High incidence of tuberculosis in patients treated for hepatitis C chronic infection

w w w . e l s e v i e r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Brief

communication

High

incidence

of

tuberculosis

in

patients

treated

for

hepatitis

C

chronic

infection

Silvia

Naomi

de

Oliveira

Uehara

,

Christini

Takemi

Emori

,

Renata

Mello

Perez

,

Maria

Cassia

Jacintho

Mendes-Correa

_,

_Adalgisa

_de

_Souza

_Paiva

_Ferreira

_,

Ana

Cristina

de

Castro

Amaral

Feldner

_,

_Antonio

_Eduardo

_Benedito

_Silva

_,

Roberto

José

Carvalho

Filho

_,

_Ivonete

_Sandra

_de

_Souza

_e

_Silva

_,

Maria

Lucia

Cardoso

Gomes

Ferraz

a_{GastroenterologyDivision,UniversidadeFederaldeSãoPaulo(UNIFESP),SaoPaulo,SP,Brazil} b_{InternalMedicineDepartment,UniversidadeFederaldoRiodeJaneiro(UFRJ),RiodeJaneiro,RJ,Brazil} c_{InfectiousDiseaseDivision,UniversidadedeSãoPaulo(USP),SaoPaulo,SP,Brazil}

d_{GastroenterologyDivision,UniversidadeFederaldoMaranhão(UFMA),SaoLuis,MA,Brazil}

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Articlehistory:

Received28August2015 Accepted6December2015 Availableonline9February2016

Keywords:

HepatitisC Tuberculosis Alpha-interferon

Latenttuberculosisinfection

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Brazilisoneofthe22countriesthatconcentrates80%ofglobaltuberculosiscases concomi-tantlytoalargenumberofhepatitisCcarriersandsomeepidemiologicalriskscenarios arecoincidentforbothdiseases.Weanalyzedtuberculosiscasesthatoccurredduring ␣-interferon-basedtherapyforhepatitisCinreferencecentersinBrazilbetween2001and2012 andreviewedtheirmedicalrecords.Eighteentuberculosiscaseswereobservedinpatients submittedtohepatitisC␣-interferon-basedtherapy.Allpatientswerehuman immuno-deficiencyvirus-negative.Ninepatients(50%)hadextra-pulmonarytuberculosis;15(83%) showedsignificantliverfibrosis.HepatitisCtreatmentwasdiscontinuedin12patients(67%) duetotuberculosisreactivationandsix(33%)hadsustainedvirologicalresponse.The major-ityofpatientshadafavorableoutcomebutonedied.Consideringtheevidencesof␣-IFN interferenceoverthecontainmentofMycobacteriumtuberculosis,theimmuneimpairment ofcirrhoticpatients,theincreaseoftuberculosiscasereportsduringhepatitisCtreatment withatypicalandseverepresentationsandthenegativeimpactonsustainedvirological response,wethinkthesearestrongargumentsforlatenttuberculosisinfectionscreening beforestarting␣-interferon-basedtherapyforanyindicationandeventoconsiderIFN-free regimensagainsthepatitisCwhenapatienttestspositiveforlatenttuberculosisinfection. ©2016ElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

∗ _{Correspondingauthorat:RuaDoutorDiogodeFaria,539,apto104–10}◦_{andar,VilaClementino,CEP:04037-001,SãoPaulo,SP,Brazil.}

E-mailaddress:[email protected](S.N.deOliveiraUehara).

http://dx.doi.org/10.1016/j.bjid.2015.12.003

1413-8670/©2016 Elsevier Editora Ltda. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).

Tuberculosis(Tb)isanair-borneinfectiousdiseasecaused by the Mycobacterium tuberculosis, considered priority for surveillanceandtreatmentbytheWorldHealthOrganization becauseofitshighincidenceandmortalityrates,especiallyin countrieswithsocio-economicandsanitaryissues.

Brazilisoneofthe22countriesintheworldthat concen-trate80%ofglobalTbcases,ranking16thinabsolutenumber ofcases(71,123casesin2013)and22ndinincidencerate(35.4 cases/100,000inhabitants).Mostofthereportedcasesoccur amongmenintheagegroupfrom40to59years,with pul-monarypresentation(86%).1

Somegroups are moresusceptible to Tb than the gen-eral population, such as patients living with the human immunodeficiency virus/acquired immunodeficiency syn-drome (HIV/Aids), patients under immunosuppressive or immunobiologicaltherapyaswithrheumatic,inflammatory boweldisease,andalsoindiabetis,chronickidney disease, andsolidorgantransplantedpatients.

ThetreatmentofTbwithrifampicin,isoniazidand pyraz-inamidewasadoptedinBraziluntil2009.From2010on,the drugregimencontainingrifampicin,isoniazid,pyrazinamide, andethambutolwasadopted.Alternativetherapyis recom-mendedforpatientswithliverdiseasesoraminotransferases abnormalities,includingstreptomycin,ofloxacin,and etham-butol(SOE).2

ThestandardtherapyforchronichepatitisChaschanged significantlyduringtheyears.Initiallypatientsweretreated with conventional interferon. When pegylated interferon becameavailablepatientshadamoreconvenientand effec-tivetherapy withaduration of24–48 weeksdependingon the hepatitisC virus (HCV) genotype and fibrosis stage.In specialsituationssuchasend-stagerenaldisease(ESRD) iso-latedIFNwasrecommendedduetothehighriskofhemolytic anemiainducedbyribavirin.Thisassociationofdrugscould alsoleadtoarelativeimmunosuppression.Nowadaysseveral directactingantiviraldrugs(DAA)areavailablewithhighcure rates,shorterdurationoftreatment,andfeweradverseevents. EveninthisneweraofCHCtreatment,IFNwillstillbeused insomesituationssuchasgenotype3infectionandrescue therapyfornon-responders.3

HepatitisCpatientstreatedwith␣-interferon(␣-IFN)and ribavirinarenotyetcharacterizedasamoresusceptiblegroup fordevelopingTb,althoughitisalreadyknownthatthereis anincreaseonhepatitisCprevalenceamongTbpatientswhen comparedtothegeneralpopulation.4_Indeed,some

epidemio-logicalriskscenariosarecoincidentforbothdiseases,suchas incarceration,homelessness,anddrugaddiction.1_Otherrisk

factorsforTbsuchasundernourishmentandrelative immun-odepressioncanalsobeinducedby␣-IFN-basedhepatitisC treatment.5

Totheextentofourknowledge,atleast16Tbcasesduring orsoonafterinterferon-basedhepatitisCtherapyinnon-HIV patients were reported in15 articles so far,some ofthem describingsevereoutcomesoftuberculosisreactivation.6–15

Theaimofthepresentstudy wastoanalyze18casesof TbobservedinreferencecentersforhepatitisCtreatmentin Brazil,countrywithahighprevalenceofTbandanexpressive numberofhepatitisCcarriers(2–3millionpeople).3

We retrospectively analyzed the records of all treated patients for hepatitis C which were seen monthly during

therapyandidentified,basedonthesignsandsymptoms,the occurrenceofTbcasesundervariousclinicalpresentations inpatientssubmittedto␣-IFN-basedtherapyforhepatitisC (pegylatedornot).

Patientswereevaluatedbetween2001and2012,infour ref-erencecentersinBrazil(twoinSaoPaulo,oneinRiodeJaneiro andoneinMaranhaowherethepeakofincidenceof tubercu-losisduringthisperiodwas43.7/100,000in2001,93.9/100,000 in 2001and 47/100,000 in2002, respectively).16 _{Cases were}

consideredrelatedtohepatitisCtreatmentwhendiagnosed duringorwithinsixmonthsaftertheendoftreatment.

Oncethecaseshadbeenidentified,theirmedicalrecords werereviewedtoobtainepidemiological,clinical,laboratory, andtherapeuticcharacteristicsrelatedtohepatitisCandTb andthedataaboutthedecisiontointerrupttreatment.This decisionwasmadebyclinicaljudgmentbasedontheseverity ofthedisease.

This study reports secondary data from a main study approvedbytheEthicsCommitteeforClinicalResearchofthe mainstudycenter.

Weidentified18casesofTbinourstudy,withanincidence rateof809cases/100,000treatedpatients.

Themajorityofpatientsweremale(78%),withameanage of49±10years;15patients(83%)hadsignificantliverfibrosis, including six(33%)withcirrhosis; HCVgenotype1wasthe mostfrequent(78%).ThemeantimeunderhepatitisC treat-mentuntiltheonsetofTbsymptomswas33±15weeks.The meanhemoglobinlevelonTbdiagnosiswas12.1±4.2g/dLand themeanofneutrophilcountswas3596±1938cells/mm3_.

Most patients were treated for hepatitis C with double therapy, including ␣-IFN (pegylatedor not) associatedwith ribavirin(89%).Thetreatmentwasdiscontinuedearlyin67% ofcasesbecauseofTbonset.Inanintentiontotreatapproach, onlysixpatients(33%)achievedsustainedvirologicalresponse (SVR),whilefiverelapsed(RR),andtheremainingwere non-responders(NR).

At least nine patients (50%) had other risk factors for Tb development(diabetesmellitus,chronic kidney disease, tobaccosmoking,oralcoholintake).BothDiabetesmellitusand chronickidneydiseasecoexistedin17%ofTbcases. Cirrho-siswaspresentin33%ofcases.Themostfrequentclinical presentationwaspulmonaryTb,in50%ofcases,withhalfof patientsdevelopingextra-pulmonaryTb.Onlyoneofcirrhotic patientshadextra-pulmonaryTb(pleuraleffusion) concomi-tantlytopulmonarydisease.

Symptoms and signsofTb usuallyappearedduringthe thirdandfourthtrimestersoftreatment(83%ofcases).Three patients presented Tb afterconcluding ␣-IFN therapy (two afterthreeandoneaftersixmonthsoftheendoftreatment). DetailsoftreatmentforhepatitisCandTbare shownin

Table1andclinicalpresentationofTbinTable2.Ninepatients were treated with the association of rifampicin, isoniazid andpyrazinamide,adoptedinBraziluntil2009forTb treat-ment.From2010on,thedrugregimencontainingrifampicin, isoniazid,pyrazinamide,andethambutolwasadopted,what explainsitspredominanceinthefourcasesidentifiedbetween 2010and2012.

The18Tbcasesreportedinthisstudyrisethepossibility ofahigherriskforinfection inpatientsunder␣-IFN-based therapyforhepatitisC.

Table1–Clinical/epidemiologicalcharacteristicsofpatientswhodevelopedtuberculosisduringorsoonafterhepatitisC treatment.

Case Gender Age (years) Liver fibrosis (METAVIR) Genotype Therapeutic regimenfor hepatitisC Outcomeof hepatitisC Riskfactors forTba Drug regimen forTb Outcomeof Tb

1 Mb _{50 2 1 IFNpeg2b}c_/RBVd _SVRe _RHZEf,g,h,i _Curewithout

sequelae

2 M 59 2 1 IFNpeg2aj_{/RBV Death DM}k_,

former smoker

RHZE Death

3 Fl _{58 2 1 IFNpeg2b/RBV SVR RHZE Curewithsequelae–}

ventriculoperitoneal shunt 4 M 40 4 3 IFNm_{/RBV NR}n _Previous Pulmonary Tb,former DAo

SOEp,q,i _Curewithout sequelae

5 M 52 1 1 IFN NR CKDr_,

smoker

S,Ets_{,E,Z Curewithout} sequelae

6 M 66 4 1 IFNpeg2a/RBV NR RHZ/SOE Curewithout

sequelae

7 F 50 3 1 IFNpeg2b/RBV RRt _{RHZ/SOE Curewithout}

sequelae

8 M 65 4 1 IFNpeg2a/RBV SVR SOE Curewithout

sequelae

9 F 52 1 1 IFNpeg2a/RBV RR RHZ Curewithout

sequelae

10 M 44 4 3 IFNpeg2b/RBV RR Alcohol

intake

RHZ Curewithout

sequelae

11 M 52 2 3 IFN/RBV NR DM RHZ Curewithout

sequelae

12 M 28 1 1 IFNalone RR CKD RHZE Curewithout

sequelae

13 M 40 2 1 IFNpeg2aalone RR CKD RHZ Curewithout

sequelae

14 F 55 4 1 IFN/RBV NR DM RHZ/SOE Curewithout

sequelae

15 M 53 4 1 IFN/RBV SVR RHE Curewithout

sequelae

16 M 41 2 1 IFNpeg2b/RBV NR AIu_,former

DA

RHZE Curewithout sequelae

17 M 32 2 3 IFNpeg2b/RBV SVR RHZ Curewithout

sequelae

18 M 47 2 1 IFNpeg2a/RBV SVR RHZ Curewithout

sequelae

a _{Tuberculosis.} b _Male.

c _{Pegylated␣-interferon2b.} d _Ribavirin.

e _{Sustainedvirologicalresponse.} f _Rifampicin.

g _Isoniazid. h _{Pyrazinamide.}

i _Ethambutol.

j _{Pegylated␣-interferon2a.} k _{Diabetesmellitus.} l _Female. m _{Standard␣-interferon.} n _{Non-responder.} o _Drugaddict. p _{Streptomycin.} q _Ofloxacin.

r _{Chronickidneydisease.} s _Ethionamide.

t _{Responseandrelapse.} u _{Alcoholintake.}

Table2–Clinicalaspectsanddiagnosticmethodsoftuberculosiscases.

Case Symptomsandsigns Damagedorgans Diagnosticmethods

1 Fever,axillarylymphadenopathy, asthenia,myalgia

Lymphnode Lymphnodebiopsy

2 Fever,diarrhea,asthenia,nightsweats, nausea,gaitdisorder

Disseminated Bonemarrowbiopsy

3 Arthralgia,irritability,transientcognitive deficit

Centralnervoussystem Cerebrospinalfluidexamination

4 Fever,cough,chills,bronchospasm Lungs Chestradiography,positivesputum

smearmicroscopy

5 Fever,cough Lymphnode Lymphnodebiopsy

6 Fever,cough,fatigue,weightloss,anemia, leukopenia,thrombocytopenia,

hemoptysis

Lungs Symptomsandpositivetuberculin

skintest 7 Fever,cough,asthenia,anorexia,myalgia,

arthralgia,weightloss,anemia, leukopenia

Lungs Positivesputumsmearmicroscopy

8 Cough,asthenia,anemia,leukopenia Lungs Positivesputumsmearmicroscopy

9 Fever,weightloss,lossofappetite, asthenia,nightsweats,chestpain, anemia,leukopenia

Lungs ChestradiographyandCTa

10 Fever,cough,weightloss,dyspnea,chest pain

Pleuraandlungs Pleuralfluidexamination,ChestCT

11 Fever,cough,weightloss Lungs Chestradiography

12 Thoracolumbarpain Spine SpineCT–Pott’sdisease

13 Ascites,weightloss Peritoneum Ascitesfluidexamination

14 Fever,cough Lungs Chestradiography

15 Leftwristpain Bone/joint Histopathology

16 Nightsweats Lungs Positivesputumsmearmicroscopy

17 Cough Lungsandrelapseinlymph

node

Positivesputumsmearmicroscopy

18 Fever,cough,chestpain Pleuraandlungs Chestradiography,pleuralfluid

examination

a _{Computerizedtomography.}

In a population-based study conducted in Taiwan, an endemicTbarea,Linetal.,2014studiedtheincidencerates ofactivetuberculosisinHCV-infectedpatientswith(n=621) or without (n=2460) interferon-based therapy (IBT). They observedanon statisticallysignificant increasedhazard of activeTbinHCVinfectedpatientsonIBTinone-year follow-up.17 _{Moreover,theymentionthatthe investigatorshadno}

accesstootherimportantTbriskfactors,detailedlaboratory results,andmedicationrecords.Theyalsoconsiderthatsome patientscouldhavediedbeforebeingregisteredintheHealth InsuranceResearch DatabaseduetoTb infection ortaking medicationsforthatcondition,underestimatingthenumber ofcases.Themagnitudeof809cases/100,000treatedpatients ismoreimpressivewhenthedataarecomparedtothe inci-denceofTbcasesinthe Brazilianpopulationin 2013(35.4 cases/100,000inhabitants).Othergroups,traditionallya pri-ority forTb control,suchastheindigenous people, havea lowerincidence(94.5cases/100,000 inhabitants)when com-paredtoourreport.1_{Ontheotherhand,comparableincidence}

rates had been described in renal transplant patients: 803 cases/100,000patients.18

Most patients were male within the age group of higher prevalence of Tb in Brazil.1 _{Diabetes mellitus and}

chronickidneydisease coexistedinlessthan 20%ofcases, comorbidities widely known to increase the risk of active tuberculosis.19_{Cirrhosis,alsoblamedasariskfactorforTb,}20

waspresentinonethirdofcases.Halfofthecaseswere extra-pulmonary tuberculosis, more compatible with a situation of immunosuppression, since in non-immunosuppressed subjects only 15–20% of extra-pulmonary forms are expected.21

WeobservedahighdiscontinuationrateofIBTduetothe onsetofTb;onethirdofpatientsachievedSVR.Oncasetwo, theacuteonsetofTbsymptomsandsevereandfataloutcome ofthediseaseinlessthan60days,bringthepossibilityof bac-teremiaandsepsiscausedbyM.tuberculosisinanearlyphase ofinfection.15

Onthepreviouscasereportstheauthorsdiscussedmany mechanisms ofassociation between hepatitis C treatment andTbreactivation.TheysuggestedthatIFNcaninducean impairmentoftheearlyimmuneresponseagainstM. tuber-culosis,specificallyobservedonseverecases,besidestherole ofleukopenia,neutropenia,aloweringonT-CD4+lymphocyte populationandabnormalitiesonchemotaxisandphagocytic functionsofmacrophages5,8,10,11,15_.

Wewouldliketoemphasizethatmanystudieshadalready showed that ␣- and ␤-IFN inhibit typeI immuneresponse whichischaracterizedbylL-12,␥-IFNandTNF-␣production, cytokinesthat restrainM. tuberculosis.Thisinhibitioncould leadtoLTBIreactivation,22_{asoccurredonmostcasesreported}

here, includingthe threecasesinwhichTb appearedafter stoppinghepatitisCtreatment.Weconsiderthattherewasa

residualimmuneeffectof␣-IFNthatcanlastuntil16weeks afterthelastdoseadministered.

Insummary,consideringtheevidencesof␣-IFN interfer-enceovertheconstrainmentmechanismsofM.tuberculosis,

theimmune impairmentofcirrhotic patients, theincrease ofTb casereports duringhepatitisC treatment, as inthis expressiveretrospectivestudy,withatypicalandsevere pre-sentations,andthe negativeimpactonSVR,we thinkthat thesearestrongargumentsforLTBIscreeningbytuberculin skintestand/orbyinterferongammareleasingassays,before starting␣-IFN-basedtherapy. Thisis evenmore important incountrieswithhighTbincidenceandinmoresusceptible populationsinwhichepidemiologicaldeterminantsofboth diseases cancoexist and interact.Inthese mediumorlow incomecountriestheuseof␣-IFN-basedtherapywillstill per-sistforsometimebeforeitispossibletoextendtheuseof direct-actingantivirals(DAA)forhepatitisC.DAAshouldbe consideredifapatient testspositiveforLTBI. Furthermore, eveninthedirectactiveantiviralsera,theinclusionofpatients in the treatment of hepatitisC is anopportunity forLTBI screening.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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1. Brasil.MinistériodaSaúde.SecretariadeVigilânciaem Saúde.BoletimEpidemiológico.Ocontroledatuberculoseno Brasil:avanc¸os,inovac¸õesedesafios;2014.

2. Brasil.MinistériodaSaúde.SecretariadeVigilânciaem Saúde.DepartamentodevigilânciaEpidemiológica.Manual deRecomendac¸õesparaocontroledatuberculoseno Brasil/MinistériodaSaúde,SecretariadeVigilânciaemSaúde. Brasília:DepartamentodevigilânciaEpidemiológica;2011.

3. Brasil.MinistériodaSaúde.SecretariadeVigilânciaem Saúde.DepartamentodeDSTAidseHepatitesVirais. ProtocoloclínicoeDiretrizesTerapêuticasparaHepatiteCe Coinfecc¸ões/MinistériodaSaúde,Secretariadevigilânciaem Saúde,DepartamentodeDST,AidseHepatitesVirais.Brasília: MinistériodaSaúde;2015.

4. WuP-H,LinY-T,HsiehK-P,ChuangH-Y,SheuC-C.HepatitisC virusinfectionisassociatedwithanincreasedriskofactive tuberculosisdisease:anationwidepopulation-basedstudy. Medicine.2015;94(33):e1328.

5. PuotiM,BabudieriS,RezzaG,etal.Useofpegylated interferonsisassociatedwithanincreasedincidenceof infectionsduringcombinationtreatmentofchronichepatitis C:asideeffectofpegylation?AntivirTher.2004;9(4):627–30.

6. FerreiraCN,BarjasER,CorreiaLA,etal.Generalized peripherallymphadenopathyinapatienttreatedforchronic HCVinfection.NatClinPractGastroenterolHepatol. 2008;5(8):469–74.

7.TsaiM-C,LinM-C,HungC-H.Successfulantiviral antituberculosistreatmentwithpegylatedinterferon-alfa andribavirininachronichepatitisCpatientwith pulmonarytuberculosis.JFormosMedAssoc.2009;108(9): 746–50.

8.BelkahlaN,KchirH,MaamouriN,etal.Reactivationof tuberculosisduringdualtherapywithpegylatedinterferon andribavirinforchronichepatitisC.RevMedIntern. 2010;31(11):e1–3.

9.VelascoJ,GonzálezS.Tuberculouslymphadenitisafter successfultreatmentofhepatitisC.EnfermInfeccMicrob Clin.2011;29:8.

10.BabudieriS,SodduA,MurinoM,etal.Tuberculosisscreening beforeanti-hepatitisCvirustherapyinprisons.EmergInfect Dis.2012;18(4):689–91.

11.LeeS,AttenMJ,AttarB.Esophagealtuberculosisduring treatmentofhepatitisC.ClinGastroenterolHepatol. 2013;11(12):A27.

12.SaitouY,HataziO,AonumaH,OguraS,YamamotoN, KobayashiT.Pulmonarytuberculomainapatientwith chronichepatitisC:aclinicalpitfallinthetreatmentstrategy. InternMed(Tokyo,Japan).2014;53(15):1669–74.

13.Rodrigues-MartínL,LinaresTorresP,AparicioCabezudoM, etal.Reactivationofpulmonarytuberculosisduring treatmentwithtripletherapyforhepatitisC.Gastroenterol Hepatol.2015.

14.FukubaR,KawarataniH,KuboT,etal.Tuberculousperitonitis duringpegylatedinterferonplusribavirincombination therapyinapatientwithchronichepatitisC.Nippon ShokakibyoGakkaiZasshi.2014;111(12):2337–45.

15.HametnerS,MonticelliF,KernJM,SchoflR,ZiachehabiA, MaieronA.TuberculoussepsisduringantiviralHCVtriple therapy.JHepatol.2013;59(3):637–8.

16.Brasil.MinistériodaSaúde.SecretariadeVigilânciaem Saúde.ProgramaNacionaldeControledaTuberculose.Série históricadataxadeincidênciadetuberculose.Brasil,regiões eunidadesfederadasderesidênciaporanodediagnóstico (1990a2014);2015.Availablefrom:http://portalsaude. saude.gov.br/images/pdf/2015/setembro/24/taxa-incid–ncia-tuberculose-1999-2014-base-JUN-2015.pdf[cited30.11.15] [Internet].

17.LinS,ChenT,LuP,etal.Incidenceratesoftuberculosisin chronichepatitisCinfectedpatientswithorwithout interferonbasedtherapy:apopulation-basedcohortstudyin Taiwan.BMCInfectDis.2014;14(1):705.

18.MarquesID,AzevedoLS,PierrottiLC,etal.Clinicalfeatures andoutcomesoftuberculosisinkidneytransplantrecipients inBrazil:areportofthelastdecade.ClinTranspl.

2013;27(2):E169–76.

19.SantinCerezalesM,NavasElorzaE.Tuberculosisinspecial populations.EnfermInfeccMicrobClin.2011;29Suppl.1: 20–5.

20.LinYT,WuPH,LinCY,etal.Cirrhosisasariskfactorfor tuberculosisinfection–anationwidelongitudinalstudyin Taiwan.AmJEpidemiol.2014;180(1):8.

21.SharmaSK,MohanA.Extrapulmonarytuberculosis.IndianJ MedRes.2004;120(4):316–53.

22.dePausRA,vanWengenA,SchmidtI,etal.Inhibitionofthe typeIimmuneresponsesofhumanmonocytesbyIFN-alpha andIFN-beta.Cytokine.2013;61(2):645–55.