The impact of exercise training on fatigue in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis

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Pleasecitethisarticleinpressas:PaneroniM,etal.Pulmonol.2020.https://doi.org/10.1016/j.pulmoe.2020.02.004

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PULMOE-1446; No.ofPages10

Pulmonol.2020;xxx(xx):xxx---xxx

www.journalpulmonology.org

REVIEW

The

impact

of

exercise

training

on

fatigue

in

patients

with

chronic

obstructive

pulmonary

disease:

a

systematic

review

and

meta-analysis

Mara

Paneroni

a

_,

_Michele

_Vitacca

a,∗

_,

_Massimo

_Venturelli

b

_,

_Carla

_Simonelli

a

_,

Laura

Bertacchini

a

_,

_Simonetta

_Scalvini

c

_,

_Federico

_Schena

b

_,

_Nicolino

_Ambrosino

d

a_Respiratory_{Rehabilitation}_of_the_Institute_of_Lumezzane,_Istituti_Clinici_Scientifici_Maugeri_IRCCS,_Lumezzane_BS,_Italy b_Department_of_{Neuroscience,}_Biomedicine_and_Movement_Sciences,_Università_Degli_Studi_di_Verona,_Verona,_Italy c_Cardiac_{Rehabilitation}_of_the_Institute_of_Lumezzane,_Istituti_Clinici_Scientifici_Maugeri_IRCCS,_Lumezzane_BS,_Italy d_Respiratory_{Rehabilitation}_of_the_Institute_of_Montescano,_Istituti_Clinici_Scientifici_Maugeri_IRCCS,_Montescano_PV,_Italy

Received6December2019;accepted3February2020

KEYWORDS COPD; Fatigue; Fatigability; Exercise; Rehabilitation Abstract

IntroductionandObjective:Fatiguecanbedividedinperceivedfatigue,thefeelingof

exhaus-tionorlackofenergy,andperformancefatigue,thereductioninmuscleforce/activationduring agiventask.Thismeta-analysisevaluatestheimpactofexercisetrainingonfatigue,compared withnormalcareinpatientswithCOPD.

MaterialandMethods:We searched randomised controlled trials on MEDLINE, EMBASE,

CochraneCentralRegisterofControlledTrialsandCINAHLdatabasesfromtheirinception to December, 31st 2019usingthe termsCOPD,Fatigue,Fatigability,Muscleactivation,Muscle endurance,MusclePerformance,VoluntaryActivation,Motoneuronexcitability,Force Develop-ment,Exercise,ANDRehabilitation.

Results:Weevaluated494potentialarticles.Sixteen,allevaluatingperceivedfatigability,

sat-isfiedtheinclusioncriteriaandwereincluded.Twelvestudies(463patients)assessedfatigue by the Chronic Respiratory Questionnaire showing that intervention improved significantly morethanthecontrolgroup[SMD0.708;95%CI0.510,0.907;p<0.001;I2₌_34.3%;_p₌_0.116]. Twostudies(68patients) usingtheFatigueImpactScale, didnotfind anysignificant differ-encesbetweengroups[SMD−0.922;95%CI−2.258,0.413;p=0.176;I2₌_83.9%;_p₌_0.013]._Two studies(82patients)assessedperceivedfatiguebytheFatigueSeverityScale:the interven-tionimprovedsignificantlymorethanthecontrolgroup[SMD_−2.282;95%CI_−2.870,_−1.699; p<0.001;I2₌_64.6%,_p₌_0.093]._No_study_evaluating_performance_fatigue_was_found.

Abbreviations: SMD,StandardizedMeanDifference;CI,ConﬁdenceInterval.

∗_{Corresponding}_author_at: _Istituti_Clinici _Scientiﬁci_Maugeri, _IRCCS,_Respiratory_{Rehabilitation}_Department,_Via_Salvatore_Maugeri,_4,

27100Pavia,Italy.

E-mailaddresses:[email protected],[email protected](M.Vitacca).

https://doi.org/10.1016/j.pulmoe.2020.02.004

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Conclusions:Thisstudyprovidedlow-qualityevidenceofapositiveimpactofdifferentexercise

trainingprogramsonperceivedfatigueinpatientswithCOPD.Furtherstudiesareneededto assesstheeffectsofexercisetrainingonfatigueandtotesttailoredprograms.

Introduction

More than half of patients with chronic obstructive pul-monarydisease(COPD)experiencefatiguewhichmayhave a substantial impact on functional impairment, physical activity, health related quality of life (HRQL), mortality, morbidity,hospitalizationrateandlengthofhospitalstay.1,2

LowerlimbmusclesofpatientswithCOPDmayshowreduced endurance capacity and are more prone to fatigue, due todisuse, the presence of limb muscledysfunction,3 _and

exercise vasoconstriction induced by respiratory muscle fatigue.4,5 _These _mechanisms _may _be _responsible _for _the

onsetofthesymptomfatigueduringdailylife.6

Itcanbedividedintoperceivedfatigueorperformance fatigue.7 _The_ﬁrst_one_is _a_normal_response_to_exercise_or

stress,amultidimensionalperceptiondeﬁnedas‘‘the sub-jectivefeelingof tiredness, exhaustionor lack of energy, which occurs on a daily basis’’.7 _However, _fatigue _may

alsooccurduring theperformance of agiven task,andis deﬁnedasperformancefatigue:anobjectiveand measur-abledomain,consistingofthereversiblereductioninforce generated by the muscles during a given task8 _such _as _a

constantloadexercise.9_It_could_be_{distinguished}_as_central,

deﬁnedasaprogressivereductioninthevoluntary activa-tionofmuscleduringexercise,10_and_peripheral_{fatigability,}

describedbythereductionofmuscleactivationinordistal totheneuromuscularjunction.11

The reduction of fatigue should be one of the aims of comprehensive management of patients with COPD.12

Exercisetrainingisstrongly recommendedinCOPD, being effective in reducing dyspnoea and improving exercise capacity and HRQL.13---15 _However, _the _effects _of _exercise

trainingonfatigueasaprimaryaiminpatientswithCOPD havebeenrarelystudied,16,17_and_to_the_best_of_our

knowl-edge,thereisnosystematicreviewoftheliteratureabout theeffectivenessofexercisetrainingonfatigueinpatients withCOPD.

Therefore,theaimofthissystematicreviewand meta-analysisof randomizedcontrolledtrials(RCTs) in patients with COPD, was to evaluate the impact of interventions includingexercise trainingonperceived andperformance fatigue,ascomparedtoordinarycareoreducationalone.

Methods

This study conforms to all Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and reports therequired information accordingly (Supplemen-taryChecklist,http://links.lww.com/PHM/A364).

Datasourcesandsearchstrategies

We searched the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and the Cumulative Index to Nursing and Allied Health Litera-ture, from their inception to December, 31st 2019, with no languagerestriction. We also reviewed the references of retrieved articles for additional studies. The search waslimited only toRCTsusingthe terms: COPD,Fatigue, Fatigability, Muscle activation, Muscle endurance, Muscle Performance,VoluntaryActivation,Motoneuronexcitability, ForceDevelopment,Exercise,andRehabilitation.

Patients

WeincludedRCTsinvolvingpatientswithCOPDaccordingto the GlobalInitiative for Chronic ObstructiveLung Disease recommendations in all stage of severity.18 _We _excluded

studies involving patients with(1) an acute exacerbation within4weeksbeforestartingtheintervention;(2)major comorbidities such as chronic heart failure, asthma, and sleep-relateddisorders.

Interventions

We included studies administering exercise training pro-grams,withthefollowingcharacteristics:

- Involving in- or out-patients, and home- or community-basedprograms;

- Programsof2weekminimumduration;

- Enduranceand/orstrengthtrainingoflowerand/orupper limbs;

- Comparingexercisetrainingwithusualcare,(deﬁnedas conventional medical care without any prescription of exercisetrainingorphysicalactivity)and/oreducation.

Outcomemeasures

Weincludedanystudyassessing:

- Perceivedfatigue:by means of scalesor questionnaires evaluatingsubjectiveperceptionoffatigue;

- Performance fatigue: by means of objective measures evaluatingchangesinmuscleperformanceaftera fatigu-ingtasksuchasmuscleforce orelectromyographytrace duringa maximalvoluntarycontraction (MVC) or stimu-latedmusclerestingTwitch.

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EffectsofexerciseonfatigueinCOPD 3

Datacollectionandanalysis

Two investigators (LB, MP) independently conducted the searchofthedatabases,screeningalltitlesand/orabstracts fortheinclusioncriteria.Reviewersthenretrievedabstracts and/orfull-textpapersofallpotentiallyeligiblestudiesand maintainedrecordsofallstudiesnotmeetingtheinclusion criteria.Theyalsoprovidedthereasonsfortheirexclusion. The investigatorsinserted thedataofpotentially eligi-ble articles in a Microsoft Excel (2013 version, Microsoft, Redmond,WA)dedicateddatabase.Disagreementbetween investigators about eligibility was resolved by discussion andconsensus.Ifconsensuscouldnotbe reached,athird investigator (MV) adjudicated. All data were checked for accuracy. Missing data were requested by e-mail to the authors.Aninvestigator(LB) retrievedthefull-textof the included studies and inserted their data into a dedicated electronic database. Another investigator (MP) indepen-dentlyextracteddatafromthesamestudies.

The information collected included the background characteristics of the research reports: characteristics of participants in the study; number of participants who dropped out or withdrew from the study; a full descrip-tionoftheexercisetrainingprograms(setting,components, duration,andcharacteristics);assessments,andassociated results. If a study reported multiple group comparisons (e.g.,exercisetrainingplusfreewalkingvsexercisetraining alonevs conventional care),treatment groups performing exercisethatcouldberelevanttooutcomeswerecombined intoonevirtualinterventiongroup,andthisgroupwas com-paredtothegroupreceivingconventionalcare.

The investigators assessed papers for bias using the Cochrane Collaboration’s toolfor assessing risk of biasin RCTs.19 _Risk_of _bias_was_assessed _according _to_the

follow-ingdomains:sequencegeneration;allocationconcealment; blindingof participants;blinding ofpersonnel;blindingof outcome assessment; incompleteoutcome data; selective outcomereporting,andotherbiases.

Statisticalanalysis

StatisticalanalysiswasperformedusingSTATAversion11.2 software(Stata,CollegeStation,TX).Alldatawere extrapo-latedfromthecorrespondingfull-textstudies.Foroutcome, werecordedmeanandstandarddeviation(SD)ofvariation frombaselinetotheendofthestudy.WhenSDwasnot avail-able,wecalculatedthemfromstandarderrors,conﬁdence intervals,ort-valuesorcontactedthetrialauthorsbyemail forclariﬁcation.Weexcludedstudieswithdataotherthan meanandSD.20

Thestandardizedmeandifference(SMD)wascalculated. Heterogeneity of studies was assessed by performing the Q-test considering values of P<0.01 as significant. The firststepof theevaluation wasconductedby fixed-effect models using the Mantel-Haenzel method. If a significant heterogeneity among studies wasfound, a randomeffect evaluationbytheDer-SimonianandLairdmethodapproach wasperformed.21_Forest_plots_were_used_to_detect

publica-tionbiasformeta-analysisevaluationincludingmorethan8 studies.22_For_the_{meta-analysis,}_only_the_outcome_measures

includedinatleasttwostudieswereanalysed.

Table1 Demographic,anthropometricandclinical char-acteristicsofincludedpatients.

Clinicalcharacteristics No.studies (No. Participants) Pre-intervention Mean(SD) Age,years 15(596) 64.2(7.7) BMI,kg/m2 ₇₍₂₈₈₎ _27.7_(4.7) FEV1,%ofpredicted 13(481) 45.6(15.2) FVC,%ofpredicted 4(168) 63.6(15.6) FEV1/FVC,%ofpredicted 6(249) 47.0(11.1) RV,%ofpredicted 4(173) 165.5(44.1) PaO2,mmHg 3(124) 72.5(8.0) PaCO2,mmHg 3(124) 42.8(5.6) MIP,%ofpredicted 2(86) 77.7(26.7) MEP,%ofpredicted 2(86) 65.9(19.3) 6MWT,m 8(315) 348.3(77.1) CRQfatiguedomain 9(348) 11.1(3.4) FISunits 2(68) 53.5(32.3) FSSunits 2(82) 45.3(11.1) CAFSunits 1(65) 53.8(17.1) SGRQunits 4(143) 52.6(14.8)

BMI,BodyMassIndex;FEV1,ForcedExpiratoryVolumeinthe1st

second; FVC,ForcedVitalCapacity;RV,ResidualVolume;MIP,

MaximalInspiratoryPressure;MEP,MaximalExpiratoryPressure;

CRQ, Chronic Respiratory Questionnaire; FIS, Fatigue Impact

Scale; FSS, Fatigue Severity Scale; CAFS, COPD and Asthma

FatigueScale;SGRQ,St.George’sRespiratoryQuestionnaire.

Results

We identiﬁed 494 potentially relevant articles. Of these, 405 were excluded after the abstracts were read and 89 full-textswereanalysed for inclusioncriteria. Sixteenout ofthe48studiesevaluatingperceivedfatiguesatisﬁedthe inclusioncriteriaandwereincludedinthemeta-analysis23---38

(Fig.1).Nostudyoutoftheother41evaluatingchangesin performancefatiguesatisﬁedtheinclusioncriteria.

Table1showsthebaselinecharacteristicsoftheincluded subjects. They suffered from moderate-to-severe COPD. Table2shows themaincharacteristics ofallinterventions carriedoutinthestudiesincluded.

Settings

Seven studies24,26,28,32---34,36 _were _conducted _mainly _in _an

out-patient setting, six at home 25,27,30,31,37,38 _and _three

studies23,29,35_in_both_settings.

Schedules

Thetotaldurationofprogramsrangedfrom6to24weeks. There were two to seven sessions per week. The dura-tion of each session ranged from 30 to 90min in eleven studies23---28,30,32,33,35,36_and_lasted_two_and_a_half_hours_in_one

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Table2 Characteristicsoftheinterventions. Reference Duration, weeks Withdrawal/ dropouts Participants,n Intervention andControl InterventionDetails Wijkstra23 ₁₂ ₂ ₂₈ _{Intervention:}_outpatient₍₂_days/week)_and

homebasedcycleergometerandupperlimb training,2times/day+inspiratorymuscle trainingandeducationsession

30minoftraining;cyclingat60%ofWmax, graduallyextendedtoamaximumof75%of Wmax

15 Control:usualmedicalcare

Cambach24 ₁₂ ₂₃ ₁₅ _{Intervention:}_outpatient_training,₃_days/week +educationsession

90minofcycleergometer/rowing

machine/stair-walkingtraining(twiceaweek) at60---75%Wmax;45minofrecreational activitiessuchasswimming/cycling/hockey (onceaweek)

Larson25 ₁₆ ₇₇ ₂₈ _{Intervention:}_cycle_ergometry_training_at home,5days/week+Inspiratorymuscle training

Intervaltrainingprotocolwith4worksetsof5 minseparatedbyrestintervals(2---4min); intensityof50%ofpeakworkrate,evaluated weeklywithprogressiveincreasesastolerated 12 Control:education

Guell26 ₂₄ ₁₃ ₂₄ _{Intervention:}_cycle_ergometer_training,₅_days/ week+breathingexerciseadeducationsession

30-minofcycleergometerat50%ofthe maximalload(Wmax);loadincreasedin incrementsof10Wprovidedaccordingto symptoms

Hernandez27 ₁₂ ₂₃ ₂₀ _{Intervention:}_home-based_walking_training,₆ days/week

1hourofwalkingrainingat70%ofthe maximumspeedattainedintheSWT 17 Control:usualmedicalcare

Man28 ₈ ₈ ₁₈ _{Intervention:}_aerobic_and_strength_training,₂ days/week+educationsession

1hourwalking/cyclingandstrengthtraining fortheupperandlowerlimb

O’Shea29 ₁₂ ₁₀ ₂₀ _{Intervention:}_resistance_exercise,₃_days/week (1athospital,2athome)

6resistanceexercisesagainstelasticbandsof increasingresistance;3setsof8to12 repetitionmaximum

Moore30 ₆ ₇ ₁₀ _{Intervention:}_video_exercise_at_home,₄ days/week+educationsession

30minofupperandlowerlimbstrengthening andaerobicexercise

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+Model PULMOE-1446; No. of P ages 10 Effects of exercise on fatigue in COPD 5 Table2(Continued) Reference Duration, weeks Withdrawal/ dropouts Participants,n Intervention andControl InterventionDetails Ghanem31 ₈ ₀ ₂₅ _{Intervention:}_home-based_endurance_and

strengthtraining,7days/week+breathing exercise

Walking/cyclingtraining+6---10upper-body andlower-bodystrengthexerciseswith 14 Control:usualmedicalcare

McNamara32 ₈ ₈ ₃₀ _{Intervention:}_water-based_and_land-based exercise,3days/week

60minofexerciseatintensityratingof3---5on modiﬁedBorgscalefordyspneaandperceived 15 Control:usualmedicalcare

Roman33 ₁₂ ₂₁ ₃₆ _{Intervention:}_Low_intensity_peripheral_muscle trainingandbreathingexercises,3/week+ educationprogram

15minutesbreathingexercisesand45minutes ofabdominalandupperandlowerlimb exercises

Wadell34 ₈ ₇ ₁₇ _{Intervention:}_graduated_exercise_training_for upperandlowerlimbs,3days/week+ educationsession

2.5hoursofgraduatedwalking/cycle ergometertraining,armergometerand strengthexercisesforupperandlowerlimbs, athighestattainableworkrateforthelongest tolerableduration

24 Control:education

Theander35 ₁₂ ₄ ₁₂ _{Intervention:}_{multidisciplinary}_pulmonary rehabilitationprogramme,2days/week+ hometrainingprogramme

10---15minutesofbicycletraining+strength exercise

Duruturk36 ₆ ₅ ₂₉ _{Intervention:}_all-body_callisthenic_exercise_and cycleergometertraining,3days/week+ educationsession

20/45minofexerciseand20---30minof continuouscyclingat50---70%ofVO2max; intensityadjustedtomaintainaperceived difﬁcultylevelof4---7ontheModiﬁedBorg Scale

13 Control:educationsession

Arslan37 ₈ ₁₅ ₃₂ _{Intervention:}_{individualized}_exercise_home program+walkingprogram,3days/week

Walkingoutdoorsonaﬂatsurface 33 Control:usualmedicalcare.

Mohammad38 ₇ ₀ ₂₀ _{Intervention:}_home-based_training_program,₃ days/week+breathingexerciseandeducation session

Walkingtraining

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Figure1 Flowchartofthestudy.

Interventions

Thirteen studies included exercise training of locomo-tor muscles: cycling in ﬁve studies,23,25,26,35,36 _walking _in

three27,37,38_and_a_combination_of_these_in_ﬁve.25,28,31,32,34_In

threestudiestheinterventionconsistedonlyofcalisthenics exercises.29,30,33

Allthestudiesincludedendurancetraining.Theintensity rangingfrom50%to75%ofeitherthemaximumworkloador oxygenconsumption(VO2)reachedduringincrementaltests inﬁvestudies.23---26,36_McNamara_et_al.32_used_the_Borg_scale39

toset theintensity of theexercise(from3to5 on modi-ﬁedBorgscale)andHernandezetal.27_used_the_70%_of_the

maximumspeedattainedintheIncrementalShuttleWalking test(ISWT);40 _nine_others_studies28---31,33---35,37,38 _reported_no

trainingintensity.

In six studies23,24,26,34,35,36 _patients _performed

continu-oustrainingonacycloergometer,whileonlyone25_used_the

intervaltraining.

Additionalcomponentsofexercisetraining

In four studies26,31,34,38 _breathing _exercises _were

admin-istered in addition to the exercise program (e.g.: pursued lip breathing and diaphragmatic breathing). In elevenstudies23---26,28,30,33---36,38_educational_sessions_were_also

administered.Inspiratorymuscletrainingwasaddedintwo studies23,25

Outcomes

Twelvestudies23---34 ₍₄₆₃_patients:₂₇₁_study_group_and₁₉₂

controls) evaluated perceived fatigue by means of the dedicateddomainofthechronicrespiratoryquestionnaire (CRQ).41_Only_in_three_studies35,37,38_(18.8%)_was_fatigue

mea-surementthe primary outcome. Fig.2-Panel A shows the relatedforestplot:theinterventionimprovedsigniﬁcantly morethanthecontrolgroup[SMD0.708;95%CI0.510,0.907; p<0.001;I2₌_34.3%;_p₌_0.116]._Figure_1SM_describes_funnel plotforstudiesonfatigueiteminCRQ.

Figure2 Forestplotofeffectoftrainingon:fatigueitemin CRQscale(PanelA),FatigueIndexScale(PanelB)andFatigue SeverityScale(PanelC).

Two studies35,36 ₍₆₈ _patients: ₄₁ _study _group _and ₂₇

controls) used the Fatigue Impact Scale (FIS), which examines patients’perceptionsoftheirlimitationscaused by fatigue on the cognitive, physical, and psychosocial domains.42_Fig.₂_-Panel_B_describes_the_related_forest_plot:

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model’’(P=0.0001),arandomeffectmodelwasperformed. No differences between intervention and control group were found. [SMD-0.922; 95%CI −2.258, 0.413; p=0.176; I2₌_83.9%;_p₌_0.013].

Fig.2-PanelCdescribestheforestplotfortwostudies36,38

(82 patients: 49 study group and 33 controls) assess-ing fatigue by the Fatigue Severity Scale (FSS), a 9-item scale assessing disabling fatigue.Each question evaluates patients’perceptionintheformof7-pointmodiﬁedLikert Scale.43_The_intervention_group_improved_{signiﬁcantly}_more

thanthecontrolgroup[SMD-2.282;95%CI−2.870,−1.699; p<0.001; I2₌_64.6%, _p₌_0.093]._Only _one _study37 _used _the

COPDandAsthmaFatigueScale.44

Riskofbias

The assessmentof therisk ofbiasby funnelplots onCRQ revealedhighvariabilityintheresultsoftheincluded stud-ies.Table3showsresultsoftheriskofbiasassessment.Half ofthestudies23,25,27,28,31,33,34,38 _did_not_report_any_detail_on

randomizationandallocation modalities,andtherewas a highdetectionbiasrate.Almostallstudiesincludedshowed ahighriskofbiasfor theblindingofparticipantsand per-sonnel.

Discussion

This systematic review investigated the current evidence ofexercisetrainingonfatigueinpatients withCOPD.The analysisofthe 16RCTsincluded evaluatingthe effectson perceived fatigue23---38 _showed_high _{heterogeneity} _of_study

design,patientsampling, exercisetrainingschedules, and outcomemeasuresassessed.Allstudiesshowedahighrisk ofbias.Asawhole,thestudiesshowedlow-gradeevidence ofpositiveeffectofexercisetrainingonperceivedfatigue. Nostudyevaluatedtheeffectsonperformancefatigue.

Fatigue is an importantdebilitatingsymptom affecting all chronic respiratory diseases, including COPD. A four-yearobservational studyonfatiguein patientswithCOPD reportedthatseverefatiguedoubledinpatientswithmild tosevere COPDdespite optimal care.45 _Fatigue_is _a

lead-ingcauseofconsultationswithmajorclinicalimplications. Despiteitswell-acknowledgednegativeimpactonpatient’s life, fatigue is still a misunderstood and underdiagnosed symptominCOPD.Asaconsequence,thereiscurrentlyno speciﬁc intervention to treat all aspects of this symptom which is quite often considered a secondary outcome in interventionsaiming primarily to increase physical ﬁtness and/orHRQL.46

Spruitetal.9_have_proposed_a_model_of_fatigue_in_patients

withCOPD.Moderatetoseverefatiguecanbetheresultsof systemic, physical, psychological andbehavioural factors. FatiguecanbeprecipitatedbyinfectiousCOPDexacerbation anditstreatment. Thismodelsuggeststhatthefatigueof thesepatientsisnotsimplytheresultofCOPDandcannot bepredictedbythesoledegree ofairﬂowobstructionbut wouldbetheconsequenceofmultiplefactorsthatmayact aloneorininteraction,atrestandduring/afterexercise.10

Rather interestinglyinoursystematicreview,the posi-tiveimpactofpulmonaryrehabilitationonperceivedfatigue

wasfoundinstudiesusingtheCRQandtheFSSbutnotthe T

able 3 Risk of bias assessment. Bias Random sequence Allocation Blinding of participants Blinding of outcome Incomplete Selective Modiﬁed by Jadad Scale W ijkstra 23 Low Unclear High High Low Low 2 Cambach 24 Low Low High High Low Low 3 Larson 25 Unclear Unclear High Low Low Low 2 Guell 26 Low High High Low Low Low 2 Hernandez 27 Low Unclear High Low High Low 2 Man 28 Low Unclear High High Low Low 3 O’Shea 29 Low Low High Low Low Low 3 Moore 30 Low Low High High Low Low 3 Ghanem 31 High Unclear High High High Low 1 McNamara 32 Low Low High Low Low Low 3 R oman 33 Low Unclear High Low Low Low 3 W adel 34 Unclear Unclear High Unclear Low Low 2 Theander 35 Low Low High High Low Low 3 Duruturk 36 Unclear Low High Unclear Low Low 2 Arslan 37 High High High High Low Low 1 Mohammadi 38 Low Unclear High Unclear High High 2

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FIS.AntoniuandUngureanu46_identiﬁed₈_{multidimensional}

scaleswhicharecommonlyusedtoassessfatigueinCOPD but75%ofRCTsincludedinouranalysisevaluatedfatigueby meansofthededicateddomainoftheCRQ.41_Houben-Wilke

andcolleaguesrecently showedthat theitem‘energy’ of theCOPDassessmenttestimproveswiththegreatesteffect onsizeafterpulmonary rehabilitation.47 _A_commonly _used

multi-dimensionalscaletoevaluatefatigueisthesubjective fatiguesubscale of the checklist individual strength (CIS-Fatigue)48 _and_Peters_and_colleagues_reported_a_signiﬁcant

meanimprovementinCIS-Fatiguescorefollowing12-week ofpulmonaryrehabilitationinpatientswithCOPD.49_The_use

ofdifferenttoolsinpaperspreventsaccuratecomparisons betweenstudiesasthescoresproducedbythescalesshow poortomoderatecorrelationsbetweenthem.50

It should be noticed that we analysed exercise train-ing,justone(althoughthemain)componentofpulmonary rehabilitation which is a comprehensive multidisciplinary interventionincluding,butnotlimitedtoit.13_Therefore_the

resultsofoursystematic reviewshouldnotbegeneralised topulmonaryrehabilitationprograms.

Onthesubjectofperformancefatigue,itisrather inter-estingtonote that, despite thefact that therearesome observationalstudiesdescribinghighprevalenceinpatients withCOPD,51 _we _were _unable _to _include _any _RCT _of _the

effectsofexercisetrainingonthisimpairment.

Differenttestshavebeenusedtoevaluateperformance fatigue,whichdependsontheabilityoftheperipheral mus-clesandthecentralnervoussystemtomeetthedemands of a prescribed task. Both systems can exhibit abnormal changesinresponsetoexerciseandcontributetoincreased performancefatigue:52,53 _we _can_test _it_by _the_changes_in

stimulated resting Twitch for peripheral involvement and by MVC for the central ones.53 _Thereafter, _speciﬁc

meth-ods to train the muscles and reduce the central and/or peripheralcomponentofperformancefatigue,suchasthe maximal strength training54 _or _{neuromuscular} _electrical

stimulation,55_should_also_be_thoroughly_investigated_in

sub-jectswithCOPD.

Conclusion

Thissystematicreviewhasprovidedlow-qualityevidenceof apositiveimpactofdifferentexercisetrainingprogrammes onperceived fatigueinpatients withCOPD.Further stud-ies withbetter standardisation and scientiﬁc validity are neededtoassesstheeffectsofexercisetrainingonfatigue andtotestdedicatedprograms.Nostudyoftheefﬁcacyof exercisetrainingonperformancefatiguewasfound.

Authors’

contributions

LB,MPandCScontributedtodataacquisition; LB,MPand CScontributedtodataanalysis;MP,MVi,MVe,CS,SS,FSand NApreparedarticledraftorcriticallyreviseditfor impor-tantintellectual content; allauthors gavecontribution to conceptionand design,datainterpretation, ﬁnalapproval oftheversiontobepublishedandagreementtobe account-ablefor allaspectsoftheworkin ensuringthatquestions relatedtotheaccuracyorintegrityoftheworkare appro-priatelyinvestigatedandresolved.

Conﬂicts

of

interest

Theauthorshavenoconﬂictsofinteresttodeclare.

Acknowledgments

This work was supported by the ¨Ricerca Corrente¨Funding scheme of the Ministry of Health, Italy. We thank Laura CominiandAdrianaOlivaresfortechnicalassistance.

Appendix

A. Supplementary

data

Supplementary material associated with this arti-cle can be found in the online version available at doi:https://doi.org/10.1016/j.pulmoe.2020.02.004.

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