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AMERICANTHORACICSOCIETYDOCUMENTSLymphangioleiomyomatosisDiagnosisandManagement:High-ResolutionChestComputedTomography,TransbronchialLungBiopsy,andPleuralDiseaseManagementAnOfcialAmericanThoracicSociety/JapaneseRespiratorySocietyClinicalPracticeGuidelineNishantGupta,GeraldineA.
Finlay,RobertM.
Kotloff,CharlieStrange,KevinC.
Wilson,LisaR.
Young,AngeloM.
Taveira-DaSilva,SimonR.
Johnson,VincentCottin,StevenA.
Sahn,JayH.
Ryu,KuniakiSeyama,YoshikazuInoue,GregoryP.
Downey,MeiLanK.
Han,ThomasV.
Colby,KathrynA.
Wikenheiser-Brokamp,CristopherA.
Meyer,KarenSmith,JoelMoss*,andFrancisX.
McCormack*;onbehalfoftheATSAssemblyonClinicalProblemsTHISOFFICIALCLINICALPRACTICEGUIDELINEWASAPPROVEDBYTHEAMERICANTHORACICSOCIETYOCTOBER2017ANDBYTHEJAPANESERESPIRATORYSOCIETYAUGUST2017Background:Recommendationsregardingkeyaspectsrelatedtothediagnosisandpharmacologicaltreatmentoflymphangioleiomyomatosis(LAM)wererecentlypublished.
WenowprovideadditionalrecommendationsregardingfourspecicquestionsrelatedtothediagnosisofLAMandmanagementofpneumothoracesinpatientswithLAM.
Methods:Systematicreviewswereperformedandthendiscussedbyamultidisciplinarypanel.
Foreachintervention,thepanelconsidereditscondenceintheestimatedeffects,thebalanceofdesirable(i.
e.
,benets)andundesirable(i.
e.
,harmsandburdens)consequences,patientvaluesandpreferences,cost,andfeasibility.
Evidence-basedrecommendationswerethenformulated,written,andgradedusingtheGRADE(GradingofRecommendations,Assessment,Development,andEvaluation)approach.
Results:Forwomenwhohavecysticchangesonhigh-resolutioncomputedtomographyofthechestcharacteristicofLAM,butwhohavenoadditionalconrmatoryfeaturesofLAM(i.
e.
,clinical,radiologic,orserologic),theguidelinepanelmadeconditionalrecommendationsagainstmakingaclinicaldiagnosisofLAMonthebasisofthehigh-resolutioncomputedtomographyndingsaloneandforconsideringtransbronchiallungbiopsyasadiagnostictool.
Theguidelinepanelalsomadeconditionalrecommendationsforofferingpleurodesisafteraninitialpneumothoraxratherthanpostponingtheprocedureuntiltherstrecurrenceandagainstpleurodesisbeingusedasareasontoexcludepatientsfromlungtransplantation.
Conclusions:Evidence-basedrecommendationsforthediagnosisandtreatmentofpatientswithLAMareprovided.
Frequentreassessmentandupdatingwillbeneeded.
ContentsOverviewIntroductionMethodsCommitteeCompositionConict-of-InterestManagementGuidelinePanelMeetingsFormulatingQuestionsandOutcomesLiteratureSearchandStudySelectionEvidenceSynthesisDevelopmentofRecommendationsManuscriptPreparationQuestionsandRecommendationsQuestion1Question2Question3Question4Conclusions*Theseauthorssharejointseniorauthorship.
ORCIDID:0000-0001-9112-1315(N.
G.
).
CorrespondenceandrequestsforreprintsshouldbeaddressedtoJoelMoss,M.
D.
,Ph.
D.
,CardiovascularandPulmonaryBranch,NHLBI,NationalInstitutesofHealth,Bethesda,MD20892.
E-mail:mossj@nhlbi.
nih.
govAmJRespirCritCareMedVol196,Iss10,pp1337–1348,Nov15,2017Copyright2017bytheAmericanThoracicSocietyDOI:10.
1164/rccm.
201709-1965STInternetaddress:www.
atsjournals.
orgAmericanThoracicSocietyDocuments1337OverviewThisguidelineisthecontinuationofapriorlymphangioleiomyomatosis(LAM)guidelinedocumentdevelopedbytheAmericanThoracicSociety(ATS)andtheJapaneseRespiratorySociety(JRS)(1).
ThecurrentguidelinecollatestheevidenceforemergingadvancementsinLAMandthenusesthisevidencetoformulaterecommendationspertainingtothediagnosisandtreatmentofpatientswithLAM.
Theintentoftheguidelineistoempowerclinicianstoapplytherecommendationsinthecontextofthevaluesandpreferencesofindividualpatientsandtotailortheirdecisionstotheclinicalsituationathand.
Theguidelinepanel'srecommendations(Table1)areasfollows:dForpatientswhohavecysticchangesonhigh-resolutioncomputedtomography(HRCT)ofthechestthatarecharacteristicofLAM,buthavenoadditionalconrmatoryfeaturesofLAM(i.
e.
,clinical,radiologic,orserologic),wesuggestNOTusingtheHRCTfeaturesinisolationtomakeaclinicaldiagnosisofLAM(conditionalrecommendation,lowcondenceintheestimatedeffects).
Remarks:Intheguidelinepanelists'clinicalpractices,aclinicaldiagnosisofLAMisbasedonacombinationofcharacteristicHRCTfeaturesplusoneormoreofthefollowing:presenceoftuberoussclerosiscomplex(TSC),angiomyolipomas,chylouseffusions,lymphangioleiomyomas(lymphangiomyomas),orelevatedserumvascularendothelialgrowthfactor-D(VEGF-D)greaterthanorequalto800pg/ml.
dWhenadenitivediagnosisisrequiredinpatientswhohaveparenchymalcystsonHRCTthatarecharacteristicofLAM,butnoadditionalconrmatoryfeaturesofLAM(i.
e.
,clinical,radiologic,orserologic),wesuggestadiagnosticapproachthatincludestransbronchiallungbiopsybeforeasurgicallungbiopsy(conditionalrecommendation,verylowcondenceintheestimatedeffects).
Remarks:Theadvantageoftransbronchiallungbiopsyisthatitoffersaless-invasivemethodtoobtainhistopathologicalconrmationofLAM,ascomparedwithsurgicallungbiopsy.
Althoughnotproven,thepanelistsbelievedthattheyieldoftransbronchiallungbiopsylikelycorrelateswithmarkersofparenchymalLAMburden(suchascystprofusion,abnormaldiffusingcapacityofthelungforcarbonmonoxide,abnormalFEV1)andthatappropriatepatientselectionisrequiredtooptimizethesafetyandefcacyofthisdiagnosticapproach.
Consultationwithanexpertcenterbeforeundertakingtransbronchiallungbiopsy,combinedwithacriticalreviewofthetissuespecimensbyapathologistwithexpertiseinLAM,canhelpavoidfalse-negativetestresultsandtheneedforasurgicallungbiopsy.
dWesuggestthatpatientswithLAMbeofferedipsilateralpleurodesisaftertheirinitialpneumothoraxratherthanwaitingforarecurrentpneumothoraxbeforeinterveningwithapleuralsymphysisprocedure(conditionalrecommendation,verylowcondenceintheestimatedeffects).
Remarks:ThisapproachisbasedonthehighrateofrecurrenceofspontaneouspneumothoracesinpatientswithLAM.
Nonetheless,thenaldecisiontoperformpleurodesisandthetypeofpleurodesis(chemicalvs.
surgical)Table1.
SummaryoftheRecommendationsProvidedinThisGuidelineContextRecommendationStrengthofRecommendationCondenceinEstimatesofEffectHRCTassoleconrmatoryfeatureforLAMdiagnosisForpatientswhohavecysticchangesonHRCTofthechestthatarecharacteristicofLAM,buthavenoadditionalconrmatoryfeaturesofLAM(i.
e.
,clinical,radiologic,orserologic),wesuggestNOTusingtheHRCTfeaturesinisolationtomakeaclinicaldiagnosisofLAM.
ConditionalLowTransbronchiallungbiopsyforhistopathologicaldiagnosisofLAMWhenadenitivediagnosisisrequiredinpatientswhohaveparenchymalcystsonHRCTthatarecharacteristicofLAM,butnoadditionalconrmatoryfeaturesofLAM(i.
e.
,clinical,radiologic,orserologic),wesuggestadiagnosticapproachthatincludestransbronchiallungbiopsybeforeasurgicallungbiopsy.
ConditionalVerylowPleurodesisafterasentinelpneumothoraxtopreventrecurrenceWesuggestthatpatientswithLAMbeofferedipsilateralpleurodesisaftertheirinitialpneumothoraxratherthanwaitingforarecurrentpneumothoraxbeforeinterveningwithapleuralsymphysisprocedure.
ConditionalVerylowPleurodesisasacontraindicationtofuturelungtransplantWesuggestthatpreviousunilateralorbilateralpleuralprocedures(i.
e.
,pleurodesisorpleurectomy)NOTbeconsideredacontraindicationtolungtransplantationinpatientswithLAM.
ConditionalVerylowDenitionofabbreviations:HRCT=high-resolutioncomputedtomography;LAM=lymphangioleiomyomatosis.
AMERICANTHORACICSOCIETYDOCUMENTS1338AmericanJournalofRespiratoryandCriticalCareMedicineVolume196Number10|November152017shouldbebasedonshareddecision-makingbetweentheclinician(s)andpatient,aftereducationaboutvariousmanagementoptions.
EveryeffortmustbemadetoensurethatthepleurodesisishandledbycliniciansfamiliarwithmanagementofpleuraldiseaseinLAM.
dWesuggestthatpreviousunilateralorbilateralpleuralprocedures(i.
e.
,pleurodesisorpleurectomy)NOTbeconsideredacontraindicationtolungtransplantationinpatientswithLAM(conditionalrecommendation,verylowcondenceintheestimatedeffects).
Remarks:Lungtransplantationsurgeryinpatientswithahistoryofpriorpleurodesiscanbechallenging.
Patientswhohaveundergonepriorpleuralprocedures(i.
e.
,pleurodesisorpleurectomy)shouldbereferredtoalungtransplantteamwithexpertiseinhandlingcomplexpleuraldissections.
IntroductionThisguidelineisthecontinuationofapriorlymphangioleiomyomatosis(LAM)guidelinedocumentdevelopedbytheATSandJRS(1).
ThecurrentguidelinecollatespertinentevidenceandthenusesthisevidencetoformulaterecommendationspertainingtothediagnosisandmanagementofLAM.
Theseguidelinesarenotintendedtoimposeastandardofcare.
TheyprovidethebasisforrationaldecisionsinthediagnosisandtreatmentofLAM.
Clinicians,patients,third-partypayers,institutionalreviewcommittees,otherstakeholders,orthecourtsshouldneverviewtheserecommendationsasdictates.
Noguidelinesorrecommendationscantakeintoaccounttheentire,oftencompelling,individualclinicalcircumstancesthatguideclinicaldecision-making.
Therefore,nooneevaluatingclinicians'actionsshouldattempttoapplytherecommendationsfromtheseguidelinesbyroteorinablanketfashion.
Statementsabouttheunderlyingvaluesandpreferences,aswellasqualifyingremarksaccompanyingeachrecommendation,areintegralpartsandservetofacilitatemoreaccurateinterpretation;theyshouldneverbeomittedwhenquotingortranslatingrecommendationsfromtheseguidelines.
MethodsCommitteeCompositionTheguidelinedevelopmentpanelwasco-chairedbyF.
X.
MandJ.
M.
andconsistedofcliniciansandresearcherswithrecognizedexpertiseinLAM(1).
Amethodologist(K.
C.
W.
)withexpertiseintheguidelinedevelopmentprocessandapplicationoftheGradingofRecommendations,Assessment,Development,andEvaluation(GRADE)approach(2)wasalsoamemberofthepanel.
PatientperspectiveswereprovidedbytheLAMFoundation(Table2).
Conict-of-InterestManagementGuidelinepanelistsdisclosedallpotentialconictsofinterestaccordingtoATSpolicies.
AllconictsofinterestweremanagedbytheATSconictofinterestanddocumentsdepartmentsusingtheproceduresdescribedinthepreviousLAMguidelines(1).
Allsevenmembersofthewritinggroupwerefreeofconictsforallquestionsrelatedtothisversionoftheguidelines.
GuidelinePanelMeetingsSeveralface-to-facemeetings,conferencecalls,ande-maildiscussionswereheldbetween2008and2017,duringwhichtheguidelinedevelopmentpaneldiscussedthescopeofthedocument,thequestionstobeaddressed,theevidence,andtherecommendations.
Thecosponsoringsocieties(theATSandJRS)providednancialsupportforthemeetingsandconferencecalls,aswellastravelexpenses.
Additionalsupportfortravelofpaneliststomeetingswasprovidedbythenot-for-protLAMFoundationandLAMTreatmentAlliance.
TheATS,JRS,andFoundationshadnoinuenceonquestionselection,evidencesynthesis,orrecommendations.
FormulatingQuestionsandOutcomesClinicalquestionsweredeveloped,circulatedamongthepanelists,andratedaccordingtoclinicalrelevance.
Patient-importantoutcomeswereselectedaprioriforeachquestionandcategorizedascritical,important,ornotimportant(3).
PatientperspectivesonthequestionstobeaddressedwereobtainedviaquestionnairesdistributedbytheLAMFoundation.
LiteratureSearchandStudySelectionAdetaileddescriptionofthesearchstrategywasprovidedintherecentlypublishedLAMguidelines(1).
AllliteraturesearcheswereperformedbyalibrarianfromtheNationalInstituteofHealth(K.
S.
),usingfourTable2.
SummaryofMethodologyMethodYesNoPanelassemblyIncludedexpertsforrelevantclinicaldisciplinesXIncludedindividualswhorepresenttheviewsofpatientsandsocietyatlargeXIncludedamethodologistwithappropriateexpertise(documentedexpertiseinconductingsystematicreviewstoidentifytheevidencebaseandthedevelopmentofevidence-basedrecommendations)XLiteraturereviewPerformedincollaborationwithalibrarianXSearchedmultipleelectronicdatabasesXReviewedreferencelistsofretrievedarticlesXEvidencesynthesisAppliedprespeciedinclusionandexclusioncriteriaXEvaluatedstudiesforsourcesofbiasXExplicitlysummarizedbenetsandharmsXUsedPRISMA1toreportsystematicreviewXUsedGRADEtodescribequalityofevidenceXGenerationofrecommendationsUsedGRADEtoratethestrengthofrecommendationsXDenitionofabbreviations:GRADE=GradingofRecommendationsAssessment,Development,andEvaluation;PRISMA1=PreferredReportingItemsforSystematicReviewsandMeta-analysis1.
AMERICANTHORACICSOCIETYDOCUMENTSAmericanThoracicSocietyDocuments1339electronicdatabases:MEDLINE,EMBASE,WebofScience,andScopus(Table2).
Theliteraturesearchwasoriginallyconductedin2009,subsequentlyupdatedinJuly2014,July2015,andMay2016,andincludedstudiespublishedbeforeMarch2016.
Asmallerworkinggroupofsevenpanelists(C.
S.
,F.
X.
M.
,G.
A.
F.
,K.
C.
W.
,N.
G.
,J.
M.
,andR.
M.
K.
)reviewedthesearchresultsandupdatedthemasnecessary.
EvidenceSynthesisThebodyofevidenceforeachquestionwassummarizedincollaborationwithoneofthemethodologists(K.
C.
W.
).
Whenpossible,datawerepooledtoderivesingleestimates.
Whenthiswasnotpossible,therangeofresultswasreported.
ThequalityofthebodyofevidencewasratedusingtheGRADEapproach(Table2)(4),asdescribedpreviously(1).
DevelopmentofRecommendationsTheguidelinedevelopmentpanelformulatedrecommendationsonthebasisoftheevidencesynthesis,asdescribedpreviously(1).
Recommendationswereformulatedbydiscussionandconsensus;noneoftherecommendationsrequiredvoting.
Thenalrecommendationswerereviewedandapprovedbyallmembersoftheentirepanel.
TherecommendationswereratedasstrongorconditionalinaccordancewiththeGRADEapproach.
Thewords"werecommend"indicatethattherecommendationisstrong,whereasthewords"wesuggest"indicatethattherecommendationisconditional.
Table3describestheinterpretationofstrongandconditionalrecommendationsbypatients,clinicians,andhealthcarepolicymakers.
ManuscriptPreparationThewritinggroup(C.
S.
,F.
X.
M.
,G.
A.
F.
,J.
M.
,K.
C.
W.
,N.
G.
,andR.
M.
K.
)draftedthenalguidelinedocument.
Themanuscriptwasthenreviewedbytheentireguidelinedevelopmentpanel,andtheirfeedbackwasincorporatedintothenaldraft.
Allmembersofthepanelhavereviewedthenalversionofthedocumentandapproveofthedocumentinitsentirety.
QuestionsandRecommendationsQuestion1ShouldpatientsbeclinicallydiagnosedwithLAMonthebasisoftheirHRCTndingsaloneiftheyhavecysticchangesinthelungparenchymathatarecharacteristicofLAMbuthavenoadditionalconrmatorycharacteristicsofLAM(i.
e.
,clinical,radiologic,orserologic)Background.
TheadventofHRCTofthechesthastransformedtheeldofdiffusecysticlungdiseases.
AcriticalreviewofHRCTfeaturescanoftenrevealpatternsthatarediagnosticinasignicantproportionofpatientswithdiffusecysticlungdiseases.
ThecharacteristicHRCTpatternofLAMisdenedasthepresenceofmultiple,bilateral,uniform,round,thin-walledcystspresentinadiffusedistribution.
IthasbeensuggestedthatthediagnosisofLAMcanbeestablishedwithafairdegreeofcertaintyonthebasisofthepresenceofcharacteristicHRCTfeaturesalone(5).
However,therationaleforpursuingadenitediagnosishasbeenstrengthenedoflate.
ArecentrandomizedcontrolledtrialdemonstratedthatsirolimusstabilizeslungfunctiondeclineandimprovesqualityoflifeandfunctionalperformanceinpatientswithLAM(6).
Onthebasisoftheseresults,sirolimusisnowU.
S.
FoodandDrugAdministrationapprovedfortreatmentofLAMandwasrecommendedastherst-linetreatmentoptionforqualiedpatientsinthepreviousLAMguidelinedocument(1).
However,effectivetherapywithsirolimusrequirescontinuousdrugexposureandisassociatedwithpotentialadverseeffects.
Giventhespecteroflong-termtherapy,itisessentialtohavearmdiagnosisbeforeinitiatingpharmacotherapy.
Summaryoftheevidence.
OursystematicreviewidentiedthreestudiesthatevaluatedtheperformancecharacteristicsofHRCTofthechestinestablishingthediagnosisofLAMinpatientswithdiffusecysticlungdiseases(7–9).
Inallthreestudies,HRCTofthechestfrompatientswithvariouscysticlungdiseaseswereevaluated,andadiagnosiswasrenderedbymultiplephysicianswhowereblindedtoclinicalandhistopathologicalinformation.
Cliniciansincludedthoracicradiologists(7–9),pulmonologists(9),andpulmonaryfellows(9).
DiseasesincludedLAM(7–9),pulmonaryLangerhanscellhistiocytosis(7–9),emphysema(7–9),usualinterstitialpneumonia(8),lymphoidinterstitialpneumonia(8,9),desquamativeinterstitialpneumonia(8),Birt-Hogg-Dubesyndrome(9),amyloidosis(9),hypersensitivitypneumonitis(9),nonspecicTable3.
InterpretationofStrongandConditionalRecommendationsforStakeholdersImplicationsforStrongRecommendationConditionalRecommendationPatientsMostindividualsinthissituationwouldwanttherecommendedcourseofaction,andonlyasmallproportionwouldnot.
Themajorityofindividualsinthissituationwouldwantthesuggestedcourseofaction,butmanywouldnot.
CliniciansMostindividualsshouldreceivetheintervention.
Adherencetothisrecommendationaccordingtotheguidelinecouldbeusedasaqualitycriterionorperformanceindicator.
Formaldecisionaidsarenotlikelytobeneededtohelpindividualsmakedecisionsconsistentwiththeirvaluesandpreferences.
Recognizethatdifferentchoiceswillbeappropriateforindividualpatientsandthatyoumusthelpeachpatientarriveatamanagementdecisionconsistentwithhisorhervaluesandpreferences.
Decisionaidsmaybeusefulinhelpingindividualstomakedecisionsconsistentwiththeirvaluesandpreferences.
PolicymakersTherecommendationcanbeadoptedaspolicyinmostsituations.
Policymakingwillrequiresubstantialdebateandinvolvementofvariousstakeholders.
AMERICANTHORACICSOCIETYDOCUMENTS1340AmericanJournalofRespiratoryandCriticalCareMedicineVolume196Number10|November152017interstitialpneumonia(9),lymphangiomatosis(9),andpleuropulmonaryblastoma(9).
Twostudiesincludedpatientswithoutcysticlungdiseaseascontrolsubjects,includingnormalvolunteersandpatientswithnoncysticinterstitiallungdiseases(7,9).
Wepooledthedatafromallthreestudies,whichincluded72patientswithLAMand141patientswithoutLAM.
OuranalysisrevealedthatexpertthoracicradiologistsdiagnosedLAMonthebasisofHRCTreviewalonewithasensitivityof87.
5%andaspecicityof97.
5%,indicatingafalse-negativerateof12.
5%andafalse-positiverateof2.
5%.
Assumingthat30%ofpatientswhopresentwithcysticlungdiseaseofunknownetiologyhaveLAM(1)andthatHRCThasasensitivityandspecicityforLAMofapproximately87%and97%,respectively,thenforevery1,000patientswithcysticlungdiseasewhoundergoHRCTofthechest,261patientswillbecorrectlydiagnosedwithLAM(true-positiveresults)and679patientswillbecorrectlydeterminedtonothaveLAM(true-negativeresults);however,21patientswillbeincorrectlydiagnosedashavingLAM(false-positiveresults)and39patientswillbeincorrectlydeterminedtonothaveLAM(false-negativeresults).
Theguidelinepanel'scondenceintheestimatedsensitivityandspecicitywaslow.
ThestudiesappropriatelycomparedtheHRCTtoagoldstandard(histopathology);however,condencewasdiminishedfortworeasons.
First,thestudiesenrolledneitherconsecutivepatientsnorpatientswithtruediagnosticuncertainty(potentialselectionbias).
Second,theresultsmaynotbegeneralizabletofacilitiesthatdonothaveaccesstoanexpertthoracicradiologisttointerpretHRCT(indirectness).
Supportingtheimportanceofthelatterlimitation,theperformancecharacteristicsofpulmonaryphysicianshavebeenshowntobeinferiortothoracicradiologistsinbeingabletodiagnoseLAMonthebasisofHRCTreview(9).
Third,thestudiesdidnotincludeallpossiblecausesofcysticlungdiseasethatcouldmimicLAM,suchasmetastatictumors,lightchaindepositiondisease,etc.
Last,isolatedcystshavebeenreportedinotherwiseasymptomatic,normalindividualsandhavebeenpostulatedtorepresentanagingmanifestationratherthanatruepathologicaldiseaseprocess(10,11).
Benets.
ThebenetofcorrectlydiagnosingLAMonthebasisofHRCTreviewaloneisthatHRCTofthechestisnoninvasive.
IfHRCTonlycouldbeusedtomakethediagnosisofLAM,neithertransbronchiallungbiopsynorsurgicallungbiopsywouldberequired,reducingtheriskofcomplicationsandtheburdensandcostsofsuchprocedures.
Harms.
False-positiveresultsmayleadtomissedopportunitiestotreatthecorrectdiseaseaswellastheadverseeffectsandcostsofinappropriatetreatmentormanagementofLAM.
Conclusionsandresearchopportunities.
TorecommendclinicaldiagnosisofLAMonthebasisofcharacteristicHRCTndingsalone,theguidelinepanelreasonedthatthespecicitymustbegreaterthan95%.
Therationalewastominimizefalse-positiveresults,becausesuchresultsleadtomissedopportunitiestotreatthecorrectdiseaseaswellastheadverseeffectsandcostsofinappropriatetreatmentandmanagementofLAM.
ThespecicityofHRCTachievedtheprespeciedthreshold;however,thepanelwasconcernedthatthespecicitywasmisleadinglyhighbecauseitwasderivedfromreferralinstitutionswiththoracicradiologistswhohaveexpertiseininterstitiallungdiseasesandcouldhavebeensubstantiallylowerifthestudieshadbeenconductedindifferentmedicalcenters.
Forthisreason,theguidelinepanelelectedtosuggestnotmakingaclinicaldiagnosisofLAMonthebasisofHRCTndingsalone.
TheonlynoninvasivediagnostictestsforLAMthathavebeensystematicallystudiedareHRCTaloneandserumVEGF-D.
Therefore,researchopportunitiesexisttostudythesensitivityandspecicityofcombinedndings,suchasaHRCTplusclinicalfeaturesofTSC,angiomyolipoma,chylouseffusion,orlymphangioleiomyoma.
Recommendation.
ForpatientswhohavecysticchangesonHRCTofthechestthatarecharacteristicofLAM,buthavenoadditionalconrmatoryfeaturesofLAM(i.
e.
,clinical,radiologic,orserologic),wesuggestNOTusingtheHRCTfeaturesinisolationtomakeaclinicaldiagnosisofLAM(conditionalrecommendation,lowcondenceintheestimatedeffects).
Remarks.
Intheguidelinepanelists'clinicalpractices,aclinicaldiagnosisofLAMisbasedonthecombinationofcharacteristicHRCTfeaturesplusoneormoreofthefollowing:presenceofTSC,angiomyolipomas,chylouseffusions,lymphangioleiomyomas,orelevatedserumVEGF-Dgreaterthanorequalto800pg/ml(Table4).
Incertaincases,suchasasymptomaticpatientswithtypicalclinicalpresentationsforLAM(i.
e.
,young-middleaged,nonsmokingfemalepatientswithoutevidenceofunderlyingconnectivetissuediseasesorotherfeaturescommonlyseenincysticlungdiseasesthatcanmimicLAM,suchasemphysemaorSj¨ogrensyndrome)andmildcysticchangeonHRCT,itmaybeappropriatetobaseaprobablediagnosisofLAMoncriticalreviewofHRCTalone(5),especiallywhenadenitivediagnosisisnotlikelytochangemanagement.
Asecondopinionregardingthediagnosisbyanexpertthoracicradiologistcanfurtherstrengthencondenceinthediagnosisinthesecases.
InpatientswithaprobablediagnosisofLAM,theguidelinepaneliststypicallymonitordiseaseprogressionwithserialmonitoringoftheirpulmonaryfunctiontests.
However,therewasgeneralagreementthatadenitediagnosisshouldbeestablishedwithoneoftheadditionalcriteria(Table4)beforeinitiationofpharmacotherapywithmechanistictargetofrapamycin(mTOR)inhibitors.
Valuesandpreferences.
Thisrecommendationplacesahighvalueonavoidingmissedopportunitiestotreatthecorrectdisease,aswellasavoidingtheadverseeffectsandcostsofinappropriatetreatmentofLAM.
Itplacesalowervalueonthepotentialcomplications,burdens,andcostsoftraditionaldiagnostictesting.
Question2ShouldpatientsundergotransbronchiallungbiopsyforthediagnosisofLAMiftheyhavecysticchangesthatarecharacteristicofLAMonHRCTofthechestbuthavenoadditionalconrmatorycharacteristicsofLAM(i.
e.
,clinical,radiologic,orserologic)Background.
TypicalfeaturesonHRCTofthechestcanbehighlysuggestiveofLAM(9).
ManyexpertsmakeadiagnosisofLAMifcharacteristiccysticlungchangesonHRCTareaccompaniedbythepresenceoftuberoussclerosiscomplex,angiomyolipomas,chylouseffusions,lymphangioleiomyomas,oraserumVEGF-Dlevelgreaterthanorequalto800pg/ml(5,12).
Althoughforsomepatients,suchasthosewithoutsymptomsandamildcystburden,astrategyofclosemonitoringonlymaybeappropriate,obtainingdiagnosticcertaintyistheoptimalapproachinthosewithsymptomsorprogressivediseasebeforeinitiatingtreatment.
Video-assistedthoracoscopicsurgery(VATS)-guidedAMERICANTHORACICSOCIETYDOCUMENTSAmericanThoracicSocietyDocuments1341surgicallungbiopsyhasbeenconsideredthegoldstandardforobtaininghistopathologicalconrmationofLAM;however,smallretrospectiveseriessuggestthattransbronchiallungbiopsycanbesafeandeffectiveinaproportionofpatientswithsuspectedLAM.
Summaryoftheevidence.
Oursystematicreviewidentied5casereports(13–17)and12caseseries(18–29)thatdescribedtransbronchiallungbiopsyforthediagnosisofLAM.
Wedidnotconsiderthecasereportsduetothehighriskofpublicationbias(i.
e.
,patientswithsuccessfuloutcomesaremorelikelytobesubmittedbycliniciansascasereports).
Instead,weconsideredonlythecaseseriestoinformtheguidelinepanel'sjudgments.
Thelargestrelevantcaseseriesreportedon108ChinesepatientswithLAM.
Thediagnosiswasconrmedbylungbiopsyin97patients,including49patientswhohadbeendiagnosedbytransbronchiallungbiopsy.
Thenumberofpatientswhohadundergonetransbronchiallungbiopsywasnotreported;however,thediagnosticyieldwouldhavebeen50%ifallpatientshadundergonetransbronchiallungbiopsyandhigheriffewerhadundergonetransbronchiallungbiopsy.
Thecomplicationratewassimilarlyunreported(29).
Fourcaseseriesprovidedsufcientcrudedatatoestimatethediagnosticyieldoftransbronchiallungbiopsy(23,24,28,30).
Inthelargestseries,twoonlinesurveyswereconductedof1,000patientswithLAMwhowereregisteredwiththeLAMFoundation.
Amongthe63patientswhounderwenttransbronchiallungbiopsywhentheywereinitiallysuspectedofhavingLAM,35patients(56%)wereconrmedtohaveLAMbytheprocedure.
Theself-reportedcomplicationratefromtransbronchialbiopsywasapproximately14%(6%withpneumothorax,4%withbleeding,2%withchestpain,and2%withpneumonia)(30).
Whenwepooledtheresultsfromthefourcaseseries,itwasdeterminedthat48outof81patients(60%)whounderwenttransbronchiallungbiopsyforsuspectedLAMwereconrmedtohaveLAM(23,24,28,30).
Ofnote,severalseriesreportedthattheinitialdiagnosisrenderedbythelocalpathologistwasoftennondiagnosticorincorrectandwassubsequentlyrevisedtoLAMwhenreviewedbyapathologistwithexpertiseinLAM.
Theguidelinepanel'sjudgmentsregardingtheutilityoftransbronchiallungbiopsyinLAMwereinformedprimarilybysmallcaseseries,whichprovidedverylowcondenceintheestimateddiagnosticyieldandcomplicationrate.
Thepanel'scondencewasfurtherloweredbythefactthatonlyasmallproportionofpatientsineachcaseseriesunderwenttransbronchiallungbiopsy,andmostoftheseriesdidnotreportthecriteriaforpatientselectionfortransbronchialbiopsy;theselimitationscollectivelyincreasethepossibilityofanoverestimateddiagnosticyieldduetoselectionbias.
ThepanelspeculatedthatthediagnosticyieldvariesaccordingtotheburdenofLAMinthelung.
Finally,oneofthelargerseriesreliedonpatient-reportedresults.
Benets.
TransbronchiallungbiopsyappearstoyieldadiagnosisofLAMingreaterthan50%ofproperlyselectedpatientswithsuspectedLAM.
Denitivediagnosisbytransbronchiallungbiopsyrendersinvasivediagnostictesting,suchassurgicallungbiopsy,unnecessary.
Harms.
Transbronchiallungbiopsyisaminimallyinvasiveprocedurethatmaybeassociatedwithbleeding,pneumothorax,oradversemedicationeffects.
TheoverallTable4.
DiagnosticCriteriaforLymphangioleiomyomatosisDeniteLAMDenitediagnosisofLAMcanbeestablishedifapatientwithcompatibleclinicalhistory*andcharacteristicHRCTofthechesthasoneormoreofthefollowingfeatures:1.
PresenceofTSC2.
Renalangiomyolipoma(s)x3.
ElevatedserumVEGF-D>800pg/ml4.
Chylouseffusion(pleuralorascites)conrmedbytapandbiochemicalanalysisoftheuid5.
Lymphangioleiomyomas(lymphangiomyomas)x6.
DemonstrationofLAMcellsorLAMcellclustersoncytologicalexaminationofeffusionsorlymphnodesjj7.
HistopathologicalconrmationofLAMbylungbiopsyorbiopsyofretroperitonealorpelvicmassesDenitionofabbreviations:D2-40=podoplanin;HMB-45=humanmelanomablack-45;HRCT=high-resolutioncomputedtomography;LAM=lymphangioleiomyomatosis;mTOR=mechanistictargetofrapamycin;TSC=tuberoussclerosiscomplex;VEGF-D=vascularendothelialgrowthfactor-D;VEGFR3=vascularendothelialgrowthfactorreceptor3.
ThediagnosisofLAMshouldbeestablishedusingtheleastinvasiveapproach(detailsinFigure1).
Insomecases,suchasasymptomaticpatientswithmildcysticchangeonHRCT,aprobablediagnosisofLAMwithserialmonitoringmaybesufcient,ifadenitediagnosiswillnotchangemanagementandsomelevelofdiagnosticuncertaintyisacceptabletothepatientandclinician.
EveryeffortmustbemadetoestablishadenitediagnosisofLAMbeforeinitiationofpharmacologicaltherapywithmTORinhibitors.
*CompatibleclinicalhistorywithLAMincludesyoungtomiddle-agedfemalepatientspresentingwithworseningdyspneaand/orpneumothorax/chylothoraxandtheabsenceoffeaturessuggestiveofothercysticlungdiseases.
Typicalcluestoanalternativeetiologyofcysticlungdiseaseonhistoryincludethepresenceofsiccasymptomsoranunderlyingdiagnosisofconnectivetissuedisease,signicantsmokinghistory,personal/familyhistoryofnon–TSC-relatedfacialskinlesions,and/orkidneytumors.
MostpatientswithLAMwillhaveanobstructivedefectonpulmonaryfunctiontests.
Somepatients,especiallyearlyintheirdiseasecourse,maybeasymptomaticandhavenormalpulmonaryfunctiontests.
CharacteristicHRCTchestfeaturesofLAMincludethepresenceofmultiple,bilateral,uniform,round,thin-walledcystspresentinadiffusedistribution,oftenwithnormal-appearinginterveninglungparenchyma.
DetailedhistoryandphysicalexaminationtoinvestigateforthepresenceofTSCisneeded.
ThediagnosisofTSCisestablishedbasedontheproposedcriteriaintheTSCGuidelines(65).
ReferraltoaTSCspecialistmaybeneededifunsureofthediagnosis.
xAngiomyolipomamaybediagnosedonthebasisofradiographicappearanceofcharacteristicfat-containinglesionseitheroncomputedtomographyscanormagneticresonanceimaging.
Contrastisnottypicallyrequiredunlessthevascularcharacteristicsofthetumorneedtobeanalyzed,suchasforevaluationofthepotentialforhemorrhageortheplanningforembolization.
Similarly,lymphangioleiomyomascantypicallybediagnosedonthebasisofcharacteristicradiographicappearance.
jjLAMcellclusterreferstoasphericalaggregateofLAMcellsenvelopedbyalayeroflymphaticendothelialcellsthatisfoundinchylouseffusionsofpatientswithLAM.
ThediagnosisofLAMcanbebasedontypicalmorphologicalappearanceofLAMcellsandpositivestainingforsmoothmusclecellmarkersandHMB-45byimmunohistochemistry.
LymphaticendothelialcellssurroundingtheLAMcellscanbehighlightedbypositiveimmunohistochemicalstainingforlymphaticendothelialcellmarkers,includingD2-40andVEGFR-3.
AMERICANTHORACICSOCIETYDOCUMENTS1342AmericanJournalofRespiratoryandCriticalCareMedicineVolume196Number10|November152017riskofanycomplicationwas14%inthelargestcaseseriesthatweconsidered(30)butisgenerallyestimatedtobeapproximately2%(31,32),whichissubstantiallylessthantherisksassociatedwithaVATS-guidedsurgicallungbiopsy,whichincludea1.
5to4.
5%mortalityrateand10to19%procedure-relatedcomplicationrate(33–36).
Intheory,patientswithcysticdiseasessuchasLAMmaybeatgreaterriskofpneumothoraxfromtransbronchiallungbiopsy.
However,ourevidencesynthesisdidnotsupportthisconclusion,asthepneumothoraxrateof0to6%iscomparabletothegeneralpopulation(23,30).
Conclusionandresearchopportunities.
Theguidelinepanelweighedtheestimateddiagnosticyield(50%)versusthecomplicationrate(2–14%)andcostofbronchoscopyanddecidedthatthebenetsClinicalsuspicionofLAM1HRCTchestwithfeaturescharacteristicofLAM2DetailedclinicalevaluationconfirmsthepresenceofTSC3ConfirmeddiagnosisofTSC-LAMYesConsideralternativediagnosisNoAreanyofthefollowingpresent1.
SerumVEGF-Dgreaterthanorequalto800pg/ml2.
RenalAMLsorlymphangioleiomyomas53.
Positivecytology6YesConfirmeddiagnosisofLAMNoIshistopathologicalconfirmationdesired/required7NoContinueclosemonitoringwithserialPFTsevery3–4monthsYesSurgicallungbiopsyConfirmeddiagnosisofLAMNoYesTransbronchiallungbiopsywithcharacteristicfeaturesofLAM8YesNoConfirmeddiagnosisofLAMObtain:1.
SerumVEGF-D42.
Non-contrastCTorMRIabdomen/pelvis53.
Chylousfluid/node/massaspiration(ifapplicable)Figure1.
Proposedalgorithmforthediagnosisoflymphangioleiomyomatosis(LAM)inapatientwithcompatibleclinicalhistory.
Thealgorithmisdesignedasastep-wise,least-invasiveapproachtoconrmthediagnosisofLAM.
Modicationsonthebasisofclinicaljudgmentarefrequentlyrequired,anddiagnosticdecisionsmustbeindividualized.
AML=angiomyolipoma;CT=computedtomography;DLCO=diffusioncapacityofthelungforcarbonmonoxide;HRCT=high-resolutioncomputedtomography;MRI=magneticresonanceimaging;mTOR=mechanistictargetofrapamycin;PFTs=pulmonaryfunctiontests;TSC=tuberoussclerosiscomplex;VEGF-D=vascularendothelialgrowthfactor-D.
1SuspectLAMclinicallyinyoungtomiddle-agedfemalepatientspresentingwithworseningdyspneaand/orpneumothorax/chylothorax.
MostpatientswithLAMwillhaveanobstructivedefectonPFTs.
Somepatients,especiallyearlyintheirdiseasecourse,maybeasymptomaticandhavenormalPFTs.
2CharacteristicHRCTfeaturesofLAMincludethepresenceofmultiple,bilateral,round,well-dened,relativelyuniform,thin-walledcystsinadiffusedistribution.
TheinterveninglungparenchymaoftenappearsnormalonHRCT.
OtherassociatedfeaturesthatcanbeseenonHRCTinsomepatientswithLAMincludethepresenceof:chylouspleuraleffusion,pneumothorax,ground-glassopacitysuggestiveofchylouscongestion,ormultipletinynodulescharacteristicofmultifocalmicronodularpneumocytehyperplasia(inpatientswithTSC-LAM).
3ReferraltoaTSCcentershouldbeconsideredifthereisuncertaintyregardingthediagnosisofTSC.
FeaturessuggestiveofTSCincludethepresenceofanyofthefollowing:subungualbromas,facialangiobromas,hypomelanoticmacules,confettilesions,Shagreenpatches,positivefamilyhistoryofTSC,historyofseizuresorcognitiveimpairment,orpresenceofcorticaldysplasias,subependymalnodules,and/orsubependymalgiantcellastrocytomasonbrainimaging.
RoutinebrainimagingisnotindicatedifclinicalsuspicionforTSCislow.
DetaileddiagnosticcriteriaforTSCtoestablishadenitivediagnosishavebeenpublished(65).
4SerumVEGF-DiscurrentlyavailableintheUnitedStatesasaCollegeofAmericanPathologists/ClinicalLaboratoryImprovementAct–certiedtestonlythroughtheTranslationalTrialsLaboratoryatCincinnatiChildren'sHospitalMedicalCenter.
Detailedinstructionsforpropercollection,handling,andshippingofVEGF-Dspecimensareavailableatthelaboratorywebsite:www.
cincinnatichildrens.
org/ttdsl.
5ThediagnosisofAMLcanusuallybemaderadiographicallyonthebasisofthepresenceoffatinthetumors.
RoutineuseofcontrastisnotrequiredorrecommendedforthediagnosisofAMLs.
Contrastisusefultodenetheaneurysmalburdenandothervascularcharacteristicsofthetumor,suchasforevaluationofthepotentialforhemorrhageorplanningforembolization.
Similarly,lymphangioleiomyomascantypicallybediagnosedonthebasisofcharacteristicradiographicappearance.
6ThesensitivityofcytologicalanalysisofpleuraluidforthediagnosisofLAMrequiresfurtherinvestigationandmayonlybeavailableatselectcenters.
Inamajorityofpatientswithchylouseffusions,thediagnosisofLAMcanbeestablishedonthebasisofelevatedserumVEGF-D.
7Thedecisiontoobtaintissueconrmationviainvasivemeansshouldbeindividualized.
Forsomepatientswithmilddiseaseandapaucityofsymptoms,aprobableclinicaldiagnosisofLAMwithserialmonitoringmaybesufcientifadenitivediagnosisofLAMwouldnotchangemanagementandsomelevelofdiagnosticuncertaintyisacceptabletothepatientandtheclinician.
EveryattemptshouldbemadetoestablishthediagnosisofLAMwithcertaintybeforeinitiationofpharmacologictherapywithmTORinhibitors.
8Transbronchiallungbiopsyhasanestimatedyieldofgreaterthan50%forthediagnosisofLAM,andmarkersofparenchymalLAMburdensuchasabnormalDLCOareassociatedwithanincreaseddiagnosticyield.
TransbronchiallungbiopsyappearstobesafeinLAMonthebasisofcasereportsandsmallseries,butadditionalstudiesarerequired.
Consultationwithanexpertcenterisrecommendedincaseswheretransbronchialbiopsyisbeingconsidered,andforinterpretationofthebiopsy.
AMERICANTHORACICSOCIETYDOCUMENTSAmericanThoracicSocietyDocuments1343oftransbronchiallungbiopsyoutweightheharmsinappropriatelyselectedpatients.
Generallyspeaking,weontheguidelinepanelbelievethatthediagnosisofLAMshouldbeestablishedinanalgorithmicapproachthatprogressesfromtheleasttomostinvasivemethodrequiredtoconrmthediagnosisofLAM(Table4andFigure1).
Manyquestionsremainunanswered.
Thediagnosticyieldoftransbronchiallungbiopsyinanunselectedpatientpopulationisunknownandneedstobedetermined,asdoestherelationshipbetweendiseaseburdenandyield.
ThesafetyproleoftransbronchiallungbiopsyinLAM,especiallypertainingtotheriskofpneumothorax,needstobebetterunderstood.
ThenumberofbiopsiesthatprovidestheoptimalbalancebetweendiagnosticyieldandriskofcomplicationsinpatientswithvaryingseverityofLAMneedstobedetermined.
Theuseofendobronchialultrasound–guidedtransbronchialneedleaspirationforthediagnosisofLAMhasnotbeenreportedbutmaybeanattractiveoptioninpatientswithLAMwhohavemediastinalorhilaradenopathy,ifstudiesdemonstrateareasonableyieldandsafetyprole.
Finally,thesafetyandefcacyoftransbronchiallungcryobiopsyneedstobebetterunderstoodforpatientswithsuspectedLAM(37).
Thedecisiontoobtainlungbiopsy(transbronchialorsurgical)fortissuediagnosisshouldbeindividualizedforeverypatient.
Forsomepatientswithmilddiseaseandapaucityofsymptoms,serialmonitoringmaybesufcient,especiallyifsomelevelofdiagnosticuncertaintyisacceptabletothepatientandclinicianandadenitediagnosisisunlikelytochangemanagement.
Incontrast,VATS-guidedsurgicallungbiopsymaybemoreappropriateforpatientswithalowcystburden,giventhepotentialforsamplingerrorassociatedwithtransbronchiallungbiopsy.
Computedtomographycanbeusedtoguidelesion-targetedtransbronchiallungbiopsyonthebasisofdistributionofparenchymalabnormalities.
Inaddition,theclinicianshouldtakeintoconsiderationthatthepathologicaldiagnosisofLAMcansometimesbemadebyless-invasivemeans,suchasbydemonstrationofLAMcellclustersinchylouseffusions(38,39)oraspiratesorcorebiopsiesofpulmonaryorextrapulmonarylymphnodesormasses(28,40–42).
Theperformancecharacteristicsanddiagnosticyieldofthesemethodologies,however,isnotwellestablishedandneedstobestudied.
ConsultationwithexpertLAMcentersisadvisedtoindividualizetheapproachtodiagnosisincomplexpatients.
Onoccasion,re-reviewofarchivaltissuesfrompriorproceduresbyexpertpathologistscanrevealthediagnosisofLAMandobviatetheneedforbiopsy.
Examplesincludelungtissueobtainedfrompriorblebresectionsforpneumothoraxoruterineandadnexaltissuesfrompriorhysterectomies.
EveryattemptshouldbemadetoestablishthediagnosisofLAMwithcertaintybeforeinitiationofpharmacologictherapywithmTORinhibitors.
Recommendation.
WhenadenitivediagnosisisrequiredinpatientswhohaveparenchymalcystsonHRCTthatarecharacteristicofLAM,butnoadditionalconrmatoryfeaturesofLAM(i.
e.
,clinical,radiologic,orserologic),wesuggestadiagnosticapproachthatincludestransbronchiallungbiopsybeforeasurgicallungbiopsy(conditionalrecommendation,verylowcondenceintheestimatedeffects).
Remarks.
Theadvantageoftransbronchiallungbiopsyisthatitoffersaless-invasivemethodtoobtainhistopathologicalconrmationofLAM,ascomparedwithsurgicallungbiopsy.
Althoughnotproven,thepanelistsbelievedthattheyieldoftransbronchiallungbiopsylikelycorrelateswithmarkersofparenchymalLAMburden(suchascystprofusion,abnormaldiffusingcapacityofthelungforcarbonmonoxide[DLCO],abnormalFEV1)andthatappropriatepatientselectionisrequiredtooptimizethesafetyandefcacyofthisdiagnosticapproach.
Arecentstudyevaluatingtheroleoftransbronchiallungbiopsyin24consecutivepatientspresentingtoaLAMClinicrevealedadiagnosticyieldof71%,whichwasinverselycorrelatedwithDLCO(43).
Consultationwithanexpertcenterbeforeundertakingtransbronchiallungbiopsy,combinedwithacriticalreviewofthetissuespecimensbyapathologistwithexpertiseinLAM,canhelpavoidfalse-negativetestresultsandtheneedforasurgicallungbiopsy.
Valuesandpreferences.
Thisrecommendationplacesahighvalueontheriskreductionandcostsavingsoftheless-invasiveandless-expensiveapproachoftransbronchiallungbiopsyasopposedtoaVATS-guidedsurgicallungbiopsy.
Itplacesalowervalueonthedesiretoconrmthediagnosiswithasinglediagnostictest.
Question3ShouldpatientswithLAMundergoipsilateralpleurodesisafteraninitialpneumothoraxorwaitforarecurrencebeforeinterveningwithapleuralsymphysisprocedureBackground.
LAMischaracterizedbyanincreasedriskofrecurrentspontaneouspneumothoraces.
OnthebasisofthehighriskofrecurrenceinpatientswithLAM,anexpertpanelsupportedpleurodesisaftertherstepisodeofpneumothoraxinpatientswithLAM(44).
Summaryoftheevidence.
OursystematicreviewdidnotidentifyanystudiesthatcomparedoutcomesamongpatientswithLAMwhounderwentpleurodesisafteraninitialpneumothoraxversusthosewhounderwentpleurodesisafterarecurrentpneumothorax.
Thepanel,therefore,usedsevencaseseriesthatreportedtheincidenceofpneumothoracesamongpatientswithLAM(19,21,28,29,44–48)andtwoobservationalstudiesthatalsocomparedtheincidenceofrecurrentpneumothoraxamongthosewhohadundergonepleurodesistothosewhohadnot(44,46)toinformtheguidelinepanel'sjudgments.
Poolingdatademonstratedthatpneumothoraxoccurredin902outof1,591(57%)patientswithLAM(19,21,28,29,44–48).
Recurrenceswerecommon,withestimatesrangingfrom29to81%,althoughmostestimateswerearound70%(28,29,44,46,48).
Patientsfrequentlyhadmultiplerecurrences,withestimatesrangingfrom3.
2to5.
0pneumothoracesperpatientinthepneumothorax-affectedgroups(21,44,45).
Theobservationalstudiesfoundthatapproximately65%ofpatientswhoweremanagedconservativelyaftertheirinitialpneumothoraxhadrecurrentpneumothoraces,comparedwithonly18to32%ofpatientswhohadpleurodesis(44,46).
Therateofcomplicationsduetopleurodesiswasnotreported.
TheguidelinepanelhadverylowcondenceintheestimatedincidenceofpneumothoracesinpatientswithLAMbecausetheyderivedfromcaseseriesandsmallobservationalstudies.
Withmultiplerecurrentpneumothoracesperpatient,thecostoftreatmentofpneumothoracescanbesubstantial.
Inoneseries,theaveragetimespentinthehospitalduetopneumothoraceswasapproximately1monthperpatient,AMERICANTHORACICSOCIETYDOCUMENTS1344AmericanJournalofRespiratoryandCriticalCareMedicineVolume196Number10|November152017whichwasassociatedwithsubstantialcostsduetohospitalexpensesandlostproductivity(44).
Benets.
Earlypleurodesisafteraninitialpneumothoraxdecreasestheriskofrecurrentpneumothoraces,therebydecreasingmorbidity,burden,andcost.
Harms.
Pleurodesisisaninvasiveprocedureassociatedwithpainandpotentialcomplications.
Priorpleurodesismayalsobeweighedwhenconsideringfuturecandidacyforlungtransplant.
Conclusionsandresearchopportunities.
Theguidelinepanelweighedthedesirableconsequencesofperformingpleurodesisafteraninitialpneumothorax(i.
e.
,aroughly30–45%lowerriskofrecurrentpneumothoraxandoverallcostsavings)againsttheundesirableconsequences(i.
e.
,pain,potentialcomplications,impactoncandidacyoftransplantation)anddecidedthatthebalancefavorspleurodesis.
Amongthepanel'sconsiderationswasthefactthattheundesirableconsequencesofpleurodesisaremerelydelayedratherthanavoided,becausemostpatientswilleventuallysufferarecurrentpneumothoraxandrequirepleurodesis.
Therearemultiplewaystoperformpleurodesis,eachwithitsownsetofadvantagesanddisadvantages.
Generallyspeaking,pleurodesiscaneitherbeachievedbychemicalinstillationofasclerosingagentviaachesttubeorbysurgicalmeansusingmechanicalabrasion,talcpoudrage,orpleurectomy.
Althoughtalcisthemostcommonsclerosantusedforpleurodesis,otheragents,suchastetracyclinederivatives,silvernitrate,iodopovidone,andbleomycin,havebeenusedwithvaryingdegreesofsuccess(49–51).
Inpractice,thepanelistsgenerallyusemechanicalabrasionwithanearnestattempttoaddresstheentireparietalpleuralsurfacefortheinitialpneumothoraxandreservemoreaggressiveapproaches,suchastalcpoudrageandpleurectomy,forrecurrentandrefractorypneumothoraces.
TheimportanceofknowledgeandpriorexperienceinmanagementofpleuraldiseaseinLAMcannotbeoverstated,andpleuralcomplicationsinLAMarebesthandledbythoracicsurgeonswithexpertiseinmanagingpatientswithLAM.
TheidealmethodofachievingpleuralsymphysisinpatientswithLAM,onethatprovidestheoptimalbalancebetweenefcacyofpreventingfuturerecurrencesandtheleastriskofintra-andpostoperativecomplicationsduringlungtransplantation,isnotclear.
Theefcacyofalternativemeansofachievingpleurodesis,suchastotalpleuralcovering,whichmaypreventadhesionsandtheassociatedsurgicalcomplicationsduringtransplant(52),andautologousbloodpatchpleurodesis,whichisassociatedwithsignicantlylesspainascomparedwiththetraditionalmeansofachievingpleuralsymphysis(53),needstobestudiedinpatientswithLAM.
Inaddition,abetterunderstandingofpneumothoracesandtheirimpactonlong-termdiseaseoutcomesneedstobeestablished.
WiththerecognitionofmTORinhibitorsaseffectivetherapeuticagentsforpatientswithLAM,theimpactandroleofmTORinhibitiononpneumothoraxoccurrenceandrecurrenceneedstobeassessed.
Recommendation.
WesuggestthatpatientswithLAMbeofferedipsilateralpleurodesisaftertheirinitialpneumothoraxratherthanwaitingforarecurrentpneumothoraxbeforeinterveningwithapleuralsymphysisprocedure(conditionalrecommendation,verylowcondenceintheestimatedeffects).
Remarks.
ThisapproachisbasedonthehighrateofrecurrenceofspontaneouspneumothoracesinpatientswithLAM.
Nonetheless,thenaldecisiontoperformpleurodesisandthetypeofpleurodesis(chemicalvs.
surgical)shouldbebasedonshareddecision-makingbetweentheclinician(s)andpatient,aftereducationaboutvariousmanagementoptions.
LungbiopsyatthetimeofpleurodesisforpneumothoraxmaybeusefulinselectedpatientswhodonotalreadyhaveaconrmeddiagnosisofLAMbutcanbeassociatedwithaddedrisk(e.
g.
,prolongedairleakandchronicbronchopleuralstulaformation)(54)andshouldonlybeusedwhenATS/EuropeanRespiratorySocietydiagnosticcriteriaforLAMarenototherwisemetandahistologicdiagnosisisabsolutelynecessary.
EveryeffortmustbemadetoensurethatthepleurodesisishandledbycliniciansfamiliarwithmanagementofpleuraldiseaseinLAM.
Valuesandpreferences.
Thisrecommendationplacesahighvalueonreductioninthemorbidityandcostassociatedwitharecurrentpneumothorax.
Itplaceslowervalueontheadverseeffectsofpleurodesis.
Question4ShouldpatientswithLAMwhohavehadapriorpleuralintervention(eitherpleurodesisorpleurectomy)beexcludedfromconsiderationforlungtransplantationBackground.
LAMtypicallyprogressesandmayultimatelyleadtorespiratoryinsufciencyifitisleftuntreated.
Lungtransplantationremainstheonlytreatmentmodalityavailableforpatientswithend-stagelungdiseaseduetoLAM.
AsignicantproportionofpatientswithLAMwhopresentfortransplantevaluationhaveundergonepriorunilateralorbilateralpleurodesisprocedures.
Thesepleuralinterventionscanincreasetheriskofbleedingcomplicationsatthetimeoflungtransplantation,andsomecentersconsiderbilateralpleurodesistobearelativecontraindicationtolungtransplantation(48).
Summaryoftheevidence.
OursystematicreviewidentiedveobservationalstudiesthatenrolledpatientswithLAMundergoinglungtransplantationandcomparedoutcomesamongthosewhohadpreviouspleurodesisorpleurectomyversusthosewhodidnot(44,55–58).
Inaddition,vecaseserieswerefoundthatdescribedoutcomesoflungtransplantationforLAMbutdidnotcompareoutcomesamongpatientswithandwithoutpriorpleuralprocedure(59–63).
Twoofthecaseserieswerepublishedinforeignlanguagesand,therefore,werenotconsidered(62,63).
Theobservationalstudiescollectivelyincluded182patientswithLAMwhowereundergoinglungtransplantation.
Thisincluded31patients(17%)whohadundergoneunilateralpleurodesis,55patients(30%)whohadundergonebilateralpleurodesis,10patients(5%)whohadundergoneunilateralpleurectomy,7patients(4%)whohadundergonebilateralpleurectomy,and79patients(43%)whohadnotundergoneapreviouspleuralprocedure.
Patientswhohadundergoneapreviouspleuralprocedureweremorelikelytohaveintra-orpostoperativehemorrhage(48%vs.
7%;relativerisk,6.
46;95%condenceinterval,2.
44–17.
11)(44,56,57),andtherewasatrendtowardsuchpatientsbeingmorelikelytohavepleuraladhesions(65%vs.
46%;relativerisk,1.
42;95%condenceinterval,0.
96–2.
12)(55,56,58).
However,therewasnosignicantdifferenceinthelengthofhospitalstay(44),lungfunction(58),mortality(58),orriskofchylouseffusions(58).
Theguidelinepanelhadverylowcondenceintheseestimatedoutcomes,becausethedatawerederivedfromsmallobservationalstudies.
Forgeneralpulmonarypopulations,theInternationalSocietyforHeartandLungTransplantationGuidelinecommitteerecentlyrecommendedthatAMERICANTHORACICSOCIETYDOCUMENTSAmericanThoracicSocietyDocuments1345pleurodesisnotbeconsideredacontraindicationtolungtransplantationandthatapneumothoraxinapotentialfuturetransplantrecipientshouldbegiventhebestimmediatemanagementwithoutundueconcernthatthechoiceofinterventionwillinuencefutureacceptancefortransplantation(64).
Therisksassociatedwithtransplantationofpatientswithpriorbilateralpleurodesiswerenotdirectlyaddressedinthisconsensusdocument,however.
Benets.
AllowingpatientswithLAMwhohavehadpriorpleuralprocedurestoundergolungtransplantationconfersallofthepotentialadvantagesoflungtransplantationinapatientwithend-stagelungdisease,includingimprovedlungfunctionandincreasedsurvival(55).
Harms.
Priorpleuralproceduresincreasetheriskofintra-andpostoperativebleedingandprolongoperativetime,althoughotheroutcomesarethesameasthoseseeninpatientswhohavenothadapriorpleuralprocedure.
Conclusionandresearchopportunities.
Theguidelinepanelweighedthedesirableconsequencesofallowingapatienttobeconsideredforlungtransplantation(i.
e.
,hopeand,forthosewhoundergotransplant,improvedlungfunctionandincreasedsurvival)againsttheundesirableconsequences(i.
e.
,morelikelytohaveintra-andpostoperativebleeding)anddeterminedthatthebalancefavorslungtransplantation.
Amongthepanel'sconsiderationswasthefactthattheundesirableconsequencesaregenerallyshorttermandrarelyfatal,whereasthepotentialbenetsarelongerlastingandlife-saving.
AnunansweredquestionregardinglungtransplantationinLAMisthedifferenceinoutcomesafterabilaterallungtransplantcomparedwithasinglelungtransplant.
Thisisespeciallyimportant,becauseifthereisnodifferenceinoutcomesafterasinglelungtransplant,thensomepatientswithpriorunilateralpleurodesismayelectivelyundergosinglelungtransplantationonthecontralateralsideandpotentiallyavoidthebleedingcomplicationsassociatedwiththetransplant.
Recommendations.
Wesuggestthatpreviousunilateralorbilateralpleuralprocedures(i.
e.
,pleurodesisorpleurectomy)NOTbeconsideredacontraindicationtolungtransplantationinpatientswithLAM(conditionalrecommendation,verylowcondenceintheestimatedeffects).
Remarks.
Lungtransplantationsurgeryinpatientswithahistoryofpriorpleurodesiscanbechallenging.
Patientswhohaveundergonepriorpleuralproceduresshouldbereferredtoalungtransplantteamwithexpertiseinhandlingcomplexpleuraldissections.
Valuesandpreferences.
Thisrecommendationplacesahighvalueonthelaterbenetsoflungtransplantationandalowervalueonsurgicalcomplications.
ConclusionsTheguidelinepanelusedcomprehensiveevidencesynthesestoinformitsjudgmentsregardingthebalanceofbenetsversusburdens,adverseeffects,andcosts;thequalityofevidence;thefeasibility;andtheacceptabilityofvariousinterventions.
ForwomenwhohavecysticchangesonHRCTofthechestcharacteristicofLAM,butwhohavenoadditionalconrmatoryfeaturesofLAM(i.
e.
,clinical,radiologic,orserologic),theguidelinepanelmadeconditionalrecommendationsagainstmakingaclinicaldiagnosisofLAMonthebasisoftheHRCTndingsaloneandforconsideringtransbronchiallungbiopsyasadiagnostictool.
Theguidelinepanelalsomadeconditionalrecommendationsforofferingpleurodesisafteraninitialpneumothoraxratherthanwaitingforarecurrentpneumothoraxandagainstpleurodesisbeingusedasareasontoexcludepatientsfromlungtransplantation.
CliniciansfacedwithmakingmanagementdecisionsforpatientswithLAMshouldindividualizetheirdecisions,becausetheevidencebaseprovidedinsufcientcondenceintheestimatedeffectstowarrantstrongrecommendationsfororagainstanyintervention.
nThisofcialclinicalpracticeguidelinewaspreparedbyanadhocsubcommitteeoftheATSAssemblyonClinicalProblems.
MembersoftheWritingGroupareasfollows:FRANCISX.
MCCORMACK,M.
D.
(Co-Chair)JOELMOSS,M.
D.
,PH.
D.
(Co-Chair)NISHANTGUPTA,M.
D.
,M.
S.
GERALDINEA.
FINLAY,M.
D.
ROBERTM.
KOTLOFF,M.
D.
CHARLIESTRANGE,M.
D.
KEVINC.
WILSON,M.
D.
Membersofthesubcommitteeareasfollows:FRANCISX.
MCCORMACK,M.
D.
(Co-Chair)JOELMOSS,M.
D.
,PH.
D.
(Co-Chair)THOMASV.
COLBY,M.
D.
VINCENTCOTTIN,M.
D.
GREGORYP.
DOWNEY,M.
D.
GERALDINEA.
FINLAY,M.
D.
NISHANTGUPTA,M.
D.
,M.
S.
MEILANK.
HAN,M.
D.
YOSHIKAZUINOUE,M.
D.
,PH.
D.
SIMONR.
JOHNSON,M.
D.
ROBERTM.
KOTLOFF,M.
D.
CRISTOPHERA.
MEYER,M.
D.
JAYH.
RYU,M.
D.
STEVENA.
SAHN,M.
D.
KUNIAKISEYAMA,M.
D.
,PH.
D.
KARENSMITH,M.
L.
S.
CHARLIESTRANGE,M.
D.
ANGELOM.
TAVEIRA-DASILVA,M.
D.
,PH.
D.
KATHRYNA.
WIKENHEISER-BROKAMP,M.
D.
,PH.
D.
KEVINC.
WILSON,M.
D.
LISAR.
YOUNG,M.
D.
AuthorDisclosures:F.
X.
M.
holdsapatentfortheuseofVEGF-Dinthediagnosisoflymphangioleiomyomatosis,servedasaconsultantforLAMTherapeutics,andservedonadataandsafetymonitoringboardforTakeda.
V.
C.
servedasaspeakerforSano-AventisU.
S.
;servedonadataandsafetymonitoringboardforPromedior;servedasaspeakerandconsultantforandreceivedtravelsupportfromBoehringerIngelheimInternational,F.
Hoffmann-LaRoche,andNovartis;andreceivedhonorariaforanadjudicationcommitteefromGileadSciences;andhisspouseownsstocks,stockoptions,orotherownershipsinterestsinSano-AventisU.
S.
M.
K.
H.
servedasaspeakerandconsultantforandreceivedresearchsupportfromNovartisPharma;servedasaconsultantforAstraZeneca,BoehringerIngelheimInternational,GlaxoSmithKline,andSunovion;andservedasaspeakerforBoehringerIngelheimInternational.
S.
R.
J.
servedonanadvisorycommitteeforPzer,receivedresearchsupportfromLAMTherapeutics,andservedasaspeakerforNovartis.
S.
A.
S.
servedonasteeringcommitteeforInterMuneandservedasaclinicalinvestigatorforActelion,Arresto,Celgene,andGilead.
C.
S.
servedasaconsultantforAstraZenecaPharmaceuticals;servedonadatasafetyandmonitoringboardforArrowheadAMERICANTHORACICSOCIETYDOCUMENTS1346AmericanJournalofRespiratoryandCriticalCareMedicineVolume196Number10|November152017Pharmaceuticals;receivedresearchsupportfromAdverum,CSLBehring,Novartis,PulmonxCorporation,andShire;servedasaconsultant,onanadvisorycommittee,andreceivedresearchsupportfromBTGInternational;servedasaconsultantandreceivedresearchsupportfromGrifolsTherapeutics;andownsstocks,stockoptions,orotherownershipsinterestsinAbeona.
J.
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,T.
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,G.
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Smith,A.
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,K.
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,K.
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,andL.
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reportednorelationshipswithrelevantcommercialinterests.
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