内科学教学课件：Pulmonary Tuberculosis 1

PulmonaryTuberculosis

江德鹏：博士，副教授，副主任医师，硕士生导师，留美学者，重庆市中青年医学高端后备人才。2000年毕业于上海第二军医大学，本科毕业后于第三军医大学西南医院中心ICU从事重症监护工作6年，后调入重庆医科大学附属第二医院呼吸科工作，已从事临床工作15年，具有多学科工作经历，擅长呼吸危重症的救治。发表SCI论著4篇，CSCD核心论著10余篇，主持国家自然科学基金1项，其他基金2项。联系方式depengjiang@163.comDefinitionTuberculosisisachronicbacterialinfectioncausedbytuberclebacillusandcharacterizedbytheformationofgranulomasininfectedtissuesandbycell-mediatedhypersensitivity.

A

contagiousbacterialinfectioncausedbytuberclebacillus.Thelungsareprimarilyinvolved,buttheinfectioncanspreadtootherorgans.Itis

characterizedbythedevelopmentofgranulomaintheinfectedtissues.ThepatientswithTBoftenhavethefollowingsymptoms:toxemiasyptoms,cough,haemoptysisorbloodstreakedsputumEpidemiology

Oneoftheleadinginfectiousdiseasekillers.

Onethirdoftheworld'spopulationiscurrentlyinfectedwithTB.Everysecondanotherpersonisnewlyinfectedwithtuberculosisaroundtheworld.

Eachyearanestimated6-8millionpeopledevelopclinicaldisease.Eachyear

1.2-1.5millionpeopledieofTB.

Theincidenceoftuberculosishasdeclineddramaticallyindevelopedcountriesduetoimprovednutrition,housing,effectivedrugs,vaccines.Itremainsasaprobleminpoorercountries(about80%oftheworld)itsoverallincidenceisincreasingworldwidebecauseoftheenhancedsusceptibilityofAIDSpatientsandtheappearanceofdrugresistantstrains.EtiologyTuberclebacillusisarod-shaped,slow-growing,gram-negative,aerobicbacterium.Thecellwallhashighacidcontent,whichmakesithydrophobic,resistanttooralfluids.TheM.tuberculosiscomplex(MTBC)includesfourTB-causingmycobacteria:M.tuberculosisvar.hominis,M.bovis,M.africanum,andM.microti.M.africanumisnotwidespread,butitisasignificantcauseoftuberculosisinpartsofAfrica.M.boviswasonceacommoncauseoftuberculosis,buttheintroductionofpasteurizedmilkhaslargelyeliminatedthisasapublichealthproblemindevelopedcountries.Becauseofthesurfacelipids,thetuberclebacilluscannotbedecolorizedwithacidalcoholafterstaining.Heatandfuchsineareusuallynecessarytoaccomplishprimarystaining.SinceMTBretainscertainstainsevenafterbeingtreatedwithacidicsolution,itisclassifiedasanacid-fastbacillus(AFB).

Themostcommonacid-faststainingtechniquesaretheZiehl–Neelsenstain,whichdyesAFBsabrightredthatstandsoutclearlyagainstabluebackground.ThisisanacidfaststainofMTB.Thetuberclebacillusdividesevery16to20hours,whichisanextremelyslowratecomparedwithotherbacteria,whichusuallydivideinlessthananhour.M.Tuberculosisistransmittedfrompersontopersonviatherespiratoryroute.ThebacteriaareputintotheairwhenapersonwithTBofthelungscoughsorsneezes.Peoplenearbymaybreatheinthesebacteriaandbecomeinfected.Adequateventilationisthemostimportantmeasuretoreducetheinfectiousnessoftheenvironment.TransmissionPathogenesisInfectiontheinitialentryoftuberclebacilliintothepreviouslyuninfectedlungselicitsanonspecificacuteinflammatoryresponsewhichaccompaniedbyfewornosymptoms.bacilliaretheningestedbymacrophagesandtransportedtotheregionallymphnodes.

numerousacidfastorganismsgrowedwithinmacrophages.Lotsofbrightredrodsareseen,particularlyinmacrophages三种效应T细胞的产生效应分子示意图CD4+TCD8+TTh0Th1：细胞免疫IL-12Th2：辅助体液免疫IL-4APC、Th1Tc（CTL）：细胞毒作用分化：AgAg

Duringthe2-8weeksafterprimaryinfection,lymphocytesenterareasofinfection,wheretheyelaboratechemotacticfactors,interleukins,andlymphokies.Monocytesentertheareaandtransformintomacrophages.tuberculosisgranulomaiscomposedofepithelioidcellLanghanstypegiantcells

caseousnecrosis,andsurroundedbylyphocyte.pathology1.infiltration2.caseousnecrosis3.hyperplasia

granulomasareseenhere.Theyhaveroundedoutlines.TheonetowardthecenterofthephotographcontainsseveralLanghansgiantcells.Granulomasarecomposedoftransformedmacrophagescalledepithelioidcellsalongwithlymphocytes.Thelocalized,smallappearanceofthesegranulomassuggeststhattheimmuneresponseisfairlygood.

caseousnecrosis(characterizedbycompletelossoftissuestructureandatextureresemblingsoftcheese)canbeseeninthecenter.

Thisisanexampleoftuberculosis,youcanseegranulomas

ofthelung.Thepatternofsmallernoduleswhichhaveapropensityforupperlobe.

Oncloserinspection,thegranulomashaveareasofcaseousnecrosis.Thispatternofmultiplecaseatinggranulomasprimarilyintheupperlobesismostcharacteristicofsecondarytuberculosis.Thetransformationof

thepathologicalchanges

1.tohealabsorptionanddissipationFibrosisandcalcification2.TodeteriorateInfiltrationDissolutionanddisseminationClinicalfindingsSymptomsPhysicalexaminationRadiographicfeatures（补）LaboratoryFindingsImagingSymptomsConstitutionalsymptomsFatigueweightlosslowfevernightsweatsThesystemicfeaturesoftuberculosisincludefeverinapproximately35%to80%,malaise,andweightloss;theremaybeavarietyofhematologicabnormalities,especiallyleukocytosisandanemia.PulmonarysymptomsCoughHaemotysisChestpainDyspnea

Tuberculosisisaverycomplicateddisease.Theextentofdiseasevariesfromminimalinfiltratesthatproducenoclinicalillnessandthatarebarelydiscernibleonchestradiographstomassiveinvolvementwithextensivecavitationanddebilitatingconstitutionalandrespiratorysymptoms.

Withtheprogressionofpulmonarytuberculosis,thenormalpulmonaryarchitectureislost.fibrosis,volumelossandupwardcontractionaretypical.however,recentlydiseasedareasmayhealwithrealtivelylittledistructionwheneffectivechemotherapyisadminstered.

TheonsetmaynotbeaccompaniedbyanyoftheacutesignsbutmayappearinsidiouslyHowever,itisincorrecttoviewthisonsetasoneofslowprogression.Infact,pulmonarytuberculosisusuallyreachesitsfullextentwithinafewweeks.

Chroniccoughisprincipalrespiratorysymptom.sputumisusuallyscantandnonpurulent.Haemoptysisisfrequentandisusuallylimitedtobloodstreaking.sputum.massive,life-threateninghaemoptysisisrare.

SpecificsymptomAnaphylaxiaanergytuberculosis

PhysicalexaminationFindingsonphysicalexaminationofthelunginpatientswithpulmonarytuberculosisaretypicallyfewandgenerallycanbeappreciatedonlyinthepresenceofextensivedisease.Cracklesmaybeheardintheareaofinvolvement,alongwithbronchialbreathsounds,whenlungconsolidationisclosetothechestwall.Amphoricbreathsoundsmaybeindicativeofacavity.Findingssuchaslymphnodeenlargement,suggestiveofextrapulmonarytuberculosis,mayalsoindicateconcurrentpulmonaryinvolvementRadiographicfeatures

Radiographicexaminationofthechestiscommonlythefirstdiagnosticstudyundertaken,afterthehistoryandphysicalexamination.Themostfrequentsitesaretheapicalandposteriorsegmentsoftheupperlobeandthedorsalsegmentofthelowerlobe.However,inpatientswithHIVinfection,achestradiographmaybenormalinupto11%ofpatientswithpositivesputumcultures.LaboratoryFindings

1.Sputumsmearmicroscopy:ThefirststepinthediagnosticsequenceisnearlyalwaysstainingandexaminingreadilyavailablespecimensforAFB.However,thesensitivityofmicroscopicexaminationisrelativelylow.

Ziehl–NeelsenstainandKinyoun-stainedsmearsofsputum

Auraminefluorochromestainofsputumsmear

MycobacteriumtuberculosisWhenthelungisinvolved,sputumistheinitialspecimenofchoice.ifexpectoratedsputumisnotreadilyavailableforexamination,expectorationmaybeinducedorsamplesobtainedbyinduction2.MycobacterialCulture：Cultureinliquidmediaisconsideredthecurrentdiagnosticgoldstandard.Cultureisanessentialstepfordiagnosisandisnecessaryforphenotypicdrugsusceptibilitytesting.3.

SerologicTests：Severalantigens,includinghighlypurifiedandrecombinantantigensspecificforM.tuberculosiscomplex,havebeenusedinserologicantibodytestswithvariableresults.

4.Fiberopticbronchoscop:Bronchoscopyhasahighyieldinthediagnosisoftuberculosis.BronchoscopicprocedureshavebeenespeciallyhelpfulinthediagnosticevaluationsofpatientswithHIVinfectionwithnegativesputumsmearmicroscopy5.

Pleuralfluidcultures:Mtuberculosisarepositiveinlessthan25%.6.

Needlebiopsyofthepleura:patientswithpleuraleffusionscausedbyMtuberculosis.7.Susceptibilitytesting:thefirstisolateofMtuberculosis(whenatreatmentisfailing).8.

ELLISAANDPCRhasbeenusedtodianosis,buttheyarerareappliedsuccessfullyinroutineclinicaltreatment.SpecialexaminationTuberculinskintest

PPDtest:0.1mLofstandardpurifiedprotein(5TU)isinjectedintradermallyonthevolarsurfaceoftheforearm.Thetransversewidth(inmillimeters)oftheinduration(redspot)attheskintestsiteshouldberecordedafter48-72hours.

Allthepeoplesusceptibleto

tuberculousisshouldhavePPDtest:

1.Peoplewhohavehadcloseday-to-daycontact

withsomeonewhohasactiveTBdisease.(afamilymember,friend,orco-worker)·

2.

PeoplewhohassymptomsofTB,suchas:

acoughthathangson,

fever,

weightloss,nightsweats,constanttiredness,lossofappetite.

3.

PeoplewhohaveloweredimmunitysuchasHIVinfectionorcertainmedicalconditions.

4.PeoplewhoneedtogiveBCG

vaccine.PPDtest(induration)Thestandardofjudgement

48-72hskinnodediameter：PPDNegative-Positive+≧5mmpositive++≧10

mmPositive+++≧20

mm(orbleb)1.Negativereactiondoesnotruleoutthediagnosisoftuberculosis.2.False-negativereactionsoccur:①malnutrition；

②oldage；③immunologicorlymphoreticulardisorders（HIVinfection、Lymphoreticularmalignancies）；④corticosteroidorimmunosuppressivetherapy；chronicrenalfailure；⑤virusvaccinationsorinfections；⑥fulminanttuberculosis；⑦impropertestingtechnique；⑧problemswiththeantigen3.False-positivereactions:①inoculationwithBCGSpecialexaminationIFN-γreleaseassays(IGRAs)

IFN-γreleaseassays(IGRAs)areusedforthediagnosisoflatenttuberculousinfection(LTBI)，TwoIGRAsarecurrentlyapprovedintheUnitedStates,theQuantiFERON-TBtestandtheT-SPOT.TBtest

TheIGRAshaveseveraladvantages:Thetestscanbeperformedinonepatientvisit,theyaremorespecificinthepresenceofBCGvaccinationorinfectionwithnontuberculousmycobacteria,theyarenotsubjecttoreadervariability,andtheydonotstimulatewanedimmunity(theboosterreaction,describedearlier).1.TheQuantiFERON-TBtests：measuretheamountofIFN-γreleasedfromsensitizedlymphocytesinwholebloodincubatedovernightwithmixturesofM.tuberculosisantigens,ESAT-6andCFP-10.2.TheT-SPOT-TBtests：utilizesanELISPOTformattoquantifythenumberofcellsinperipheralbloodthatsecreteIFN-γwhenstimulatedwithESAT-6andCFP-10Clinicalclassification1.Primarytuberculosis2.hematogenouspulmonarytuberculosis

3.secondarypulmonarytuberculosisinfiltrativeTBcavitaryTBtuberculomacaseouspneumoniafibrocavitaryTB4.tuberculouspleurisy5.extrapulmonarytuberculosis肺结核病自然过程示意图

thecombinationofperipherallunglesion,lymphangitisandhilarlymphnode.Thereisasmalltan-yellowsubpleuralgranulomainthemid-lungfieldontheright.Inthehilumisasmallyellowtangranulomainahilarlymphnode.Primarytuberculosis

TheGhoncomplexisseenhereatcloserrange.Primarytuberculosisisthepatternseenwithinitialinfectionwithtuberculosisinchildren.Reactivation,orsecondarytuberculosis,ismoretypicallyseeninadults.Usuallyasymptomatic.AnonspecificpneumoniaHilarlymphnodeenlargementBronchialobstruction(Segmentalatelectasis)Pleuraleffusionmaybepresent

Smallhomogeneousinfiltrates(usuallyintheupperlobe)HilarandparatracheallymphnodeenlargementhematogenouspulmonarytuberculosisInthepast,hematogenousTBoccurredchieflyininfantsandadolescentespeciallyinthepeoplewithlowimmunefunction.Currently,however,exceptamongHIV-infectedpersons,itismorecommonamongolderpersons,asaresultofendogenousreactivationandbloodstreaminvasion.SeveretoxemiasymptomsDyspneaisrare

Uniformsize,densitydistributionthebilateral,diffusesmallgranulomasoftencontainnumerousmycobacteriumInfiltrativetuberculosisTheusuallocation:apicalorposteriorsegmentsoftheupperlobes;dorsalsegmentsofthelowerlobes.Variousradiographicmanifestations:

fibrocavity-nodules-infiltratesTheTBlesionoftenlocatesatposteriororapicalsegmentoftheupperlobeorthesuperiorsegmentofthelowerlobe,especiallyattheapexoflungjustasthepicturepointsout.

Caseousnecrosis

bilateral

upperinfiltrates

Whenthereisextensivecaseationandthegranulomasinvolvealargerbronchus,itispossibleformuchofthesoft,necroticcentertodrainoutandleavebehindacavity.Cavitationistypicalforlargegranulomaswithtuberculosis.Cavitationismorecommonintheupperlobes.cavitarytuberculosisPulmonarycavitiesmaypersisteventhougheffectivechemotherapyhasresultedinapparentcure.cavities,aspergillomainachronictuberculouscavinandbronchiectasisisthecommonreasonhaemoptysis.Pulmonarycavitiesmaypersisteventhougheffectivechemotherapyhasresultedinapparentcure.

Rightupperlobecavitywithabcessformationtuberculoma

Satellitelisionsdevelopconcomitantly.theycanusuallyberecognizedonchestX-rayfilmsandareoftenhelpfulindistinguishingtuberculosisfrompulmonaryneoplasms.

caseouspneumonia

FibrocavitaryTB

Cavitiesmaybesourceofmajorhemoptysis,especiallyinthepresenceofcontinuedactivedisease.persistentterminalpulmonaryarterieswithincavtiesmaybeasourceofprofoundbleeding.Extensivedestruction:widespreadcavitation,fibrosisscarsWiththeprogressionofpulmonaryTB,thenormalpulmonaryarchitectureislost.fibrosis,volumeloss,andupwardcontractionaretypical.pleuraltuberculosisPleuraleffusionoftenappearsinpleuraltuberculosis.presenceoffluidbetweenthevisceralandparietalpleura.Itcanbeseenwhen>300ml

offluidispresentonachest

radiograph.

AstuberculosisbecomesinactiveorHeals,fibroticscarringbecomesapparentonthechestradiograph.

Fibroticlessionsmaydevelopcalcifications.TheactivityoftuberculosismaybejudgedfromCT.ItisneverwisetojudgetuberculosistobeinactiveonlyontheXrayfilm.Diagnosis

1.ThediagnosisoflatentTBinfection(LTBI)LTBIisoneofexclusion,basedonthefindingofdelayed-typehypersensitivity(DTH)andtheabsenceofactiveTB.IFN-γreleaseassays(IGRAs)andtuberculinskintest(TST)areusedforthediagnosisoflatenttuberculousinfection(LTBI)

2.DiagnosisofPulmonary

tuberculosis

Historyand

clinicalsymptoms:fatigue,weightloss,fever,nightsweats,cough,orbloodsputumPulmonaryinfiltratesonchestradiograph,mostoftenapical.Positivetuberculinskintestreaction(mostcases).Acid-fastbacillionsmearofsputumorsputumculturepositiveforMycobactenumtuberculosis.TreatmentAllprovedcasesshouldbereportedtolocalpublichealthdepartments.(CDC)Treatmentofpatientsshouldbeconductedbyskillfulphysicians.PayattentiontoimprovenutritionHospitalizationnotnecessaryinmostpatients.Hospitalizedpatientswithactivediseaserequireaprivateroomwithappropriateventilationuntiltheybecomesputumsmear-negativeforacid-fastbacilli.(一)Drugtherapy

Tuberculosisrequiresearly,regular,long-timetreatmentwithacombinationofspecialandappropriatedrugs.

1.AntituberculosisdrugsFirst-linedrugs

Second-linedrugsIsoniazid(INH)Kanamycin(KM)Rifampin(RFP)Paminosalacylicacid(PAS)Pyrazinamide(PZA)Amikacin(AM)Ethambutol(EMB)Capreomycin(C)Streptomycin(SM)

Tuberculouspatientsexitsinthreepools:ametabolicallyactiveextracellularpoolandrelativelymetabolicallyinactiveintracellularandnecroticcaseumpools.RifapinandisoniazidarebactericideforextracellularandintracellularpoolsTB.Streptomycinisbactericideagainstextracellularandpyrazinamideareagainstintracellularorganisms.

isoniazidIsoniazidhavebeenusedclinicallyfor50years.ItisthemostefficientbactericideforTB,especialintheearlydays.isoniazidisbactericideforextracellularandintracellularpoolsTB.Isoniazidcancrosstheblood-brainbarrier(tubercularmeningitis)

Sideeffect:drughepatitis,peripheralneuritis.VataminB6canbeusedasthetreatmentofperipheralneuritiscausedbyisoniazid,butitwillalsoalleviatetheeffectofisoniazid.sotherearenogoodsolutiontopreventtheperipheralneuritis.Isoniazidisalsotheonlychoicetopreventthetuberculosis.RifampinisoniazidisbactericidalforextracellularandintracellularpoolsTB.ItisalsothemostpowerfuldruginthetreatmentofTB.Sideeffect:drughepatitis,gastroentericreaction

pyrazimidepyrazinamideareagainstintracellularorganisms.Pyrazimidehasbeenfoundtobepaticularlyusefulduringthefirst2monthsoftreatment.Pyrazimidecancrosstheblood-brainbarrierSideeffect:drughepatitis,hyperuricemia(arthralgia)ethambutolEthambutolisonlybacteriostatic.Sideeffect:opticneuritis(monitorvisionandfieldofview)StreptomycinStreptomycinisbactericideagainstextracellularSideeffect:ototoxicity,nephrotoxicity(creatinine

ureanitrogen)

TreatmentforTBusesantibioticstokillthebacteria.Thethreeantibioticsmostcommonlyusedarerifampicin,isoniazidandethambutol.TBrequiresmuchlongerperiodsoftreatment(around6to12months)toentirelyeliminatemycobacteriafromthebody.Therecommendedbasictreatmentregimenforpreviouslyuntreatedpatientswithpulmonarytuberculosisconsistsofaninitial(orintensive)phaseofisoniazid,rifampin,pyrazinamide,andethambutolgivenfor2months,followedbya4-monthcontinuationphaseofisoniazidandrifampin.Theinitialphaserapidlyreducesthebacterialburden,bykillingtheactivelygrowingbacteria,whilethecontinuationphaseisprotractedandintendedtoeliminatethesubpopulationofbacteriathatarereplicatingmoreslowly.Thechoiceofregimenforthecontinuationphasedependson3factors:1)thepresenceorabsenceofcavitationontheinitialchestradiograph2)theculturestatusatthecomp