Populationff

FibroblasticFociinUsualInterstitialPneumoniaIdiopathicversusCollagenVascularDiseaseKevinR.
Flaherty,ThomasV.
Colby,WilliamD.
Travis,GalenB.
Toews,JeanetteMumford,SusanMurray,VictorJ.
Thannickal,EllaA.
Kazerooni,BarryH.
Gross,JosephP.
LynchIII,andFernandoJ.
MartinezDepartmentofRadiology,DivisionofPulmonaryandCriticalCareMedicine,UniversityofMichiganHealthSystem,AnnArbor,Michigan;ArmedForcesInstituteofPathology,Washington,DC;MayoClinic,Scottsdale,Arizona;andDepartmentofBiostatistics,UniversityofMichiganSchoolofPublicHealth,AnnArbor,MichiganAhistologicfeatureofusualinterstitialpneumoniaisthepresencegatorshavenotedaprognosticvalueofquantifyingbro-offibroblasticfoci.
Assomepatientswithusualinterstitialpneumo-blasticfoci(FF)inpatientswithidiopathicinterstitialpneu-niaandanunderlyingcollagenvasculardiseasehaveabetterprog-monia(19,20).
Furthermore,severalgroupshavesuggestednosis,wehypothesizedthattheywouldhavefewerfibroblasticfoci.
differencesinthealveolarmicroenvironmentandbroblastPathologistsreviewedsurgicallungbiopsiesfrom108patientswithphenotypebetweenpatientswithidiopathicandcollagen-usualinterstitialpneumonia(ninewithcollagenvasculardisease)vascularassociatedpulmonarybrosis(21–24).
Wehypothe-andassignedascore(absent0,mild1,moderate2,andmarkedsizedthatpatientswithCVD-associatedUIPwouldhavean3)forfibroblasticfoci.
Patientswithidiopathicusualinterstitialimprovedsurvivalcomparedwithpatientswithidiopathicpneumoniahadahighermedianprofusionoffibroblasticfoci(1.
75UIPandthatthisimprovedsurvivalwouldcorrelatewithvs.
1.
0,p0.
003).
Baselinecharacteristicsweresimilar,althoughtheprofusionofFF.
patientswithacollagenvasculardiseasewereyounger,hadashorterdurationofsymptoms,andhadahigherpercentageofMETHODSpredictedtotallungcapacity.
ProfusionoffibroblasticfociwasthemostdiscriminativefeatureforseparatingidiopathicfromcollagenPatientRecruitmentandTherapyvasculardisease–associatedusualinterstitialpneumonia(oddsratioThisstudyusedinformationfromtheUniversityofMichiganSpecial-8.
31;95%confidenceinterval,1.
98,59.
42;p0.
002foraone-izedCenterofResearchinthePathobiologyofFibroticLungDiseaseunitincreaseinfibroblasticfociscore).
Nodeathswerenotedinthedatabase.
Patientswerereferredforenrollmentinstudyprotocolsforcollagenvasculardisease–associatedusualinterstitialpneumoniasuspectedIPFandunderwentsurgicallungbiopsybetweenOctobergroup;52deathsoccurredintheidiopathicusualinterstitialpneu-1989andFebruary2000.
Inthesepatients,asuspicionofIPFwasbasedmoniagroup(logrank;p0.
005).
Weconcludethatpatientswithonsymptoms,physiologicabnormalities,andradiographicndings(3).
collagenvasculardisease–associatedusualinterstitialpneumoniaPatientswereexcludediftheywerefoundtohaveadiseaseotherhavefewerfibroblasticfociandimprovedsurvival.
thanIPFduringtheenrollmentevaluation.
Diseasesthatwereexclusion-aryincludedpneumoconiosis,sarcoidosis,carcinoma,lymphoma,Langer-Keywords:idiopathicpulmonaryfibrosis;usualinterstitialpneumonia;han'scellhistiocytosis,andlymphangioleiomyomatosis.
Thestudywasnonspecificinterstitialpneumonia;fibroblasticfocusapprovedbytheinstitutionalreviewboardattheUniversityofMichigan.
PatientswithpulmonarybrosisassociatedwithacollagenPathologicAssessmentvasculardisease(CVD)haveanimprovedprognosiscom-Twopathologists(T.
V.
C.
andW.
D.
T.
)reviewedsurgicallungbiopsyparedwithpatientswithidiopathicpulmonarybrosis(IPF)slidesduringthreereviewsessionsbetweenMarch1999andFebruary(1,2).
Recently,anAmericanThoracicSocietystatement2000.
ThepathologistsassignedadiagnosisofUIP,nonspecicintersti-concludedthatIPFshouldreectonlythehistologicpicturetialpneumonia(NSIP),respiratorybronchiolitisinterstitiallungdis-ofusualinterstitialpneumonia(UIP)andexcludepatientsease/desquamativeinterstitialpneumonia,orother(4,11,25).
OnlywithassociatedCVD,thusmakingIPFamorehomogeneouspatientswithUIPwereincludedinthisstudy.
TheprofusionofFFforeachlobewasscoredsemiquantitativelyas0–3(absent0,mild1,groupwithaworseprognosisthanpreviouslydescribed(3,moderate2,andmarked3)byeachpathologist(Figures1A–1C).
A4).
HistologicpatternsotherthanUIPhavebeennotedwithmeanFFscoreforeachpatientwascalculatedbyaveragingtheFFgreaterfrequencyinCVD-associatedinterstitiallungdiseasescorefromeachlobe.
AmaximalFFscorewasrecordedasthehighest(5–10).
Assuch,theimprovedprognosisforpatientswithFFscoreforanylobe.
ThemeanFFscoreforpatientswithidiopathicCVD-associatedinterstitiallungdiseasehasbeenfelt,poten-discordantUIPversusidiopathicconcordantUIP(26)wascompared.
tially,torelatetoanincreasedfrequencyofalternativehisto-FewpatientswithCVDhadabiopsyinmultiplelobes,whichprecludedlogiccategories.
theevaluationofhistologicvariabilityinthisgroupofpatients.
Patho-Recentstudieshaveemphasizedtheimportanceofthelogicscoreswerealsoevaluated(T.
V.
C.
)usingotherpublishedscoringbroblasticfocus,amanifestationofongoinglunginjuryinsystemsforFF(20,27),interstitialmononuclearcellinltrate(MC),patientswithestablishedbrosis(EF)(11–20).
Someinvesti-EF,andintra-alveolarmacrophages(20).
PhysiologicAssessmentPhysiologicassessmentwasperformedbeforesurgicallungbiopsyandbeforetheinitiationoftherapy.
Pulmonaryfunctiontests,including(ReceivedinoriginalformApril26,2002;acceptedinfinalformFebruary14,2003)spirometry,lungvolumes,anddiffusioncapacityforcarbonmonoxide,SupportedinpartbyNationalInstitutesofHealthNationalHeart,Lung,andBloodwereperformed(28).
Institutegrant#P50HL46487,NIH/NCRR3MO1RR00042–33S3,NIH/NIAP60AG08808–06,NHLBI1K24HL04212,and1K23HL68713.
High-ResolutionComputedTomographyProtocolCorrespondenceandrequestsforreprintsshouldbeaddressedtoFernandoJ.
High-resolutioncomputedtomography(HRCT)examinationswereMartinez,M.
D.
,3916TaubmanCenter,1500EastMedicalCenterDrive,Annperformedwith1.
0-or1.
5-mmthicksectionstakenat1-cmintervalsArbor,MI48109–0360.
E-mail:fmartine@umich.
eduthroughouttheentirelungsduringinspirationinthesupinepositionAmJRespirCritCareMedVol167.
pp1410–1415,2003andthroughthecaudal10cmofthelungsat2-to3-cmincrementsinOriginallyPublishedinPressasDOI:10.
1164/rccm.
200204-373OConFebruary20,2003Internetaddress:www.
atsjournals.
orgtheproneposition.
Twothoracicradiologists(E.
A.
K.
andB.
H.
G.
)Flaherty,Colby,Travis,etal.
:ProfusionofFibroblasticFoci1411prospectivelyandindependentlyscoredalllobesonHRCTforgroundglassopacity(CT-alv)andinterstitialopacity(CT-b)onascaleof0–5asdescribedpreviously(28,29).
TheradiologistswerealsoaskedtogiveanHRCTdiagnosisofUIP,indeterminate(equalprobabilityofUIPandNSIP),orNSIP(30).
Theradiologistswereunawareofthehistologicdiagnosisatthetimeofinterpretation.
StatisticalAnalysisCategoricaldatawerecomparedbetweenpatientswithidiopathicUIPandCVD-associatedUIPusingFisher'sexacttests(31),andcontinuousdatawerecomparedusingWilcoxonrank-sumtests(32).
Nonparamet-rictestswereusedbecauseofthesmallnumberofpatientsintheCVD-associatedUIPgroup.
BecausetheWilcoxonrank-sumtestisdesignedtodetectmediandifferences,continuousbaselinecharacteristicsaresummarizedusingmedianvalueswithranges.
Theoverallsurvivalexpe-rienceforeachgroupofpatientswasestimatedusingKaplan–Meiercurves(33).
ThelackofdeathsintheCVD-associatedUIPgroupprecludedtheuseofCoxregressionanalysistoevaluatethepotentialimpactofbaselinefactorsonsurvivalinthisgroup(34).
ToevaluatewhetherbaselinedifferencesbetweenpatientswithidiopathicUIPandCVD-associatedUIPaccountedfordifferencesinsurvival,stratiedlog-rankanalyseswereperformedacrossvariablesthatweredifferentatbaseline.
Tertileswereusedtostratifyonageandpercentagepre-dictedtotallungcapacity(TLC);themediantimebeforebiopsywasusedasacutoffforthestrataofonsetofsymptoms.
Stuart'sTau-cstatisticswereusedtocomparethedifferentscoringsystemsofFF.
Inaddition,logisticregressionwasusedtoexaminerelationshipsbetweenthepresence/absenceofCVDandothervariables(35).
RESULTSPatientPopulationDuringthestudyperiod,99patientswithidiopathicUIPand9withCVD-associatedUIPwereidentied.
Fiveadditionalpa-tientswithhistologicNSIPincombinationwithCVDthatarenotincludedinthisresearchwereevaluatedduringthesametimeperiod.
TheassociateddiagnosesintheCVD-associatedUIPpatientswererheumatoidarthritis(n4),polymyositis(n2),mixedconnectivetissuedisease(n1),systemiclupuserythematosis(n1),andsystemicsclerosis(n1).
BaselineCharacteristicsPatientswithidiopathicUIPhadahigherprofusionofFFcom-paredwithpatientswithUIPassociatedwithCVD(Figure2andTable1)wheneitherthemeanFFprofusion(p0.
003)ormaximalFFprofusionwasexamined(p0.
0004).
ThelevelofagreementforFFscoresbetweenpathologistswasexcellent,withstatisticsrangingfrom0.
81–1.
0withineachlobe.
Baselinedemographic,physiologic,andHRCTcharacteristicsweresimi-lar,althoughpatientswithCVD-associatedUIPwereyounger,hadashorterdurationofsymptoms,andhadahigherpercentageofpredictedTLC(Table1).
InpatientswithCVD-associatedUIP,theHRCTdiagnosiswascompatiblewithNSIPin67%ofthepatientscomparedwithUIPin33%.
Therewerenootherunique/discriminatoryndingsnotedontheHRCTscansfromthepatientswithCVD-associatedUIP.
PatientswithidiopathicdiscordantUIPhadalowermedianprofusionofFFcomparedwithpatientswithidiopathicconcordantUIP(1.
3[0.
3,2.
5]versus2[0.
5,3.
0],p0.
0005,Wilcoxonranksumtest).
AlackofmultiplelobebiopsiesforpatientswithCVD-associatedUIPprecludedasimilaranalysisinthesepatients.
AssociationsBetweenScoringSystemsFigure1.
(A–C)RepresentativephotomicrographsfromhistopathologicAssociationsbetweenthethreepathologicscoringsystemsforsectionsofsurgicallungbiopsyspecimensfrompatientswithaFFscoreFFwerepositiveforeachtwo-waycomparison.
Apositiverela-of1(mild,A),2(moderate,B),and3(marked,C).
tionshipwasfoundinthecomparisonoftheBromptonFFmethod(20)andourmethod(0.
56,95%condenceinterval[CI],0.
46–0.
67),theDenverFFmethod(27)andourmethod1412AMERICANJOURNALOFRESPIRATORYANDCRITICALCAREMEDICINEVOL1672003(0.
55,95%CI,0.
43–0.
66),andtheBromptonFFandDenverFFmethods(0.
48,95%CI,0.
36–0.
60).
AssociationofBaselineCharacteristicsWithCVDThemeanFFandmaxFFwerethemostdiscriminativebaselinefeaturesforseparatingidiopathicUIPfromCVD-associatedUIP.
Inunivariateanalysis(Table2),theoddsratioofhavingidiopathicUIPcomparedwithUIPassociatedwithaCVDwas8.
31foraunitincreaseinmeanFFscore(95%CI,1.
98,59.
42;p0.
002)and16.
99higherforaunitincreaseinmaxFFscore(95%CI,3.
28,316;p0.
0001).
TheresultsweresimilarfortheBromptonFFmethod(oddsratio3.
23;95%CI1.
17,15.
4;p0.
02)andtheDenverFFmethod(oddsratio1.
87;95%CI,0.
89,5.
03;p0.
10),althoughtheseassociationswerelessextremeinmagnitudeandstatisticalsignicance.
MeanFFremainedsignicantormarginallysignicantwhenaddedtoamodelcon-tainingageatbiopsy(likelihoodratiopvalue0.
005)oronsetofsymptoms(likelihoodratiopvalue0.
065)orTLCpercentagepredicted(likelihoodratiopvalue0.
003).
Models,includingotherpathologicfeatures(MC,EF,intra-alveolarmacrophages),FEV1,FVC,diffusioncapacityforcarbonmonoxide,andHRCTFigure2.
DotplotsshowingthemeanFFscoreforeachlobeevaluatedinterstitialoralveolarvalues,werenotstatisticallysignicant.
frompatientswithidiopathicUIPorCVD-associatedUIP.
ThemedianSurvivalprofusionofFFwasgreaterinthelobesfrompatientswithidiopathicUIPcomparedwiththosewithCVD-associatedUIP(median[range]2PatientswithCVD-associatedUIPhadanimprovedsurvivalcom-[0,3]versus1[0,2];p0.
003;Wilcoxonranksumtest).
paredwithpatientswithidiopathicUIP(Figure3).
NodeathswerenotedintheCVD-associatedUIPgroupduringamedianfollow-upof3.
5years(95%CI2.
5,∞).
Thissurvivaladvantagewasinmarkedcontrasttothe52deaths(53%)intheidiopathicTABLE1.
BASELINECHARACTERISTICSFORPATIENTSWITHIDIOPATHICUSUALINTERSTITIALPNEUMONIAANDPATIENTSWITHCOLLAGENVASCULARDISEASE–ASSOCIATEDUSUALINTERSTITIALPNEUMONIAIdiopathicUIPCVDUIPpValueCharacteristicMedian(Range)Median(Range)Fisher'sExactSex,male/female46/536/30.
31Ageatbiopsy,yr62(26,78)54(34,71)0.
02Symptomonset,yr2.
0(0.
1,20.
0)0.
5(0.
3,2.
0)0.
01Packsperdayyears(pack-years)10(0,100)0(0,50)0.
30FibroblasticfociMeanoflobes1.
75(0.
3,3.
0)1.
0(0.
7,2)0.
003Maxinanylobe2(1,3)1(1,2)0.
0004BFF2.
3(1,6)1.
3(1,3)0.
02DFF2.
1(0,7)1.
3(0,3)0.
17OtherpathologicfeaturesEstablishedfibrosis(20)3.
7(1.
3,5)2.
7(2,4)0.
10Mononuclearcellinfiltrate(20)2.
5(0.
5,6)2.
8(2,4)0.
12Intra-alveolarmacrophages(20)2.
3(1,5.
3)1.
5(1,5.
3)0.
35SpirometryFVC,L2.
18(0.
81,5.
57)2.
35(1.
46,5.
05)0.
39FVC,percentagepredicted61(23,114)68(39,109)0.
20FEV1,L1.
76(0.
71,4.
37)2.
01(1.
18,3.
09)0.
51FEV1,%predicted68(26,131)73(41,94)0.
78LungvolumeTLC,L3.
65(2.
12,7.
80)4.
52(3.
32,9.
12)0.
08TLC,%predicted72(42,121)92(69,135)0.
04GasexchangeDLCO,ml/min/mmHg11.
3(3.
42,25.
9)13.
29(6.
97,19.
33)0.
11DLCO,%predicted45(13,89)61(29,66)0.
14HRCTAlveolar(CT-Alv)1.
65(0.
5,4.
2)1.
75(0.
8,3.
2)1.
0Interstitial(CT-Fib)1.
9(0,3.
6)1.
65(0.
7,3.
6)0.
68Definitionofabbreviations:BFFBromptonfibroblasticfociscoringmethod(20);CVDcollagenvasculardisease;DFFDenverfibroblasticfociscoringmethod(27);DLCOdiffusingcapacityforcarbonmonoxide;HRCThigh-resolutioncomputedtomography;TLCtotallungcapacity;UIPusualinterstitialpneumonia.
Flaherty,Colby,Travis,etal.
:ProfusionofFibroblasticFoci1413TABLE3.
UNIVARIATECOXPROPORTIONALHAZARDTABLE2.
UNIVARIATELOGISTICREGRESSIONPREDICTINGTHEPRESENCEOFIDIOPATHICUSUALINTERSTITIALMODELSEXAMININGTHEEFFECTOFPATHOLOGICFEATURESONSURVIVALPNEUMONIACOMPAREDWITHCOLLAGENVASCULARDISEASE–ASSOCIATEDUSUALINTERSTITIALPNEUMONIAHRPredictor(95%CI)pValuePredictorOddsRatio95%CI*pValue*Ageatbiopsy,yr1.
06(1.
00,1.
12)0.
048AllpatientsMeanfibroblasticfoci*1.
62(1.
08,2.
44)0.
02Meanfibroblasticfociscoreoflobes8.
31(1.
98,59.
42)0.
002Maxfibroblasticfociscoreoflobes16.
99(3.
28,316)0.
0001Maxfibroblasticfoci*1.
61(1.
05,2.
47)0.
03DFF1.
21(0.
97,1.
51)0.
09Symptomonset,years2.
9(1.
3,11.
9)0.
004TLC,%predicted0.
95(0.
90,0.
99)0.
011BFF1.
31(1.
04,1.
66)0.
02Mononuclearcellinfiltrate0.
90(0.
63,1.
28)0.
06DFF1.
87(0.
89,5.
03)0.
10BFF3.
23(1.
17,15.
4)0.
02Establishedfibrosis1.
54(1.
04,2.
28)0.
03Intra-alveolarmacrophages1.
01(0.
77,1.
33)0.
93Mononuclearcellinfiltrate0.
53(0.
21,1.
20)0.
12Establishedfibrosis2.
03(0.
83,5.
6)0.
12OnlyidiopathicUIPpatientsMeanfibroblasticfoci*1.
33(0.
86,2.
05)0.
20Intra-alveolarmacrophages1.
18(0.
56,3.
01)0.
68Maxfibroblasticfoci*1.
23(0.
78,1.
94)0.
38Definitionofabbreviations:BFFBromptonfibroblasticfociscoringsystem(20);DFF1.
11(0.
87,1.
41)0.
39CIconfidenceinterval;DFFDenverfibroblasticfociscoringsystem(27);TLCBFF1.
21(0.
95,1.
54)0.
13totallungcapacity.
Mononuclearcellinfiltrate0.
97(0.
69,1.
37)0.
87*Confidenceintervalsandpvaluesbasedonlikelihoodratiotest.
Establishedfibrosis1.
3(0.
88,1.
93)0.
19AsdescribedbyNicholsonandcolleagues(20).
Intra-alveolarmacrophages1.
02(0.
76,1.
35)0.
91Definitionofabbreviations:BFFbromptonfibroblasticfociscoringsystem(20);CIconfidenceinterval;DFFDenverfibroblasticfociscoringsystem(27);HRhazardratio;UIPusualinterstitialpneumonia.
UIPgroup(logrankp0.
005),wherethemediansurvivalwas*FibroblasticfociscoreasdescribedinMETHODS.
2.
7years(95%CI,2.
4,5.
1).
ToaccountforbaselinedifferencesAsdescribedbyNicholsonandcolleagues(20).
inage,percentagepredictedTLCandonsetofsymptomsstrati-edlog-rankanalyseswereusedtocomparesurvivalbetweenthetwodiseasegroups.
ImprovedsurvivalforpatientswithCVD-associatedUIPwasconrmedinallstratiedanalyses,withpprofusionofFFbetweenpatientswithidiopathicUIPandCVD-valuesof0.
006,0.
05,and0.
04forage,percentagepredictedTLC,associatedUIP.
Infact,theprofusionofFFwasthemostdiscrim-andonsetofsymptoms,respectively.
WhenallpatientswereinativebaselinefeaturebetweenidiopathicandCVD-associatedanalyzedasagroupinunivariatemodels,theprofusionofFFUIP,asidentiedbylogisticregression.
ThemagnitudeofthisandtheamountofEFwereassociatedwithsurvival(Table3).
differencepersistedevenwhenaccountingfordemographic,ThismaybeaconsequenceofFFactingasasurrogateforthephysiologic,andradiographicfeatures.
Thisiscontrasttothepresence/absenceofCVD;whenonlyidiopathicUIPpatientsresultsofothers(24)andmayreectdifferencesinthepatientwereevaluated,nopathologicfeaturewasassociatedwithsur-population,histopathologicclassication,orthescoringsystemsvival.
ThelackofdeathsintheCVD-associatedUIPgroupusedforprofusionofFF.
Severalpatientspreviouslyclassiedprecludedtheanalysisofthisgroupindependently.
asUIPhavebeenreclassiedasNSIPafteranotherreviewusingthelatesthistopathologiccriteria(4,11,25).
RecentdatasuggestsDISCUSSIONthatahistologicpictureofNSIPisfrequentlyidentiedinpatientswithCVD(5–10).
Inaddition,NSIPappearstobeInthisstudy,weidentiedalowerprofusionofFFinpatientsassociatedwithanimprovedprognosis(7,26,36–40).
ToensurewithCVD-associatedUIPcomparedwithpatientswithidio-accuratehistopathologicclassication,thehistologicsamplespathicUIP.
WealsoconrmanimprovedsurvivalforpatientsfromeachorourpatientswerefelttorepresentthehistologicwithCVD-associatedUIP.
patternofUIPwhenreviewedindependentlybytwoexpertAnovelfeatureofthisstudyisthemarkeddifferenceinthepulmonarypathologists(W.
T.
andT.
C.
)usingthelatestdiagnos-ticcriteria(4,11,25).
ThedifferentialprofusionofFFdespiteasimilaramountofbrosisonHRCTsuggeststhattheunderlyingpathogenesisofbrosisinthesediseasesmaybedistinctlydifferent.
IdiopathicUIPisadiseasethatislocalizedtothelungparenchyma.
ThisobservationhasledtothesuggestionthattheetiologicagentinUIPmightrepresentanunidentiedinhaledantigen.
CVDsaresystemicillnessesthatarecharacterizedbytheinvolvementofmultipleorgansystemssuggestingthattheetiologicagentmightrepresentacirculating"autoantigen.
"Thus,onemightspeculatethattheformationofFFinUIPispromotedbyinitialinjurytothealveolarepitheliumversusthevascularendothelium.
Indeed,UIPhasbeenrecentlycharacterizedasan"epithelial-broblasticdisease"inwhichinammationplaysonlyaminorrole(41).
ImprovedsurvivalwasnotedforpatientswithCVD-associ-atedUIPcomparedwithpatientswithidiopathicUIP.
Theim-provedsurvivalforpatientswithCVD-associatedUIPmayberelatedtoeitherthedecreasedprofusion,orperhapsdifferen-tialfunction,oftheFF.
MorphologicstudieshavesuggestedbroblastsplayanactiveroleintheremodelingofthelunginFigure3.
Kaplan-MeiersurvivalcurvesinpatientswithCVDUIP(dashedline)andidiopathicUIP(solidline;log-ranktest,p0.
005).
pulmonarybrosis(13,16),andincreasingdatasuggestthat1414AMERICANJOURNALOFRESPIRATORYANDCRITICALCAREMEDICINEVOL1672003thebroblasticfocusrepresentsasiteofactive,ongoinginjuryAlimitationofthisstudyisthesmallnumberofpatientswithaddingtotheEF(11,13–17,38,41).
Severalauthorshavesug-CVD-associatedUIP.
Thismaybeduetomorepatientswithgestedthatdifferencesinbroblastfunctionandcytokinepro-CVDhavingotherhistologicpatternssuchasNSIP(5–10)oralesexistinpatientswithCVD(22,23,42–44).
Althoughourdecreasedtendencytoperformasurgicallungbiopsyinthesestudydidnotdirectlyaddressthephenotypeofthebroblastspatients.
TheoverallsimilarityofphysiologicandradiographiccontainedinFF,itclearlydemonstratesthatincreasedprofusioncharacteristicsforthepatientsinthisstudyarguesagainstaofFFinidiopathicUIPisassociatedwithapoorerprognosissignicantselectionbiasinselectingpatientsforbiopsy.
ThewhencomparedwithCVD-associatedUIP.
strikingresults,evenwithasmallsamplesize,alsoarguethatSeveralscoringsystemsforFFhavebeendescribed(19,20).
genuinedifferencesexistforpatientswithahistologicpatternWedemonstrateamoderatecorrelationbetweenthesemethods.
ofUIPwith,versuswithout,anassociatedCVD.
FuturestudiesUnlikeotherreports(19,20),wedidnotndtheprofusionofarerequiredtoclarifytheroleofFFinthepathogenesisofUIP.
FF,byanymethod,tobeasignicantpredictorofsurvivalforInsummary,wehaveshownthatpatientswithCVD-associ-patientswithidiopathicUIP.
ThismayreectsubtledifferencesatedUIPhaveamarkedlyimprovedsurvivalcomparedwithininclusioncriteria.
AdifferentialapplicationofthescoringpatientswithidiopathicUIP.
Furthermore,patientswithCVD-systemsisalsopossiblebutseemslesslikelygiventhatthesameassociatedUIPhaveadecreasedprofusionofFFcomparedwithpathologist(T.
V.
C.
)participatedinallstudies.
FurtherstudiespatientswithidiopathicUIP.
areneededtodenetheimportanceofandoptimalwaytoscoretheprofusionofFF.
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