REVIEW Open Access Chronic cough hypersensitivity syndrome Alyn H Morice Abstract Chronic - PDF document

REVIEWOpenAccess Chroniccoughhypersensitivitysyndrome AlynHMorice Abstract Chroniccoughhasbeensuggestedtobeduetothreeconditions,asthma,postnasaldrip,andrefluxdisease.A differentparadigmhasevolvedinwhichcoughisviewedastheprimaryconditioncharacterisedbyafferent neuronalhypersensitivityanddifferentaspectsofthissyndromearemanifestinthedifferentphenotypesofcough. Thereareseveraladvantagestoviewingcoughhypersensitivityastheunifyingdiagnosis;Communicationwith patientsisaided,aetiologyisnotrestrictedandtherapeuticavenuesopened.CoughHypersensitivitySyndromeisa moreapplicablelabeltoembracetheclinicalmanifestationsofthisdisablingdisease. Introduction Ourcontinuingdifficultyindealingwithpatientspre- sentingwithchroniccoughisanexampleofan establisheddogmafailingtomeasureuptoawkward clinicalfacts.Inthe1980spatientspresentingwithiso- latedchroniccoughweresuggestedtofallintooneof threediagnosticcategories.Indeed,thishypothesiswas crystallisedinto ‘ thediagnostictriadofcough ’ [1]. Coughwaseitherduetoaformofasthma,gastroesoph- agealrefluxdisease,oranebulousandpoorlydefined conditionvariouslycalled,PostNasalDripSyndromeor theUpperAirwaysCoughSyndrome[2].Unfortunately, forthosepromulgatingthisparadigmpatientspresenting totheclinicoftenfailedtofitintothesediagnostic categories.Thetermidiopathiccoughwasdulycoined toovercomethedifficultiesarisingfromthefailureto pigeonholesuchawkwardpatients[3]. Tomanyworkinginthefieldthisclassificationwas deeplyunsatisfactory.Firstly,whenoneofthethree diagnosticlabelswasattachedtoapatientfurtherinves- tigationfrequentlyrevealedagrosslyatypicalpatternof disease.Thus,patientswith ‘ asthmaticcough ’ sometimes didnotwheeze,asymptommostwouldregardassine quanonofasthma.Thesepatientswithcoughvariantor coughpredominantasthmaweresuggestedtohavea differentiallocationoftheinflammationwithintheair- way.However,anevenmorebizarreformof ‘ asthma ’ , knownaseosinophilicbronchitis,wasalsoclearlya significantcauseofcoughintheclinic[4].Herethereis nobronchialhyperresponsivenessbutevidence,usually obtainedatinducedsputum,ofeosinophilicinflamma- tionwithintheairways.Isthisaformofasthma?Some wouldsuggestthatthisisaseparatecondition.Inthe clinichoweverpatientsfrequentlystraddlediagnostic boundariesandthefurtherdescriptionofsubtypes expandsthenumbersof “ diseases ” causingcough. Secondly,therearepatientswhosepredominantsymp- tomiscoughbutclearlyhaveconditionswhicharea recognisedillness,suchaspulmonaryfibrosisdueto interstitiallungdiseaseornoncysticfibrosisbronchiec- tasis.Insomepatientstheirchroniccough,ondetailed history,isvirtuallyidenticalinnatureandinassociated featurestothecoughseeninpatientswithotherforms ofchroniccough[5].Doestheillnesscausethecoughor isthecough(throughitsunderlyingaetiology)actually thecauseoftheillness? Inanattempttoclarifythisstateofaffairstheconcept arosethatthesimilaritiesintheclinicalfeaturesof patientspresentingwithachroniccoughoutweighedthe differences.Thus,coughbecametobeviewedinacom- pletelydifferentparadigm.Inthemajorityofpatients withchroniccoughitwassuggestedthattherewerenot aseriesofindividualdiseasesleadingtothesymptom butitwasratherthattherewasasingleunderlyingcon- dition,chroniccough,whichgaverisetoavarietyofdif- ferentphenotypes.Sincevirtuallyallpatientsexhibita hypersensitivityofthecoughreflexthetermCough HypersensitivitySyndromewascoinedasanoverarching diagnosticlabel[6,7].Aswithanyattempttocharacter- iseandcodifytheclinicalworldtheCoughHypersensi- tivitySyndromedoeshaveanumberofdrawbacks[8]. However,thegreaterunderstandingofthediagnosisand Correspondence: a.h.morice@hull.ac.uk Cardiovascular&RespiratoryStudies,RespiratoryMedicine,HullYorkMedical School,CastleHillHospital,CastleRoad,Cottingham,EastYorkshire HU165JQ,UK Coug h ©2013Morice;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycited. Morice Cough 2013, 9 :14 http://www.coughjournal.com/content/9/1/14 symptomprofileexhibitedbythepatient,coupledwithin- sightsintotheepidemiology,managementandpotential futuredevelopmentshaveestablishedCoughHypersensi- tivityasthemostaccurateandconvenientdiagnostic groupingforpatientssufferingwithchroniccough.Inthe clinicadoptingtheapproachofestablishingtheCough HypersensitivitySyndromeastheprimarydiagnosisand thenrecognisingthedifferentphenotypesofallergicupper andlowerairwayinflammationandinthemajoritynon allergicinflammatorychangeprovideslucidityinboth managementandtherapy. Evidenceforcoughhypersensitivity Thathypersensitivityofthecoughreflexoccursduring anupperrespiratorytractinfectionisauniversalexperi- ence.Duringacough/coldweallexperienceboutsof coughingastheresultofminorenvironmentinsults, suchaschangeintemperatureorexposuretonoxious stimulilikecigarettesmoke.Objectiveevidenceofthis hypersensitivityreliesonchallengeexperiments.Ashift inthecoughdoseresponsecurvewithalowerthreshold inURTI,hasbeendemonstratedtocapsaicinchallenge [9,10].Recoveryofthecoughreflextoamorenormal levelisseenastheinfectionabates.Isuggestthatcough reflexhypersensitivityinducedbyvirusisafundamental partofthepathogenesisofURTIenablingthevirusesto disseminatethemselvesthroughthepopulationusing droplettransmission.Asimilarmechanismformanual transmissionexistsinthecoryzasocharacteristicof humancough/cold.ExperimentalstudiesdonebyTyrrel intheCommonColdResearchUnitinthe1950sclearly demonstratethisasthemajormechanismofviraltrans- mission[11]. Whethertheseobservationsofafferentneuronalhyper- sensitivityarerelevanttosubjectswithachroniccough havebeendifficulttoprovewithcertaintyandstillcause manifestconfusioninthemindsofcliniciansandinthe publishedliterature.Thereasonforthislackofclarityis thatunlikethebronchialhyperresponsivenessseeninthe asthmaticpopulationwhereincreasedbronchomotortone isreflectedinbronchoconstrictionto,forexample methacholine,coughreflexhypersensitivityasmanifestby increasedresponsetocapsaicinoracidstimulususually stilllieswithinthewidenormalrange.Thus,bronchial hyperresponsivenesstomethacholineisdemonstrated byshiftinpc20fromatypicalnormalvalueof�16mg/ml tothatbelow4mg/ml.Incapsaicinresponsivenessand individualsubjectmayshowaC5responseof1micro- molarcapsaicin,whichforthemcorrespondsto hyperresponsivenessbutth isvalueiswellwithinthe normalrangeseeninthegeneralpopulation.Thisindi- vidual ’ snormalvaluemaybe30micromolarandthisis onlyrevealedbythesuccessfultreatmentoftheir chroniccough.Coughhypersensitivityistherefore unreliableasatestofabnormalityforanindividual patient.Coughhypersensitivitycanberevealedinpop- ulationsasillustratedinFigure1[12].Ashiftinthe capsaicinsensitivityinducedbyACEinhibitorsisseen buttheoverwhelmingmajorityofindividualsremain withinthebroadpopulationnormalrange.Thus,inthe clinicthereisverylimitedutilityinperformingcough challengetodemonstratecoughhypersensitivitysince itisofnovalueindiagnosisandisonlyroughlycorre- latedwiththeclinicalperceptionofcough. Epidemiologicalevidence Theassociationofcoughhypersensitivitywithclinically importantchroniccoughisperhapsbestillustratedby theepidemiologicalevidenceofcoughhypersensitivity inthesexes.Severalstudiesshowthatwomenhave heightenedcoughreflextoinhalationchallengewith capsaicin,citricacid,andtartaricacid[13,14].However thisfindingisnotuniversal.Forexamplewehave recentlyanalysedapopulationofnormalvolunteers39 malesmeanage31and63femalesmeanage37and foundaneardoublingofcoughevokedbyinhalationof 500mMcitricacid(Figure2).Whereasinasimilar volunteerpoolof54females,meanage34and46males, meanage31therewasnosignificantdifferencefoundin capsaicindoseresponsewithC2(11and15uM)andC5 (39and66uM)valuesrespectivelybeingsimilarbe- tweenthesexes.Giventhepreviouslydescribedwide rangeincoughsensitivitythenlargenumbersare requiredtodetectanysignificantpopulationdifferences withcertainty. Thisfemalehypersensitivityappearstooccurafterpu- berty,sincegirlsandboyshavethesamereflexsensitivity [15,16].Ithasbeensuggestedthatcoughhypersensitivity inwomenisanevolutionarymechanismtoprotectagainst aspirationduringpregnancy.Preliminaryevidencefrom functionalmagneticimagingstudiessuggeststhatcough Figure1 Capsaicindoseresponsecurveoncaptopril(squares) orplacebo(circles). Leftwardshiftindicatesanincreasedcough sensitivityonACEinhibitor. Morice Cough 2013, 9 :14 Page2of4 http://www.coughjournal.com/content/9/1/14 centresareenlargedinwomen.Thissexdifferenceincoughreflexsensitivityisreflectedinthepopulationattendingcoughclinics.Inademographicsurveyofover5000presentationswithchroniccoughtospecialistserviceswomenattendedtwiceasfrequentlyasmen,withapeakageofpresentationinthe5and6decade.Herewomenalsohaveaheightenedcoughreflexsensitivitytocapsaicincomparedtomen[17].MechanismofcoughhypersensitivityThemechanismwherebythehypersensitivitystatewithintheupperairwaysisproducediscurrentlyunknown.Severalpossiblemechanismshavebeenhypothesised.Acentralresponsemaywellunderliethesexrelateddiffer-encetocauseofthefemalepreponderance.However,itisunlikelytoexplainthelocaleffectsseeninairwaydisease.Thus,patientswitheosinophilicbronchitisappearstohaveaparticularformofmastcellinfiltrationassociatedwithairwaynerves[18].Incontrast,inclassicasthmathesameinfiltrateisdistributedwithintheairwaysmoothmuscle.Thus,targetingofinflammationtoparticularair-waystructuresmayberesponsibleforsomeofthediffer-entphenotypesseenwithinthespectrumofasthmaticcough.Thedistributionofnervesmaywellbealteredbydisease.InacarefulbiopsystudyGronebergetal[19]showedthattherewasanincreaseinTRPV1containingsubepithelialsensorynerveswithinthebronchialwallofchroniccoughpatients.However,Mitchelletal[20]didnotfindthis.Samplingerrorisboundtobeanim-portantfactorinstudiesofsmallnumbersinwhatisahighlyvariableautonomicsysteminhumanlung.ThatproinflammatorymediatorscaninduceTRPreceptorfunctionhasbeendemonstratedinprimaryhumanlungcellculture[21].Withinthevagusnervevariousmechanismsofhyper-sensitivityhavebeenestablished,includingthatinducedbyprostaglandins,particularPGE2[22].InthenodoseandjugulargangliaworkfromJohnsHopkinshasdem-onstratedthatadistinctsubsetofneuronesmediatethecoughresponse[23]andthesemayberesponsibleofsomemanifestationsofcoughhypersensitivity.PathogenesisofcoughhypersensitivityItisclearthatawiderangeofdifferentinsultsmayleadtotheinflammationandepithelialdamagerequiredtopro-duceafferentsensoryhypersensitivityoftheupperair-ways.Simplethermalortoxicdamageinducedby,forexamplesmokeinhalationorexposuretoextremecolddryairisresponsibleforanumberofclinicalscenarios.Humanmodelsofthisareproducedintheindustrialsetting.Thus,exposuretohotacidicgasinbottlemanu-facturingleadstoanincreaseincoughreflexhypersensi-tivityandanincreaseofcoughrelatedsymptoms[24].Locallythefactorywasknownastheasthmafactoryalthoughinvestigationrevealedcoughhypersensitivityratherthanbronchialhyperresponsiveness.Amajorandmuchoverlookedcauseofcoughhyper-sensitivityisgaseousnonacidreflux.Becauseofthelackofassociatedclassicrefluxsymptomsofheartburnandregurgitationthisformofreflux,althoughdescribedover150yearsagoascausingtypicalupperrespiratorysymp-toms[25]hasbeenlargelymissed.Aquestionnaire(HARQ)hasbeendevelopedtodeterminetheassociatedfeaturesofrefluxinducedcough[26].BecauseofthelackofclassicsymptomsthesyndromehasbeenentitledsilentrefluxbytheENTsurgeonssincethereisassoci-atedlossofvoice[27].However,itisperhapsnotanappropriatetermforasyndromecausingcough.Becauseofthelackofacid,conventionaloesophagealstudies,suchas24hourpHmonitoringareuninformative.Thesinglemostusefulinvestigationishighresolutionman-ometry,whichprovidesinformationastotheunderlyingneuromechanicaldefectofoesophagealfunctionleadingtoexcessivegaseousreflux[28].CoughhypersensitivityasadiseaseTheparadigmshiftfromregardingcoughasasymptomofvariousdiseasesintocoughasadiseasewithdifferentfacetsallowsforanumberofadvantagesinbothdiagno-sisandtherapyofthiscondition.Firstly,theideaofcoughhypersensitivityasthediseaseremovesthenecessitytohaveasubgroupofchroniccougherswhohaveidiopathiccough.Thepatientdoeshaveadisease;itisjustthatitsoriginmaybemysterious.Ifaconsiderableportionofpatientswithcoughhypersen-sitivityhaveoccultairwayrefluxthenthedegreeofcer-taintyforindividualcliniciansisdependentontheiracceptanceofthestrengthofevidencesupportingthediagnosis.Thus,theauthorwouldplacemanypatientsinthecategoryofcoughhypersensitivitysyndromesecond-arytoairwayrefluxwhereasothers,whohavelessagree-mentwiththisasanaetiologicalmechanism,wouldplacemorepatientsincoughhypersensitivitysyndromeofunknownaetiology.Coughhypersensitivitysyndromeisthusaunifyingconceptallowingdifferingopinionsto Female (N=63)Male (N=33) Gender and cough response to 500 Figure2Meancoughresponsetocitricacidinmenvswomen.Page3of4http://www.coughjournal.com/content/9/1/14 beheldwithindifferingdegreesofprecisionastothe pathobiologicalbasisoftheillness. Thesecondgreatstrengthofcoughhypersensitivityas adiagnosisisthatbyconcentratingonaunifyingpatho- logicalfeatureitpointsthewaytopossibletherapeutic avenueswhichwouldnototherwiseberevealed. Thirdly,communicatingwiththepatientisfacilitatedby thediagnosisofthecoughhypersensitivitysyndrome. Manypatientsintheclinicexpresstheirextremefrustra- tioninthelackofunderstandingandthelackofafirm diagnosisprovidedbytheprofession[29].Bygivingthe syndromeanameandunderstandingthedistinctepi- demiologicalfeaturesoutlinedaboveallowsthephysician tocommunicateourunderstandingofwhatisknown aboutthecondition.Toooftenanisolatedchroniccough isdismissedaspsychogenicorworse,whenobjective coughcountingclearlydemonstratestheextremefre- quencyofcoughingparoxysmsandexplainsthegreatdis- tresssufferedbythepatient[30]. Competinginterests Theauthorsdeclaresthathehasnocompetinginterests. 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Cough 2007, 3: 5. 30.DecalmerSC,WebsterD,KelsallAA,McGuinnessK,WoodcockAA,SmithJA: Chroniccough:howdocoughreflexsensitivityandsubjective assessmentscorrelatewithobjectivecoughcountsduringambulatory monitoring? Thorax 2007, 62: 329 – 334. doi:10.1186/1745-9974-9-14 Citethisarticleas: Morice: Chroniccoughhypersensitivitysyndrome. Cough 2013 9 :14. Submit your next manuscript to BioMed Central and take full advantage of: € Convenient online submission € Thorough peer review € No space constraints or color “gure charges € Immediate publication on acceptance € Inclusion in PubMed, CAS, Scopus and Google Scholar € Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit Morice Cough 2013, 9 :14 Page4of4 http://www.coughjournal.com/content/9/1/14