity and its J-shaped hypothesis

      Regular exercise can induce adaptations, modifying each arm of the immune system depending on exercise intensity.
      • Chamorro-Viña C.
      • Fernandez-del-Valle M.
      • Tacón A.M.
      Excessive exercise and immunity: the J-shaped curve.
      However, factors such as sex-related differences, age, nutrition, and psychological stress might also play an influential role.
      This J-shaped curve explains the association between exercise intensity and infection susceptibility.
      • Nieman D.
      Exercise, infection, and immunity.
      This hypothesis advocates that medium-intensity workouts can enhance the body's defense mechanism in inactive individuals, while high-intensity workouts may weaken the body's defense mechanism.
      • Nieman D.
      Exercise, infection, and immunity.
      Niemen et al. previously used this hypothesis to explain the 2–6-fold increase in the risk of developing respiratory infections among marathon runners.
      • Nieman D.
      Exercise, infection, and immunity.
      Mounting research evidence advocates that athletes involved in vigorous workouts are more likely to develop upper respiratory tract infections.
      • Chamorro-Viña C.
      • Fernandez-del-Valle M.
      • Tacón A.M.
      Excessive exercise and immunity: the J-shaped curve.
      After long periods of intensive exercise, the immune system may experience physiological stress and suppression. This period is called an “open window” and usually lasts 3 to 72 h. Therefore, the host remains vulnerable to microbes and pathogens such as bacteria and viruses, with a greater likelihood of contracting infections.
      • Scudiero O.
      • Lombardo B.
      • Brancaccio M.
      • Mennitti C.
      • Cesaro A.
      • Fimiani F.
      • et al.
      Exercise, immune system, nutrition, respiratory and cardiovascular diseases during COVID-19: a complex combination.
      Therefore, advocating exercise training in cardiorespiratory disease, especially high-intensity exercises, may require caution and knowledge about the J curve theory since patients with cardiorespiratory diseases are already susceptible to infections. However, if the exercise training program does not attain the desired intensity, it may fail to produce the required effects on the body's inflammatory state.
      • Cerqueira É.
      • Marinho D.A.
      • Neiva H.P.
      • Lourenço O.
      Inflammatory effects of high and moderate intensity exercise—a systematic review.

      Role of nitric oxide (NO) in inflammation and exercise

      NO plays a key role in defense systems protecting against infections by various organisms. It differentiates the growth and death of immune and inflammatory cells, which include mast cells, macrophages, neutrophils, NK cells, and T lymphocytes.
      • Coleman J.W.
      Nitric oxide in immunity and inflammation.
      One study found that four weeks of home-based exercise training enhanced the release of endothelium-derived NO in hypercholesterolemic patients without altering risks for other comorbidities. Therefore, current evidence indicates that exercise training has both cardioprotective and blood pressure normalizing effects.
      • Lewis T.V.
      • Dart A.M.
      • Chin-Dusting J.P.F.
      • Kingwell B.A.
      Exercise training increases basal nitric oxide production from the forearm in hypercholesterolemic patients.

      The anti-inflammatory effects of exercise training in cardiorespiratory diseases

      It is well-known that chronic build-up of inflammatory biomarkers, such as fibrinogen, C-reactive protein (CRP) and cytokines, may develop and progress toward cardiorespiratory disease.
      • Pedersen B.K.
      Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease.
      Skeletal muscles generally interconnect with other tissues through peptides called myokines which are secreted by the myocytes during muscle contractions.
      • Pedersen B.K.
      Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease.
      The exercising muscle usually produces and discharges several peptides, including leukemia inhibitory factor and interleukins (IL)−4, IL-6, IL-7, and IL-15.
      Studies exploring exercise's role also specifically reported that exercise induces the release of myostatin inhibitors usually released from wasted or disuse muscles, which act on myostatin and negatively affect muscle mass and hypertrophy.
      • Pedersen B.K.
      Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease.
      Exercises stimulate the release of follistatin and myostatin inhibitors from the liver.
      • Pedersen B.K.
      Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease.
      The first cytokine released from active skeletal muscle cells into the blood during exercise is IL-6. Exercise increases the amount of muscle-derived IL-6 in the blood.
      • Pedersen B.K.
      Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease.
      The training period is usually the primary factor regulating the extent of systemic IL-6 release.
      • Pedersen B.K.
      Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease.
      Therefore, longer workout periods lead to a more distinctive total IL-6 release. This release of IL-6 is primarily related to workout intensity, approximately around 70%–85% of VO2 max.
      • Pedersen B.K.
      Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease.
      A direct relationship exists between IL-6 levels and several dependent factors such as exercise capacity, duration, and intensity.
      • Docherty S.
      • Harley R.
      • McAuley J.J.
      • Crowe L.A.N.
      • Pedret C.
      • Kirwan P.D.
      • et al.
      The effect of exercise on cytokines: implications for musculoskeletal health: a narrative review.
      Evidence from in vivo studies indicates IL-6 has beneficial effects since its deficiency can accelerate the atherosclerotic process.
      • Pedersen B.K.
      Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease.
      In contrast, tumor necrosis factor-alpha (TNF-α) in the arteries may promote the atherosclerosis process via specific adhesion factors. Additionally, inflammatory cytokines modify skeletal muscle histology and deleteriously affect cardiac contractility and left ventricular remodeling.
      • Smart N.A.
      • Larsen A.I.
      • Le Maitre J.P.
      • Ferraz A.S
      Effect of exercise training on interleukin-6, tumour necrosis factor alpha and functional capacity in heart failure.
      Notably, while a structured exercise training regime can adversely affect plasma IL-6 levels, muscular IL-6 receptor levels are increased, indicating improved IL-6 signaling in expert compared to amateur individuals.
      • Pedersen B.K.
      Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease.
      Some studies discussing the resolutory effects of exercise training in cardiac and pulmonary conditions are discussed in Table 3. It should be noted that most studies listed in Table 3 report the beneficial effects of exercise.
      Table 3A qualitative view of anti-inflammatory effect of exercise training in cardiorespiratory conditions.
      AuthorsStudy designConditionOutcomes related to anti-inflammatory effectsReported results
      1.Normandin et al
      • Normandin E.
      • Nigam A.
      • Meyer P.
      • Juneau M.
      • Guiraud T.
      • Bosquet L.
      • et al.
      Acute responses to intermittent and continuous exercise in heart failure patients.
      Unclear (N = 20)CHFC-reactive proteins, Cardiac troponin T (cTnT) and brain natriuretic peptide (BNP)Neither high intensity Interval exercise nor moderate-intensity continuous exercise caused any significant change in CRP, BNP, or cTnT levels
      2.Gielen S et al
      • Gielen S.
      • Adams V.
      • Möbius-Winkler S.
      • Linke A.
      • Erbs S.
      • Yu J.
      • et al.
      Anti-inflammatory effects of exercise training in the skeletal muscle of patients with chronic heart failure.
      RCT (Exc=10; Con=10)CHFInterleukin (IL)−6, and IL-1-beta levels, Serum tumor necrosis factor (TNF)-alpha, local cytokine, and iNOS expressionExercise training significantly reduced the local expression of TNF-alpha, IL-1-beta, IL-6, and iNOS in the skeletal muscle of CHF patient
      3.Conraads et al
      • Conraads V.
      Combined endurance/resistance training reduces plasma TNF-α receptor levels in patients with chronic heart failure and coronary artery disease.
      Non randomized (Exc=23; Con=18)CAD/IDCMInterleukin (IL)−6, tumor necrosis factor (TNF)-alpha, soluble TNF receptor 1 (sTNFR1) and 2 (sTNFR2)Exercise training has an anti-inflammatory effect in patients with CHD and CAD
      4. Darmian et al
      • Darmian M.A.
      • Hoseini R.
      • Amiri E.
      • Golshani S.
      Downregulated hs-CRP and MAD, upregulated GSH and TAC, and improved metabolic status following combined exercise and turmeric supplementation: a clinical trial in middle-aged women with hyperlipidemic type 2 diabetes.
      RCT (Exc+TS (n= 11), Exc+placebo (Exc; n= 10), TS (n= 11), and Con (C; n= 10)HT2DMhs-CRP levels, HDL, cholesterol, and TGExc + TS is recommended as a conclusive lifestyle approach to manage metabolic status, oxidative stress biomarkers, and CRP in middle-aged females with T2DM
      5.Larsen et al
      • Larsen A.I.
      • Aukrust P.
      • Aarsland T.
      • Dickstein K.
      Effect of aerobic exercise training on plasma levels of tumor necrosis factor alpha in patients with heart failure.
      Pre-Post (n = 28)CHFTNF-alpha, IL-6, IL-8Present study demonstrates that aerobic exercise training reduces pathologically increased TNF- alpha levels in patients with CHF
      6. Kitzman et al
      • Kitzman D.W.
      • Brubaker P.H.
      • Herrington D.M.
      • Morgan T.M.
      • Stewart K.P.
      • Hundley W.G.
      • et al.
      Effect of endurance exercise training on endothelial function and arterial stiffness in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial.
      RCT (n = 63) Exc=32, Con=31CHFB-type natriuretic peptide (BNP), Carotid stiffness index, Brachial FMDExercise training didn't alter endothelial functions or arterial stiffness
      7.Larsen et al
      • Larsen A.I.
      • Lindal S.
      • Aukrust P.
      • Toft I.
      • Aarsland T.
      • Dickstein K.
      Effect of exercise training on skeletal muscle fibre characteristics in men with chronic heart failure. Correlation between skeletal muscle alterations, cytokines and exercise capacity.
      Pre-Post (n = 15)CHFMuscle biopsies, TNF-alpha, IL-6, IL-8Increase in muscle fiber area%. Moderate negative correlation between the level of interleukin 6 and fiber thickness at baseline,
      8.Ahmad et al
      • Ahmad T.
      • Fiuzat M.
      • Mark D.B.
      • Neely B.
      • Neely M.
      • Kraus W.E.
      • et al.
      The effects of exercise on cardiovascular biomarkers in patients with chronic heart failure.
      RCT n = 928

      Exc=477, Con=451
      CHFPlasma levels of amino-terminal pro-brain natriuretic peptide (NT-proBNP), high- sensitivity C-reactive protein (hs-CRP), and cardiac troponin T (cTnT)A 12-week exercise training

      program did not lead to improvements in plasma concentrations of cytokines nor NT-proBNP, when compared with usual care
      9. Vogiatzis et al
      • Vogiatzis I.
      • Stratakos G.
      • Simoes D.C.M.
      • Terzis G.
      • Georgiadou O.
      • Roussos C.
      • et al.
      Effects of rehabilitative exercise on peripheral muscle TNFα, IL-6, IGF-I and MyoD expression in patients with COPD.
      Pre-post, COPD n = 15COPDMuscle Biopsies, TNFa,

      C-reactive protein (CRP), tumor necrosis factor-a (TNFa) and (C) interleukin-6 (IL-6)
      Pulmonary rehabilitation induced muscle adaptations and skeletal muscle hypertrophy without decreasing the levels of systemic or local muscle inflammation
      10. Rabinovich et al
      • Tirakitsoontorn P.
      • Nussbaum E.
      • Moser C.
      • Hill M.
      • Cooper D.M.
      Fitness, acute exercise, and anabolic and catabolic mediators in cystic fibrosis.
      Case control, COPD (n)= 11, Con =6COPDTNF-a, soluble TNF receptors (sTNFRs: sTNFR55 and sTNFR75) and interleukin (IL)−6 and TNF-a mRNAModerate-intensity exercise increases plasma tumor necrosis factor-a levels in COPD without exercise-induced upregulation of the tumor necrosis factor-a gene in skeletal muscle
      11.Nguyen et al
      • Nguyen T.
      • Obeid J.
      • Ploeger H.E.
      • Takken T.
      • Pedder L.
      • Timmons B.W.
      Inflammatory and growth factor response to continuous and intermittent exercise in youth with cystic fibrosis.
      Case control, CF(n)= 12, Con=12Cystic fibrosisIL-6, TNF-α, GH, and IGF-1High Intensity, Intermittent exercise of adequate intensity can increase GH in children with CF, without affecting systemic inflammation, whereas Continuous mode of moderate-intensity exercise is associated with significant increase in IL-6 levels
      12.Spruit et al
      • Spruit M.A.
      • Gosselink R.
      • Troosters T.
      • Kasran A.
      • Van Vliet M.
      • Decramer M.
      Low-grade systemic inflammation and the response to exercise training in patients with advanced COPD.
      Open prospective intervention study, Exc (n)=78Advanced COPDCRP, TNF-ἀ, sTNFR-p55, sTNFR-p75, and IL-8No change in CRP post-training, but other factors had a significant change post-training
      13. Pinho et al
      • Pinho R.A.
      • Chiesa D.
      • Mezzomo K.M.
      • Andrades M.E.
      • Bonatto F.
      • Gelain D.
      • et al.
      Oxidative stress in chronic obstructive pulmonary disease patients submitted to a rehabilitation program.
      Unclear, n = 15.

      Exc =8 and Con = 7
      COPDIndex of lipid peroxidation, thiobarbituric acid reactive species (TBARS), total radical-trapping antioxidant parameter (TRAP) and xanthine oxidase (XO) activityPR program is associated with decreased systemic exercise-induced oxidative damage
      14. Mercken et al
      • Mercken E.M.
      • Hageman G.J.
      • Schols A.M.W.J.
      • Akkermans M.A.
      • Bast A.
      • Wouters E.F.M.
      Rehabilitation decreases exercise-induced oxidative stress in chronic obstructive pulmonary disease.
      Case-control (n)=22, Exc =11, Con=11COPDUrinary MDA, H2O2 in breath condensate8 week PR program is related to increased exercise capacity and reduced exercise-induced oxidative stress
      CHF- Cardiac Heart failure, cTnT – cardiac troponin, Coronary artery disease (CAD) or idiopathic dilated cardiomyopathy (IDCM), TS-turmeric, Hyperlipidemic Type 2 Diabetes Mellitus (HT2DM), C-reactive protein (CRP), hs-CRP- high- sensitivity CRP, TG- Triglycerides, HDL-High- Density Lipoprotein, FMD = flow-mediated arterial dilation, IL- Interleukin, TNF-ἀ- Tumour Necrosis factor-alpha, Soluble tumor necrosis factor receptor (TNF), Placebo- no treatment, PR- Pulmonary rehabilitation, Exc= exercise training, Con= Controls, MDA- malondialdehyde, H2O2- Hydrogen peroxide in breath condensate, GH- growth hormone, COPD- Chronic obstructive pulmonary disease, idiopathic dilated cardiomyopathy-IDCM, CAD- coronary artery disease, CHF- chronic heart failure, HT2DM- Hyperlipidemic Type 2 Diabetes Mellitus, MDA- malondialdehyde.
      The elevated levels of inflammation in disorders such as COPD can be resolved with exercise training regimes.
      • Pedersen B.K.
      Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease.
      Unfortunately, abdominal adiposity and physical inactivity
      • Yudkin J.
      Inflammation, obesity, and the metabolic syndrome.
      ,
      • Laye M.J.
      • Thyfault J.P.
      • Stump C.S.
      • Booth F.W.
      Inactivity induces increases in abdominal fat.
      combine to create a persistent secondary exacerbated condition in the whole body. Ancillary studies support the direct association between sedentariness and visceral fat deposition.
      • Harder-Lauridsen N.M.
      • Nielsen S.T.
      • Mann S.P.
      • Lyngbæk M.P.
      • Benatti F.B.
      • Langkilde A.R.
      • et al.
      The effect of alternate-day caloric restriction on the metabolic consequences of 8 days of bed rest in healthy lean men: a randomized trial.
      Studies have identified important factors concerning the harmful outcomes of visceral fat deposition in the liver and skeletal muscles that may further accelerate systemic inflammation.
      • Pedersen B.K.
      Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease.
      Exercise training improves cardiorespiratory fitness and anti-inflammatory effect in patients with chronic heart failure.
      • Bolton C.E.
      • Bevan-Smith E.F.
      • Blakey J.D.
      • Crowe P.
      • Elkin S.L.
      • Garrod R.
      • et al.
      British Thoracic Society guideline on pulmonary rehabilitation in adults: accredited by NICE.
      This anti-inflammatory effect further attenuates chronic heart failure progression. However, there remains a dearth of studies on the anti-inflammatory potential of exercise training in PR in COPD cases.
      • Rosano G.
      • Jankowska E.A.
      • Ray R.
      • Metra M.
      • Abdelhamid M.
      • Adamopoulos S.
      • et al.
      COVID-19 vaccination in patients with heart failure: a position paper of the Heart Failure Association of the European Society of Cardiology.
      A prominent reason for this could be the failure to reach the optimum intensity to produce the desired blood parameter effects. In addition, most studies failed to calculate exercise adherence for participants (Tables 1 and 2).

      Role of nutritional interventions in cardiorespiratory rehabilitation

      The surveillance ability of the immune system can be increased through a mild to moderate intensity exercise training regime.
      • Scudiero O.
      • Lombardo B.
      • Brancaccio M.
      • Mennitti C.
      • Cesaro A.
      • Fimiani F.
      • et al.
      Exercise, immune system, nutrition, respiratory and cardiovascular diseases during COVID-19: a complex combination.
      In contrast, the lower immune response in the upper airway after high-intensity exercises may be due to decreased salivary and nasal release and a reduction in nasal neutrophil numbers.
      • Scudiero O.
      • Lombardo B.
      • Brancaccio M.
      • Mennitti C.
      • Cesaro A.
      • Fimiani F.
      • et al.
      Exercise, immune system, nutrition, respiratory and cardiovascular diseases during COVID-19: a complex combination.
      ,
      • Wang L.
      • Qiao X.
      • Ai L.
      • Zhai J.
      • Wang X
      Isolation of antimicrobial resistant bacteria in upper respiratory tract infections of patients.
      The results of nutrition and exercise interventions for cardiorespiratory problems in decreasing inflammation are discussed in Table 2. It is perhaps already known that exercise capacity is inversely associated with the body's inflammatory status.
      • Rahimi K.
      • Secknus M.-.A.
      • Adam M.
      • Hayerizadeh B.-.F.
      • Fiedler M.
      • Thiery J.
      • et al.
      Correlation of exercise capacity with high-sensitive C-reactive protein in patients with stable coronary artery disease.
      Individuals following a diet combining numerous nutrients and food items experience additional cardioprotective and anti-inflammatory effects.
      • Casas R.
      • Castro-Barquero S.
      • Estruch R.
      • Sacanella E.
      Nutrition and cardiovascular health.
      Diets rich in vegetable seeds, legumes, fruits, nuts, and whole grains, have been associated with lower inflammation.
      • Wood A.D.
      • Strachan A.A.
      • Thies F.
      • Aucott L.S.
      • Reid D.M.
      • Hardcastle A.C.
      • et al.
      Patterns of dietary intake and serum carotenoid and tocopherol status are associated with biomarkers of chronic low-grade systemic inflammation and cardiovascular risk.
      • Sijtsma F.P.C.
      • Meyer K.A.
      • Steffen L.M.
      • Van Horn L.
      • Shikany J.M.
      • Odegaard A.O.
      • et al.
      Diet quality and markers of endothelial function: the CARDIA study.
      • Piccand E.
      • Vollenweider P.
      • Guessous I.
      • Marques-Vidal P.
      Association between dietary intake and inflammatory markers: results from the CoLaus study.
      In contrast, diets high in meat have been associated with greater inflammation.
      • Wood A.D.
      • Strachan A.A.
      • Thies F.
      • Aucott L.S.
      • Reid D.M.
      • Hardcastle A.C.
      • et al.
      Patterns of dietary intake and serum carotenoid and tocopherol status are associated with biomarkers of chronic low-grade systemic inflammation and cardiovascular risk.
      • Quintana Pacheco D.A.
      • Sookthai D.
      • Wittenbecher C.
      • Graf M.E.
      • Schübel R.
      • Johnson T.
      • et al.
      Red meat consumption and risk of cardiovascular diseases—is increased iron load a possible link?.
      • Oude Griep L.M.
      • Wang H.
      • Chan Q
      Empirically derived dietary patterns, diet quality scores, and markers of inflammation and endothelial dysfunction.
      The American Heart Association Nutrition Committee and the European Society of Cardiology have reported that the daily consumption of vegetables and fruits can decrease CVD risk.
      • Dauchet L.
      • Amouyel P.
      • Dallongeville J.
      Fruits, vegetables and coronary heart disease.
      ,
      • Dauchet L.
      • Amouyel P.
      • Hercberg S.
      • Dallongeville J.
      Fruit and vegetable consumption and risk of coronary heart disease: a meta-analysis of cohort studies.
      An analysis of 83 studies (two cohort studies and12 observational, 10 cross-sectional, and 71 clinical trials) showed that greater vegetable and fruit consumption was inversely associated with decreases in TNF-α and CRP levels and total airway inflammation.
      • Hosseini B.
      • Berthon B.S.
      • Saedisomeolia A.
      • Starkey M.R.
      • Collison A.
      • Wark P.A.B.
      • et al.
      Effects of fruit and vegetable consumption on inflammatory biomarkers and immune cell populations: a systematic literature review and meta-analysis.
      Another study comprising 792 participants with a mean age of 70 years found that plant-based diets appeared superior and were associated with lower plasma fibrinogen and CRP levels.
      • Corley J.
      • Kyle J.A.M.
      • Starr J.M.
      • McNeill G.
      • Deary I.J.
      Dietary factors and biomarkers of systemic inflammation in older people: the Lothian Birth Cohort 1936.
      A diet rich in nuts, especially walnuts and peanuts, has been shown to lower CVD morbidity and mortality.
      • Aune D.
      • Keum N.
      • Giovannucci E.
      • Fadnes L.T.
      • Boffetta P.
      • Greenwood D.C.
      • et al.
      Nut consumption and risk of cardiovascular disease, total cancer, all-cause and cause-specific mortality: a systematic review and dose-response meta-analysis of prospective studies.
      Moreover, a recent meta-analysis of 23 randomized control trials assessing the effectiveness of nuts in reducing inflammation markers found that dietary management with nuts could meaningfully decrease intercellular adhesion molecule-1 and inflammatory biomarker levels.
      Nevertheless, research has shown the various benefits of a vegetable-based diet. However, there remains a dearth of studies evaluating the long-term effects of dietary management programs.
      • Casas R.
      • Castro-Barquero S.
      • Estruch R.
      • Sacanella E.
      Nutrition and cardiovascular health.
      Consequently, the long-term effects of exercise and nutrition on inflammatory and immune biomarkers must be assessed as an indicator of its long-term efficacy, simultaneously evaluating the effects on several adverse events, hospitalizations, and adherence to exercise programs (Table 2).

      A conceptual basis for rehabilitation programs: their theoretical foundation in practice

      Cardiac rehabilitation and PR programs are essential for people recovering from cardiac surgery, myocardial infarction, heart failure, or transplants.
      • Dalal H.M.
      • Doherty P.
      • Taylor R.S.
      Cardiac rehabilitation.
      There is increasing evidence that cardiac rehabilitation (CR) effectively decreases morbidity and mortality, increasing mental well-being, quality of life, and exercise capacity.
      • Dalal H.M.
      • Doherty P.
      • Taylor R.S.
      Cardiac rehabilitation.
      The American Association of Cardiovascular and Pulmonary Rehabilitation and the American Heart Association have reported that the essential core rehabilitation program components help reduce cardiovascular risk, augment healthy behaviors, and decrease cardiovascular-related morbidity and mortality.
      • Thomas R.J.
      • Beatty A.L.
      • Beckie T.M.
      • Brewer L.C.
      • Brown T.M.
      • Forman D.E.
      • et al.
      Home-based cardiac rehabilitation.
      The fundamental components are exercise training, dietary counseling, assessment, psychosocial mediation, and controlling risk factors.
      • Thomas R.J.
      • Beatty A.L.
      • Beckie T.M.
      • Brewer L.C.
      • Brown T.M.
      • Forman D.E.
      • et al.
      Home-based cardiac rehabilitation.
      Therefore, it is essential to design programs that effectively modify risky health behaviors and immunomodulation.
      Similarly, PR has proven beneficial in patients with lung diseases, breathlessness, reduced functional capacity, decreased quality of life, and frequent hospital admissions.
      • Corhay J.L.
      • Nguyen D.
      • Van Cauwenberge H.
      • Louis R.
      Pulmonary rehabilitation and COPD: providing patients a good environment for optimizing therapy.
      There is a current consensus that greater physical activity intensity is associated with lower mortality from noncommunicable diseases.
      • Geidl W.
      • Schlesinger S.
      • Mino E.
      • Miranda L.
      • Pfeifer K.
      D.ose–response relationship between physical activity and mortality in adults with noncommunicable diseases: a systematic review and meta-analysis of prospective observational studies.
      However, the exact dose-response providing anti-inflammatory effects in cardiorespiratory disease remains unknown. Moreover, some animal studies have reported enhanced acute immunosurveillance, the effect of which remains unknown in healthy and diseased populations.
      • Adams G.R.
      • Zaldivar F.P.
      • Nance D.M.
      • Kodesh E.
      • Radom-Aizik S.
      • Cooper D.M.
      Exercise and leukocyte interchange among central circulation, lung, spleen, and muscle.
      ,
      • Gupta P.
      • Bigley A.B.
      • Markofski M.
      • Laughlin M.
      • LaVoy E.C.
      Autologous serum collected 1 h post-exercise enhances natural killer cell cytotoxicity.
      The specific concepts discussed in the current review will enhance the decision-making process when designing CR or PR programs. It is believed that exercise causes an acute increase in IL-6, which is known for its anti-inflammatory effects.
      • Nieman D.C.
      • Wentz L.M.
      The compelling link between physical activity and the body's defense system.
      Over time, this effect can be vital for interventions focusing on patients suffering from cardiac or pulmonary diseases.

      The cytokine storm in COVID-19

      In moderate to severe COVID-19 infection, a destructive inflammatory reaction is often observed in which enormous quantities of proinflammatory cytokines are discharged, called a cytokine storm.
      • Ragab D.
      • Salah Eldin H.
      • Taeimah M.
      • Khattab R.
      • Salem R.
      The COVID-19 cytokine storm; what we know so far.
      Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; also known as 2019-nCoV) infected individuals show an enhanced response leading to an unwarranted adverse reaction in the body. Greater cytokine quantities are released in severe COVID-19 cases, including interferon-gamma IL-1β, IL-2, IL-6, IL-8, IL-10, IL-17, TNF-α, gamma-induced protein 10, monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein 1 alpha, and granulocyte-colony stimulating factor. This enhanced response can cause an auto-immunological attack, causing extensive damage to the primary organs such as the heart, lung, brain, and kidneys, eventually leading to multiple organ failures.
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      Physical exercise as a tool to help the immune system against COVID-19: an integrative review of the current literature.

      COVID-19 and its ongoing impacts on cardiorespiratory rehabilitation

      Wuhan became the epicenter of the COVID-19 pandemic in 2019. Scientists rapidly discovered a new coronavirus named SARS-CoV-2.
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      Exercise, immune system, nutrition, respiratory and cardiovascular diseases during COVID-19: a complex combination.
      As the pandemic evolved, COVID-19 survivors began experiencing disorders or residual impairments called post-COVID-19 syndrome.
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      • et al.
      Exercise, immune system, nutrition, respiratory and cardiovascular diseases during COVID-19: a complex combination.
      Recent data suggests that around 20% of individuals infected with SARS-CoV-2 may suffer from serious symptoms for over 12 weeks postdiagnosis. While studies have begun exploring this novel condition, the best practice for management in this field remains to be determined.
      • Scudiero O.
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      • et al.
      Exercise, immune system, nutrition, respiratory and cardiovascular diseases during COVID-19: a complex combination.
      It has been reported that COVID-19 has severely obstructed CR care worldwide. A survey evaluating the impact of the COVID-19 pandemic on healthcare in 70 countries reported that it caused a temporary interruption in approximately 75% of CR programs.
      • Ghisi GL de M.
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      Impacts of the COVID-19 pandemic on cardiac rehabilitation delivery around the world.
      Additionally, it should be noted that substantial psychosocial and economic impacts have affected cardiorespiratory providers.
      • Ghisi GL de M.
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      Impacts of the COVID-19 pandemic on cardiac rehabilitation delivery around the world.
      ,
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      • Brooks D.
      • et al.
      Delivering pulmonary rehabilitation during the COVID-19 pandemic: a Canadian Thoracic Society position statement.
      Therefore, CR models should promote a healthy lifestyle through home-based, virtual programs to ensure a safe, accessible healthcare system.
      • Ghisi GL de M.
      • Xu Z.
      • Liu X.
      • Mola A.
      • Gallagher R.
      • Babu A.S.
      • et al.
      Impacts of the COVID-19 pandemic on cardiac rehabilitation delivery around the world.
      ,
      • Dixit S.
      • Nandakumar G.
      Promoting healthy lifestyles using information technology during the COVID-19 pandemic.
      It remains advisable to evaluate exercise capacity virtually.
      • Dechman G.
      • Aceron R.
      • Beauchamp M.
      • Bhutani M.
      • Bourbeau J.
      • Brooks D.
      • et al.
      Delivering pulmonary rehabilitation during the COVID-19 pandemic: a Canadian Thoracic Society position statement.
      Specific tests such as the one-minute sit-to-stand test can be used to remotely assess aerobic capacity and leg strength since they are quite sensitive to changes, particularly pulmonary problems in COPD patients.
      • Dechman G.
      • Aceron R.
      • Beauchamp M.
      • Bhutani M.
      • Bourbeau J.
      • Brooks D.
      • et al.
      Delivering pulmonary rehabilitation during the COVID-19 pandemic: a Canadian Thoracic Society position statement.
      Evaluation of exercise responses can be made using a pulse oximeter to measure oxygen desaturation, a common finding that may become complex with COVID-19. Electronic blood pressure monitors can similarly be used. Exercise intensity can be self-evaluated using a rating of perceived exertion scale and a modified Borg dyspnea scale.
      • Dechman G.
      • Aceron R.
      • Beauchamp M.
      • Bhutani M.
      • Bourbeau J.
      • Brooks D.
      • et al.
      Delivering pulmonary rehabilitation during the COVID-19 pandemic: a Canadian Thoracic Society position statement.
      A walking test can also be used to evaluate cardiorespiratory fitness in patients with CVD by remotely monitoring them after administering a structured exercise program.
      • Batalik L.
      • Dosbaba F.
      • Konecny V.
      • Batalikova K.
      Remotely monitored cardiac rehabilitation based on a walking test during the COVID-19 pandemic.
      Evidence suggests that CR using a walking test and telemonitoring using a heart rate monitor can efficiently administer and increase cardiorespiratory fitness in cardiac patients with mild-to-moderate risk factors.
      • Batalik L.
      • Dosbaba F.
      • Konecny V.
      • Batalikova K.
      Remotely monitored cardiac rehabilitation based on a walking test during the COVID-19 pandemic.
      Self-management approaches are another core aspect in the remote management of COPD and asthma, which requires the patient to have sufficient knowledge and self-care skills.
      • Yu S.-.H.
      • Guo A.-.M.
      • Zhang X.-.J.
      Effects of self-management education on quality of life of patients with chronic obstructive pulmonary disease.
      An organized self-management strategy can decrease the number of episodes of exacerbations requiring hospitalization, improving the patient's mental, social and physical health
      • Yu S.-.H.
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      • Zhang X.-.J.
      Effects of self-management education on quality of life of patients with chronic obstructive pulmonary disease.
      ,
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      Revisiting pulmonary rehabilitation during COVID-19 pandemic: a narrative review.
      during the COVID-19 pandemic.

      Integrating current evidence into best practices

      High-quality studies have clearly shown the beneficial effect of rehabilitation on exercise capacity, dyspnea, and physical activity post-enrolment.
      • Bolton C.E.
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      • Garrod R.
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      British Thoracic Society guideline on pulmonary rehabilitation in adults: accredited by NICE.
      Anxiety and depression could reflect different aspects of the same situation. After an appropriate referral process, the rehabilitation process should consider an appropriate support system to manage them.
      • Bolton C.E.
      • Bevan-Smith E.F.
      • Blakey J.D.
      • Crowe P.
      • Elkin S.L.
      • Garrod R.
      • et al.
      British Thoracic Society guideline on pulmonary rehabilitation in adults: accredited by NICE.
      Goal setting in the rehabilitation program should be patient-centered and individually tailored rather than generally applied for a specific intensity to provide beneficial results. Structured home-based PR also has beneficial effects that will be vital for remotely managing complex clinical scenarios, such as individuals with pre-existing pulmonary or cardiac problems isolating due to COVID-19.
      While clinically assessing affected patients, comorbidities should be assessed as part of good practice to rule out absolute contraindications to the treatment sessions. Moreover, the exercise sessions should be modified per the assessment status in relative contraindication cases. In addition to good practices, it is essential to acquire patient suggestions and feedback to further develop the program.
      • Bolton C.E.
      • Bevan-Smith E.F.
      • Blakey J.D.
      • Crowe P.
      • Elkin S.L.
      • Garrod R.
      • et al.
      British Thoracic Society guideline on pulmonary rehabilitation in adults: accredited by NICE.

      Guidelines for minimizing the risk of COVID-19 infection and transmission and optimizing rehabilitation sessions

      Patients with pre-existing cardiorespiratory disease exposed to COVID-19 may have a combination of complex sequelae with signs of myocardial injury, arrhythmias, and heart failure. Such patients often remain at a higher risk of mortality and morbidity.
      • Scudiero O.
      • Lombardo B.
      • Brancaccio M.
      • Mennitti C.
      • Cesaro A.
      • Fimiani F.
      • et al.
      Exercise, immune system, nutrition, respiratory and cardiovascular diseases during COVID-19: a complex combination.
      ,
      • Dechman G.
      • Aceron R.
      • Beauchamp M.
      • Bhutani M.
      • Bourbeau J.
      • Brooks D.
      • et al.
      Delivering pulmonary rehabilitation during the COVID-19 pandemic: a Canadian Thoracic Society position statement.
      Patients with heart failure have reported low immune status, especially heart transplant recipients. Therefore, vaccination is a must in these patients
      • Rosano G.
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      • Ray R.
      • Metra M.
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      • Adamopoulos S.
      • et al.
      COVID-19 vaccination in patients with heart failure: a position paper of the Heart Failure Association of the European Society of Cardiology.
      to significantly reduce their chances of exposure. However, no vaccine provides 100% protection against COVID-19.
      • Rosano G.
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      • Ray R.
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      • Adamopoulos S.
      • et al.
      COVID-19 vaccination in patients with heart failure: a position paper of the Heart Failure Association of the European Society of Cardiology.
      Noncommunicable diseases such as diabetes and hypertension may further exacerbate the situation. Nevertheless, heart failure in recovering patients might be a potent indicator of the impending danger of death.
      • Rosano G.
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      • Ray R.
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      • Adamopoulos S.
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      COVID-19 vaccination in patients with heart failure: a position paper of the Heart Failure Association of the European Society of Cardiology.
      Therefore, minimizing infection or reinfection in existing patients with comorbidities is vital. It will be essential to prevent disease transmission by using a well-ventilated room, personal protective equipment (PPE), and frequently checking for temperature and symptoms. A separate room with outpatient facilities for patients already infected with COVID-19 requiring rehabilitation

      Faghy M.A., Arena R., Stoner L., Haraf R.H., Josephson R. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID- 19 . The COVID-19 resource centre is hosted on Elsevier Connect, the company ’ s public news and information . 2020;(January).

      will be of paramount importance. A high-efficiency particulate air filtration system should be used for COVID-19-infected patients, particularly during transportation. However, wearing PPE is recommended in all circumstances as the second line of control in system failure.
      • Spruit M.A.
      • Holland A.E.
      • Singh S.J.
      • Tonia T.
      • Wilson K.C.
      • Troosters T
      COVID-19: interim guidance on rehabilitation in the hospital and post-hospital phase from a European Respiratory Society- And American Thoracic Society-coordinated international task force.
      Patients hospitalized with COVID-19 symptoms should receive therapy at their bedside
      • Spruit M.A.
      • Gosselink R.
      • Troosters T.
      • Kasran A.
      • Van Vliet M.
      • Decramer M.
      Low-grade systemic inflammation and the response to exercise training in patients with advanced COPD.
      until their situation enables discharge.
      When preparing the patient for discharge, oxygen saturation, need for oxygen therapy, baseline respiratory function, and exercise capacity should be determined both at rest and during activity. A structured exercise program should always be pursued post-discharge for at least 6–8 weeks.
      • Spruit M.A.
      • Holland A.E.
      • Singh S.J.
      • Tonia T.
      • Wilson K.C.
      • Troosters T
      COVID-19: interim guidance on rehabilitation in the hospital and post-hospital phase from a European Respiratory Society- And American Thoracic Society-coordinated international task force.
      Additionally, mild-to-moderate exercises should be pursued at home with patient education, self-evaluation, and management skills with access to remote monitoring of vitals for immediate assistance, if required.
      • Dixit S.
      • Nandakumar G.
      Promoting healthy lifestyles using information technology during the COVID-19 pandemic.
      ,
      • Spruit M.A.
      • Holland A.E.
      • Singh S.J.
      • Tonia T.
      • Wilson K.C.
      • Troosters T
      COVID-19: interim guidance on rehabilitation in the hospital and post-hospital phase from a European Respiratory Society- And American Thoracic Society-coordinated international task force.
      Once the impairments in the cardiorespiratory system are identified among the COVID-19 survivors, they should receive a complete rehabilitation program per the standards.
      • Spruit M.A.
      • Holland A.E.
      • Singh S.J.
      • Tonia T.
      • Wilson K.C.
      • Troosters T
      COVID-19: interim guidance on rehabilitation in the hospital and post-hospital phase from a European Respiratory Society- And American Thoracic Society-coordinated international task force.
      Baseline evaluation of mental and physical health will also be essential since they may also hinder the rehabilitation program. In addition, COVID-19 survivors with disuse atrophy post-discharge should receive nutritional support.
      • Spruit M.A.
      • Holland A.E.
      • Singh S.J.
      • Tonia T.
      • Wilson K.C.
      • Troosters T
      COVID-19: interim guidance on rehabilitation in the hospital and post-hospital phase from a European Respiratory Society- And American Thoracic Society-coordinated international task force.

      Future directions

      This review clearly outlines the anti-inflammatory effects of exercise-based interventions. Therefore, future trials should focus on both the short- and long-term implications of interventions in patients with cardiorespiratory diseases. Well-controlled trials are needed to understand the optimal regimen required to produce immune system effects.

      Conclusions

      A structured exercise program appears a prudent approach for elevating the immune status among patients with cardiorespiratory diseases. The use of exercise in these patients for its anti-inflammatory and immune-protective effects is recommended. However, high-intensity exercises should be used with caution as they can temporarily increase susceptibility to infection post-exercise. It should be noted that moderate-intensity exercises should be performed for <60 min with <60% oxygen consumption to attain maximum benefits from the rehabilitation program. While sufficient trials highlight exercise's positive effects, there remains a need to investigate the long-term effects of cardiorespiratory rehabilitation programs in pandemic situations with a better methodological design.

      Funding

      King Khalid University, RGP.2/134/43

      Authors’ contributions

      The authors confirm their contributions to the paper as follows: Study conception and design: SD. Conceptualization: SD; Data curation: SD and KG; Formal analysis: SD, RR, and VN; Investigation: SD, KG, and RR; Methodology: SD, VN, and SL; Project administration: SD; Resources: SD; Supervision: SD; Writing-original draft: SD, VN, and RR.; Writing-review and editing: SD, KG, and SL. All authors reviewed the results and approved the final version of the manuscript.

      Declaration of Competing Interest

      None

      Acknowledgment

      King Khalid University for providing the resources required to fulfill the completion of the review

      Appendix. Supplementary materials

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