Volumetric capnography versus spirometry for the evaluation of pulmonary function in cystic ﬁbrosis and allergic asthma 夽,夽夽

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www.jped.com.br

ORIGINAL ARTICLE

Volumetric capnography versus spirometry for the evaluation of pulmonary function in cystic ﬁbrosis and allergic asthma ^夽,夽夽

Armando Almeida-Junior

^a

, Fernando Augusto Lima Marson

^b^,^c^,∗

,

Celize Cruz Bresciani Almeida

^a

, Maria Ângela Gonc ¸alves Oliveira Ribeiro

^a^,^c

, Ilma Aparecida Paschoal

^d

, Marcos Mello Moreira

^d

, José Dirceu Ribeiro

^a^,^c^,∗

aUniversidadeEstadualdeCampinas(Unicamp),FaculdadedeCiênciasMédicas,DepartamentodePediatria,Campinas,SP,Brazil

bUniversidadeEstadualdeCampinas(Unicamp),FaculdadedeCiênciasMédicas,DepartamentodeGenéticaMédicaeMedicina Genômica,Campinas,SP,Brazil

cUniversidadeEstadualdeCampinas(Unicamp),FaculdadedeCiênciasMédicas,LaboratóriodeFisiologiaPulmonar(LAFIP), CentrodeInvestigac¸ãoemPediatria(CIPED),Campinas,SP,Brazil

dUniversidadeEstadualdeCampinas(Unicamp),FaculdadedeCiênciasMédicas,DepartamentodeClínicaMédica,Campinas,SP, Brazil

Received15August2018;accepted14October2018 Availableonline7December2018

KEYWORDS Asthma;

Cysticﬁbrosis;

Pulmonaryfunction;

Spirometry;

Volumetric capnography

Abstract

Objective: Tocomparethevaluesofthemarkersforvolumetriccapnographyandspirometry and their ability toclassifychildren andadolescentswith asthma, cysticﬁbrosis (CF), and healthycontrols.

Methods: Thiswasacross-sectionalstudythatincluded103patientswithcontrolledpersistent allergicasthma,53withCFandahealthycontrolgroupwith40volunteers(aged6to15years), ofbothsexes.Theindividualsunderwentvolumetriccapnographyandspirometry.

Results: PhaseIIIslope(SIII),SIIIstandardized byexhaledtidalvolume(SIII/TV)andcapno- graphicindex(SIII/SII)×100(KPIv)weredifferentamongthethreegroupsassessed,withhighest valuesforCF.Therelationbetweentheforcedexpiratoryvolumeinonesecondandtheforced vital capacity(FEV1/FVC)was theonlyspirometricmarkerthatpresenteddifferenceonthe threegroups.Onindividualswithnormalspirometry,KPIvandFEV1/FVCweredifferentamong

夽 Pleasecitethisarticleas:Almeida-JuniorA,MarsonFA,AlmeidaCC,RibeiroMÂ,PaschoalIA,MoreiraMM,etal.Volumetriccapnography versusspirometryfortheevaluationofpulmonaryfunctionincysticﬁbrosisandallergicasthma.JPediatr(RioJ).2020;96:255---63.

夽夽ThestudywasperformedattheLaboratóriodeFisiologiaPulmonar(Laﬁp),CentrodeInvestigac¸ãoemPediatria(Ciped),Faculdadede CiênciasMédicas,UniversidadeEstadualdeCampinas,Campinas,SP,Brazil.

∗Correspondingauthors.

E-mails:fernandolimamarson@hotmail.com(F.A.Marson),jdirceuribeiro@gmail.com(J.D.Ribeiro).

https://doi.org/10.1016/j.jped.2018.10.008

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256 Almeida-JuniorAetal.

thethreegroups.TheROCcurveidentiﬁedtheindividualswithasthmaorCFfromthecontrol group, boththrough volumetric capnography (better toidentify CF inrelation to thecon- trolusingKPIv)andthroughspirometry(bettertoidentifyasthmainrelationtothecontrol).

KPIvwasthebestparametertodistinguishasthmafromCF,eveninindividualswithnormal spirometry.

Conclusion: Volumetric capnography andspirometry identiﬁed different alterationsin lung functiononasthma,CF,andhealthycontrols,allowingthethreegroupstobedistinguished.

4.0/).

PALAVRAS-CHAVE Asma;

Fibrosecística;

Func¸ãopulmonar;

Espirometria;

Capnograﬁa volumétrica

Capnografiavolumétricaversusespirometriaparaavaliaçãodafunçãopulmonarna fibrosecísticaenaasmaalérgica

Resumo

Objetivo:: Compararosvaloresdosmarcadoresparacapnografiavolumétricaeespirometriae suacapacidadedeclassificarcriançaseadolescentescomasma,fibrosecística(FC)econtroles saudáveis.

Métodos:: Foirealizadoumestudotransversalqueincluiu103pacientescomasmaalérgicaper- sistentecontrolada,53comFCeumgrupocontrolesaudávelcom40voluntários(6a15anos), deambosossexos.Osindivíduosforamsubmetidosacapnograﬁavolumétricaeespirometria.

Resultados: OslopedafaseIII(SIII),SIIIpadronizadapelovolumetidalexalado(SIII/VT)eo índicecapnográfico(SIII/SII)×100(KPIv)foramdiferentesentreostrêsgruposavaliados,com maioresvalores paraogrupoFC. Arelação entreovolumeexpiratórioforçado noprimeiro segundoeacapacidadevitalforçada(VEF1/CVF)foioúnicomarcadordeespirometriacom diferençasnostrêsgrupos.Nosindivíduoscomespirometrianormal,oKPIveVEF1/CVFforam diferentesentreostrêsgrupos.AcurvaROCdiferenciouosindivíduoscomasmaouFCdaqueles dogrupocontrole,ambosatravésdacapnografiavolumétrica(melhorparaidentificaraFCem relaçãoaoscontrolespeloKPIv)epormeiodaespirometria(melhorparaidentificaraasmaem relaçãoaoscontroles).OKPIvfoiomelhorparâmetroparadistinguiraasmadaFC,mesmoem indivíduoscomespirometrianormal.

Conclusão: Acapnografiavolumétricaeaespirometriaidentificaramdiferentesalteraçõesde função pulmonarnaasma,naFC e noscontrolessaudáveis, permitiramque ostrês grupos fossemdiferenciados.

0/).

Introduction

Asthmaisamongthemostcommonchronicdiseaseinchil- dren andadolescents; inturn, cystic ﬁbrosis (CF) is little prevalent.¹ Both chronic lung diseases (CF and asthma) present withairwayobstruction, but eachhas adifferent pathophysiology.Severalinstrumentshavebeenstudiedand proposedtoassess theanatomicaland functionaldamage caused by both diseases. Volumetric capnography (VCap) allowsthegraphical analysisof theconcentrationpattern ofcarbon dioxide(CO2) inthe exhaledair volume,repre- senting the anatomical source of CO2. Three phases can beidentiﬁed during VCap,^2,3 includingthe phase III slope (SIII),whichisdirectlycorrelatedwiththedegreeofvaria- tionontheventilation/perfusioninpulmonaryinjurymodel andvaries ina highnumberof diseases.^4---7 Fornewborns, SIIIcan possiblyidentifypreterm infantswithbronchopul- monarydysplasia frompreterminfantswithnopulmonary disease.⁸ TheanglebetweentheslopesinphasesIIandIII isknownascapnographicindex(KPIv) andcanbeusedas

a screening test for the severity of pulmonary disease in CF.⁹Whencomparedwithothertestsofpulmonaryfunction evaluation,VCaphastheadvantageofbeingportable,non- invasive, not usingexpensive gases, and beingperformed withspontaneousbreathing.^10---12

Also,theauthorshadobservedthattheSIIIstandardized by the exhaled tidal volume (SIII/TV) is higher in children withasthma, andmayreﬂect thein homogeneity of ventilation, suggesting chronic structural respiratory diseases.Afterthemethacholinechallengetest,SIIIincreased, and subsequently decreased afterinhalation therapy with bronchodilator agents. This fact suggests the asynchro- nism on the emptying of the alveolar units due to the constrictor action of methacholine on the periph- eralairways.¹⁰ An increase of theSIII value wasobserved on people with CF when compared with healthy children and adolescents. SIII values were higher in patients withnormalspirometry,suggesting thatVCap canidentify patients with alterations in ventilation homogeneity very early.¹³

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Inhypothesis,theauthorsbelievetheVCapcanpickup early pulmonary function abnormalities in the context of normal spirometry. Furthermore, while asthma is primar- ilyan airwaydiseasethatcanbedescribedbyspirometric abnormalities,CFisamixedparenchymal/smallairwaydis- easethatwouldbebetterdescribedbyVCap andinSIIIof the capnogram. Thus, the objective of this study was to comparethemarkersforVCap andspirometryamongchil- drenandadolescentswithasthma,CF,andhealthycontrols.

Moreover,theauthorsassessedtheabilityofthemarkersto identifytowhichgroupeachindividualbelonged.

Methods

This was a cross-sectional, analytical, observational, and non-randomized study, conducted for three years at the PulmonaryFunctionLaboratory(LAFIP)oftheUniversityof Campinas to complete the recruitment. The project was approvedbytheResearchEthicsCommitteeoftheInstitu- tion(No.419/2005andNo.430/2008).Theguardiansofthe childrensignedaninformedconsentform.

The study included threegroups of individuals: (i)103 with controlled persistent allergic asthma (AAG); (ii) 53 withCF (CFG) --- outsidethe periodof pulmonary exacer- bations;and(iii) 40volunteers ashealthycontrols (HCG).

Patientswereagedfromsixto15years,ofbothsexes.They werefollowed-upat thePediatricPulmonologyOutpatient ClinicfromUniversity Hospitaloftheinstitution andwere recruitedduringroutinevisits.Allthepatientsfollowed-up attheservicewereinvitedtoparticipateinthestudyand onlythosewhoacceptedtoparticipatewereincluded.

The diagnosis andclassiﬁcationof asthmafollowed the criteriaoftheGlobalInitiativeforAsthma(GINA).Patients with asthma presented a dosage of serum immunoglobu- linEgreaterthan180IU/mLonatleastonebloodsample, peripheralbloodeosinophils>4%,andpositiveresponsetoat leastonetestedantigenonskintestsofimmediatehyper- sensitivity. The inclusioncriteriafor patientswithasthma werethosewhousedinhaledcorticosteroid(budesonide)as drypowderatadosageof400---800mcg/day,andformoterol 12mcgtwice/day,foratleast30days.Nopatienthadhistory ofasthmaattackrequiringhospitalizationinintensivecare unitinthepreviousyear,exacerbationorworseningofsymp- tomswithneedforincreaseduseofinhaledbronchodilators orsystemiccorticosteroidsforfourweeksbeforethetests wereperformed.

TheCFwasdiagnosedusingthesweattestwithstimula- tionofsweatingthroughpilocarpineiontophoresis(atleast twodosesofchlorideconcentrationgreaterthan60mEq/L) and/oridentiﬁcation oftwocysticﬁbrosistransmembrane conductance regulator (CFTR) mutations recognized as pathogenicmutations.

The HCGwascomposed ofhealthy volunteers,withno historyof activeor passivesmoking, withoutprior orcur- rentrespiratorydisease,whousednomedication andhad noknowncomorbidities.Theindividualsincludedpresented nogreatdifﬁcultiestoperformspirometryandVCap.

Theclinicalcharacteristicsoftheparticipantsweredoc- umentedby themedicalstaffduring thevisitstoperform thespirometryandVCap.

Volumetriccapnography

ToperformtheVCap,therespiratoryprofilemonitorCO2SMO Plus^® model DX-8100 (Novametrix, Wallingford, USA) was used;thesoftwareAnalysisPlus(OasisAnalysisPlus^®,MS, USA)wasusedtoregisterthemeasurementsandcurvesof theVCap.Participantswereaskedtositwiththeirbackto themonitor,touseanasalclip,andtobreaththroughthe mouthpiece.VCapmarkerswererecordedforfiveminutes afterobservingthenormalizationoftherespiratorypattern, andanofflinesequenceoftherespiratorycyclesofpatients wasselectedafter thecollection, excluding the cyclesof thefirstminute,consideringitasaperiodofadaptationof theindividual.Afterthatprocedure,therespiratorycycles thatshowedirregularpatternsof theVCap curve,suchas theabsence of the plateau due toair leak or depression oftheplateauduetocough,wereexcluded.Thecyclesin whichtheTVvariationwasgreaterorlessthan25%ofthe averageandinwhich theexhaledCO2wasgreateror less than5%oftheaveragewerealsoexcluded.^10,13,14

The average of the markers of the remaining cycles werecalculated andconsidered asthe ﬁnal result.Three phasescanbeidentiﬁedduringVCap:phaseIcorresponds totheanatomicdeadspace;phaseII,toarapidincreaseof CO2;phaseIII,totheformationof theplateauofexhaled CO2correspondingtothealveolarairvolume.^2,3Themark- ers analyzed were: SII and SIII. The capnographic index [(SIII/SII)×100](KPIv)wasalsoused.^8,9,15Thenormalization ofSIIandSIIIby TV(SII/TVandSIII/TV) wasperformed to compensateforvariationsonthesizeoftheindividuals.

Spirometry

FortheevaluationofspirometrythespirometerCPFS/Dand theBREEZEPF^® version3.8Bsoftware(MedGraphics,MN, USA)wereused.Thescreeningwasperformedaccordingto therecommendationsof theEuropeanRespiratory Society andAmericanThoracicSociety.¹⁶ Patientswereinstructed nottousebronchodilatorsofshortorlongdurationfor12h beforethe exam. The spirometry markers were adjusted totheZ-scoreusingtheGLI2012softwareprovidedbythe Global Lung initiative (GLI) of the European Respiratory Society.¹⁷ The following markers were used in this study:

forcedvitalcapacity(FVC),forcedexpiratoryvolumeinone secondoftheFVC(FEV1),indexofobstruction(FEV1/FVC), andforcedexpiratoryﬂowbetween25%and75%oftheFVC (FEF25---75%),expressedasZ-scoreandpredictedpercentage.

Statisticalanalysis

Comparisonsbetweenindependentmarkerswithoutnormal distributionwereperformedusingtheMann---Whitneytest.

The receiver operatingcharacteristic (ROC) curve and the area under the ROC curve (AUC) were calculated to assess the potential of the spirometry and VCap markers to identify patients with asthma from healthy controls, patients with CF from healthy controls, and between patientswithCFfromthosewithasthma.VCapmarkersthat weredifferentinthethreegroupsintheassociationstudy wereusedfortheanalysisoftheROCcurve.

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Thepredictedpercentagewasusedduetoitsextensive useinclinicalpractice.¹⁸Valuesbelow80%ofthepredicted for spirometry markers were considered to be below the lowerlimitofnormal(LLN).TheZ-scoresoftheVCapmark- ersfor theHCG were calculated. The LLN and theupper limitofnormal(ULN)fortheVCapmarkerswereconsidered as<−2and>+2oftheHCGZ-score.Asubgroupofindividu- alsfromthethreegroupswasconsideredtohave‘‘normal’’

spirometry, using as inclusion criteriathe results of FVC, FEV1,andFEV1/FVCgreater thantheLLN (atleast 80%of thepredictedtoallthesemarkersfromspirometry).

TocomparethegroupsandanalyzetheROCcurve,SPSS (SPSSInc.,Statistical Packagefor Social Sciences,version 16.0,Chicago,IL,USA)wasused.Thevalueofalphaadopted wasof0.05.

Thegraphsformedianandconﬁdenceintervalwereper- formed using MedCalc 16.4.3 (MedCalc Software bvba --- Ostend,Belgium;https://www.medcalc.org,2016).

Results

Thedescriptiveanalysisoftheanthropometricvariablesand dataobtainedfromtheVCapandspirometrybetweenAAG, CFGandHCGarepresentedinTable1andFig.1.CFpatients hadsmallerheightandweightwhencomparedwithhealthy controlsandpatientswithasthma.TheSIII,SIII/TV,andKPIv werehigher in the groups of respiratory diseases in rela- tion to the control group, being worse in the CFG. Only theFEV1/FVCpresented the same degree ofevidence (p- value<0.05),withthelowestvaluesontheAAG.Withthe exceptionof SII,theother markersof VCap andallmark- ersofspirometryseparatedtheHCGfromtheAAGandCFG (p-value<0.05).

The analysisof individuals withnormalspirometry evi- dencedthat,withtheexception ofFVC,allmarkerswere different between the HCG and patients (AAG and CFG).

However,onlythe valuesofKPIv(higheronthe CFG)and FEV1/FVC(lowerontheAAG) weredifferentbetweenthe AAGandCFG.

TheAUCfortheVCapandspirometrybetweentheHCG andpatients(AAGandCFG),aswellasbetweentheAAGand CFG,arepresentedinTable1andFig.2.Onthediscrimina- tionoftheHCGfromtheAAG,themarkersweredifferent (p-value<0.05);however,onlyFEV1andFEV1/FVCpresented AUCvaluesgreaterthan0.800.

On the discrimination of the HCG from the CFG, the markerspresenteddifferencesbetweenthegroups(p-value

<0.05),withthehighestAUCvalueforFEV1/FVCandVCap markers; the highest AUC value was observed for KPIv (0.900).Similarly, theVCap and FEV1/FVC markersdiffer- entiatedtheAAGandCFG,andKPIvpresentedthehighest AUCvalue(0.763).

When the individuals with normal spirometry were evaluated, the VCap presented AUC values capable of discriminating the HCG from the AAG (SIII=0.768, p- value<0.001;SIII/TV=0.730, p-value <0.001;KPIv=0.686, p-value=0.002); as well as the HCG from the CFG (KPIv=0.866, p-value <0.001; SIII=0.822, p-value <0.001;

SIII/TV=0.742,p-value=0.001). The AUCs that differenti- atedtheHCGfromtheAAGinspirometrywere:FEV1/FVC (predicted%)=0.814 (p-value<0.001)andFEV1 (predicted

%)=0.726(p-value<0.001).BetweentheHCGandCFG,the FEV1andFEV1/FVC(predicted%)valuesweredifferent(p- value<0.05;AUC=0.712and0.702,respectively).

The discrimination of the AAG from the CFG in individuals with normal spirometry was done by KPIv (AUC=0.702, p-value=0.003) and FEV1/FVC (%) (AUC=0.683,p-value=0.006).

Fig.3presentstherelationbetweenspirometryandKPIv markersonthethreegroupsstudied.

Discussion

To the best of the authors’ knowledge, no other studies assessed the ability of the VCap markers to discriminate individualswithasthmafromindividualswithCFandhealthy controls,incomparisontospirometrymarkers.Moreover,an unprecedentedandrobustﬁndingwasthatSIII,SIII/TVand KPIvweredifferentamongthethreegroupsassessed,with highestvaluesforCF.TheFEV1/FVCwastheonlymarkerof spirometrywithdifferenceonthethreegroups.Inaddition, onindividualswithnormalspirometry, KPIv,andFEV1/FVC weredifferentamongthethreegroups.Moreover,theROC curveidentiﬁedtheindividualswithasthmaorCFfromthe controlgroup,boththroughVCap (bettertoidentifyCFin relationtothecontrolusingKPIv)andspirometry(betterto identifyasthmainrelationtothecontrol).KPIvwasthebest parametertodistinguishasthmafromCF,eveninindividuals withnormalspirometry.

Thesearchformethodstoevaluatepulmonaryfunction inchildrenandadolescentswithchroniclungdiseaseswith airway obstruction is a constant struggle in the scientiﬁc community.Spirometryisthemostusedinstrumentforran- domized clinical trials asprimary outcome.^19---22 However, theuseofspirometrywillalwaysbecriticized,despiteits importance,mainlyduetothelargeintrapersonalvariability and thelack of equations for distinct populations.There- fore,comparingspirometrytoothermethodsispromising.

Children present numerous chronic lung diseases with airway obstruction, and each of them presents greater or lesserdegreesof inﬂammationand bronchialreactivity on upper and/or lower airways.¹ Each assessment instru- ment willmost likelyhave greater or lessereffectiveness depending onthechroniclung disease,asshown inFig.3 for VCap and spirometry. The search to characterize the usefulness of these methods focuses on ﬁnding anatomical (computed tomography of the thorax) and functional (spirometry, impulse oscillometry system, lung clereance index[LCI],andplestimography,amongothers)alterations.

Among thediseases includedin thepresent study,asthma differs from CF considering the initial predominance of obstruction,maintenance,andprogressionoftheﬁxedair- wayobstruction.Asthmaaffectsthelargerairways;ifleft untreated,progressestothesmallerairways.²³Inturn,the opposite happens in CF: the disease starts on the small airways and progresses toward thelarge airways.²⁴ These ﬁndingsareillustratedinFig.3.

VCap slopesassess thevolumetric partof the airways, where the movement of gases occurs by diffusion. Con- versely, spirometry better evaluates ﬂow alterations on the conductingairways, asthemovement of gasesin this regionismoreintenseduetoconvection.Therefore,itwas

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olumetriccapnographyandspirometry259

Table1 Associationofanthropometricvariablesanddataobtainedthroughvolumetriccapnographyandspirometrybetweenthehealthycontrolgroup(HCG)andpatients withasthma(AAG)orcysticﬁbrosis(CFG).

Markers HCG

(n=40)

AAG (n=103)

CFG (n=53)

HCGversus AAG(p-value)

HCGversus CFG(p-value)

AAGversusCFG (p-value)

Age(years) 10.51(6.52to15.01) 10.91(6.21to15.56) 10.29(6.02to15.79) 0.167 0.647 0.071

Weight(kg) 39.55(18.60to89.30) 36.5(15.80to65.50) 28.60(16.90to62) 0.096 0.001 0.001

Height(cm) 147(110to168.40) 143.50(110to175) 135(108to181) 0.613 0.021 0.007

SII(mmHg/L) 461.59(255.60to857.30) 506.60(267to1051.10) 467.15(236.60to1179.30) 0.101 0.798 0.23 SIII(mmHg/L) 12.31(4.50to27.70) 17.55(5.60to51.90) 27.86(6.50to69.80) <0.001 <0.001 <0.001

SII/TV 1.17(0.35to3.42) 1.44(0.21to4.82) 1.41(0.32to5.44) 0.043 0.203 0.688

SIII/TV 0.03(0.004to0.12) 0.05(0.004to0.25) 0.08(0.012to0.37) <0.001 <0.001 0.001

KPIv 2.53(1.25to4.09) 3.41(1.79to10.78) 4.96(1.63to16.94) <0.001 <0.001 <0.001

FEV1(predicted%) 101.27(74.64to126.70) 81.71(26.32to121.90) 82.01(35.42to113.56) <0.001 <0.001 0.741 FEV1(Z-score) 0.11(−2.12to2.34) −1.57(−5.79to1.77) −1.47(−5.27to1.14) <0.001 <0.001 0.789 FVC(predicted%) 97.15(82.48to118.77) 90.42(51.63to148.01) 86.40(53.05to116.77) 0.001 <0.001 0.051 FVC(Z-score) −0.24(−1.51to1.56) −0.82(−4.27to3.82) −1.17(−4.16to1.33) 0.001 <0.001 0.062 FEV1/FVC(predicted%) 104.19(89.26to112.26) 90.43(50.52to112.63) 95.79(67.06to109.03) <0.001 <0.001 0.011 FEV1/FVC(Z-score) 0.75(−1.49to2.48) −1.31(−4.44to2.12) −0.60(−3.55to1.46) <0.001 <0.001 0.013

FEF25---75%(predicted%) 107.59(35.48to142.48) 62.79(8.75to137.55) 67.79(12.23to129.85) <0.001 <0.001 0.294

FEF25---75%(Z-score) 0.34(−3.31to1.85) −1.79(−6.28to1.59) −1.60(−5.83to1.24) <0.001 <0.001 0.203

Individualswithnormalspirometryvalues

Markers HCG

(n=39)

AAG (n=57)

CFG (n=28)

AAGversusCFG (p-value) SIII(mmHg/L) 12.31(4.53to27.73) 16.88(6.78to37.85) 21.77(6.46to56.82) <0.001 <0.001 0.065

SIII/TV 0.03(0.004to0.13) 0.05(0.01to0.18) 0.08(0.01to0.32) <0.001 0.001 0.350

KPIv 2.55(1.25to4.09) 3.14(1.79to10.78) 4.47(1.63to14.33) 0.002 <0.001 0.003

FEV1(predicted%) 101.41(84.27to126.70) 90.93(80.23to121.90) 92.78(80.65to113.56) <0.001 0.003 0.779 FEV1(Z-score) 0.13(−1.30to2.34) −0.75(−1.67to1.77) −0.61(−1.67to1.14) <0.001 0.003 0.793 FVC(predicted%) 97.25(82.48to118.77) 95.79(80.14to148.01) 92.15(81.70to112.46) 0.389 0.069 0.266 FVC(Z-score) −0.23(−1.51to1.56) −0.37(−1.65to3.82) −0.67(−1.57to1) 0.389 0.071 0.282 FEV1/FVC(predicted%) 104.31(90.67to112.26) 95.23(80.58to112.63) 99.67(90.30to109.03) <0.001 0.005 0.006 FEV1/FVC(Z-score) 0.77(−1.27to2.48) −0.69(−2.32to2.12) −0.06(−1.37to1.46) <0.001 0.005 0.007

FEF25---75%(predicted%) 108.20(63.49to142.48) 82.61(63.28to135.56) 90.56(72.94to129.85) <0.001 0.221 0.081

FEF25---75%(Z-score) 0.35(−1.64to1.85) −0.78(−1.64to1.59) −0.42(−1.19to1.24) <0.001 0.204 0.069

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260Almeida-JuniorAetal.

Table1(Continued)

Areaunderthecurveforvolumetriccapnographyandspirometrybetweencontrolgroup(HCG;n=40),groupofpatientswithasthma(AAG;

n=103)andgroupofpatientswithcysticﬁbrosis(CFG;n=53)

Markers HCGversus

CFG

HCGversus CFG

AAGversus CFG

HCGversusAAG (p-value)

HCGversusCFG (p-value)

SIII(mmHg/L) 0.782â 0.899â 0.722â <0.001 <0.001 <0.001

SIII/TV 0.732â 0.831â 0.660â <0.001 <0.001 0.001

KPIv 0.737â 0.927â 0.763â <0.001 <0.001 <0.001

FEV1(predicted%) 0.836^b 0.836^b 0.516^b <0.001 <0.001 0.741

FEV1(Z-score) 0.839^b 0.838^b 0.513^b <0.001 <0.001 0.789

FVC(predicted%) 0.685^b 0.756^b 0.596^b 0.001 <0.001 0.051

FVC(Z-score) −0.24(−1.51to1.56) −0.82(−4.27to3.82) −1.17(−4.16to1.33) 0.001 <0.001 0.062 FEV1/FVC(predicted%) 104.19(89.26to112.26) 90.43(50.52to112.63) 95.79(67.06to109.03)<0.001 <0.001 0.011 FEV1/FVC(Z-score) 0.75(−1.49to2.48) −1.31(−4.44to2.12) −0.60(−3.55to1.46) <0.001 <0.001 0.013

FEF25---75%(predicted%) 107.59(35.48to142.48) 62.79(8.75to137.55) 67.79(12.23to129.85)<0.001 <0.001 0.294

FEF25---75%(Z-score) 0.34(−3.31to1.85) −1.79(−6.28to1.59) −1.60(−5.83to1.24) <0.001 <0.001 0.203

Individualswithnormalspirometryvalues

Markers HCG

(n=39)

AAG (n=57)

CFG (n=28)

AAGversusCFG (p-value) SIII(mmHg/L) 12.31(4.53to27.73) 16.88(6.78to37.85) 21.77(6.46to56.82) <0.001 <0.001 0.065

SIII/TV 0.03(0.004to0.13) 0.05(0.01to0.18) 0.08(0.01to0.32) <0.001 0.001 0.350

KPIv 2.55(1.25to4.09) 3.14(1.79to10.78) 4.47(1.63to14.33) 0.002 <0.001 0.003

FEV1(predicted%) 101.41(84.27to126.70) 90.93(80.23to121.90) 92.78(80.65to113.56) <0.001 0.003 0.779 FEV1(Z-score) 0.13(−1.30to2.34) −0.75(−1.67to1.77) −0.61(−1.67to1.14) <0.001 0.003 0.793 FVC(predicted%) 97.25(82.48to118.77) 95.79(80.14to148.01) 92.15(81.70to112.46) 0.389 0.069 0.266 FVC(Z-score) −0.23(−1.51to1.56) −0.37(−1.65to3.82) −0.67(−1.57to1) 0.389 0.071 0.282 FEV1/FVC(predicted%) 104.31(90.67to112.26) 95.23(80.58to112.63) 99.67(90.30to109.03) <0.001 0.005 0.006 FEV1/FVC(Z-score) 0.77(−1.27to2.48) −0.69(−2.32to2.12) −0.06(−1.37to1.46) <0.001 0.005 0.007

FEF25---75%(predicted%) 108.20(63.49to142.48) 82.61(63.28to135.56) 90.56(72.94to129.85) <0.001 0.221 0.081

FEF25---75%(Z-score) 0.35(−1.64to1.85) −0.78(−1.64to1.59) −0.42(−1.19to1.24) <0.001 0.204 0.069

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olumetriccapnographyandspirometry261

Table1(Continued)

Areaunderthecurveforvolumetriccapnographyandspirometrybetweencontrolgroup(HCG;n=40),groupofpatientswithasthma(AAG;

n=103)andgroupofpatientswithcysticﬁbrosis(CFG;n=53)

Markers HCGversus

CFG

HCGversus CFG

AAGversus CFG

HCGversusAAG (p-value)

SIII(mmHg/L) 0.782â 0.899â 0.722â <0.001 <0.001 <0.001

SIII/TV 0.732â 0.831â 0.660â <0.001 <0.001 0.001

KPIv 0.737â 0.927â 0.763â <0.001 <0.001 <0.001

FEV1(predicted%) 0.836^b 0.836^b 0.516^b <0.001 <0.001 0.741

FEV1(Z-score) 0.839^b 0.838^b 0.513^b <0.001 <0.001 0.789

FVC(predicted%) 0.685^b 0.756^b 0.596^b 0.001 <0.001 0.051

FVC(Z-score) 0.686^b 0.754^b 0.591^b 0.001 <0.001 0.062

FEV1/FVC(predicted%) 0.863^b 0.799^b 0.624^a <0.001 <0.001 0.011

FEV1/FVC(Z-score) 0.864^b 0.800^b 0.622^a <0.001 <0.001 0.013

FEF25---75%(predicted%) 0.839^b 0.778^b 0.551^a <0.001 <0.001 0.294

FEF25---75%(Z-score) 0.843^b 0.780^b 0.562^a <0.001 <0.001 0.203

Patientswithnormalspirometry.HCG(n=39),AAG(n=57)andCFG(n=28)

Markers HCGversus

CFG

HCGversus CFG

AAGversus CFG

SIII(mmHg/L) 0.768â 0.822â 0.623â <0.001 <0.001 0.065

SIII/TV 0.730â 0.742â 0.563â <0.001 0.001 0.350

KPIv 0.686â 0.866â 0.702â 0.002 <0.001 0.003

FEV1(predicted%) 0.726^b 0.712^b 0.519^b <0.001 0.003 0.779

FEV1(Z-score) 0.732^b 0.717^b 0.518^b <0.001 0.003 0.793

FVC(predicted%) 0.552^b 0.631^b 0.575^b 0.389 0.069 0.266

FVC(Z-score) 0.552^b 0.630^b 0.572^b 0.389 0.071 0.282

FEV1/FVC(predicted%) 0.814^b 0.702^b 0.683^a <0.001 0.005 0.006

FEV1/FVC(Z-score) 0.815^b 0.701^b 0.681^a <0.001 0.005 0.007

FEF25a75%(predicted%) 0.740^b 0.596^b 0.634^a <0.001 0.221 0.081

FEF25a75%(Z-score) 0.745^b 0.600^b 0.640^a <0.001 0.204 0.069

kg,kilogram;cm,centimeter;mL,milliliters;mmHg,millimetersofmercury;L,liters;TV,exhaledtidalvolume;SII,phaseIIslope;SIII,phaseIIIslope;KPIv,ratiobetweentheSIIand theSIIImultipliedby100;FEV1,forcedexpiratoryvolumeinonesecondoftheFVC;FVC,forcedvitalcapacity;FEF25---75%,forcedexpiratoryﬂowbetween25%and75%oftheFVC.Data arepresentedasmedian(minimum---maximum).StatisticalanalysiswasperformedusingtheMann---Whitneytest,andtheauthorscomparedtwogroupseachtime.Alpha=0.05.p-Values withpositiveassociationarepresentedinbold.TheareaunderthecurvewasmeasuredbytheROCcurve.

a Asmallerresultindicatesapositivetest.

b Ahigherresultindicatesapositivetest.

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Figure1 Associationoftheparametersmeasuredinvolumetriccapnographybetweenhealthycontrolindividuals(n=40)and patientswithasthma(n=103),andcysticfibrosis(n=53).Datapresentedby themedian(reddot)and95%confidenceinterval (green intersection).(A) SIII (healthy control) 12.08; (asthma) 17.55; (cystic fibrosis --- CFG) 27.86. (B) SIII/TV: SIII: (healthy control) 0.03;(asthma) 0.05; (CFG) 0.08. (C).KPIv: (healthy control) 2.53; (asthma) 3.41; (CFG)4.96. Data arepresented as median.Alpha=0.05.Alldatapresentedp-valuewithpositiveassociation(p-value<0.05).TheSIIandSIIIarepresentedinmmHg, millimetersofmercury.StatisticalanalysiswasperformedusingtheMann---Whitneytest,andtheauthors comparedtwo groups eachtime.mmHg,millimetersofmercury;L,liters;TV,exhaledtidalvolume;SII,phaseIIslope;SIII,phaseIIIslope;KPIv,ratio betweentheSIIandSIIImultipliedby100.

Figure2 Areaunderthecurveforvolumetriccapnographyandspirometrybetweenthecontrolgroup(HCG,n=40),thegroup ofpatientswithasthma(AAG,n=103),andthegroupofpatientswithcysticﬁbrosis(CFG,n=53).TV,exhaledtidalvolume;SIII, phaseIIIslope;KPIv,ratiobetweentheSIIandSIIImultipliedby100;FEV1,forcedexpiratoryvolumeinonesecondoftheFVC;FVC, forcedvitalcapacity;FEF25---75%,forcedexpiratoryﬂowbetween25%and75%oftheFVC.

expectedthatthereweredifferencesbetweentheresultsof theseinstrumentsontheevaluationofthenumerouschronic lungdiseaseswithairwayobstructioninchildren,resulting fromcompromisesinproximalordistalairways.

Gustafssonetal.comparedasthmaandCFusingLCIand spirometry; their results, as well as the present results, suggest that the airway alterations in CF affect the lung periphery more extensively than in asthma.²⁵ Moreover, Fuchsetal.presented theassociation between KPIvfrom VCap and LCI.⁹ In the present data, differences were observedbetween spirometryandVCap in theHCG,AAG,

and CFG,as well asthepresence of concurrently altered spirometryandKPIvintheCFG.Additionally,normalspirom- etryoccurred in theCFG andAAG (as well asinthe HCG group). Numerous patients with CF and normal spirometry presentedalteredKPIv,suggestingthatthe alterations assessedbyVCapcanoccurearlierthaninspirometry;this factwaspreviouslydocumentedregardingotherVCapmark- ers andLCI.^13,26 Asimilarbehaviorwasobserved between theLCIandFEV1inCF.²⁷ Inturn,patientswithasthmamay presentalteredspirometrywithnormalKPIv,suggestingthat ﬂowalterationsaremorefrequentandaffecttheproximal

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Figure3 AssociationofKPIvonvolumetriccapnographywithspirometrymarkersbetweenhealthycontrolindividuals(n=40)and patientswithasthma(n=103)orcysticfibrosis(n=53),consideringthedistinctionbetweenspirometrymarkersaboveandbelowthe LLN(80%)andKPIvaboveandbelowtheULN(KPIv=4.23).(A)KPIvversusFEV1(predicted%).(B)KPIvversusFVC(predicted%).(C) KPIvversusFEV1/FVC(predicted%).(D)KPIvversusFEF25---75%(predicted%).Eachgraphisdividedintofourquadrantscorresponding tothefollowingconditions: AlteredKPIvandspirometry marker;alteredKPIv andnormalspirometrymarker;normalKPIv and alteredspirometrymarker;normalKPIvandspirometrymarker.KPIv,ratiobetweentheSIIandSIIImultipliedby100;FEV1,forced expiratoryvolumeinonesecondoftheFVC;FVC,forcedvitalcapacity;FEF25---75%,forcedexpiratoryflowbetween25%and75%of theFVC;LLN,lowerlimitofnormal;ULN,upperlimitofnormal.Blackcircle,healthycontrolindividuals;greencircle,patients withasthma;redtriangle,patientswithcysticfibrosis.

airways.Patientswithasthmawhopresent normalspirom- etry and altered KPIv would be harder toexplain. These individualscouldpresentlessknownphenotypesthatshould beassessedwithfunctionalandinﬂammatorybiomarkersto characterizethetypeofasthma.

TohighlighttheimportanceofVCapontheassessmentof pulmonarydiseasesversusspirometry,theauthorsusedthe ROCcurvetodiscriminatebetweenthedifferentgroups.In thepresentdata,VCapwasproventobeausefulinstrument todifferentiatepatientswithCFfromhealthycontrols(on bothadultsandchildren)^6,13 andtodifferentiatechildren, adolescents, and adults with asthma from their healthy peers.^10,28

Thespirometrymarkers(FEV1andFEV1/FVC)werebetter thantheVCaptodifferentiatetheAAGandHCGontheROC curve.Conversely,VCapmarkerspresentedagreaterAUCto distinguishCFGandHCG.O’Nealetal.foundahigherAUC withLCIthanwithspirometry,whendifferentiatingCFand healthycontrols.¹⁸

Spirometry and VCap were effective to differentiate healthyindividuals frompatients withpulmonary disease.

Regarding the difference between AAG and CFG, only KPIv and FEV1/FVC were signiﬁcant, and KPIv was higher (AUC>0.700).

Whenevaluatingtheindividualswithnormalspirometry, VCapmarkersindicatedagreatercompromiseoftheventi- lationhomogeneityonCFandAAGcomparedtothecontrol group.However,VCapwasbetterthanspirometrytodiffer- entiatetheHCGfromtheCFG.Inthissituation,VCap was alsobetterthanspirometrytodiscriminatebetweentheCFG andAAG,consideringanAUC≥0.700.

The present study had some limitations: (i) it did not haveaprospectivedesignandtheVCapmeasureswerenot repeated;(ii)VCapislimitedtoassessclinimetricproper- tiesandthisdoesnotchangetheperceptionofthepotential ofVCapasclinicalandscientiﬁcinstrumentinthecontext of pulmonary diseases in pediatrics; (iii) the sample size waschosenby convenience; and(iv) onlyone center was enrolled.

In conclusion, the present study showed that the SIII, SIII/TV, and KPIv obtained from VCap, and the FEV1 and FEV1/FVCfromspirometry,were goodmarkers todiscrim- inate the HCG from AAG and CFG. The authors believe that for each chronic lung diseases with airway obstruction,differentmarkersofpulmonaryfunctiondeterioration will be more useful. Finally, VCap can describe ear- lier and more accurately the pathophysiology of CF than spirometry.

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Conﬂicts of interest

Theauthorsdeclarenoconﬂictsofinterest.

Acknowledgements

FALM: Fundac¸ão de Amparo à Pesquisa do Estado de São Paulo (FAPESP) for research grants and scholar- ships #2011/12939-4, #2011/18845-1, #2015/12183-8 and

#2015/12858-5; Fundode ApoioàPesquisa, ao Ensinoe à ExtensãodaUniversidadeEstadualdeCampinasforresearch support#0648/2015; JDR: FAPESP for research assistance 2011/18845-1and#2015/12183-8.

To Luciana Montes Rezende, Luciana Cardoso Bonadia, Maria de Fátima Corrêa Pimenta Servidoni, Carlos Emílio Levy, Adressa Oliveira Peixoto, Adyléia Aparecida Contr- eraDalboToro,RenanMarrichiMauch,RobertoJoséNegrão Nogueira,Eulália Sakano,Antônio FernandoRibeiro,Carla CristinadeSouzaGomez,ElizeteAparecidaLomazi,Paloma LopesFranciscoParazzi,LarissaLazzariniFurlan,Emíliada SilvaGonçalves,AlineCristinaGonçalves,MilenaBaptistella GrottaSilva,andAletheaGuimarãesFaria,whocontribute tostudiescarriedoutoncysticfibrosisinourreferencecen- ter.

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