An application of the 2002 ATSERS consensus classification of the idiopathic interstitial pneumonias Y Ohtani S Saiki M Kitaichi Y Usui N Inase U Costabel Y Yoshizawa See end o ID: 87379
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INTERSTITIALLUNGDISEASEChronicbirdfancierslung:histopathologicalandclinicalcorrelation.Anapplicationofthe2002ATS/ERSconsensusclassificationoftheidiopathicinterstitialpneumoniasYOhtani,SSaiki,MKitaichi,YUsui,NInase,UCostabel,YYoshizawaSeeendofarticleforauthorsaffiliationsCorrespondenceto:ProfessorYYoshizawa,IntegratedPulmonology,TokyoMedicalandDentalUniversity,5-45,Yushima1-chome,Bunkyo-ku,Tokyo113-8519,Japan;yoshizawa.pulm@tmd.Received15May2004Accepted15April2005:665…671.doi:10.1136/thx.2004.027326Chronicbirdfancierslung(BFL)hasoftenbeenmisdiagnosedasoneoftheidiopathicinterstitialpneumonias(IIPs).TodefinetheclinicalandpathologicalcharacteristicsofchronicBFL,26patientswithchronicBFLfromwhomasurgicallungbiopsyspecimenwastakenbetweenOctober1992andJune2001wereevaluated.Thehistopathologicalcharacteristicsofthesurgicallungbiopsyspecimenswereexaminedandcorrelationsbetweenthehistopathologyandclinicalcharacteristicswereanalysed.Thequalityofchronicinflammatoryandfibroticchangeswasexpressedaccordingtothe2002ATS/ERSconsensusclassificationofIIPs.Twopatientswerediagnosedashavingbronchiolitisobliteransorganisingpneumonia(BOOP)-likelesions,fiveashavingcellularnon-specificinterstitialpneumonia(NSIP)-likelesions,andeightashavingfibroticNSIP-likelesions.Theother11patientswereconsideredtohaveusualinterstitialpneumonia(UIP)-likelesionsbecauseofthetemporalheterogeneousappearancesofthefibroticchanges.However,fibrosisinthesepatientshaddevelopedincentrilobularaswellasperilobularareas,suggestiveofhypersensitivitypneumonitis.Nineteenpatients(73.1%)hadmultinucleatedgiantcells,oftenwithcholesterolclefts,whileonlyfivepatients(19.2%)hadgranulomas.PatientswithBOOP-likeorcellularNSIP-likelesionstendedtohaverecurrentacuteepisodes,whereaspatientswithUIP-likelesionshadaninsidiousonset.PatientswithBOOP-likeorcellularNSIP-likelesionshadamorefavourableoutcomethanthosewithfibroticNSIP-likeandUIP-likelesions.ThequalitiesofchronicinflammatoryandfibroticlesionsvarysignificantlyamongpatientswithchronicBFLbutcorrelatewithclinicalfeaturesandprognosis.ypersensitivitypneumonitis(HP)comprisesagroupofallergiclungdiseasescausedbyinhalationofvariousantigenscontainedinorganicdusts.Birdfancierslung(BFL)isaformofHPresultingfromairborneexposuretoavianantigens.InmostcasesofHPhistologicalconfirma-tionisunnecessary.Histopathologically,HPischaracterisedbyfeaturesofagranulomatousinterstitialpneumonia„namely,chronicinflammatoryinfiltratesalongthesmallairways(cellularbronchiolitis);diffuseinterstitialinfiltratesofchronicinflammatorycells;andscattered,small,non-necrotisinggranulomas.Thistriadisfoundinmostbutnotallcases.AnepidemiologicalsurveyofchronicHPcasesinJapanrevealedthatgranulomaswereusuallynotobservedinBFL(16.7%);theyweremorefrequentinsummertypeHP(44.4%)andwereprevalentinisocyanateHP(60.0%).PreviousstudiesofthepathologyofHPfocusedalmostentirelyonfarmerslung.ThepathologyofBFLwasreportedbyPerez-PadillaetalThesestudieswerepublishedbeforetheconceptofnon-specificinterstitialpneumonia(NSIP)wasdeveloped.Aninternationalclassificationofidiopathicinterstitialpneumonias(IIPs)hasbeenproposedbytheAmericanThoracicSociety(ATS)andtheEuropeanRespiratorySocietyUsualinterstitialpneumonia(UIP)isthehisto-pathologicalpresentationthatisassociatedwithidiopathicpulmonaryfibrosis(IPF).1112Intheoriginalreportincludedinterstitialpneumonia,eitheridiopathicorsecond-ary,associatedwithdisorderssuchascollagenvasculardiseasesorexposures.Further,twosubgroupsofNSIPwerecategorisedhistologicallywitheitheracellularorafibroticNSIPpattern.111314RecentarticleshavereportedthatthehistologicalfeaturesofchronicBFLcanbeUIP-likeorNSIP-like.InthisstudyweappliedthehistopathologicaldescriptionoftheATS/ERSinternationalconsensusclassificationoftheIIPstothechronicinflammatoryandfibroticlesionsinchronicBFL,andrelatedthehistologicalchangestotheclinicalcourseandoutcomeofourpatientsclinicallycharacterisedinapreviousDiscussionofthehistologyofthesecaseswasminimalinthepreviousstudybecausethemainfocusofthatstudywasontheclinicalfeaturesofchronicBFL.Incontrast,thispaperfocusesonthevarioushistopathologicalpatternsinchronicBFL.SubjectsTherecordsandhistopathologicalreportsof26patientswithchronicBFL(15men)admittedtoourhospitalwhohadundergonesurgicallungbiopsybetweenOctober1992andJune2001wereexamined.Allthepatientswerereferredtoourhospitalforclinicalmanagement.ThediagnosticcriteriaforchronicBFLincluded(1)ahistoryofaviancontact,(2)antibodiesand/orlymphocyteproliferationtoavianantigens,(3)reproductionofsymptomsofHPbyanenvironmentalprovocationorlaboratorycontrolledinhalationofavianeither(4)evidenceofpulmonaryfibrosiswithorwithoutgranulomasonhistopathologicalanalysis,or(5) Abbreviations:BFL,birdfancierslung;BOOP,bronchiolitisobliteransorganisingpneumonia;HP,hypersensitivitypneumonitis;IIP,idiopathicinterstitialpneumonia;NSIP,non-specificinterstitialpneumonia;UIP,usualinterstitialpneumoniawww.thoraxjnl.com honeycombingoncomputedtomographic(CT)scans,(6)progressivedeteriorationofarestrictiveimpairmentonpulmonaryfunctionover1year,and(7)respiratorysymp-tomsrelatedtoHPof6monthsduration.81718onHRCTscansisanalternativetothepulmonaryfibrosisonhistopathologicalanalysisandwasincludedinthediagnosticcriteriaasanalternativeintheoriginalstudy.consentwasobtainedfromallpatients.HistopathologicalevaluationLungtissueswereobtainedeitherbyopenlungbiopsyorvideo-assistedthoracoscopicsurgery,usuallywithin1weekofadmissiontohospital.Histologicalsectionsofbiopsymaterialswerestainedwithhaematoxylin-eosinandelasticavanGieson.Thehistologicalexaminationswereinterpretedblindlybyfivepulmonarypathologyspecialistswithoutknowledgeofthepatientsclinicalcourse.Whentheinterpretationsdifferedbetweenthefivepathologists,thefinaldecisionwasreachedbyconsensus.ThechronicinflammatoryandfibroticlesionswereclassifiedaccordingtotheATS/ERSinternationalconsensusclassificationasUIP-likelesions,NSIP-likelesions,andbronchiolitisobliteransorganisingpneumonia(BOOP)-likelesionsbasedonthequalityoffibroticchangesincludingthelooseanddensefibrosis,andthetemporalappearance.10…14ThekeyhistopathologicaldifferencebetweenNSIP-likelesionsandUIP-likelesionsisanabsenceoftemporalPatientswithNSIPweresubdividedintotwogroups:cellularNSIPpatternandfibroticNSIP111314CorrelationofhistopathologywithclinicalfeaturesandprognosisInadditiontotheassessmentofthehistopathologicalpatterninthesurgicallungbiopsyspecimens,weevaluatedtherelationshipbetweenthesepatternsandtheclinicalchar-acteristicswhichincludedlaboratoryfindings,pulmonaryfunctiontests,HRCTscans,bronchoalveolarlavage(BAL)findings,andresponsetotreatment.InhalationchallengeAntigeninhalationprovocationtestswereconductedaspreviouslyreported.Briefly,patientsinhaled2mlofpigeondroppingextract(PDE,340g/ml)throughahandheldnebuliser.Thefollowingmonitoringparameterswereusedtodeterminethecriteriaforinhalationprovocationchallenge;patientswhofulfilledthreeormoreofthefollowingwereconsideredpositiveandthosewhofulfilledtwowereconsideredasprobablepositive:(1)increasedradiologicalabnormalities;(2)anincreaseinthealveolar-arterialdifferenceinoxygentension(A-aD)ofmorethan10mmHgand/oradecreaseinthecarbonmonoxidetransferfactor(T)ofmorethan20%;(3)adecreaseinvitalcapacity(VC)ofmorethan15%;(4)anincreaseinperipheral Table1Characteristicsofstudypatients(years)SexSmokingOnsetQualityoflungfibroticlesionsBALlymphocytes(%)TreatmentObservationperiodResponsetosteroid165MSRecurrentBOOP-like66.2CS77Favourable275FNSRecurrentBOOP-like83.0CS77Favourable349FSRecurrentCellularNSIP-like73.0CS84Favourable445MExRecurrentCellularNSIP-like74.5CS114Favourable545MExRecurrentCellularNSIP-like82.0CS98Favourable655FNSRecurrentCellularNSIP-like86.0CS72Favourable764FNSInsidiousCellularNSIP-like74.3CS64Favourable865FNSRecurrentFibroticNSIP-like57.7CS138Favourable960MNSRecurrentFibroticNSIP-like76.0CS60Failure1061FExRecurrentFibroticNSIP-like51.3CS66Stable1150FNSRecurrentFibroticNSIP-like62.2CSIS63Failure(died)1264FNSInsidiousFibroticNSIP-like27.0None……1353MExInsidiousFibroticNSIP-like28.0CSIS60Failure(died)1458MExInsidiousFibroticNSIP-like12.2CSIS16Failure(died)1556MSInsidiousFibroticNSIP-like11.8CSIS48Failure(died)1654MSInsidiousUIP-like18.2None……1749MSInsidiousUIP-like7.0CSIS7Failure(died)1872FNSInsidiousUIP-like38.8CS42Stable1965MExInsidiousUIP-like22.3CSIS29Failure(died)2067MExInsidiousUIP-like10.2CSIS12Failure(died)2170MSInsidiousUIP-like32.0None……2269MSInsidiousUIP-like16.5CSIS25Failure(died)2364MExInsidiousUIP-like17.0CS36Stable2469FNSInsidiousUIP-like9.0CSIS6Failure(died)2565FNSInsidiousUIP-like15.0CSIS48Failure(died)2668MSInsidiousUIP-like24.1CS48FavourableBAL,bronchoalveolarlavage;M,male;F,female;S,currentsmoker;NS,non-smoker;Ex,ex-smoker;BOOP,bronchiolitisobliteransorganisingpneumonia;NSIP,non-specificinterstitialpneumonia;UIP,usualinterstitialpneumonia;CS,corticosteroid;IS,immunosuppressant.Chronicbirdfancierslung(BFL)canbesubgroupedclinicallyintotwotypes:onesubgroupdevelopsinterstitialpulmonaryfibrosisafterrecurrentacuteepisodes(recurrentBFL)andtheothersubgrouphasnohistoryofacuteepisodesbuthasaslowlyprogressivechronicrespiratorydisease(insidiousBFL). Figure1Bronchiolitisobliteransorganisingpneumonia(BOOP)-likelesions(patient2intable1).Lowmagnificationphotographofthesurgicallungbiopsyspecimenshowingpatchylunginvolvementbylooseplugsofconnectivetissuewithinalveolarductsandalveolarspaces.Stain:haematoxylin-eosin;originalmagnification666Ohtani,Saiki,Kitaichi,etalwww.thoraxjnl.com leucocytecountofmorethan30%;(5)anincreaseinCreactiveprotein(CRP)ofmorethan1.0mg/dl;(6)anincreaseinbodytemperatureofmorethan1.0Cand/orthedevelopmentofsystemicmanifestationsincludingchillsandgeneralfatigue;and(7)thedevelopmentofrespiratorysymptoms(coughanddyspnoea).ImmunologicalfindingsAntibodiesinseraandBALfluidstoPDEorbudgerigardroppingextract(BDE)weremeasuredbyanenzymelinkedimmunosorbentassay(ELISA).Antigeninducedlymphocyteproliferationwasperformedaspreviouslyreported.Peripheralorbronchoalveolarlymphocytes(2cells)wereculturedinquadruplicatewitha1:100dilutionofpigeonseraorbudgerigarserain96-wellflatbottomplates.Theplateswereincubatedfor5daysat37Cina5%COincubatorwithH-thymidineforthelast16hoursofculture.Theresultswereexpressedasastimulationindex,whichisthegeometricmeancountsperminuteofstimulatedcultureswithpigeonorbudgerigarseradividedbythegeometricmeancountsperminuteofunstimulatedculturesascontrol(mediumonly).Experi-mentsshowedthatapositivestimulationindexwas(datanotshown).TherapeuticresponsesThedefinitionofatherapeuticresponseisasdescribedintheATSconsensusreport.StatisticalanalysisDataareexpressedasmean(SE).Forstatisticalanalysis,StatView5.0andStatcelStatisticalSoftwarerunningonanAppleMacintoshpersonalcomputerwereused.TheresultsfromthethreegroupswerecomparedusingtheKruskal-Wallistest.Post-hocanalysisbetweentwovariableswasperformedusingtheScheffetest.ComparisonbetweengroupswasperformedusingtheorFishersexacttestforcategoricalvariables.CumulativesurvivalprobabilitieswereestimatedusingtheKaplan-Meiermethod.Thelogranktestwasusedtocomparesurvivalbetweenthepatientsofeachgroup.Allstatisticalcomparisonsweretwosidedandwerecarriedoutatthe0.05significancelevel.RESULTSClinicalfeaturesAllofthe26patientsfulfilledtheabovementioneddiagnosticcriteriaforchronicBFL.ChronicBFLwasclinicallydividedintotwosubgroups:recurrentandinsidious.The10patientswithrecurrentBFLshowedreproductionofsymptomsrelatedtoHPbyenvironmentalprovocationatthebeginningofthediseaseprocess,whilethe16patientswithinsidiousBFLhadapositiveresultfollowingalaboratorycontrolledinhalationprovocationtestbutnotfollowingenvironmentalexposure.AllofthepatientswithchronicBFLhadpulmonaryfibrosisonhistopathologicalexamination,andmostofthe � Figure2Cellularnon-specificinterstitialpneumonia(NSIP)-likelesions(patient4intable1).(A)Lowmagnificationphotographofthesurgicallungbiopsyspecimenshowingmoderatetosevereinterstitialinflammation.(B)Highermagnificationofleftmiddleportionof(A)showinglymphoidfollicleinbronchovascularbundlethatwasoftenseeninallgroups.(C)Highermagnificationoftherightupperportionof(A)showingmultinucleatedgiantcellswithcholesterolcleftsconsideredanotherfindingsuggestiveofbirdfancierslung.Stain:haematoxylin-eosin;originalmagnifications:A18,B50,C Figure3Fibroticnon-specificinterstitialpneumonia(NSIP)-likelesions(patient11intable1).Lowmagnificationphotographofthesurgicallungbiopsyspecimenshowingloosefibrosiswithmoderateinfiltrationoflymphoidcells,notonlyinsubpleuralareasbutalsointhecentrilobulararea.Stain:haematoxylin-eosin;originalmagnificationChronicbirdfancierslungwww.thoraxjnl.com patientsclassifiedashavingaUIP-likepatternhadhoney-combingontheHRCTscan.Elevenofthe26patientshadbeendiagnosedashavingIPFandoneashavingNSIPbeforethefirstvisittothehospital.HistologicalclassificationOfthe26patientswithchronicBFL(table1),two(onemanandonewoman)wereclassifiedashavingBOOP-likelesions(fig1),five(twomenandthreewomen)wereclassifiedashavingcellularNSIP-likelesions(fig2A),eight(fourmenandfourwomen)wereconsideredtohavefibroticNSIP-likelesions(fig3),and11(eightmenandthreewomen)wereclassifiedashavingUIP-likelesions.ThecriteriaforUIP-likelesionswereheterogeneousappearanceatlowmagnificationwithalternatingareasofnormallungstructure,scarceinterstitialinflammation,densefibrosisandhoneycombing,andthepresenceoffibroblasticfoci(fig4A…C).AlthoughonlyasmallproportionofpatientswithUIP-likelesionshadcellularbronchiolitis(table2),fibrosisinthesepatientshaddevelopedinbothcentriacinarandperilobularregions,suggestinganHP-likepattern(fig4B).However,oneofthe11patientswithUIP-likelesionswasindistinguishablefromUIP/IPFexceptforthepresenceofmultinucleatedgiantcells.Multinucleatedgiantcellswithcholesterolcleftsintheircytoplasmandlymphoidfollicleswerefrequentlyobserved(fig2B,Candtable2).ThefindingsofcentriacinarfibrosisandmultinucleatedgiantcellsareinconsistentwithIPFpatientswhohavethehistopathologicalpatternofUIP,suggestinganHP-likepattern.Granulomaswerefoundinonlyfiveofthe26cases(onewithBOOP-likelesions,twowithcellularNSIP-likelesions,andtwowithfibroticNSIP-likelesions).NopatientwithchronicBFLhaddesquamativeinterstitialpneumonia(DIP)-likeordiffusealveolardamage(DAD)-likelesions.ClinicalcharacteristicsandprognosisaccordingtohistopathologicalgroupThetwopatientswithBOOP-likelesionsandthefivepatientswithcellularNSIP-likelesionswerecategorisedasgroupAbecauseneitheroftheselesionsshowedmarkedinterstitialfibroticlesions.EightpatientswithfibroticNSIP-likelesionswerecategorisedasgroupBand11patientswithUIP-likelesionswerecategorisedasgroupC.Therewerenosignificantdifferencesinage,sex,smokinghabit,antigenexposureperiods,%VC,or%Tbetweenthethreegroups(table3).PatientsingroupAtendedtohaverecurrentacuteepisodesincludingmildexertionaldyspnoea,coughandlowgradefever,whereaspatientsingroupCexperiencednoacuteepisodes,suggestingthattheypre-sentedwithchronicdiseaseofinsidiousonset.SpecificantibodiesweremorefrequentlypositiveingroupApatientsthaningroupCpatients.Antigeninducedlymphocyteproliferationwasfrequentlypositiveinallgroups.ThestimulationindexforperipherallymphocyteproliferationwashigheringroupApatients(8.1(1.9))thaningroupBpatients(2.8(0.3))orgroupCpatients(3.1(0.4)).Thestimulationindexforantigeninducedperipherallymphocyteproliferationwas1.1(0.1)inIPFpatients(n=21)and1.3(0.2)inasymptomaticbirdowners(n=20).HoneycombingonHRCTscanswasmorefrequentlyobservedingroupCpatientsthaningroupApatients,althoughemphysemawasnotseeninneversmokingpatientsinanyofthegroups.BALlymphocytesweresignificantlyloweringroupCpatientsthaninpatientsingroupsAandB.Whileallthe26patientswithchronicBFLhadbasicallydiscontinuedtheirantigenexposure,23werebeingtreatedwithoralprednisolonedependingontheseverityoftheinitialsignsandsymptoms,withaninitialdailydoseof30…40mgfor2weekswhichwasthentapered.Onepatient(no12)refusedtreatmentwithprednisolonebecauseofdiabetes.Theremainingtwopatients(nos16and21)werenottreatedbecausetheyhadnorespiratorycomplaintsandhadcometothehospitalbecauseofabnormalchestshadowsobservedduringageneralexamination.PatientsingroupAhadamorefavourableresponsetoprednisolonetreatmentthanthoseingroupsBandC(table3).SevenpatientsingroupA,seveningroupB,andnineingroupCwerefollowedfor83.7(6.4),64.4(13.9),and28.1(5.6)months,respectively,afterstartingsteroidtreatment.PatientsingroupAhadasignificantlybettersurvivalthanthoseingroupsBandC(p=0.016andp=0.015,respectively;fig5).Tenpatients(fouringroupBandsixingroupC)died46.8(10.8)and30.5 � Figure4Usualinterstitialpneumonia(UIP)-likelesions(patient23intable1).(A)Lowmagnificationphotographofthesurgicallungbiopsyspecimenshowingtemporalheterogeneousappearancewithalternatingareasofnormallungstructure,interstitialinflammation,densefibrosis,andhoneycombchangeswhichwasindistinguishablefromUIP/idiopathicpulmonaryfibrosis(IPF).(B)Lowmagnificationphotographofanotherportionof(A)showingnotonlysubpleuralfibrosisasseeninUIPbutalsodistinctcentrilobularfibrosis,whichisinconsistentwithidiopathicpulmonaryfibrosis(IPF).(C)Highermagnificationofthemiddleportionof(B)showingfibroblasticfoci.Stain:haematoxylin-eosin,originalmagnifications:A22,B18,C668Ohtani,Saiki,Kitaichi,etalwww.thoraxjnl.com (8.8)months,respectively,aftersurgicallungbiopsy,despitesteroidtreatment.DISCUSSIONThisclinicopathologicalcorrelationstudywasconductedin26patientswithadiagnosisofchronicBFLbasedonclinicalcharacteristicsandapositiveprovocationtest,thegoldstandardindiagnosingHP.Thedetailedclinicalfeaturesotherthanthehistopathologyofthesepatientsweredescribedinapreviouspaper.Wefoundthatthehistopathologicalpatternsdescribedinthe2002ATS/ERSconsensusclassifica-tionofIIPsweresignificantlycorrelatedwiththeclinicalcourseofthedisease,BALfindingsand,inparticular,withresponsetotreatmentandprognosis.PatientswithBOOP-likeorcellularNSIP-likelesionshadabetteroutcomethanthosewithfibroticNSIP-likeorUIP-likelesions.AlthoughgranulomasaregenerallyconsideredtobecharacteristichistologicalfindingsofHP,Reyesandcollea-reviewedthepathologyof60casesoffarmerslungandreportedthatinterstitialalveolarinfiltrates„consistingofplasmacells,lymphocytes,andoccasionallyeosinophils„werepresentinallcaseswhilegranulomaswerefoundinonlyabout70%.Sealetalreportedthattheprincipalhistopathologicalfindinginsixcasesofchronicfarmerslungwasinterstitialfibrosiswithoutgranulomas.PathologicalstudiesofendstageBFLhaveshownthatthealveoliarealmostcompletelyreplacedbyconnectivetissueandhoneycombing,althoughnogranulomaswerefound.Inourstudy,granulomaswereseeninonlyasmallproportionofpatientswithchronicBFL.TheUIPpatternisthehistopathologicalfeatureofIPFwhichisaclinicopathologicaldiseaseentity.Inourstudy,11 Table2Histopathologicalcharacteristicsofsurgicallungbiopsyspecimensinchronicbirdfancierslung(BFL)GroupA:BOOP-likeorcellularNSIP-like(N=7)GroupB:fibroticNSIP-likelesions(N=8)GroupC:UIP-likelesions(N=11)Cellularbronchiolitis(%)100.050.027.3Honeycombing(%)0.0Fibroblasticfoci(%)0.0Lymphoidfollicles(%)100.062.563.6Interstitialinfiltratesofchronicinflammatorycells(%)100.087.5100.0Intraalveolarfoamyhistiocytes(%)28.625.036.4Cholesterolclefts(%)57.137.545.5Multinucleatedgiantcells(%)71.475.072.7Granulomas(%)42.925.00.0Dataarepresentedas%ofpositivefindings.BOOP,bronchiolitisobliteransorganisingpneumonia;NSIP,non-specificinterstitialpneumonia;UIP,usualinterstitialpneumonia.0.01,groupAgroupC;0.01,groupAgroupB. Table3Clinicalcharacteristicsandhistologicalpatterninpatientswithchronicbirdfancierslung(BFL)GroupA:BOOP-likeorcellularNSIP-like(N=7)GroupB:fibroticNSIP-likelesions(N=8)GroupC:UIP-likelesions(N=11)Age(years)56.9(4.3)58.4(1.8)64.7(2.1)Casesofrecurrentacuteepisodes(%)85.7Exertionaldyspnoea(%)85.7100.090.9Durationofsymptomsbeforesurgicallungbiopsy(months)19.3(7.5)46.3(14.2)24.2(5.3)Exposureperiods(years)11.6(2.8)18.0(2.8)11.0(2.5)Fingerclubbing(%)0.050.081.8Anti-PDEorBDEantibodies(%)85.762.518.2Antigeninducedlymphocyteproliferation(%)100.087.590.9VC(%pred)80.2(9.1)60.6(5.3)74.8(7.2)(%pred)58.7(5.8)49.1(6.0)52.3(5.7)MicronodulesonHRCT(%)57.125.00.0TractionbronchiectasisonHRCT(%)28.6**`HoneycombingonHRCT(%)0.050.090.9BALlymphocytes(%)77.0(2.6)**`40.8(8.6)19.1(2.9)Favourableresponsetotreatment(%)7/7(100.0%)**`1/7(14.3%)1/9(11.1%)Noresponsetotreatment(%)0/7(0.0%)5/7(71.4%)6/9(66.7%)Alive/dead7/04/45/6BOOP,bronchiolitisobliteransorganisingpneumonia;NSIP,non-specificinterstitialpneumonia;UIP,usualinterstitialpneumonia;PDE,pigeondroppingextracts;BDE,budgerigardroppingextracts;VC,vitalcapacity;,carbonmonoxidelungtransferfactor;HRCT,highresolutioncomputedtomography;BAL,bronchoalveolarDataarepresentedasmean(SE)ornumberor%ofpositiveunlessotherwiseindicated.Dataarepresentedasnumberor%ofpositiveinsevengroupApatientswithBOOP-likeorcellularNSIP-likelesions,insevengroupBpatientswithfibrosingNSIP-likelesions,andinninegroupCpatientswithUIP-likelesionswhoweretreatedwithsteroid.0.05,groupAgroupC;0.01,groupAgroupC;0.05,groupBgroupC;0.01,groupAgroupB;0.05,groupAgroupB.Chronicbirdfancierslungwww.thoraxjnl.com patientswithchronicBFLwerefoundtohaveUIP-likelesionswithatemporalheterogeneousappearanceatlowmagnificationandalternatingareasofnormallungstructure,scarceinterstitialinflammation,fibrosis,andhoneycombchangesaswellasfibroblasticfoci.Thesepatientsexperi-encednoacuteepisodesandmostofthemhadnospecificantibodiesandnolymphocytosisintheBALfluid,althoughantigeninducedlymphocyteproliferationtestsandlabora-torycontrolledinhalationprovocationtestswerepositive.Infact,eightofthese11patientshadbeendiagnosedwithIPFbeforevisitingourhospital.However,thefibroticchangeswerelocatedinbothcentrilobularandperilobularareas,suggestinganHP-likepattern,whereastheyareexclusivelyperilobularinIPF.MultinucleatedgiantcellswithcholesterolcleftswerealsoconsideredsuggestiveofBFL;thesearerarelyseeninIPF.SurgicallungbiopsiesontwoseparateoccasionsinapatientwithchronicHPshowedthattheprogressionofchronicdiseasewasassociatedwiththedisappearanceofthecentrilobularpatternleadingtodensefibrosis.Inaddition,necroscopicspecimensfrompatientswithUIP-likelesions,whohadfibrosisinbothcentrilobularandperilobularareasonspecimensobtainedbysurgicallungbiopsy,demonstratedwidespreadhoneycombingwhichwasindistinguishablefromInfact,patientswithUIP-likelesionswerediagnosedashavingUIP/IPFbyageneralpathologist,notbylungexperts,beforereferraltoourhospital.CurrentobservationsweretheconsensusresultsreviewedbyfiveexperiencedJapaneselungpathologists;therefore,chronicinsidiousBFLisonedisorderthatcanbedifficulttodifferentiatefromUIP/IPF.TheinternationalconsensusstatementbytheATSpointedoutthatapatternofinterstitialinflammationandfibrosis,sometimesindistinguishablefromUIP,canoccurinpatientswithchronicHPwhichisdistinguishedbyclinical,serological,orradiographicmanifestations.However,surgi-callungbiopsiesshouldbeconductedearlyenoughtoidentifyclearlythehistopathologicalpatternsofHPduringthecourseofthedisease.IdiopathicNSIPcouldbeseparatedintocellularandfibroticpatternsbecausethesehistologicalpatternsareassociatedwithdifferentclinicalcharacteristicsandprog-111314PatientswithidiopathiccellularNSIPhadamorefavourableoutcomethanthosewithidiopathicfibroticNSIPandIPF.111314Inthecurrentstudy,patientswithBOOP-likeorcellularNSIP-likelesionshadamorefavourableoutcomethanthosewithfibroticNSIP-likelesionsorUIP-likelesionsasobservedinidiopathicNSIPandIPF.PatientswithchronicBFLwhohadUIP-likelesionswerefoundtohaveapoorprognosisinastudyfromMexico.BALlymphocytosiswasseeninpatientswithidiopathicNSIPandinchronicBFLpatientswithNSIP-likelesions,whereastheproportionofBALlymphocytesinchronicBFLpatientswithUIP-likelesions(19.1(2.9)%)washigherthaninpatientswithUIP/IPF(7.2%)asreportedbyNagaietalPatientswithBOOP-likeorcellularNSIP-likelesionstendedtohaverecurrentacuteepisodes,whereaspatientswithUIP-likelesionshadaninsidiousonset.OnepatientwithcellularNSIP-likelesionswithinsidiousonsethadafavourableresponsetosteroidtreatmentandtwopatientswithfibroticNSIP-likelesionswithrecurrentepisodesdidnotrespondfavourablytosteroids.Theprimarydeterminantofthemorefavourableresponsetosteroidtreatmentthere-foreseemstodependonthehistologicalappearanceratherthantheclinicalpresentation.Emphysemahasbeenreportedtooccurfrequentlyinpatientswithfarmerslung,eveninthosewhoneveranditisamoreprevalentlongtermoutcomeoffarmerslungthaninterstitiallungfibrosis.ThisisdifferentfromchronicBFLwherelungfibrosisisthemajoroutcome.InthisstudyweappliedthehistopathologicaldescriptionoftheATS/ERSinternationalconsensusclassificationofIIPstothechronicinflammatoryandfibroticlesionsinchronicBFL,althoughemphysemahasnotbeenseeninpatientswithchronicBFLwhoneversmoked.Thepatientsinourstudyhadawiderangeofhistopatho-logicalfindings.JacobsetalreviewedconsecutivecasesofIIPsreferredbypulmonologistsingeneralpracticeandreportedthatUIP,BOOP,NSIP,andnon-classifiablemor-phologicalpatternsrepresentedaspectrumofinterstitiallungdiseasethatmaybecausedbyinhalationoforganicdustsinthehomeorworkplaceasdescribedwithHP.TheyemphasisedthatallpatientswithIIPsmustbesuspectedofhavinganHPuntilaggressiveevaluationprovesotherwise.etalcomparedthehistopathologyofchronicBFL,IPF,andUIPwithbirdexposure,althoughUIPwithbirdexposureintheirpopulationmayrepresentpatientswithanadvancedstageofBFLbecausetheydidnotconductantigeninducedlymphocyteproliferationorlaboratorycontrolledinhalationprovocationtests.OurstudyshowsthatpatientswithchronicBFLcanproducethewholerangeofhistologicalfeaturescoveredbythenewconsensusclassificationforidiopathicformsofdiffuseinterstitiallungdisease.Thissuggeststhatthesefeaturesaremoreareflectionofnaturalhistoryatdifferentstagesofdiseaseevolutionorofdifferencesinhostresponsesthanoffundamentaldifferencesinthepathologyofdifferentclinicaldiseases.Inconclusion,chronicBFLshouldbeincludedinthelistofdifferentialdiagnosesofinterstitiallungdisease,especiallyinpatientswithaviancontact,evenwhengranulomasareabsent.ApathologistcansuggestadiagnosisofchronicBFLonthebasisofcentriacinarfibroticlesionsatlowpowermagnification.ItisimportanttoobtainadetailedclinicalhistoryandtoperformadequatepathologicaldiagnosticproceduresformakingacorrectdiagnosisofchronicBFL.AntigeninducedlymphocyteproliferationandlaboratorycontrolledinhalationtestsarehelpfultoconfirmthediagnosisandtoexcludethepossibilityofIPFandidiopathicNSIP.ThepatternsofchronicinflammatoryandfibroticlesionsarediverseamongpatientswithchronicBFLbutcorrelatewithclinicalfeaturesandprognosis.TheauthorsthankDrYKobashi,DivisionofPathology,TenriHospital,DrTTakemura,DivisionofPathology,JapanRedCrossCenter,andDrYKawabata,DivisionofLaboratoryMedicine,SaitamaCardiovascularandRespiratoryCenterfordiscussionsonhistopathology;DrTShibataandDrHTanaka,DepartmentofBioinformatics,TokyoMedicalandDentalUniversityforstatisticalanalysis;andDrVLMoore,MerckResearchLaboratories(retired),Phillips,Wisconsinforthecriticalreviewofthemanuscript. \b\t\n \f\b\t Figure5Kaplan-Meiersurvivalcurvesforthethreegroupsofpatients:groupA(bronchiolitisobliteransorganisingpneumonia(BOOP)-likeorcellularnon-specificinterstitialpneumonia(NSIP)-likelesions,n=7);groupB(fibroticNSIP-likelesions,n=8);andgroupC(usualinterstitialpneumonia(UIP)-likelesions,n=11).PatientsingroupAhadasignificantlybettersurvivalthanthoseingroupsBandC(p=0.016andp=0.015,respectively).670Ohtani,Saiki,Kitaichi,etalwww.thoraxjnl.com 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