A different paradigm has evolved in which cough is viewed as the primary condition characterised by afferent neuronal hypersensitivity and different aspects of this syndrome are manifest in the different phenotypes of cough There are several advanta ID: 44026
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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 byshiftinpc20fromatypicalnormalvalueof16mg/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