Is the COPD assessment test (CAT) effective in demonstrating the systemic inflammation and other components in COPD?

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www.revportpneumol.org

ORIGINAL

ARTICLE

Is

the

COPD

assessment

test

(CAT)

effective

in

demonstrating

the

systemic

inﬂammation

and

other

components

in

COPD?

N. Sarioglu

a_,_∗

_,

_A.A.

_{Hismiogullari}

b

_,

_C.

_Bilen

c

_,

_F.

_Erel

a

a_Balikesir_University_Medical_Faculty,_Department_of_Pulmonology,_Balikesir,_Turkey b_Balikesir_University_Medical_Faculty,_Department_of_{Biochemistry,}_Balikesir,_Turkey

c_Balikesir_University_Science_and_Art_Faculty,_Department_of_{Chemistry/Biochemistry}_Division,_Balikesir,_Turkey

Received28April2015;accepted2August2015 Availableonline31October2015

KEYWORDS COPD; Inﬂammatorymarker; CAT; Qualityoflife Abstract

Introduction:Chronic obstructive pulmonary disease (COPD) is currently acomplex, multi-component disorder. The COPDAssessment Test(CAT) hasbeen increasingly used toassess COPDpatients.ThisstudyaimstoinvestigatetherelationshipbetweenCATandinﬂammation markersandotherCOPDcomponents.

Methods:Weenrolled110stableCOPDpatientsand65controlsubjectsinthisstudy.Allpatients completed theCAT questionnaire andthe modiﬁed Medical ResearchCouncil (mMRC) disp-neascale. Thequality oflife ofthese patientswas measuredwithSt.George’sRespiratory Questionnaire(SGRQ).LevelsofTNF␣,IL-6,CRPweredeterminedinbloodsamples.

Results:InCOPDpatients,serumlevelsofTNF␣(109.5±58pg/ml),IL-6(10.3±18pg/ml),and C-reactiveprotein (CRP)(1.6±1.7mg/L)werefound tobesigniﬁcantlyhighercompared to controls(TNF-_␣:14.6_±18pg/ml,IL-6:2.14_±1.9pg/ml,CRP:0.4_±0.3mg/L,p<0.001).These markerswere correlated withsmoking(rfrom 0.27to0.35, p<0.001),FEV1 (rfrom −0.39

to_−0.57,p<0.001),FVC(rfrom_−0.32to_−0.37,p<0.001)andFEV1/FVC(rfrom−0.31to

−0.66,p<0.001).TheCATscorecorrelatedwithGOLDspirometricstages,mMRCdyspneascore, numberofexacerbationsinthepreviousyearandFEV1(p<0.001).Therewasasigniﬁcant

cor-relationbetweenlevelsofCRPandtheCATscore(r=0.43,p<0.001)butnosimilarrelationship betweenlevelsofTNF␣andIL-6andtheCATwasobserved.

Conclusion: SystemicinflammationpersistsinthestableperiodofCOPD.CRP,oneofthe inflam-mation markers, was correlated withthe CAT. Further studies are required to confirmthe relationshipbetweenCATandbiomarkers.

∗_{Corresponding}_author.

E-mailaddress:nurhangencer@hotmail.com(N.Sarioglu).

http://dx.doi.org/10.1016/j.rppnen.2015.08.007

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Introduction

Chronicobstructive pulmonary disease (COPD) is a signif-icantcause ofmortalityand morbidityacross themodern world.Themortalityrateof thisdiseaseisincreasingand itispredicted thatitwillbecome thethirdleadingcause of deathworldwide by 2020.1 _It _is _not _possible _to _define COPDbased solely onforced expiratory volume in the 1s (FEV1)sotheGlobalInitiativeforChronicObstructivelung Disease(GOLD)hasdevisedamultidimensionaldefinitionto assessCOPD.2 _The _new_definition_includes _the _prevalence of symptomsand theprevious historyof exacerbations in additiontotheFEV1valueandalsoemphasizesthe assess-ment of comorbidities. In order to assess for symptoms, eitherthemodifiedMedicalResearchCouncil(mMRC)orthe COPDAssessmentTest(CAT)isrecommended.Additionally, adisease-specific qualityoflife scale (SGRQ,SF-36, CCQ) wasused to evaluate the impactof the disease on daily life.Somestudieshavedemonstratedastrongrelationship between CAT and St. George’s Respiratory Questionnaire (SGRQ).3,4_Ladeira_et_al.5 _showed_that_CAT _was_correlated totheBODEindex.

COPDisa complexdiseaseandincludesgenetic, cellu-lar and molecular components. There are many different cells and molecules involved in the inflammatory path-ways.Severalindicatorshavebeen usedtodemonstratea potentialdisease-relatedsystemicinflammation.6---9 _Airway andlungparenchymal inflammationis amajorpathogenic mechanismofCOPD.Inaddition,persistentsystemic inflam-mation may be associated witha various extrapulmonary comorbiditiesandpulmonaryeffects.10_Recent_research_has providedproofoftheexistenceofdistinct‘‘novelsystemic inflammatoryCOPDphenotype.’’7_In_a_recent_study,_it_has been shown that cardiovascularcomorbidity and diabetes were associated with higher levels for some markers of systemicinflammation.11_Therefore,_genetic_load,_systemic inflammation and comorbid diseases are associated with variousphenotypes in COPD.It is essential that new per-spectives shouldbedeveloped in themanagement ofthis disease.

Currently,CAT hasbeen usedincreasingly for assessing andmonitoring COPD. Although severalserumbiomarkers have been defined in COPD,there is not onesingle suffi-cient and effective singlebiomarker that can be used to assessthestatusofCOPDpatients.Ithasbeenshownthat biomarkersareassociatedwithseveralparameterssuchas inflammation, hospitalization, andmortality.7---13 _However, therelationshipbetweenCATandbiomarkershasnotbeen clearlydemonstrated.Therefore,thepresentstudyaimsto investigatethelevelsofsystemicinflammationinCOPDand determinetherelationshipbetweenCATandinflammation markersandqualityoflife.

Materials

and

methods

Studydesign

This wasa cross-sectional single-visitobservational study. OnehundredandtenpatientswithCOPDdiagnosed accord-ingtoGOLD criteria14 _and_sixty-ﬁve_control_subjects_were recruitedbetweenFebruary2013andAugust2013.Control

subjectswerechosenfromthosereferredtoapulmonology andinternalmedicineclinicatBalikesirUniversityHospital, undergoing routine investigations. Written informed con-sent wasobtainedfromallparticipantsandthestudywas approvedbytheInstitutionalEthicsCommitteeofthe Fac-ultyofMedicineatBalikesirUniversity.

All patients were subjected to physical examination, chest X-ray, respiratory function test, and routine blood analysistests.Thenumberofexacerbationsintheprevious year and the history of smokingwere recorded.The CAT, mMRCdyspneascorewascarriedoutviaface-to-face inter-viewsbypulmonary specialist.SGRQscoreswerereported bythepatients.Forthehealthycontrolgrouponlya respi-ratoryfunction test androutineblood analysis testswere done.

Thepopulationofthestudy

Inclusioncriteria:Patientswereincludedifthey;(1)were older than 40 years;(2) were current or ex-smokerswith a smoking history ≥10 pack-years; (3) exhibited a post-bronchodilator FEV1<80% and an FEV1/FVC<0.7. Control subjects were included if they: (1) were older than 40 years; (2) were free from lung disease as determined by a physician; (3) had a normal spirometry (FEV1>85% and FEV1/FVC>0.7);and(4)hadasmokinghistoryof<5 pack-year.

Exclusioncriteria:Patientswereexcludedwho;(1)had an exacerbationofCOPDwithintheprevious 6weeks;(2) hadarespiratorydisorderotherthanCOPDormalignancy; (3)hada chronicinﬂammatory disease(vasculitis, inﬂam-matory bowel disease, rheumatoid arthritis etc.) (4) had uncontrolledorsevereconcomitantdisease(MI,arrhythmia etc.).

Measurements

Demographicfeatures,age,gender,smokinghabits, admis-siontoanemergencyserviceorhospitalizationoverthepast year,accompanyingdiseases,andexistingtreatmentswere allrecorded appropriately.We definedanexacerbationas worsening of symptoms that required oral corticosteroids and/or antibiotics and/or hospitalization. Comorbid dis-easeswereestablishedusingtheclinicalhistoryandphysical examination findings during the visit and were supported by a review of the available medical records. Current medications including inhalers, antihypertensive or other medications were documented. The height, weight, and BMI indexes were measured, and a spirometry was also performed inaccordancewiththeinternationalguidelines (ATS/ERS).15_The_disease_was_classified_according_to_the_old andnewversionofGOLDstaging.14_First,_GOLD_spirometric staging(FEV1based(1---4)staging)andsecond,GOLD stag-ing(A---Dclass).DyspneawasassessedbythemMRCdyspnea scale.16_The_patients_with_COPD_were_categorized_into_A,_B, CandDcombiningsymptomassessmentbymMRCdyspnea scoresandexacerbationrisk.

CAT:ThevalidityandreliabilityoftheTurkishversionof thisscale hasbeenpreviouslyveriﬁed.17 _The _CAT_includes 8itemsandyieldstotalscoresrangingfrom0to40;higher

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scoresindicateamoresevere healthstatusimpairmentor lesssuccessfulcontrolofCOPD.3

Quality of life Questionnaire: The quality of life was assessed by using the Turkish translation of St. George’s RespiratoryDiseasesQuestionnaire(SGRQ).18

Biomarkers

We chose the biomarkers based on previous studies.7,9---13 Thebloodsamplestakenfromallsubjectswerecentrifuged andstoredat−80◦C.Allsampleswereanalyzedwhenthe studywascompleted.Theserumwasstudiedina diagnos-ticdevice (BioTek, ELx800, USA) withuseof commercial kits (eBioscience, HumanTNF-␣and HumanIL-6Platinum ELISA, Austria), and with the methods of tumor necrosis alpha(TNF-␣)andaninterleukin-6(IL-6)levelenzymelinked immunosorbentassay(ELISA).ThelevelsofC-reactive pro-tein(CRP)wereevaluatedwithaclinicalchemistryanalyzer (CobesIntegra800,Rochediagnostics)usingacommercial kit.ThereferencevalueofCRPis0---0.5mg/L,whilethe ana-lyzedlowestvalueofIL-6is0.92pg/ml.Theanalyzedlowest valueofTNF␣is2.3pg/ml.TNF-␣andIL-6concentrationsof somesampleswerebelowthelowerlimitofquantiﬁcation (LLQ).Intheanalysisofindividuals withvaluesbelow the LLQ,anominallevelof halfoftheLLQvalue wasusedto avoidadownwardbiasofthepopulationdata.19

Statisticalanalysis

The average CRP values of COPD and control groups (3.2 (1.5,7.1), 1.3 (0.6,2.7)) were identiﬁed from similar studies.7 _After _that, _in _each _group, _the _sample _size _was calculated by using average calculating formula with80% accuracy and 5% error. Accordingly, the sample size was found to be at least 55 subjects in each group. Results are presented as mean±SD, median, or percentage, as appropriate.TheStudent’st-testandANOVAwereusedfor parametrictests;theMann---WhitneyU-test,Kruskal---Wallis andchi-squarestatisticswereusedfornon-parametrictests forgroupcomparisons.Fisher’sexacttestevaluatedthe dif-ferencesbetweenthepercentagesofcomorbiditiesandthe differencesbetween sexes. The chi-squaretest evaluated thedifferencesbetweenthepercentagesofcomorbidities. Pair-wisecorrelationofcontinuousvariablesinpatientswith COPD was examined by Pearson correlation. A value of

p<0.05 was considered statistically signiﬁcant. All statis-ticalanalyseswereperformedwiththeSPSS(version20.0) software.

Results

Clinicalcharacterizationofsubjects

Thestudyincluded110patients(meanageof64±8.9years; 100 male (90.9%)), and65 control subjects (mean age of 61.5±9.2 years, 55 male (84.6%)). The demographic and clinical characteristics of the patient and control groups are given in Table 1. Forty-ﬁve (40.9%) patients with COPD had an accompanying disease (Ischemic heart dis-ease(n=21),hypertension(n=13),diabetesmellitus(n=8), other (n=3)).The mean FEV1 was48.8% of thepredicted value andmeanFEV1/FVC: 55.4%in theCOPD group.The

meanCATscorewas22.6(±9.2),mMRC:1.9(±0.9)andtotal SGRQ:58.4(±22.2).Ofthe110patients,9.1%werestage1, 37.3%werestage2,42.7%werestage3,10.9%werestage4 accordingtoGOLDspirometricstaging.Whenpatientswere classiﬁedwithrespecttoGOLDstaging, 27.3%weregroup A,30.9%weregroupB,7.3%weregroupCand34.5%were groupD.

COPD/controlcomparisons

There was no significant difference between the ages (p=0.080, Student’s t-test) and sexes of the two groups (p=0.453,fisher’s exacttest)(Table1).Thegroups exhib-ited similar incidences of comorbidities (p=0.095, 2 test). As expected, COPDpatients hadsignificantly lower pulmonary function parameters (FEV1, FVC, FEV1/FVC) compared to controls (p<0.001, Student’s t-test). In general, COPD patients exhibited higher serum levels of CRP (1.6±1.7mg/L) and TNF-␣ (109.5±58pg/ml) and IL-6 (10.3±18pg/ml) than healthy controls (CRP: 0.4±0.3mg/L,p<0.001;TNF-␣:14.6±18pg/ml,p<0.001; IL-6:2.14±1.9pg/ml,p<0.001,Student’st-test)(Table1).

AssociationofCATquestionnairesandpatient

characteristics

There was a correlation between the CAT score and the GOLDspirometricstage(Pearson’sr=0.43;p<0.001). The CATscoreincreasedinparallelwithdiseaseseverity.There wasastatisticallysigniﬁcantrelationshipbetweentheCAT score and number of exacerbations in the previous year (Pearson’s r=0.35, p<0.001), disease duration (Pearson’s

r=0.29,p<0.001),smoking(pack-year)(Pearson’sr=0.27,

p=0.014) and mMRC (Pearson’s r=0.59, p<0.001). The CAT score was found to be signiﬁcantly correlated with FEV1 (Pearson’s r=−0.39, p<0.001) and FVC (Pearson’s

r=−42,p=0.003). Atthe sametime,astrong correlation wasobservedbetweenthe CATscoreandtheSGRQ symp-tom,activity, impact and total scores (Pearson’s r=0.72;

p<0.001).

Associationbetweenbiomarkersandpatient

characteristics

Inﬂammatorymarkersandpulmonary functionparameters werecompared.AstheFEV1decreased,levelsofbiomarker increasedsigniﬁcantly.CRPlevelswerecorrelatedwithFEV1 (Pearson’s r=−0.39, p<0.001), FVC (Pearson’s r=−0.33,

p<0.001) and FEV1/FVC (Pearson’s r=−0.38, p<0.001). TNF-␣ levels were also correlated with FEV1 (Pearson’s

r=−0.57,p<0.001),FVC(Pearson’sr=−0.37,p<0.001)and FEV1/FVC (Pearson’sr=−0.66,p<0.001).IL-6levelswere alsocorrelated with FEV1 (Pearson’s r=−0.31,p<0.001), FVC (Pearson’s r=−0.32, p<0.001) and FEV1/FVC (Pear-son’s r=−0.34, p<0.001). A signiﬁcant correlation was observedbetweenCRP,TNF-␣,IL-6andsmoking(pack-year) (Pearson’sr=0.35,r=0.44,r=0.27,p<0.001,respectively). COPDpatientswithcardiovasculardiseasehadanincreased levelofCRP (2.98±2.4mg/L)comparedtopatients with-out comorbidities (1.56±1.5mg/L, p=0.008 ANOVA test

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Table1 Demographic,functional,clinicalfeaturesofthepatientandcontrolgroups.

Patient(n=110) Control(n=65) p-value

Age 64.0_±8.9 61.5_±9.2 0.080 Malen,(%) 100(90.9) 55(84.6) 0.224 BMI,kg/m2 _26.5_±_5.6 ₂₅_.6_±₂ _0.064 Pack-years 38.9±23 0.1±1.2 <0.001 Co-morbidities,n(%) Any 65(59.1) 42(64.6) 0.95

Ischemicheartdisease 21(19.1) 11(16.9)

HT 13(11.8) 6(9.2) DM 8(7.3) 4(6.2) Other 3(2.7) 2(3.1) mMRC 1.94±0.9 0.04±0.2 <0.001 FEV1,%predicted 48.8±17.8 89.4±5.6 <0.001 FVC,%predicted 68.7±17.8 92.1±5.8 <0.001 FEV1/FVC,% 55.4±12.9 89.6±4.7 <0.001

GOLDspirometricstage,n(%)

1 10(9.1) 2 41(37.3) 3 47(42.7) 4 12(10.9) GOLDstage,n(%) A 30(27.3) B 34(30.9) C 8(7.3) D 38(34.5) SGRQ-totalscore 58.4_±22.2 CATscore 22.6±9.2 TNF␣(pg/ml) 109.5±58 14.6±18 <0.001 IL-6(pg/ml) 10.3±18 2.14±1.9 <0.001 CRP(mg/L) 1.6±1.7 0.4±0.3 <0.001

Abbreviations:BMI,bodymassindex,HT:hypertension,DM:diabetes,FEV1:forcedexpiratoryvolumein1second,FVC:forcedvital

capacity,CAT:COPDassessmenttest.

followed by LSD post hoc test). There was no significant associationwithotherbiomarkersandcomorbidities.Asthe IL-6 increased, the mMRC score increased, but this rela-tionship was not statistically significant (p=0.06). When inflammatorymarkerswerecomparedwithCATscore,CRP levelswereshowntohaveasignificantcorrelation(r=0.43,

p<0.001)(Fig. 1)while no correlation wasobserved with TNF-␣andIL-6.TherewasacorrelationbetweenCRP lev-elsandTNF␣(r=0.48,p<0.001).Nodirectassociationwas observedbetweenbiomarkersandA-Dclassorspirometric stages.

Discussion

Someassessmenttoolsareusedsuchasclinicaltests(CAT, BODE),inﬂammation markersandqualityof life question-naires toevaluate COPD. It is commonly accepted that a multidimensionalassessmentisrequiredtounderstandand manage the disease. COPD is a complex disorder with a systemiccomponent andsomepatientsappeartohave an inﬂammatoryphenotype. Inthisstudy,CAT wasperformed

0 0 5 10 15 20 25 30 35 40 1 2 3 4 5 CRP (mg/L) CA T score 6 7 8 9

Figure 1 The relationship between CAT scores and CRP (r=0.43,p<0.001).

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asanewclinicaltest,andtherelationshipofCATwithother COPDcomponentswasinvestigated.

Oneofthesecomponentsissystemicinflammation.The biomarkers most often studied in COPD to indicate sys-temicinflammationwhicharecommonlyusedareCRP,IL-6, TNF-␣,IL-8andfibrinogen.Severalstudieshavepreviously reported elevated circulating levels of these markers in patientswithstableCOPD.6---9,20---23_In_a_recent_study,_Agustí et al.showed that 30% of COPDpatients did not present evidenceofsystemicinflammationand16%ofthepatients didpresentpersistentsystemicinflammation.7_{Interestingly,} in this study, the serum levels of TNF-␣ and IL-8 were foundtobehigherinsmokerswithnormalspirometry com-paredtoCOPDpatients.Theothermarkersaswhiteblood cells, IL-6,CRP andfibrinogen werefoundtobehigherin COPD patients than in the smokerswith normal spirome-tryandnon-smokers.Inourstudy,thelevelsofCRP,TNF-␣, IL-6 were significantly higher in all COPD patients when compared to the control group. All the biomarkers were foundtobecorrelatedwiththecumulativesmoking expo-sureandreductionof pulmonaryfunctiontest parameters (FEV1, FVC, and FEV1/FVC). The biomarkers level relate to the degree of airflow obstruction. These results are consistent withthosereported in previous crosssectional studies.13 _In _another_study _which _examined _the _results_of ECLIPSE, cardiovascular comorbidities and diabetes were correlated with some systemic inflammation markers.9 _In our study,COPD patients with cardiovascular disease had an increased level of CRP compared to patients without comorbidities. Increased systemic inflammation in COPD with cardiovascular diseases supporta pathophysiological mechanismbetweenCOPDandthesecomorbidities.

TherelationshipbetweenCATandsystemicinflammation hasnotbeenclarifiedbythestudiesconductedsofar.Inone study,asignificantcorrelationwasshowntoexistbetween the LCN1, LCN2 andCAT.8 _In _our_study,_a _significant rela-tionshiphasbeenshownbetweenCATandCRP.However,a similarcorrelationcouldnotbeshownwithTNF-␣andIL-6. In the present study, COPD patients were categorized into four groups (A---D) and stages (1---4) according to old andnewversionofGOLDclassification.Itcanbeobserved thatStage1andStage4constitutethesmallestproportion ofthepopulationwith10%eachaccordingtotheold classi-fication.Inthenewversion,thepopulationwasdistributed almostequallyamonggroupsA,BandD;thesmallest dis-tributionwasthatofgroupC.Inother studies,ithasalso been shown thatgroup Cconstitutesthe smallest propor-tionofthedistribution.24,25_The_new_{classification}_indicates that theremaybesome patients withmultiple symptoms butmild airwayobstruction aswell assome patientswith fewsymptomsbutwithsevereairwayobstructions. Comor-biditiesandsystemicinflammationcanleadtoincreasesin exacerbationandsymptomsinpatientswithmild/moderate obstruction, and in this way, it causes these patients to be placed in the high risk groups (C or D class). In one study,itwasshown that subtypeC includes patientswith highercomorbiditystatus andsubtypeD includespatients withthemostsevereexacerbation,ahighrateof exacer-bation related tohospitalization and poorest outcomes.26 Ina recentstudy,Agustíetal.comparedtwogroups with andwithout persistentsystemic inflammation andshowed that patients presenting persistent inflammation during

follow-uphadincreasedexacerbationratesper year com-paredtotheothergroupalthoughpulmonaryabnormalities weresimilarinthesetwogroups.7

GOLD recommends the use of CAT or mMRC scale to assess symptoms. We used mMRC scale for group assign-ment,becausewhen we considered the symptomsonthe basisofCAT,thenumberofthepatientswithlessthan10 breakpoints was very small (8 patients). The higher CAT scores may be associated with the higher perceptions of patients’symptoms.ItwasalsoshownthatCATandmMRC arenot equivalent, and this may cause some differences inclassification.24,25,27 _In_the _new_{classification,}_the _other cut-off points are composed of number of exacerbations per year. The relationship between basal CAT score and the frequency of exacerbations was shown in the COPD patients.28 _Pothirat _et_al. _have _shown _that _the _change _in CATscoreduringmonitoringvisitsisausefultoolfor detec-tingacutedeteriorationinhealthstatusofCOPDpatients.29 In ourstudy, a strong relationship was observed between CAT,mMRCand theexacerbationrates. The CAT wasalso foundtobecorrelatedtothedurationofillness,and smok-ing(pack-year).ThemeanFEV1ofthepatientswasfoundto be48.8%ofthepredictedvalueandthemeanCATscorewas 22.6.AstrongassociationwasshownbetweenCATandFEV1, FVCandtheGOLDspirometricstage.AstheFEV1andFVC decreased,theCATscoreincreased.TheCATscorealso pos-itivelycorrelatedwithaheavierGOLDstage.Theseresults showthatCATreflectstheseverityofdiseaseverywell.

Another important component of COPD management is quality of life. A variety of life-questionnaires have been usedtoevaluatethe effectsof the diseaseondaily life. The reliabilityand validity of the Turkish version of SGRQ has been proved.30 _A _few _studies _have _shown _that signiﬁcantly correlation was observed between CAT and SGRQ.3,4 _In _a_study,_it _has_been _reported _that_CAT _is sen-sitivetothechangeinhealthstatusassociatedwithCOPD exacerbations.31 _In _our _study, _a _strong _relationship _was shown between CAT and SGRQ. Since CAT, compared to SGRQ,is a shorterand easier test tounderstand, theuse ofCATismorepractical.

Thepresentstudyhasseverallimitations,suchas cross-sectionaldesign,asinglecenterstudyandsmallsamplesize. In addition,the inflammation markers couldnot be com-paredin smokerswhohave normal lung function because theywerenotincludedinthepresentstudy.Themedications forpatientsmayexertaninfluenceonsystemic inflamma-toryresponseandhealthstatusandtheymayalsoaffectthe results.

Insummary,CATisatestthatcanbeusedinthe assess-mentof COPD,sinceitsreliabilityand validityhave been clearlydemonstrated.Theresultsofourstudyindicatethe relationship between CAT andCRP aswell asother COPD components(clinical,functionalparameters).However, lon-gitudinalmulticenterstudiesarerequired toevaluatethe relationshipbetweenCATandbiomarkers.

Ethical

disclosures

Protection of human and animal subjects.The authors declarethatnoexperimentswereperformedonhumansor animalsforthisstudy.

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Conﬁdentialityofdata.Theauthorsdeclarethattheyhave followedtheprotocolsoftheirworkcenteronthe publica-tionofpatientdataandthatallthepatientsincludedinthe studyreceivedsufﬁcientinformationandgavetheirwritten informedconsenttoparticipateinthestudy.

Righttoprivacyandinformedconsent.Theauthorshave obtainedthe written informed consentof the patients or subjectsmentionedinthearticle.Thecorrespondingauthor isinpossessionofthisdocument.

Authorship

Studydesign:NS,FEandAAH;Datacollection:NS,CB;Data analysisandinterpretation:NS,AAH,andCB;Critical revi-sionofthemanuscript:NS,FE,CBandAAH.

Conﬂicts

of

interest

Theauthorsdeclarethattheyhavenoconﬂictofinterestin thepreparationofthismanuscript.

Acknowledgements

This study wassupported by Balikesir University Research Funds(Project number:BAP 2012/95). The authorsthank Prof.Dr.A.SaidBODURfromBalikesirUniversity,Facultyof Medicine,DepartmentofPublicHealthforhisassistancein statisticalanalysis.

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