Drug tx of Pulmonary TB 09/10/07 3rd medical year Pharmacology.
GAFFI Fact Sheet TB and its sequela chronic pulmonary … · 2019. 9. 4. · When pulmonary TB is...
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GAFFI Fact Sheet TB and its sequela chronic pulmonary aspergillosis (CPA) Summary CPA is a slowly destructive lung infection, with marked systemic features (weight loss, fatigue) and pulmonary features (productive cough, haemoptysis, breathlessness) almost indistinguishable from TB. CPA presents like ‘smear negative TB’. It usually follows a pulmonary insult, especially TB, sarcoidosis, pneumothorax and emphysema/COPD). Most patients are not immunocompromised, although HIV infection may be present. Some patients have subtle immune defects including reduced natural killer, T helper and/or B cells and sometimes reduced gamma interferon or interleukin 12 production. Rates of progression vary, but worsening symptoms and lung destruction or fibrosis occur over many months or years. The key diagnostic features are cavitary lung lesions on radiology, sometimes containing a fungal ball (aspergilloma) and elevated serum Aspergillus antibody. A simple aspergilloma (<10% of cases) is best surgically removed. Antifungal therapy is effective at controlling symptoms and progression in about 60% of patients. Untreated mortality is 75-80% over 5 years, reduced to ~40% with long term antifungal therapy. Estimates suggest a prevalence of ~1.2M CPA cases after pulmonary TB, and probably ~3 million overall. Prevalence The prevalence of CPA is not known with confidence. In the late 1960s, one year after completion of anti-TB treatment in the UK, 25% of 544 patients with a residual cavity had Aspergillus antibodies and at least 14% CPA (aspergilloma) on chest Xray. On resurvey three years later, 34% of all patients had developed Aspergillus antibodies, >20% had CPA and 42% of these were coughing up blood. Overall 63% of patients with Aspergillus antibodies developed CPA with an aspergilloma within 3 years 1,2 . In Japan 20% of treated TB patients had antibodies to Aspergillus 3 . Two surveys in India showed Aspergillus antibodies in 23% and 25% of patients with “chronic lung diseases”, 90% of whom had had prior TB 4,5 . In Brazil 65% patients at a tertiary chest clinic with positive Aspergillus antibodies had an GLOBAL ACTION FUND FOR FUNGAL INFECTIONS CXR showing left upper lobe cavitation with pleural thickening, with reduced lung volume - CPA
Transcript of GAFFI Fact Sheet TB and its sequela chronic pulmonary … · 2019. 9. 4. · When pulmonary TB is...
GAFFIFactSheet
TBanditssequelachronicpulmonaryaspergillosis(CPA)SummaryCPAisaslowlydestructivelunginfection,withmarkedsystemicfeatures(weightloss,fatigue)andpulmonaryfeatures(productivecough,haemoptysis,breathlessness)almostindistinguishablefromTB.CPApresentslike‘smearnegativeTB’.Itusuallyfollowsapulmonaryinsult,especiallyTB,sarcoidosis,pneumothoraxandemphysema/COPD).Mostpatientsarenotimmunocompromised,althoughHIVinfectionmaybepresent.Somepatientshavesubtleimmunedefectsincludingreducednaturalkiller,Thelperand/orBcellsandsometimesreducedgammainterferonorinterleukin12production.Ratesofprogressionvary,butworseningsymptomsandlungdestructionorfibrosisoccurovermanymonthsoryears.Thekeydiagnosticfeaturesarecavitarylunglesionsonradiology,sometimescontainingafungalball(aspergilloma)andelevatedserumAspergillusantibody.Asimpleaspergilloma(<10%ofcases)isbestsurgicallyremoved.Antifungaltherapyiseffectiveatcontrollingsymptomsandprogressioninabout60%ofpatients.Untreatedmortalityis75-80%over5years,reducedto~40%withlongtermantifungaltherapy.Estimatessuggestaprevalenceof~1.2MCPAcasesafterpulmonaryTB,andprobably~3millionoverall.PrevalenceTheprevalenceofCPAisnotknownwithconfidence.Inthelate1960s,oneyearaftercompletionofanti-TBtreatmentintheUK,25%of544patientswitharesidualcavityhadAspergillusantibodiesandatleast14%CPA(aspergilloma)onchestXray.Onresurveythreeyearslater,34%ofallpatientshaddevelopedAspergillusantibodies,>20%hadCPAand42%ofthesewerecoughingupblood.Overall63%ofpatientswithAspergillusantibodiesdevelopedCPAwithanaspergillomawithin3years1,2.InJapan20%oftreatedTBpatientshadantibodiestoAspergillus3.TwosurveysinIndiashowedAspergillusantibodiesin23%and25%ofpatientswith“chroniclungdiseases”,90%ofwhomhadhadpriorTB4,5.InBrazil65%patientsatatertiarychestclinicwithpositiveAspergillusantibodieshadan
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CXR showing left upper lobe cavitation with pleural thickening, with reduced lung volume - CPA
aspergilloma6.Mostpatientswith‘recurrentTB’inIranhadAspergillusantibodydetectable7.BasedonthisdataandglobalmodelingofTB,theglobalCPAprevalencewasestimatedatbetween0.8and1.37million,aftertuberculosis(Table)8.Itdoesnotaccountforcasesmis-diagnosedasTBinitiallyorCPAcomplicatingotherunderlyingconditions.Table.RelativefrequencyofpulmonarytuberculosisandCPAforcountrieswithpopulationsexceeding50M(population2005andTBdata2007).Country Population
(2005)Annual
pulmonaryTBcases,aliveat1year
EstimatedannualCPAcaseloadfrom
TB
5yearestimatedCPAprevalencefromTB
5yearprevalencerateper100,000population
Globaltotal 6,512,276,000 5,899,619 372,385 1,173,881 18.0China 1,312,253,000 1,052,925 67,387 212,427 16.2India 1,130,618,000 1,297,047 83,011 261,679 23.1USA 302,741,000 8,907 588 1,853 0.6Indonesia 219,210,000 420,853 26,935 84,907 38.7Brazil 186,075,000 70,789 5,663 17,852 9.6Pakistan 165,816,000 204,955 13,117 41,350 24.9Bangladesh 153,122,000 243361 15,575 49,098 32.1Russia 143,470,000 116,234 7,439 23,450 16.3Nigeria 140,879,000 299,297 19,155 60383 42.9Japan 127,449,000 17,724 1,134 3,576 2.8Mexico 105,330,000 15,326 981 3,092 2.9Philippines 85,496,000 216,228 13,839 43,624 51.0Vietnam 84,074,000 97,497 3412 10,757 12.8Germany 82,409,000 3,339 100 316 0.4Egypt 77,154,000 9,266 593 1,869 2.4Ethiopia 74,661,000 124,710 7,981 25160 33.7Turkey 71,169,000 11,042 707 2,228 3.1Iran 70,765,000 9278 594 1,872 2.6Thailand 65,946,000 64,566 4,132 13,026 19.8France 61,013,000 5,517 166 522 0.9UK 60,261,000 4,189 118 370 0.6Congo(DR) 59,077,000 125,538 8,034 25,327 42.9Italy 58,645,000 2,807 84 265 0.5Sincethen,across-sectionalstudyofTBpatientsinNigeria,foundbothHIVpositiveandnegativepatientshadCPA(8.7%),withthehighestproportion(19%)insmearandGeneXpertnegative,HIVnegativepatients9.InUganda,a2yearprospectivestudyin285patientswhohadhadTB2-7yearsearlier,foundCPApresentin14(4.9%,95%CI2.8–7.9%)10.CPAwassignificantlymorecommoninthosewithchestradiographycavitation(26%versus0.8%;p<0.001),butpossiblylessfrequentinHIVco-infectedpatients(3%versus6.7%;p=0.177).TheannualrateofnewCPAdevelopmentbetweensurveyswas6.5%inthosewithchestradiographycavitationand0.2%inthosewithout(p<0.001).SeriesofCPApatientshavebeenreportedfromChinaandHongKong11-13,India14,Korea15,Japan16,Cuba17,France18-19,Spain20andUK21intheyears2017-2019.
IncountrieswithahighpulmonaryTBincidence,TBisthedominantunderlyingdiseaseaccountingforupto80%ofcases22.WhenpulmonaryTBislessfrequent,otherpulmonarydisordersaremoreimportant,notablyCOPDandnon-tuberculousmycobacterialinfection,andpriorTBwaspresentin<20%ofcases22.Overalltherefore,aprovisionalprevalenceestimateof3millionCPApatientswasmade23.ClinicalpresentationPatientswithchronicpulmonaryaspergillosispresentmostcommonlywithweightloss,chronicproductivecough,hemoptysisofvariableseverity,significantfatigue,and/orshortnessofbreath23,24.Fever,nightsweatsandchestdiscomfortoccuroccasionally.Thesystemicsymptomsofchroniccavitarypulmonaryaspergillosisareanimportantpointofdistinctionfromasimpleaspergilloma,inwhichthesedonotoccur25.RadiologyRadiographicexaminationusuallyrevealsoneormorecavities,typicallywithintheupperlobes,whichmayormaynotcontainfungusballs24,26.Pleuralthickeningiscommon.
Asimpleaspergillomaisafungusballinasinglepulmonarycavitywithlimitedsurroundinginflammation,pleuralthickening,orfibrosis,andfewsymptoms25.Chroniccavitarypulmonaryaspergillosisusuallybeginsasill-definedregionsofconsolidationthatprogresstoformclearlydefinedcavities23,24,26.Cavitiesmaycontainfungusballs,debris,orfluid.Thereareoftenmultiplecavitiesofdifferentsizes.Theinteriorofthecavitymayshowmarkedirregularity,representingfungalgrowthonthecavitywall.Cavitiesmaybethick-orthin-walled.Pleuralthickeningiscommonbutnotuniversal.Newcavityformationorexpansionofoneormoreexistingcavitiesovertimeishighlycharacteristic,andtypicallyoccursovermonthsintheabsenceoftreatment.SomepatientsgetAspergillusnodules–whichmaybesingleormultiple,andoccasionallycavitate27.Someareasymptomatic,othersareassociatedwithmanypulmonarysymptomsandhaemoptysis.
Matching CT and PET scan from a woman with CPA showing remarkable inflammatory response in the pleura and multiple cavities with an irregular inside surface
Chronicfibrosingpulmonaryaspergillosis28,otherwiseknownas‘destroyedlung’isalatestageofdiseaseandcharacterizedbythesameradiographicfindingsthatoccurwithchroniccavitarypulmonaryaspergillosisincombinationwithsignificantfibrosis.DiagnosisThekeytestforCPAisapositiveAspergillusantibodytest(precipitins)inserum24,26.Thebesttestshave>90%sensitivityanda85%specificity11,19,26.Anaffordablenewlateralflowdevicewithexcellentperformancecharacteristicshasrecentlybeencommercialized19,29.Raisedinflammatorymarkers(CRP,plasmaviscosityorESR)areseeninabout50%ofpatients23.Aspergillusantigenissometimesdetectableinserum,butusuallyinbronchoalveolarlavage14,30,andinsputum,butthecut-offismuchhigher31.CulturesarepositiveforAspergillusspp.(usuallyA.fumigatus)in~25%ofpatients24,.AspergillusPCRismoreoftenpositive(~80%)31-33.Guidelinesondiagnosis,includingradiologicalfeatures,arepublished24,andforlowresourcesettingsanalgorithmisnowavailablefordiagnosis26.Manypatientshavesomedegreeofimpairedimmunity.LowThelper,Bcelland/ornaturalkillercellsarefrequent34.LowpneumococcalandHaemophilusantibodiesarefrequentandusuallypartiallyresponsivetoconjugatevaccine35.Poorproductionofgammainterferonorinterleukin12(whichisrequiredtoproducegammainterferon)iscommoninthemorecomplexpatients.Multiplegeneticvariantsarealsodescribed.TypicaluntreatedexampleAnexampleofaGujeratiwomanwhohadhadTBanddevelopedCPAwasdiagnosedin199223.Withouttreatment,shelostthefunctionofherwholeleftlung(chronicfibrosingpulmonaryaspergillosis)over5yearsandsubsequentlydied.Incontrastotherpatientshaveremainedwellontreatmentfor20+years.
1992 1994 1997ManagementSimpleaspergillomashouldberesected,usuallyrequiringalobectomy36.Survivalratesaftersuchsurgeryisexcellent,ifpatientsarecarefullyselected12,36-38.About5%ofpatientswithCPAareimmediatelysuitableforresectionsurgery.Recurrencedoesoccurin>25%ofcases39.Surgeryinpatientswithmulticavitydiseasewhoare
systemicallyunwell,hasaconsiderablemortalityandmorbidity,andisrarelycurative.Antifungaltherapywithoralitraconazoleisabout60-70%effectiveinimprovingorstabilisingsymptomsandarrestingprogression16,21,24,.ResponseanddeteriorationratesdocumentedinanRCTcomparingoralitraconazole(400mgdaily)withstandardcareover6months,followedby6monthsoffollowup40isshowninthefigurebelow.Ofthoseonstandardcare,61%deterioratedat6monthsand71%at12months.Incontrast,76%ofpatientsimprovedorstabilizedonitraconazole.Discontinuationofitraconazoleleadtoa30%relapserate6monthslater.Voriconazoletherapyisprobablyslightlysuperiorintermsoflaterdeterioration16,41andareducedrateofazoleresistanceemergence21,especiallyinthosewithlargefungalballs.Responsecanbeassessedbysymptomreduction,weightgain,reducedfatigue,fallinginflammatorymarkersandAspergillusIgGantibodytitre21,24,andreductioninpleuralthickeningonCTscanningorchestradiograph42.
SimilarresponseratesareseenwithIVamphotericinB(shortterm),IVmicafungin(shortterm),IVcaspofungin(shortterm),oralvoriconazole,oralposaconazoleandoralisavuconazole24.Therapyneedstobelongterm(>6months)21.Druginteractionsareproblematic,especiallyrifampicin,anticonvulsants,someanti-retroviralagentsandcardiacdrugs.Itraconazoleandpan-azoleresistanceinA.fumigatusoccursinsomepatients,andthisisdifficulttotreat24.OutcomeRecentseriesindicateasteepmortalityshortlyafterpresentation,withstabilizationovertime43,44,probablybecauseofantifungaltherapyandalessseverephenotype(slowerprogressors).Continuousantifungaltherapywithemergenceofresistanceprobablyprolongssurvival45.
Japanesemortalitydata43 Koreanmortalitydata44
MorbidityimpactTheimpactofCPAonqualityoflifeiscanbemeasuredwiththeStGeorge’sRespiratoryScorewhichrangesfrom1(excellenthealth)to100(extremelyill).ThespreadofscoresisshowninthisprospectivelycollecteddatafromalargecohortofUKpatients(n=88)41.Respondersgetgoodimprovementsintheirqualityoflife21.
Keyquestionsandobservations:
Ø CPAisaglobaldiseasebutprevalencedatashowsomevariabilityinfrequency,dependinginpartonlocalpulmonaryTBincidenceandprobablyCOPDprevalence.Moreprevalencestudiesarerequired.
Ø TheimpactofHIVinfectiononprevalenceanddiagnosisisnotwellstudied.Ø SubstantialnumbersofsmearnegativeTBcasesdon’thaveTBbuthaveCPA,
butthisisnotyetwellassessed.Ø Dualmycobacterial(TBandNTM)infectionsaredifficulttomanageandneed
morestudyandnewnon-interactingantifungalagents.Ø AnewlateralflowassayforAspergillusIgGantibodyisnowavailableandcould
transformdiagnosis.Ø Oralantifungaltherapyispartiallysuccessful(~60%),butazoleresistanceis
anissue.Ø Progressionratesvaryandsomepatientsneedreallyaggressivetherapy,
othersarestableforlongperiods.
DavidDenning
TheUniversityofManchesterandGAFFIAugust2019
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