Aerobic Exercises Recommendations And Specifications For Patients With .

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European Review for Medical and Pharmacological Sciences2020; 24: 13049-13055Aerobic exercises recommendations andspecifications for patients with COVID-19:a systematic reviewM. ALAWNA1,2, M. AMRO2, A.A. MOHAMED1Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Istanbul GelisimUniversity, Istanbul, Turkey2Department of Physiotherapy and Rehabilitation, Faculty of Allied Medical Sciences, ArabAmerican University, Jenin, Palestine1Abstract. – OBJECTIVE: This review wasconducted to systematically analyze the effectsof aerobic exercise on immunological biomarkers to provide safe aerobic exercise recommendations and specifications for patients withCOVID-19.MATERIALS AND METHODS: A systematic search was conducted through MEDLINE(PubMed), Science Direct, Web of Science, Scopus, Cochrane Library, and SciELO databases.The search included the following keywords “immune system”, “immune cell”, or “immune function”; “aerobic training”, “aerobic exercise”, or“physical activity”; “human” or “adult”; and “cytokine”, “killer cell”, “T cell”, “interleukin”, “lymphocyte”, “leukocyte” or “adhesion molecule”.RESULTS: Eleven studies met the inclusionand exclusion criteria of this search. The mostused exercise prescriptions included walking, cycling, or running. The duration of exercise ranged from 18 to 60 min with an intensity of 55% to 80% of VO 2max or 60%-80% of maximum heart rate. The frequency range was1 to 3 times/week. The mainly increased immunological biomarkers included leukocytes,lymphocytes, neutrophils, monocytes, eosinophils, IL-6, CD16-56, CD16, CD4, CD3, CD8,and CD19.CONCLUSIONS: This review demonstratedthat patients with COVID-19 should follow a regular program of aerobic exercise for 20-60 min.This program should be in the form of cycling orwalking with an intensity of 55%-80% VO2max or60%-80% of maximum heart rate. This programshould be repeated 2-3 sessions/week. Theseprevious parameters could safely enhance immune functions without producing any exhaustion.Key Words:COVID-19, Aerobic exercises, Immunological markers, Exercise prescription.IntroductionWorld Health Organization (WHO) has announced that COVID-19 is a public world disasterand it fastly propagates through all world countries1. On the 5th of September 2020, there werearound 26,171,112 COVID-19 confirmed cases onthe world2. COVID-19 is a fresh enclosed RNAbeta-coronavirus. COVID-19 is recognized assevere acute respiratory syndrome coronavirus-2(SARS-CoV-2)3,4. The common COVID-19 symptoms are fever and cough5. The fever occurs inabout 43.8% of the patients on hospital admissionand could increase to 88.7% throughout the hospitalization. The cough occurs in approximately67.8% of all COVID-19 patients3. Other associated symptoms include fatigue, myalgia, anddyspnea.COVID-19 is a self-limited infection. Thestrength of host immunity plays a key role in countering it6. Previously, we have demonstrated thatincreasing the aerobic capacity produces shortterm effects on immune and pulmonary functions7.We have demonstrated that the increase in the aerobic capacity improves immune functions throughincreasing serum immune cells and immunoglobulins, regulating serum C-reactive proteins (CRP),and reducing depression and anxiety.Also, we have demonstrated that increasingthe aerobic capacity protects and decreases theseverity of COVID-19 associated disorders andsymptoms through increasing lung immunity, increasing lung tissue flexibility, increasing pulmonary muscle endurance and strength, decreasingfree radicals production and oxidative damage,decreasing dry cough, and clearing respiratoryairway7.Corresponding Author: Ayman Mohamed, Ph.D, MSc, PT;e-mail: amohamed@gelisim.edu.tr; dr ayman pt@hotmail.com13049

M. Alawna, M. Amro, A.A. MohamedDue to the importance of increasing the aerobiccapacity on immune and lung functions and thelack of studies that described safe specificationsof aerobic exercise for patients with COVID-19,this review summarized aerobic exercise recommendations and specifications for patients withCOVID-19. These specifications mainly includedthe mode, intensity, frequency, and duration ofaerobic exercises.Materials and MethodsSearch StrategyThis systematic review was designed according to the recommendations and guidelines of thePRISMA Systematic Review and Meta-AnalysisPreferred Report Items8. The search includedMedline (PubMed), Science Direct, Web of Science, Scopus, Cochrane Library, and SciELOdatabases. The authors considered the followingBoolean operators, (MESH) terms, and searchstrategies: ”immune system”, “immune cell” or“immune function”; “aerobic training”, “aerobicexercises”, or “physical activity”; “human” or“adult”; and “cytokine”, “killer cell”, “t cell”,“interleukin”, “lymphocyte”, “leukocyte”, or “adhesion molecule”.The Mode of Aerobic ExercisesThe inclusion criteria included randomizedcontrolled trials (RCTs) and non-randomized(Non-RCTs) published from 1990 to 2020, theperformance of aerobic exercises, non-athletesof both sexes, age range is between 18 and 55years (menopausal women excluded from thisage group due to the hormonal effects9), and theEnglish language. The exclusion criteria includedathletes or patients with any cardiac or immunitydisorders, pregnant women, and smokers.Quality AssessmentThe risk of bias and quality of each includedstudy was independently assessed by three independent persons using the PEPDro scale10. Thisscale consists of 11 items; 8 items to measure thetrial’s internal validity and 3 items to measure thetrial’s statistical reporting10. The quality assessment of the included studies by PEDro scale isshown in Table I.ResultsSearch StrategyInitially, 12411 studies were found and 5235studies of them were excluded because of duplication. Additional 7003 studies were excludedTable I. PEDro scale quality assessment strategy of the included studies.13050

Aerobic exercises recommendations and specifications for patients with COVID-19after reading their titles and abstracts. The remaining 173 studies were fully analyzed and 162studies were excluded because they did not meetour inclusion criteria. Finally, 11 studies were included in this review. The flow and outcomes ofthe search strategy are shown in Figure 1.Study FeaturesAll the included studies investigated the effectof aerobic exercises on the immune system profilein non-athletes. Eight studies were RCTs and threestudies were non-RCTs. Six studies performedaerobic exercise for a short period and five studiesperformed aerobic exercise for a long period11-15.The physical characteristics of the included studiesare shown in Supplementary Table I.InterventionThe performed interventions in short-term studies were cycling16-20 and walking21. The performedinterventions in long-term studies were cycling11,12,walking/running14,15, and cycling/running13. Wefound that exercise approaches in the includedresearches had some heterogeneity. To determinethe exercise intensity in the short-term studies,four short-term studies used VO2max17-20, one studyused peak power output16, and one study usedboth VO2max and maximum heart rate (MHR)21. Todetermine the exercise intensity in the long-termstudies, two studies used the VO2max12,15, and threestudies used MHR13,14.The exercise duration ranged between 18 min60 min in ten studies. The remaining study performed aerobic exercise until exhaustion15. Theduration used in short-term studies was approximately 18-60 min and they performed them for1-2 times/week. Four studies performed aerobicexercise for one time17-19,21, one study performedaerobic exercise for one week 20, and one studyperformed aerobic exercise for two weeks16. Inlong-term studies, the exercise duration rangedbetween 18-80 minutes. One study performedaerobic exercise for 30 minutes12, one study performed aerobic exercise for 45 minutes11, onestudy performed aerobic exercise for 50 minutes14, one study performed aerobic exercise for80 minutes13, and one study performed aerobicexercise for 5 km running15. The physical characteristics of aerobic exercise in the includedstudies are shown in Table II.Immunological MarkersIn the short-term studies, six of them showedsignificant increases in leukocytes (Leuk), lymphocytes (Linf), neutrophils (Neut), monocytes(Mon), eosinophils (Eosin), IL-6, CD16-56,CD16, CD4, CD3, CD8, CD19, and granulocytes(Gran)16-20. One study showed significant increases in all immunomarkers except Mon and Gran21.Immunological markers differently increased insome of the included studies as follows: IL-616,CD16-5617,19,21, CD1618, CD319, CD419,21, CD819, andCD1919. CD3 and CD18 significantly decreased inone study17. CD4 and CD8 significantly decreasedin one study19. Four studies had nonsignificantchanges in CD321, CD418, CD818, or CD2021.In the long-term studies, Leuk nonsignificantlyincreased in one study11. Linf and Leuk nonsignificantly increased in two studies11,12. CD4, CD8,and CD20 significantly increased in one study11.CD4/CD8 and CD56 nonsignificantly increasedin one study11. IL-6 and IL-10 significantly decreased in one study15. IgG, IgA, and IgM significantly increased in one study14, and nonsignificantly increased in one study12. Serum C-reactiveprotein significantly decreased in one study13.The regulation of immunological markers in theincluded investigations is shown in Table III.DiscussionFigure 1. Search strategy findings.This review aimed to systematically analyzethe studies that investigated the effects of aerobicexercise on immune functions among non-ath13051

M. Alawna, M. Amro, A.A. MohamedTable II. Association of circ 001680 expression with clinicopathologic characteristics of glioma.StudyModeIntensityDurationLi and Cheng (2007)20Cycling55% VO2max60 MinKoichi Okita et al (2004)13Cycling or running60% to 80% MHR80 minutes dance 30-60 minaerobic exercisesMohamed and Taha (2016)14Walking/running60-75% of the50 minon a treadmillpredicted MHRFabio Santos Lira1Running70% of VO2max5 km runet al (2017)15intermittently(MAS)Edwards et al (2006)16Cycling55% of maximum45 minpower outputLaPerriere et al (1994)11Cycling70-80% Age45 minPMHRMoyna et al (1996a)17Cycling55-85% of VO2 peak18 minKurokawa et al (1995)18Cycling60% of VO2max60 minMitchell et al (1996)12Cycling75% VO2 peak30 minNehlsen-CannarellaWalking60% of VO2max45 minet al (1991)21or 70% of MHRMoyna et al (1996b)19Cycling55-85% of VO2max18 minletes to provide evidence-based aerobic exerciserecommendations for patients with COVID-19.This study is unique because it is the first onethat provided safe aerobic exercise prescriptionsfor patients with COVID-19 to improve their immune functions and help to decrease the diseaseseverity and death rate without any exhaustion.130521 day/week for2 weeks2 days a week for8 weeks3 sessions/week for12 weeks3 sessions/week for5 weeks3 sessions /week for1 week3 sessions/week for10 weeks1 Session1 Session3 sessions/week for12 weeks1 Session1 SessionImmunological markers differently changedin the included short term studies. Leuk significantly increased in three studies18,20,21. Linfsignificantly increased in three studies18,19,21. Gransignificantly increased in two studies18,19. Neutsignificantly increased in three studies19-21. Monsignificantly increased in three studies17,19,20. Eo-Table I. Table III. Post-aerobic exercise regulation and immunological markers. : increased, : decreased, : not changed.Frequency

Aerobic exercises recommendations and specifications for patients with COVID-19sin significantly increased in one study19. IL-6significantly increased in one study14. CD3 significantly increased in one study19. CD4 significantly increased in two studies19,21. CD16-56 significantly increased in three studies17,19,21. CD16significantly increased in one study18. CD19 significantly increased in one study19.Immunological markers differently changed inthe included long-term studies. IL-1ra, IL-6, IL-8,and IL-10 significantly increased in response to anaerobic exercise that lasts for more than 2 hours,like cycling, marathons, and triathlons23,24. Neuts,Leuk, TNF-a, adhesion molecules (ICAM-1), andinterleukins (IL-6, IL-10, IL-8, IL-12) significantly increased in response to long-running for 42.2km25. Mon, Neut, and Leuk significantly increasedin response to 21.1 km half-marathon22. Neut,Mon, and NK cells significantly increased in response to moderate cycling for 2 hours, while IL-6remained high in response to the same exercise26.Immunoglobulins significantly increased in response to moderate walking for 45 min21, while interleukin-2 and T-cell (CD5 and CD25) increasedinsignificantly in response to the same exercise.Lymphocytes significantly increased in responseto cycle ergometer sessions (70-80% of MHR intensity, 45min/week, for 10 weeks)15. Lymphocytesnonsignificantly increased in response to cycle ergometer sessions (75% of VO2max, 30 min/session,3 times/week for 12 weeks)12.The modes of aerobic exercise were mainlycycling or walking. Seven studies performedcycling on an ergometer11,12,16-20. Two studies performed running on a treadmill14,21. Two studiesperformed cycling on an ergometer and runningon a treadmill13,15. Based on these findings,treadmill walking or cycling (recumbent bikeor upright with minimal resistance) would be asuitable exercise method for sedentary patientswith COVID-19. Also for older adults with balance problems, cycling may be a good choicefor them 27.The exercise intensities in the included investigations were determined using VO2max or MHR.The short-term studies used VO2max to determinetheir intensities and they performed the exerciseat an intensity of 55% VO2max16,20, 55%-85% VO17,19, or 60% VO2max18. While one short-term2maxstudy used the MHR to determine the exercise intensity and it performed the exercise at 60%-70%MHR 21. Two long-term studies used VO2max todetermine their intensities and they performedthe exercise at an intensity of 70% VO2max15, or75%VO2max12. The other three long-term studiesused the MHR to determine the exercise intensityand it performed the exercise at an intensity of60%-80% MHR13, 60%-75% MHR14, or 70%80% MHR11. Based on these findings, an aerobicexercise at an intensity of 55%-85% VO2max shouldbe recommended for patients with COVID-19because it increases immune functions. Besides,patients with COVID-19 should feel “somewhatlight” exertion during the exercise and should beable to continue a conversation without breathlessness. Inconclusion, patients with COVID-19should feel “fairly light” during warming-upand cooling-down periods and “somewhat hard”during the main time of the exercise session27,28.The duration of aerobic exercise in all theincluded investigations ranged from 18-80 minutes. In the short-term studies, exercise durationswere 18 min17,19, 45 min16,21, and 60 min18,20. In thelong-term studies, the exercise durations were30 min12, 45 min11, 50 min14, and 60 min13. Onestudy did not perform the exercise at a specifictime instead, it used a distance of 5km running15.Thus, 18-60 minutes of aerobic exercise wouldbe a suitable exercise duration for patients withCOVID-19. If the patients are sedentary or cannot handle the session time, daily multiple shortbursts of aerobic exercise, with avoiding overexhaustion and fatigue, can be an effective wayto increase the time of exercise29.The frequencies of aerobic exercise rangedfrom one session/week to three sessions/week. Inthe short-term studies, exercise frequencies wereone session/week for one week17, one session/week for two weeks20, and three sessions/weekfor one week16. In the long-term studies, the exercise frequencies were two sessions/week for eightweeks13, three sessions/week for five weeks15,three sessions/week for nineweeks12, three sessions/week for ten weeks11, and three sessions/week for twelve weeks14. Based on these findings,an exercise frequency of three sessions/weekwould be a safe and helpful frequency for patientswith COVID-19. If the patients are active and didnot feel any exhaustion during aerobic exercisesessions, the frequency could be increased to fivesessions/week 29.There were some limitations in these reports.Some of the included studies investigated theeffect of aerobic exercise on immune biomarkersresponse by recruiting both males and females inthe same group30,31. This may affect their resultsbecause males and females differently respond toaerobic exercise32. Some researches included onlyfemales without considering the use of contra13053

M. Alawna, M. Amro, A.A. Mohamedceptives21. Contraceptives can induce changes inimmune biomarkers such as raising the absolutecount of leukocytes and other biomarkers abovetheir normal levels in healthy individuals33. Thenumber of the included investigations was smallbecause there are a small number of studies thatinvestigated the effect of aerobic exercise onhealthy individuals. Future systematic reviewsare required to investigate the effect of aerobicexercise to improve immune biomarkers in patients with COVID-19 and other diseases, suchas diabetes mellitus, hypertension, or obesity.Also, systematic reviews are highly required toinvestigate the effect of aerobic exercise to improve immune biomarkers in older patients withCOVID-19.ConclusionsThis review demonstrated that patients withCOVID-19 should follow a regular program ofaerobic exercise for 20-60 min. This programshould be in the form of cycling or walking withan intensity of 55%-80% VO2max or 60%-80% ofmaximum heart rate. This program should berepeated 2-3 sessions/week. These previous parameters could safely enhance immune functionswithout producing any exhaustion.Conflict of InterestThe Authors declare that they have no conflict of interests.FundingThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.References1) Singhal T. A Review of Coronavirus Disease-2019(COVID-19). Indian J Pediatr 2020; 87: 281-286.2) World Health Organization. Corona-virus disease(COVID-19) outbreak. Available at: onavirus-2019?gclid CjwKCAjw NX7BRA1EiwA2dpg0hCSX5jvxF1vgawdkc pQINqBMv7m5wV GhJlKe9iJk1ee qmrKkahoCI50QAvD BwE.3) Guan WJ, Ni ZY, Hu Y, L iang WH, Ou CQ, He JX,L iu L, Shan H, L ei CL, Hui DSC, Du B, L i LJ, Zeng G,Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, XiangJ. Clinical Characteristics of Coronavirus Disease2019 in China. N Engl J Med 2020; 382: 17081720.130544) P errell a A, Trama U, B ernardi FF, Russo G, M onastra L, Fragranza F, O rl ando V, Coscioni E. Editorial - COVID-19, more than a viral pneumonia.Eur Rev Med Pharmacol Sci 2020; 24: 51835185.5) He F, Deng Y, L i W. Coronavirus Disease 2019(COVID-19): what we know? J Med Virol 2020; 92:719-725.6) C ascella M, R ajnik M, Cuomo A, Dulebohn SC, DiNapoli R. Features, Evaluation and TreatmentCoronavirus (COVID-19). In: StatPearls. TreasureIsland (FL): StatPearls Publishing 2020.7) Mohamed A, A lawna M. Role of increasing theaerobic capacity on improving the function of immune and respiratory systems in patients withcoronavirus (COVID-19): a review. Diabetes Metab Syndr Clin Res Rev 2020; 14: 489-496.8) Moher D, L iberati A, Tetzlaff J, A ltman DG, A ltmanD, A ntes G, Atkins D, Barbour V, Barrowman N, Ber lin JA, Clark J, Clarke M, Cook D, D’A mico R, DeeksJJ, Devereaux PJ, Dickersin K, Egger M, Ernst E. Preferred reporting items for systematic reviews andmeta-analyses: the PRISMA statement. Ann Intern Med 2009; 151: 264-269.9) Chen G, Xie RG, G ao YJ, Xu ZZ, Zhao LX, Bang S,Berta T, Park CK, L ay M, Chen W, Ji RR. β-Arrestin-2regulates NMDA receptor function in spinal lamina II neurons and duration of persistent pain. NatCommun 2016; 7: 1-12.10) de Morton NA. The PEDro scale is a valid measure of the methodological quality of clinical trials:a demographic study. Aust J Physiother 2009; 55:129-133.11) L aPerriere A, A ntoni MH, Ironson G, Perry A, McC abe P, K limas N, Helder L, Schneiderman N, Fletch er MA. Effects of aerobic exercise training on lymphocyte subpopulations. Int J Sports Med 1994;15: 5-8.12) Mitchell JB, Paquet AJ, Pizza FX, Starling RD, HoltzRW, Grandjean PW. The effect of moderate aerobic training on lymphocyte proliferation. Int JSports Med 1996; 17: 384-389.13) Okita K, Nishijima H, Murakami T, Nagai T, Mori ta N, Yonezawa K, Iizuka K, K awaguchi H, K itabatakeA. Can exercise training with weight loss lower serum C-reactive protein levels? ArteriosclerThromb Vasc Biol 2004; 24: 1868-1873.14) Mohamed G, Taha M. Comparison between the effects of aerobic and resistive training on immunoglobulins in obese women. Bull Fac Phys Ther2016; 21: 11.15) L ira FS, dos Santos T, C aldeira RS, Inoue DS, Panissa VLG, C abral-S antos C, C ampos EZ, Rodrigues B,Monteiro PA. Short-term high- and moderate-intensity training modifies inflammatory and metabolic factors in response to acute exercise. FrontPhysiol 2017; 8: 1-8.16) Edwards KM, Burns VE, Ring C, C arroll D. Individual differences in the interleukin-6 responseto maximal and submaximal exercise tasks. JSports Sci 2006; 24: 855-862.

Aerobic exercises recommendations and specifications for patients with COVID-1917) Moyna NM. Exercise-induced alterations in natural killer cell number and function. Eur J ApplPhysiol Occup Physiol 1996; 74227-74233.18) Kurokawa Y, Shinkai S, Torii J, Hino S, Shek PN. Exercise-induced changes in the expression of surface adhesion molecules on circulating granulocytes and lymphocytes subpopulations. Eur J Appl Physiol Occup Physiol 1995; 71: 245-252.19) M oyna NM. The effects of incremental submaximal exercise on circulating leukocytes in physically active and sedentary males and females.Eur J Appl Physiol Occup Physiol 1996; 74:211-218.20) L i TL, Cheng PY. Alterations of immunoendocrineresponses during the recovery period after acuteprolonged cycling. Eur J Appl Physiol 2007; 101:539-546.21) Nehlsen -C annarella SL, Nieman DC, Jessen J, ChangL, Gusewitch G, Blix GG, A shley E. The effects ofacute moderate exercise on lymphocyte functionand serum immunoglobulin levels. Int J SportsMed 1991; 12: 391-398.22) L ippi G, Salvagno GL, Danese E, Skafidas S, Tarperi C,Guidi GC, Schena F. Mean platelet volume (MPV)predicts middle distance running performance.PLoS One 2014; 9: 8-13.23) Ronsen O, L ea T, Bahr R, Pedersen BK. Enhancedplasma IL-6 and IL-1ra responses to repeated vs.single bouts of prolonged cycling in elite athletes.J Appl Physiol 2002; 92: 2547-2553.24) Suzuki K. Cytokine response to exercise and itsmodulation. Antioxidants 2018; 7: 17.25) M agalhães T, Ribeiro F, Pinheiro A, Oliveira J, BahrR, K rosshaug T, Bartlett MJ, Warren PJ, BeckermanH, Roebroeck ME, L ankhorst GJ, Becher JG, Bezemer PD, Verbeek AL, Bishop D, Bouet V, G ahery Y,Bullock-Saxton JE, Wong WJ. Warming-up before26)27)28)29)30)31)32)33)sporting activity improves knee position sense.Phys Ther Sport 2010; 11: 86-90.Scharhag J, Meyer T, G abriel HHW, Schlick B, FaudeO, K indermann W. Does prolonged cycling of moderate intensity affect immune cell function? Br JSports Med 2005; 39: 171-177.Traynor K. Planning an exercise regimen for thesedentary patient: what a cardiologist needs toknow - American College of Cardiology. Am CollCardiol 2016. Available at: the-sedentary-patient.Gennuso KP, Gangnon RE, Matthews CE,Thraen-Borowski KM, Colbert LH. Sedentary behavior, physical activity, and markers of health in olderadults. Med Sci Sports Exerc 2013; 45: 1493-1500.health.gov.Physical Activity Guidelines forAmericans, 2008. Available at: Qian L, L i B, Xu H-L, L i Y-F. Change in the redblood cell immunity function and T-lymphocyteand its subpopulations before and after acute incremental load exercise. Biomed Res 2017; 28:6844-6847.Morgado JP, Monteiro CP, M atias CN, A lves F, Pessoa P, Reis J, M artins F, Seixas T, L aires MJ. Sexbased effects on immune changes induced by amaximal incremental exercise test in well-trainedswimmers. J Sport Sci Med 2014; 13: 708-714.K lein SL, Flanagan KL. Sex differences in immuneresponses. Nat Rev Immunol 2016; 16: 626-638.Gough L, Penfold RS, Godfrey RJ, C astell L. Theimmune response to short-duration exercise intrained, eumenorrhoeic women. J Sports Sci2015; 33: 1396-1402.13055

of aerobic exercises on the immune system profile in non-athletes. Eight studies were RCTs and three studies were non-RCTs. Six studies performed aerobic exercise for a short period and five studies performed aerobic exercise for a long period11-15. The physical characteristics of the included studies are shown in Supplementary Table I .

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