ATS/CDC Guidelines for Treating LTBI · EXAM: Mild obese Somali male NAD VSS WNL ATS/CDC Guidelines...

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TB IntensiveHouston, Texas

November 10 12 2009November 10-12, 2009

ATS/CDC Guidelines for Treating LTBI

Ti th Ak it MDTimothy Aksamit, MD

November 10, 2009

ATS/CDC Guidelines for ATS/CDC Guidelines for Treating LTBITreating LTBI

Tuberculosis IntensiveTuberculosis Intensive


Tuberculosis IntensiveTuberculosis IntensiveUniversity of Texas Medical School at HoustonUniversity of Texas Medical School at Houston

Heartland National TB CenterHeartland National TB Center10 Nov 0910 Nov 09

University of Texas Medical School at HoustonUniversity of Texas Medical School at HoustonHeartland National TB CenterHeartland National TB Center

10 Nov 0910 Nov 09

Timothy R. Timothy R. AksamitAksamit, MD, MD

Assistant Professor of MedicineAssistant Professor of MedicineMayo Clinic Mayo Clinic

Timothy R. Timothy R. AksamitAksamit, MD, MD

Assistant Professor of MedicineAssistant Professor of MedicineMayo Clinic Mayo Clinic

College of MedicineCollege of Medicine

ConsultantConsultantPulmonary Disease and Critical Care MedicinePulmonary Disease and Critical Care Medicine

Department of Internal MedicineDepartment of Internal MedicineMayo ClinicMayo Clinic

Rochester, MinnesotaRochester, Minnesota

College of MedicineCollege of Medicine

ConsultantConsultantPulmonary Disease and Critical Care MedicinePulmonary Disease and Critical Care Medicine

Department of Internal MedicineDepartment of Internal MedicineMayo ClinicMayo Clinic

Rochester, MinnesotaRochester, Minnesota

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DISCLOSUREDISCLOSUREDISCLOSUREDISCLOSUREDISCLOSUREDISCLOSURE

Relevant Financial Relationship(s)Relevant Financial Relationship(s)NoneNone

DISCLOSUREDISCLOSURE

Relevant Financial Relationship(s)Relevant Financial Relationship(s)NoneNone


ObjectiveObjective


ObjectiveObjective

••Discuss the ATS/CDC guidelines for Discuss the ATS/CDC guidelines for treating LTBItreating LTBI••Discuss the ATS/CDC guidelines for Discuss the ATS/CDC guidelines for treating LTBItreating LTBI

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Backgro ndBackgro ndBackgro ndBackgro nd

Latent Tuberculosis Infection (LTBI) Latent Tuberculosis Infection (LTBI) UpdateUpdate


••BackgroundBackground

••DiagnosisDiagnosis

••TreatmentTreatment




••SummarySummary••SummarySummary











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CCCC:Positive TST:Positive TST

HPIHPI: 35 year: 35 year--old male nonold male non--smokersmoker

CCCC:Positive TST:Positive TST

HPIHPI: 35 year: 35 year--old male nonold male non--smokersmokeryy

••Immigration evaluation, 20 mm positive TSTImmigration evaluation, 20 mm positive TST••No cough, sputum, hemoptysis, fever, chills, sweats, weight lossNo cough, sputum, hemoptysis, fever, chills, sweats, weight loss••No known TB exposure or BCGNo known TB exposure or BCG

••No DM, polyneuropathy, h/o hepatitis, renal insufficiency, sz No DM, polyneuropathy, h/o hepatitis, renal insufficiency, sz disorderdisorder••HIV unknown, no risk factors;HIV unknown, no risk factors;NO E OH IDUNO E OH IDU

yy

••Immigration evaluation, 20 mm positive TSTImmigration evaluation, 20 mm positive TST••No cough, sputum, hemoptysis, fever, chills, sweats, weight lossNo cough, sputum, hemoptysis, fever, chills, sweats, weight loss••No known TB exposure or BCGNo known TB exposure or BCG

••No DM, polyneuropathy, h/o hepatitis, renal insufficiency, sz No DM, polyneuropathy, h/o hepatitis, renal insufficiency, sz disorderdisorder••HIV unknown, no risk factors;HIV unknown, no risk factors;NO E OH IDUNO E OH IDU••NO EtOH or IDUNO EtOH or IDU

SHx: School teacher, married without children.SHx: School teacher, married without children.

EXAMEXAM: Mild obese Somali male NAD VSS: Mild obese Somali male NAD VSSWNLWNL

••NO EtOH or IDUNO EtOH or IDU

SHx: School teacher, married without children.SHx: School teacher, married without children.

EXAMEXAM: Mild obese Somali male NAD VSS: Mild obese Somali male NAD VSSWNLWNL



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The chance of this patient developing active TB The chance of this patient developing active TB disease over his life time is greater than thedisease over his life time is greater than the

The chance of this patient developing active TB The chance of this patient developing active TB disease over his life time is greater than thedisease over his life time is greater than thedisease over his life time is greater than the disease over his life time is greater than the chance of an American personal injury attorney chance of an American personal injury attorney flying on commercial airlines with active flying on commercial airlines with active pulmonary XDR tuberculosis?pulmonary XDR tuberculosis?

A. TrueA. True

disease over his life time is greater than the disease over his life time is greater than the chance of an American personal injury attorney chance of an American personal injury attorney flying on commercial airlines with active flying on commercial airlines with active pulmonary XDR tuberculosis?pulmonary XDR tuberculosis?

A. TrueA. True

B. FalseB. FalseB. FalseB. False



The chance of this patient developing active TB The chance of this patient developing active TB disease over his life time is greater than thedisease over his life time is greater than the

The chance of this patient developing active TB The chance of this patient developing active TB disease over his life time is greater than thedisease over his life time is greater than thedisease over his life time is greater than the disease over his life time is greater than the chance of an American personal injury attorney chance of an American personal injury attorney flying on commercial airlines with active flying on commercial airlines with active pulmonary XDR tuberculosis?pulmonary XDR tuberculosis?

A. TrueA. True

disease over his life time is greater than the disease over his life time is greater than the chance of an American personal injury attorney chance of an American personal injury attorney flying on commercial airlines with active flying on commercial airlines with active pulmonary XDR tuberculosis?pulmonary XDR tuberculosis?

A. TrueA. True

B. FalseB. FalseB. FalseB. False

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Targeted Tuberculin Testing Targeted Tuberculin Testing and Treatment of Latent and Treatment of Latent

Tuberculosis Infection, 2005Tuberculosis Infection, 2005

Targeted Tuberculin Testing Targeted Tuberculin Testing and Treatment of Latent and Treatment of Latent

Tuberculosis Infection, 2005Tuberculosis Infection, 2005

Applying CDC/ATS Guidelines in Your Clinical Applying CDC/ATS Guidelines in Your Clinical PracticePractice

Applying CDC/ATS Guidelines in Your Clinical Applying CDC/ATS Guidelines in Your Clinical PracticePractice

Division of Tuberculosis EliminationDivision of Tuberculosis EliminationDivision of Tuberculosis EliminationDivision of Tuberculosis EliminationDivision of Tuberculosis EliminationDivision of Tuberculosis Elimination

Centers for Disease Control and PreventionCenters for Disease Control and Prevention

Division of Tuberculosis EliminationDivision of Tuberculosis Elimination

Centers for Disease Control and PreventionCenters for Disease Control and Prevention

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Treatment of LTBI Treatment of LTBI –– MilestonesMilestonesTreatment of LTBI Treatment of LTBI –– MilestonesMilestones

For more than 3 decades an essentialFor more than 3 decades an essentialFor more than 3 decades an essentialFor more than 3 decades an essentialFor more than 3 decades, an essential For more than 3 decades, an essential component of TB prevention and control in the component of TB prevention and control in the U.S. has been the treatment of persons with LTBI U.S. has been the treatment of persons with LTBI to prevent TB disease.to prevent TB disease.

For more than 3 decades, an essential For more than 3 decades, an essential component of TB prevention and control in the component of TB prevention and control in the U.S. has been the treatment of persons with LTBI U.S. has been the treatment of persons with LTBI to prevent TB disease.to prevent TB disease.


1965: 1965: American Thoracic Society (ATS) recommends American Thoracic Society (ATS) recommends treatment of LTBI for those with previously treatment of LTBI for those with previously

1965: 1965: American Thoracic Society (ATS) recommends American Thoracic Society (ATS) recommends treatment of LTBI for those with previously treatment of LTBI for those with previously p yp yuntreated TB, tuberculin skin test (TST) untreated TB, tuberculin skin test (TST) converters, and young children.converters, and young children.

1967: 1967: Recommendations expanded to include all TST Recommendations expanded to include all TST positive reactors (positive reactors (>10 mm).>10 mm).

p yp yuntreated TB, tuberculin skin test (TST) untreated TB, tuberculin skin test (TST) converters, and young children.converters, and young children.

1967: 1967: Recommendations expanded to include all TST Recommendations expanded to include all TST positive reactors (positive reactors (>10 mm).>10 mm).

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1974:1974: CDC and ATS guidelines established for CDC and ATS guidelines established for t t t i t d i k ft t t i t d i k f

1974:1974: CDC and ATS guidelines established for CDC and ATS guidelines established for t t t i t d i k ft t t i t d i k fpretreatment screening to decrease risk of pretreatment screening to decrease risk of

hepatitis associated with treatmenthepatitis associated with treatment

•• Treatment recommended for persons Treatment recommended for persons ≤ ≤ 35 years of age35 years of age

pretreatment screening to decrease risk of pretreatment screening to decrease risk of hepatitis associated with treatmenthepatitis associated with treatment

•• Treatment recommended for persons Treatment recommended for persons ≤ ≤ 35 years of age35 years of age


1983:1983: CDC recommends clinical and CDC recommends clinical and laboratory monitoring of persons laboratory monitoring of persons 35 35

1983:1983: CDC recommends clinical and CDC recommends clinical and laboratory monitoring of persons laboratory monitoring of persons 35 35 y g py g pwho who require treatment for LTBIrequire treatment for LTBI

1998: 1998: CDC recommends 2 months of rifampin CDC recommends 2 months of rifampin (RIF) plus pyrazinamide (PZA) as an (RIF) plus pyrazinamide (PZA) as an option for HIVoption for HIV--infected patients (later infected patients (later changed)changed)

y g py g pwho who require treatment for LTBIrequire treatment for LTBI

1998: 1998: CDC recommends 2 months of rifampin CDC recommends 2 months of rifampin (RIF) plus pyrazinamide (PZA) as an (RIF) plus pyrazinamide (PZA) as an option for HIVoption for HIV--infected patients (later infected patients (later changed)changed)

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2000:2000: CDC and ATS issue updated guidelines for CDC and ATS issue updated guidelines for targeted testing and LTBI treatmenttargeted testing and LTBI treatment11

99 th i f i i id (INH) ith i f i i id (INH) i

2000:2000: CDC and ATS issue updated guidelines for CDC and ATS issue updated guidelines for targeted testing and LTBI treatmenttargeted testing and LTBI treatment11

99 th i f i i id (INH) ith i f i i id (INH) i•• 99--month regimen of isoniazid (INH) is month regimen of isoniazid (INH) is preferredpreferred

•• 22--month regimen of RIF and PZA and month regimen of RIF and PZA and a 4a 4--month regimen of RIF month regimen of RIF recommended as options (later recommended as options (later changed)changed)

•• 99--month regimen of isoniazid (INH) is month regimen of isoniazid (INH) is preferredpreferred

•• 22--month regimen of RIF and PZA and month regimen of RIF and PZA and a 4a 4--month regimen of RIF month regimen of RIF recommended as options (later recommended as options (later changed)changed)

11 MMWRMMWR June 9, 2000; 49(No. RRJune 9, 2000; 49(No. RR--6)6)11 MMWRMMWR June 9, 2000; 49(No. RRJune 9, 2000; 49(No. RR--6)6)


2001:2001: Owing to liver injury and death associated with 2Owing to liver injury and death associated with 2--month regimen of RIF and PZA, use of this option month regimen of RIF and PZA, use of this option dede--emphasized in favor of other regimensemphasized in favor of other regimens2 2

2001:2001: Owing to liver injury and death associated with 2Owing to liver injury and death associated with 2--month regimen of RIF and PZA, use of this option month regimen of RIF and PZA, use of this option dede--emphasized in favor of other regimensemphasized in favor of other regimens2 2 dede emphasized in favor of other regimensemphasized in favor of other regimens

2003:2003: 22--month regimen of RIZ and PZA generally not month regimen of RIZ and PZA generally not recommended recommended —— to be used only if the potential to be used only if the potential benefits outweigh the risk of severe liver injury benefits outweigh the risk of severe liver injury and deathand death33

dede emphasized in favor of other regimensemphasized in favor of other regimens

2003:2003: 22--month regimen of RIZ and PZA generally not month regimen of RIZ and PZA generally not recommended recommended —— to be used only if the potential to be used only if the potential benefits outweigh the risk of severe liver injury benefits outweigh the risk of severe liver injury and deathand death33

________________________________________________________________________________________________________

2 2 MMWR MMWR August 31, 2001; 50(34): 733August 31, 2001; 50(34): 733--735735


________________________________________________________________________________________________________



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What’s New: What’s New: ATS/CDC Guidelines for ATS/CDC Guidelines for

Treating LTBITreating LTBI

What’s New: What’s New: ATS/CDC Guidelines for ATS/CDC Guidelines for


Tuberculin skin testing Tuberculin skin testing

•• Emphasis on targeting persons at high riskEmphasis on targeting persons at high risk

•• 55--mm induration cutoff level for organ transplant mm induration cutoff level for organ transplant recipients and other immunosuppressed patients recipients and other immunosuppressed patients being treated with prednisone or TNFbeing treated with prednisone or TNF--αα antagonistsantagonists44

Tuberculin skin testing Tuberculin skin testing

•• Emphasis on targeting persons at high riskEmphasis on targeting persons at high risk

•• 55--mm induration cutoff level for organ transplant mm induration cutoff level for organ transplant recipients and other immunosuppressed patients recipients and other immunosuppressed patients being treated with prednisone or TNFbeing treated with prednisone or TNF--αα antagonistsantagonists44

•• SkinSkin--test conversion defined as increase of test conversion defined as increase of 10 mm of 10 mm of induration within a 2induration within a 2--year period, regardless of ageyear period, regardless of age

•• SkinSkin--test conversion defined as increase of test conversion defined as increase of 10 mm of 10 mm of induration within a 2induration within a 2--year period, regardless of ageyear period, regardless of age

________________________________________________________________________________________________________


________________________________________________________________________________________________________


What’s New:What’s New:ATS/CDC Guidelines for ATS/CDC Guidelines for




Treatment of LTBITreatment of LTBI

•• HIVHIV--negative persons negative persons –– INH for 9 months preferred INH for 9 months preferred regimenregimen

•• HIVHIV--positive persons and those with fibrotic lesions positive persons and those with fibrotic lesions on chest xon chest x--ray (consistent with previous TB) ray (consistent with previous TB) –– INH INH should be given for 9 monthsshould be given for 9 months

Treatment of LTBITreatment of LTBI

•• HIVHIV--negative persons negative persons –– INH for 9 months preferred INH for 9 months preferred regimenregimen

•• HIVHIV--positive persons and those with fibrotic lesions positive persons and those with fibrotic lesions on chest xon chest x--ray (consistent with previous TB) ray (consistent with previous TB) –– INH INH should be given for 9 monthsshould be given for 9 monthsshould be given for 9 months should be given for 9 months

•• For all persons For all persons –– RIF for 4 months is an optionRIF for 4 months is an option

should be given for 9 months should be given for 9 months

•• For all persons For all persons –– RIF for 4 months is an optionRIF for 4 months is an option

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Clinical and laboratory monitoringClinical and laboratory monitoring

•• Routine baseline and followRoutine baseline and follow--up monitoring not up monitoring not required except forrequired except for

•• HIVHIV--infected personsinfected persons•• Pregnant women or those in early postpartum Pregnant women or those in early postpartum

periodperiod

Clinical and laboratory monitoringClinical and laboratory monitoring

•• Routine baseline and followRoutine baseline and follow--up monitoring not up monitoring not required except forrequired except for

•• HIVHIV--infected personsinfected persons•• Pregnant women or those in early postpartum Pregnant women or those in early postpartum

periodperiod•• Persons with chronic liver disease or who use Persons with chronic liver disease or who use

alcohol regularlyalcohol regularly

•• Monthly monitoring for signs or symptoms of Monthly monitoring for signs or symptoms of possible adverse effectspossible adverse effects

•• Persons with chronic liver disease or who use Persons with chronic liver disease or who use alcohol regularlyalcohol regularly

•• Monthly monitoring for signs or symptoms of Monthly monitoring for signs or symptoms of possible adverse effectspossible adverse effects

Latent TB Infection (LTBI)Latent TB Infection (LTBI)Latent TB Infection (LTBI)Latent TB Infection (LTBI)

LTBI is the presence of LTBI is the presence of M. tuberculosisM. tuberculosisorganisms (tubercle bacilli) without symptomsorganisms (tubercle bacilli) without symptomsLTBI is the presence of LTBI is the presence of M. tuberculosisM. tuberculosisorganisms (tubercle bacilli) without symptomsorganisms (tubercle bacilli) without symptomsorganisms (tubercle bacilli) without symptoms organisms (tubercle bacilli) without symptoms or radiographic evidence of TB disease.or radiographic evidence of TB disease.

No GOLD STANDARDNo GOLD STANDARD

organisms (tubercle bacilli) without symptoms organisms (tubercle bacilli) without symptoms or radiographic evidence of TB disease.or radiographic evidence of TB disease.

No GOLD STANDARDNo GOLD STANDARD

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ERJ 33: 956, 2009ERJ 33: 956, 2009ERJ 33: 956, 2009ERJ 33: 956, 2009


LTBI is the presence of LTBI is the presence of M. tuberculosisM. tuberculosis organisms organisms (tubercle bacilli) without symptoms or radiographic(tubercle bacilli) without symptoms or radiographicLTBI is the presence of LTBI is the presence of M. tuberculosisM. tuberculosis organisms organisms (tubercle bacilli) without symptoms or radiographic(tubercle bacilli) without symptoms or radiographic(tubercle bacilli) without symptoms or radiographic (tubercle bacilli) without symptoms or radiographic evidence of TB disease.evidence of TB disease.

No GOLD STANDARD No GOLD STANDARD –– Natural history is uncertainNatural history is uncertain

(tubercle bacilli) without symptoms or radiographic (tubercle bacilli) without symptoms or radiographic evidence of TB disease.evidence of TB disease.

No GOLD STANDARD No GOLD STANDARD –– Natural history is uncertainNatural history is uncertain

????“LTBI” = Persistent adaptive M.“LTBI” = Persistent adaptive M. TbTb immune responseimmune response“LTBI” = Persistent adaptive M.“LTBI” = Persistent adaptive M. TbTb immune responseimmune response

????

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LTBI vs. Pulmonary TB DiseaseLTBI vs. Pulmonary TB DiseaseLTBI vs. Pulmonary TB DiseaseLTBI vs. Pulmonary TB Disease

Latent TB InfectionLatent TB Infection

•• TST* or IGRATST* or IGRA†† positivepositive

N i h di hN i h di h

Latent TB InfectionLatent TB Infection

•• TST* or IGRATST* or IGRA†† positivepositive

N i h di hN i h di h

Pulmonary TB DiseasePulmonary TB Disease

•• TST or IGRA usually positiveTST or IGRA usually positive

•• Chest radiograph may beChest radiograph may be

Pulmonary TB DiseasePulmonary TB Disease

•• TST or IGRA usually positiveTST or IGRA usually positive

•• Chest radiograph may beChest radiograph may be•• Negative chest radiographNegative chest radiograph

•• No symptoms or physical No symptoms or physical findings suggestive of TB findings suggestive of TB disease (pulmonary or XP)disease (pulmonary or XP)

•• Negative chest radiographNegative chest radiograph

•• No symptoms or physical No symptoms or physical findings suggestive of TB findings suggestive of TB disease (pulmonary or XP)disease (pulmonary or XP)

•• Chest radiograph may be Chest radiograph may be abnormalabnormal

•• Symptoms Symptoms maymay include one or include one or more of the following: fever, more of the following: fever, cough, night sweats, weight cough, night sweats, weight loss, fatigue, hemoptysis, loss, fatigue, hemoptysis, decreased appetitedecreased appetite

•• Respiratory specimensRespiratory specimens maymay bebe

•• Chest radiograph may be Chest radiograph may be abnormalabnormal

•• Symptoms Symptoms maymay include one or include one or more of the following: fever, more of the following: fever, cough, night sweats, weight cough, night sweats, weight loss, fatigue, hemoptysis, loss, fatigue, hemoptysis, decreased appetitedecreased appetite

•• Respiratory specimensRespiratory specimens maymay bebe•• Respiratory specimens Respiratory specimens maymay be be smear or culture positivesmear or culture positive

•• Respiratory specimens Respiratory specimens maymay be be smear or culture positivesmear or culture positive

*tuberculin skin test*tuberculin skin test

††IGRA (interferon gamma release assay) is a blood test to detect IGRA (interferon gamma release assay) is a blood test to detect M. tuberculosisM. tuberculosis infection.infection.

*tuberculin skin test*tuberculin skin test

††IGRA (interferon gamma release assay) is a blood test to detect IGRA (interferon gamma release assay) is a blood test to detect M. tuberculosisM. tuberculosis infection.infection.

Testing for Latent TB InfectionTesting for Latent TB InfectionTesting for Latent TB InfectionTesting for Latent TB Infection

PPD (TST):PPD (TST):PPD (TST):PPD (TST):PPD (TST):PPD (TST):

“…A purified protein derivative (PPD) “…A purified protein derivative (PPD) -- TST … at TST … at initial evaluation, … a negative PPDinitial evaluation, … a negative PPD--TST TST does not does not exclude the diagnosis of active tuberculosisexclude the diagnosis of active tuberculosis……

…However, a positive PPD…However, a positive PPD--TST supports … TST supports … diagnosis of diagnosis of cultureculture--negative pulmonary negative pulmonary

PPD (TST):PPD (TST):

“…A purified protein derivative (PPD) “…A purified protein derivative (PPD) -- TST … at TST … at initial evaluation, … a negative PPDinitial evaluation, … a negative PPD--TST TST does not does not exclude the diagnosis of active tuberculosisexclude the diagnosis of active tuberculosis……

…However, a positive PPD…However, a positive PPD--TST supports … TST supports … diagnosis of diagnosis of cultureculture--negative pulmonary negative pulmonary tuberculosistuberculosis, as well as , as well as LTBILTBI in persons with stable in persons with stable abnormal chest radiograph consistent with inactive abnormal chest radiograph consistent with inactive tuberculosis.”tuberculosis.”

tuberculosistuberculosis, as well as , as well as LTBILTBI in persons with stable in persons with stable abnormal chest radiograph consistent with inactive abnormal chest radiograph consistent with inactive tuberculosis.”tuberculosis.”

AJRCCM 167: 603, 2003AJRCCM 167: 603, 2003AJRCCM 167: 603, 2003AJRCCM 167: 603, 2003

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TerminologyTerminologyTerminologyTerminology

•• “Treatment of latent TB infection”“Treatment of latent TB infection” replaces the terms replaces the terms “preventive therapy” and “chemoprophylaxis“preventive therapy” and “chemoprophylaxis”” to to

•• “Treatment of latent TB infection”“Treatment of latent TB infection” replaces the terms replaces the terms “preventive therapy” and “chemoprophylaxis“preventive therapy” and “chemoprophylaxis”” to to p py p p yp py p p ypromote greater understanding of the concept for promote greater understanding of the concept for both patients and providers.both patients and providers.

•• Targeted tuberculin testingTargeted tuberculin testing is used to focus program is used to focus program activities and provider practices on groups at the activities and provider practices on groups at the highest risk for TB.highest risk for TB.

p py p p yp py p p ypromote greater understanding of the concept for promote greater understanding of the concept for both patients and providers.both patients and providers.

•• Targeted tuberculin testingTargeted tuberculin testing is used to focus program is used to focus program activities and provider practices on groups at the activities and provider practices on groups at the highest risk for TB.highest risk for TB.

Testing for Testing for TB Disease and InfectionTB Disease and Infection

Testing for Testing for TB Disease and InfectionTB Disease and Infection

TB TB DISEASEDISEASEPulm and Pulm and

XPXP

TB TB DISEASEDISEASEPulm and Pulm and

XPXP

TB INFECTION (LTBI)TB INFECTION (LTBI)TB INFECTION (LTBI)TB INFECTION (LTBI)

XPXPXPXP

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Targeted Tuberculin TestingTargeted Tuberculin TestingTargeted Tuberculin TestingTargeted Tuberculin Testing

•• Detects persons with LTBI who would benefit fromDetects persons with LTBI who would benefit from•• Detects persons with LTBI who would benefit fromDetects persons with LTBI who would benefit fromDetects persons with LTBI who would benefit from Detects persons with LTBI who would benefit from treatmenttreatment

•• DeDe--emphasizes testing of groups that are not at emphasizes testing of groups that are not at high risk for TBhigh risk for TB

•• Can help reduce the waste of resources and Can help reduce the waste of resources and prevent inappropriate treatmentprevent inappropriate treatment

Detects persons with LTBI who would benefit from Detects persons with LTBI who would benefit from treatmenttreatment

•• DeDe--emphasizes testing of groups that are not at emphasizes testing of groups that are not at high risk for TBhigh risk for TB

•• Can help reduce the waste of resources and Can help reduce the waste of resources and prevent inappropriate treatmentprevent inappropriate treatment


Targeted Tuberculin Testing:Targeted Tuberculin Testing:Targeted Tuberculin Testing:Targeted Tuberculin Testing:Targeted Tuberculin Testing:Targeted Tuberculin Testing:

“… strategic component of TB control … identify “… strategic component of TB control … identify (patients with high) risk for developing TB …(patients with high) risk for developing TB …

… residents immigrating from high prevalence … residents immigrating from high prevalence countries (and other individuals at risk for countries (and other individuals at risk for infection)infection)

Targeted Tuberculin Testing:Targeted Tuberculin Testing:

“… strategic component of TB control … identify “… strategic component of TB control … identify (patients with high) risk for developing TB …(patients with high) risk for developing TB …

… residents immigrating from high prevalence … residents immigrating from high prevalence countries (and other individuals at risk for countries (and other individuals at risk for infection)infection)

… recent M Tb infection (new conversion)…… recent M Tb infection (new conversion)…

… clinical conditions associated with … clinical conditions associated with progression to active tuberculosisprogression to active tuberculosis.”.”

… recent M Tb infection (new conversion)…… recent M Tb infection (new conversion)…

… clinical conditions associated with … clinical conditions associated with progression to active tuberculosisprogression to active tuberculosis.”.”

AJRCCM 161: S221, 2000AJRCCM 161: S221, 2000AJRCCM 161: S221, 2000AJRCCM 161: S221, 2000

16


WhatWhat areas of the worldareas of the world are consideredare consideredWhatWhat areas of the worldareas of the world are consideredare consideredWhat What areas of the worldareas of the world are considered are considered high TB incidence or prevalence?high TB incidence or prevalence?

AsiaAsiaAfricaAfrica

Latin AmericaLatin AmericaEastern EuropeEastern Europe

What What areas of the worldareas of the world are considered are considered high TB incidence or prevalence?high TB incidence or prevalence?

AsiaAsiaAfricaAfrica

Latin AmericaLatin AmericaEastern EuropeEastern EuropeEastern EuropeEastern Europe

RussiaRussiaEastern EuropeEastern Europe

RussiaRussia

Core Curriculum on Tuberculosis CDC 2000Core Curriculum on Tuberculosis CDC 2000Core Curriculum on Tuberculosis CDC 2000Core Curriculum on Tuberculosis CDC 2000



“… “… individuals at risk for exposure to or infection individuals at risk for exposure to or infection with TB…with TB…

… residents immigrating from high prevalence … residents immigrating from high prevalence countries (select foreigncountries (select foreign--born individuals)born individuals)


“… “… individuals at risk for exposure to or infection individuals at risk for exposure to or infection with TB…with TB…

… residents immigrating from high prevalence … residents immigrating from high prevalence countries (select foreigncountries (select foreign--born individuals)born individuals)

•• close contacts new/suspected diseaseclose contacts new/suspected disease•• residents and employees highresidents and employees high--risk settingsrisk settings•• HCWs serving highHCWs serving high--risk individualsrisk individuals•• medically underservedmedically underserved•• those using IV drugs.”those using IV drugs.”

•• close contacts new/suspected diseaseclose contacts new/suspected disease•• residents and employees highresidents and employees high--risk settingsrisk settings•• HCWs serving highHCWs serving high--risk individualsrisk individuals•• medically underservedmedically underserved•• those using IV drugs.”those using IV drugs.”


17



“… “… individuals at higher risk for TB disease once individuals at higher risk for TB disease once infectedinfected ……

...recent M Tb infection (new conversion)...recent M Tb infection (new conversion)

… clinical conditions associated with … clinical conditions associated with


“… “… individuals at higher risk for TB disease once individuals at higher risk for TB disease once infectedinfected ……

...recent M Tb infection (new conversion)...recent M Tb infection (new conversion)

… clinical conditions associated with … clinical conditions associated with progression to active tuberculosisprogression to active tuberculosis•• HIV infectionHIV infection•• certain medical conditionscertain medical conditions•• those using IV drugsthose using IV drugs•• h/o inadequately treated TB”h/o inadequately treated TB”

progression to active tuberculosisprogression to active tuberculosis•• HIV infectionHIV infection•• certain medical conditionscertain medical conditions•• those using IV drugsthose using IV drugs•• h/o inadequately treated TB”h/o inadequately treated TB”


Conditions That Increase the Risk of Conditions That Increase the Risk of Progression to TB DiseaseProgression to TB Disease

Conditions That Increase the Risk of Conditions That Increase the Risk of Progression to TB DiseaseProgression to TB Disease

•• Diabetes mellitusDiabetes mellitus•• SilicosisSilicosis•• Prolonged corticosteroid therapyProlonged corticosteroid therapy•• Other immunosuppressive therapyOther immunosuppressive therapy•• Cancer of the head and neckCancer of the head and neck•• Hematologic and reticuloendothelial diseasesHematologic and reticuloendothelial diseases•• EndEnd--stage renal diseasestage renal disease•• Intestinal bypass or gastrectomyIntestinal bypass or gastrectomy

•• Diabetes mellitusDiabetes mellitus•• SilicosisSilicosis•• Prolonged corticosteroid therapyProlonged corticosteroid therapy•• Other immunosuppressive therapyOther immunosuppressive therapy•• Cancer of the head and neckCancer of the head and neck•• Hematologic and reticuloendothelial diseasesHematologic and reticuloendothelial diseases•• EndEnd--stage renal diseasestage renal disease•• Intestinal bypass or gastrectomyIntestinal bypass or gastrectomy•• Chronic malabsorption syndromesChronic malabsorption syndromes•• Low body weight (10% or more below the ideal)Low body weight (10% or more below the ideal)•• Chronic malabsorption syndromesChronic malabsorption syndromes•• Low body weight (10% or more below the ideal)Low body weight (10% or more below the ideal)

18












Tuberculin Skin Test (TST)Tuberculin Skin Test (TST)Tuberculin Skin Test (TST)Tuberculin Skin Test (TST)

oror

InterferonInterferon--γγ Release Assay (IGRA):Release Assay (IGRA):

QuantiFERONQuantiFERON®®--TBTB Gold Gold

oror


QuantiFERONQuantiFERON®®--TBTB Gold Gold

QuantiFERONQuantiFERON®®--TBTB GoldGold--IT (InIT (In--Tube)Tube)

TT--SPOTSPOT®.®.TBTB

QuantiFERONQuantiFERON®®--TBTB GoldGold--IT (InIT (In--Tube)Tube)

TT--SPOTSPOT®.®.TBTB

19



oror


QuantiFERON®QuantiFERON®--TB Gold TB Gold

oror



QuantiFERON®QuantiFERON®--TB GoldTB Gold--IT (InIT (In--Tube)Tube)

TT--SPOT®.SPOT®.TBTB



New Insights in the Diagnosis of New Insights in the Diagnosis of Tuberculosis InfectionTuberculosis Infection

Tuberculin Skin Test (TST)Tuberculin Skin Test (TST)


Tuberculin Skin Test (TST)Tuberculin Skin Test (TST)

••Century oldCentury old

••False +ve: False +ve: BCGBCG and and NonNon--tuberculous tuberculous mycobacteriamycobacteria

••Limited sensitivity: Limited sensitivity:

••Century oldCentury old

••False +ve: False +ve: BCGBCG and and NonNon--tuberculous tuberculous mycobacteriamycobacteria

••Limited sensitivity: Limited sensitivity: LTBI and active LTBI and active diseasedisease

••Variable interpretation Variable interpretation and need for return and need for return visitvisit

LTBI and active LTBI and active diseasedisease

••Variable interpretation Variable interpretation and need for return and need for return visitvisit

20

Classifying the Tuberculin ReactionClassifying the Tuberculin ReactionClassifying the Tuberculin ReactionClassifying the Tuberculin Reaction

5 mm is classified as positive in5 mm is classified as positive in5 mm is classified as positive in5 mm is classified as positive in

•• HIVHIV--positive personspositive persons

•• Recent contacts of TB caseRecent contacts of TB case

•• Persons with fibrotic changes on chest Persons with fibrotic changes on chest radiograph consistent with old healed TB radiograph consistent with old healed TB

P ti t ith t l t d thP ti t ith t l t d th

•• HIVHIV--positive personspositive persons

•• Recent contacts of TB caseRecent contacts of TB case

•• Persons with fibrotic changes on chest Persons with fibrotic changes on chest radiograph consistent with old healed TB radiograph consistent with old healed TB

P ti t ith t l t d thP ti t ith t l t d th•• Patients with organ transplants and other Patients with organ transplants and other immunosuppressed patientsimmunosuppressed patients

•• Patients with organ transplants and other Patients with organ transplants and other immunosuppressed patientsimmunosuppressed patients

Classifying the Tuberculin Classifying the Tuberculin Reaction (cont.)Reaction (cont.)


10 mm is classified as positive in10 mm is classified as positive in

R t i l f hi hR t i l f hi h l t il t i


R t i l f hi hR t i l f hi h l t il t i•• Recent arrivals from highRecent arrivals from high--prevalence countriesprevalence countries

•• Injection drug usersInjection drug users

•• Residents and employees of highResidents and employees of high--risk congregate risk congregate settingssettings

•• Mycobacteriology laboratory personnelMycobacteriology laboratory personnel

•• Recent arrivals from highRecent arrivals from high--prevalence countriesprevalence countries

•• Injection drug usersInjection drug users

•• Residents and employees of highResidents and employees of high--risk congregate risk congregate settingssettings

•• Mycobacteriology laboratory personnelMycobacteriology laboratory personnel

•• Persons with clinical conditions that place them at Persons with clinical conditions that place them at high riskhigh risk

•• Children <4 years of age, or children and adolescents Children <4 years of age, or children and adolescents exposed to adults in highexposed to adults in high--risk categoriesrisk categories

•• Persons with clinical conditions that place them at Persons with clinical conditions that place them at high riskhigh risk

•• Children <4 years of age, or children and adolescents Children <4 years of age, or children and adolescents exposed to adults in highexposed to adults in high--risk categoriesrisk categories

21



15 mm is classified as positive in15 mm is classified as positive in15 mm is classified as positive in15 mm is classified as positive in15 mm is classified as positive in15 mm is classified as positive in

•• Persons with no known risk factors for TBPersons with no known risk factors for TB

•• Targeted skin testing programs should only be Targeted skin testing programs should only be conducted among highconducted among high--risk groupsrisk groups


•• Persons with no known risk factors for TBPersons with no known risk factors for TB

•• Targeted skin testing programs should only be Targeted skin testing programs should only be conducted among highconducted among high--risk groupsrisk groups

BoostingBoostingBoostingBoosting

•• Some people with LTBI may have negative skin Some people with LTBI may have negative skin t t ti h t t d ft i f tit t ti h t t d ft i f ti•• Some people with LTBI may have negative skin Some people with LTBI may have negative skin t t ti h t t d ft i f tit t ti h t t d ft i f titest reaction when tested years after infectiontest reaction when tested years after infection

•• Initial skin test may stimulate (boost) ability to Initial skin test may stimulate (boost) ability to react to tuberculinreact to tuberculin

•• Positive reactions to subsequent tests may be Positive reactions to subsequent tests may be misinterpreted as a new infectionmisinterpreted as a new infection

test reaction when tested years after infectiontest reaction when tested years after infection

•• Initial skin test may stimulate (boost) ability to Initial skin test may stimulate (boost) ability to react to tuberculinreact to tuberculin

•• Positive reactions to subsequent tests may be Positive reactions to subsequent tests may be misinterpreted as a new infectionmisinterpreted as a new infection

22

TwoTwo--Step TestingStep TestingTwoTwo--Step TestingStep Testing

Use twoUse two--step testing for initial skin testing of step testing for initial skin testing of adults who will be retested periodicallyadults who will be retested periodically

Use twoUse two--step testing for initial skin testing of step testing for initial skin testing of adults who will be retested periodicallyadults who will be retested periodicallyyy

•• If first test positive, consider the person infectedIf first test positive, consider the person infected

•• If first test negative, give second test 1If first test negative, give second test 1--3 weeks 3 weeks laterlater

•• If second test positive, consider person infectedIf second test positive, consider person infected

yy

•• If first test positive, consider the person infectedIf first test positive, consider the person infected

•• If first test negative, give second test 1If first test negative, give second test 1--3 weeks 3 weeks laterlater

•• If second test positive, consider person infectedIf second test positive, consider person infected

•• If second test negative, consider person If second test negative, consider person uninfecteduninfected

•• If second test negative, consider person If second test negative, consider person uninfecteduninfected



oror



oror







23


IFNIFN--γγ Release Assays (IGRAs)Release Assays (IGRAs)



•• QuantiFERONQuantiFERON®®--TB GoldTB Gold (QFT(QFT--G) FDA approved G) FDA approved 3 D b 2004 (C ll ti )3 D b 2004 (C ll ti )

•• QuantiFERONQuantiFERON®®--TB GoldTB Gold (QFT(QFT--G) FDA approved G) FDA approved 3 D b 2004 (C ll ti )3 D b 2004 (C ll ti )3 December 2004 (Cellestis)3 December 2004 (Cellestis)

•• QuantiFERONQuantiFERON®®--TB Gold InTB Gold In--TubeTube (QFT(QFT--IT) FDA IT) FDA approved 10 October 2007 (Cellestis)approved 10 October 2007 (Cellestis)

•• TT--SPOTSPOT®® TBTB approved 30 July 2008approved 30 July 2008

3 December 2004 (Cellestis)3 December 2004 (Cellestis)

•• QuantiFERONQuantiFERON®®--TB Gold InTB Gold In--TubeTube (QFT(QFT--IT) FDA IT) FDA approved 10 October 2007 (Cellestis)approved 10 October 2007 (Cellestis)

•• TT--SPOTSPOT®® TBTB approved 30 July 2008approved 30 July 2008•• TT--SPOTSPOT®.®.TBTB approved 30 July 2008approved 30 July 2008(Oxford Immunotec)(Oxford Immunotec)

•• TT--SPOTSPOT®.®.TBTB approved 30 July 2008approved 30 July 2008(Oxford Immunotec)(Oxford Immunotec)





•• Quantifies IFNQuantifies IFN-- release by peripheral blood cells release by peripheral blood cells •• Quantifies IFNQuantifies IFN-- release by peripheral blood cells release by peripheral blood cells (T(T--cells CMI response) after stimulation with cells CMI response) after stimulation with M. M. tuberculosistuberculosis specific:specific:

•• ESATESAT--66: early: early--secreted antigen target 6secreted antigen target 6•• CFPCFP--1010: culture filtrate protein 10: culture filtrate protein 10•• TB 7.7(p4)TB 7.7(p4): (QuantiFERON: (QuantiFERON®®--TBTB Gold IT only)Gold IT only)

(T(T--cells CMI response) after stimulation with cells CMI response) after stimulation with M. M. tuberculosistuberculosis specific:specific:

•• ESATESAT--66: early: early--secreted antigen target 6secreted antigen target 6•• CFPCFP--1010: culture filtrate protein 10: culture filtrate protein 10•• TB 7.7(p4)TB 7.7(p4): (QuantiFERON: (QuantiFERON®®--TBTB Gold IT only)Gold IT only)TB 7.7(p4)TB 7.7(p4): (QuantiFERON: (QuantiFERON®® TBTB Gold IT only)Gold IT only)TB 7.7(p4)TB 7.7(p4): (QuantiFERON: (QuantiFERON®® TBTB Gold IT only)Gold IT only)

24





•• ESATESAT--6 and CFP6 and CFP--10 (and TB 7.7(p4))10 (and TB 7.7(p4))•• ESATESAT--6 and CFP6 and CFP--10 (and TB 7.7(p4))10 (and TB 7.7(p4))•• no cross reactivity withno cross reactivity with

•• BCG (TST no impact)BCG (TST no impact)•• most NTM, except M. kansasii, M. most NTM, except M. kansasii, M.

szulgai, and M. marinumszulgai, and M. marinum•• + reactivity with M. bovis, africanum, microti+ reactivity with M. bovis, africanum, microti

C t l tiC t l ti

•• no cross reactivity withno cross reactivity with•• BCG (TST no impact)BCG (TST no impact)•• most NTM, except M. kansasii, M. most NTM, except M. kansasii, M.

szulgai, and M. marinumszulgai, and M. marinum•• + reactivity with M. bovis, africanum, microti+ reactivity with M. bovis, africanum, microti

C t l tiC t l ti•• Control antigensControl antigens•• nil (negative) control antigennil (negative) control antigen•• mitogen phytohemagglutinin (positive) mitogen phytohemagglutinin (positive)

control antigencontrol antigen

•• Control antigensControl antigens•• nil (negative) control antigennil (negative) control antigen•• mitogen phytohemagglutinin (positive) mitogen phytohemagglutinin (positive)

control antigencontrol antigen





•• POSITIVEPOSITIVE IFNIFN--γγ signal:signal:•• POSITIVEPOSITIVE IFNIFN--γγ signal:signal:•• ESATESAT--6 6 -- nil ornil or•• CFPCFP--10 10 -- nil ornil or•• (or TB 7.7(p4) (or TB 7.7(p4) -- nil) nil)

•• NEGATIVENEGATIVE IFNIFN--γγ signal:signal:

•• ESATESAT--6 6 -- nil ornil or•• CFPCFP--10 10 -- nil ornil or•• (or TB 7.7(p4) (or TB 7.7(p4) -- nil) nil)

•• NEGATIVENEGATIVE IFNIFN--γγ signal:signal:

•• INDETERMINATEINDETERMINATE::•• Low mitogen response (positive control)Low mitogen response (positive control)•• Large nil response (negative control)Large nil response (negative control)

•• INDETERMINATEINDETERMINATE::•• Low mitogen response (positive control)Low mitogen response (positive control)•• Large nil response (negative control)Large nil response (negative control)

25





Advantages over TST:Advantages over TST:Advantages over TST:Advantages over TST:•• Single visitSingle visit•• Blood draw versus ID injection Blood draw versus ID injection --acceptanceacceptance•• Less variation in application and Less variation in application and

interpretationinterpretation•• No cross reactivity with BCGNo cross reactivity with BCG•• No boosting with serial IGRA testingNo boosting with serial IGRA testing•• CostCost--effectiveness in select populationseffectiveness in select populations

•• Single visitSingle visit•• Blood draw versus ID injection Blood draw versus ID injection --acceptanceacceptance•• Less variation in application and Less variation in application and

interpretationinterpretation•• No cross reactivity with BCGNo cross reactivity with BCG•• No boosting with serial IGRA testingNo boosting with serial IGRA testing•• CostCost--effectiveness in select populationseffectiveness in select populations•• CostCost--effectiveness in select populationseffectiveness in select populations

•• ContactsContacts•• HCWHCW•• FB(?)FB(?)

•• CostCost--effectiveness in select populationseffectiveness in select populations•• ContactsContacts•• HCWHCW•• FB(?)FB(?)



Diagnosis of LTBI:Diagnosis of LTBI:

1. TST versus IGRAs ?1. TST versus IGRAs ?


1. TST versus IGRAs ?1. TST versus IGRAs ?

2. QFT2. QFT--Gold IT versus TGold IT versus T--SPOT.SPOT.TB TB ??2. QFT2. QFT--Gold IT versus TGold IT versus T--SPOT.SPOT.TB TB ??

26




1. TST versus IGRAs ?: 1. TST versus IGRAs ?: DEPENDSDEPENDS


1. TST versus IGRAs ?: 1. TST versus IGRAs ?: DEPENDSDEPENDS

2. QFT2. QFT--Gold IT versus TGold IT versus T--SPOT.SPOT.TB TB ?: ?: DEPENDSDEPENDS2. QFT2. QFT--Gold IT versus TGold IT versus T--SPOT.SPOT.TB TB ?: ?: DEPENDSDEPENDS



BMJ 327 1459 2003BMJ 327 1459 2003BMJ 327:1459, 2003BMJ 327:1459, 2003

27



BMJ 327 1459 2003BMJ 327 1459 2003BMJ 327:1459, 2003BMJ 327:1459, 2003

New Insights in the Diagnosis of New Insights in the Diagnosis of Tuberculosis InfectionTuberculosis Infection--LTBILTBI

5 Aug 20085 Aug 2008

New Insights in the Diagnosis of New Insights in the Diagnosis of Tuberculosis InfectionTuberculosis Infection--LTBILTBI

5 Aug 20085 Aug 2008

Ann Intern Med 149: 177, 2008Ann Intern Med 149: 177, 2008Ann Intern Med 149: 177, 2008Ann Intern Med 149: 177, 2008

28

New Insights in the Diagnosis of New Insights in the Diagnosis of Tuberculosis InfectionTuberculosis Infection-- LTBI LTBI Systematic Review: Pai, et al.Systematic Review: Pai, et al.


SensitivitySensitivity: studies of microbiologically confirmed: studies of microbiologically confirmedSensitivitySensitivity: studies of microbiologically confirmed: studies of microbiologically confirmedSensitivitySensitivity: studies of microbiologically confirmed : studies of microbiologically confirmed TB disease, not only immunocompromised TB disease, not only immunocompromised patientspatients

SpecificitySpecificity: studies of healthy, low: studies of healthy, low--risk individuals risk individuals without known exposure to tuberculosis who without known exposure to tuberculosis who were from low TB incidence countrieswere from low TB incidence countries

Separated BCGSeparated BCG vaccinated from nonvaccinated from non BCG patientsBCG patients

SensitivitySensitivity: studies of microbiologically confirmed : studies of microbiologically confirmed TB disease, not only immunocompromised TB disease, not only immunocompromised patientspatients

SpecificitySpecificity: studies of healthy, low: studies of healthy, low--risk individuals risk individuals without known exposure to tuberculosis who without known exposure to tuberculosis who were from low TB incidence countrieswere from low TB incidence countries

Separated BCGSeparated BCG vaccinated from nonvaccinated from non BCG patientsBCG patientsSeparated BCGSeparated BCG--vaccinated from nonvaccinated from non--BCG patients BCG patients

Included: TST, QFT (QFTIncluded: TST, QFT (QFT--Gold and Gold and --IT), and TIT), and T--SPOTSPOT

38 articles; at least 10 participants/study38 articles; at least 10 participants/study

Separated BCGSeparated BCG--vaccinated from nonvaccinated from non--BCG patients BCG patients

Included: TST, QFT (QFTIncluded: TST, QFT (QFT--Gold and Gold and --IT), and TIT), and T--SPOTSPOT

38 articles; at least 10 participants/study38 articles; at least 10 participants/study

Ann Intern Med 149: 177, 2008Ann Intern Med 149: 177, 2008Ann Intern Med 149: 177, 2008Ann Intern Med 149: 177, 2008



Sensitivity*Sensitivity* PhPhSensitivity*Sensitivity* PhPhSensitivity*Sensitivity* PharmaPharma

(range)(range)

TSTTST 0.77 (0.710.77 (0.71--0.82)0.82) 0.75: 0.64 0.75: 0.64 -- 0.880.88

QFTQFT--GoldGold 0.78 (0.730.78 (0.73--0.82)0.82) 0.84: 0.64 0.84: 0.64 -- 1.001.00

QFTQFT--ITIT 0.70 (0.630.70 (0.63--0.78)0.78) 0.91: 0.70 0.91: 0.70 -- 1.001.00

Sensitivity*Sensitivity* PharmaPharma

(range)(range)

TSTTST 0.77 (0.710.77 (0.71--0.82)0.82) 0.75: 0.64 0.75: 0.64 -- 0.880.88

QFTQFT--GoldGold 0.78 (0.730.78 (0.73--0.82)0.82) 0.84: 0.64 0.84: 0.64 -- 1.001.00

QFTQFT--ITIT 0.70 (0.630.70 (0.63--0.78)0.78) 0.91: 0.70 0.91: 0.70 -- 1.001.00(( ))

TT--SPOTSPOT 0.90 (0.860.90 (0.86--0.93)0.93) 0.96: 0.92 0.96: 0.92 -- 0.980.98

(( ))

TT--SPOTSPOT 0.90 (0.860.90 (0.86--0.93)0.93) 0.96: 0.92 0.96: 0.92 -- 0.980.98

Ann Intern Med 149: 177, 2008Ann Intern Med 149: 177, 2008Ann Intern Med 149: 177, 2008Ann Intern Med 149: 177, 2008**( 95%CI)( 95%CI)**( 95%CI)( 95%CI)

29



Specificity*Specificity*Specificity*Specificity*Specificity*Specificity*BCGBCG nonnon--BCGBCG PharmaPharma

TSTTST 0.590.59 0.970.97 0.870.87

QFTQFT--G & ITG & IT 0.960.96 0.990.99 0.990.99

TT--SPOTSPOT 0.93 0.93 0.970.97

Specificity*Specificity*BCGBCG nonnon--BCGBCG PharmaPharma

TSTTST 0.590.59 0.970.97 0.870.87

QFTQFT--G & ITG & IT 0.960.96 0.990.99 0.990.99

TT--SPOTSPOT 0.93 0.93 0.970.97

Ann Intern Med 149: 177, 2008Ann Intern Med 149: 177, 2008Ann Intern Med 149: 177, 2008Ann Intern Med 149: 177, 2008**( 95%CI)( 95%CI)**( 95%CI)( 95%CI)





QFTQFT--GoldGold--ITIT TT--SPOTSPOT®.®.TBTBQFTQFT--GoldGold--ITIT TT--SPOTSPOT®.®.TBTB

ImmunocompromisedImmunocompromised XX XXXX

Children less than 5 yr Children less than 5 yr XX XXXX

Contact investigationsContact investigations XX XXXX

Indeterminate resultsIndeterminate results XX XXXX

S ifi itS ifi it XXXX XXXX

ImmunocompromisedImmunocompromised XX XXXX

Children less than 5 yr Children less than 5 yr XX XXXX

Contact investigationsContact investigations XX XXXX

Indeterminate resultsIndeterminate results XX XXXX

S ifi itS ifi it XXXX XXXXSpecificitySpecificity XXXX XXXX

Laboratory intensityLaboratory intensity XXXX XX

Specimen time to processSpecimen time to process XXXX XX

SpecificitySpecificity XXXX XXXX

Laboratory intensityLaboratory intensity XXXX XX

Specimen time to processSpecimen time to process XXXX XX

ERJ 28: 24, 2006ERJ 28: 24, 2006Lancet 367: 1328, 2006Lancet 367: 1328, 2006ERJ 28: 24, 2006ERJ 28: 24, 2006Lancet 367: 1328, 2006Lancet 367: 1328, 2006

30





Serial IGRAs testingSerial IGRAs testing for response to treatment to LTBI for response to treatment to LTBI Serial IGRAs testingSerial IGRAs testing for response to treatment to LTBI for response to treatment to LTBI or TB disease?or TB disease?

NONO (at this time…)(at this time…)

•• Natural history of conversion and reversions is Natural history of conversion and reversions is unknown and unpredictable.unknown and unpredictable.

or TB disease?or TB disease?

NONO (at this time…)(at this time…)

•• Natural history of conversion and reversions is Natural history of conversion and reversions is unknown and unpredictable.unknown and unpredictable.

•• IGRA may increase, decrease, or demonstrate no IGRA may increase, decrease, or demonstrate no changechange

•• IGRA may increase, decrease, or demonstrate no IGRA may increase, decrease, or demonstrate no changechange

AJRCCM 174:349: 2006 CID 40: 1301, 2005AJRCCM 174:349: 2006 CID 40: 1301, 2005JID 193: 354, 2006JID 193: 354, 2006 JImmun 167: 5217, 2001JImmun 167: 5217, 2001IJTLD 9: 1034, 2005IJTLD 9: 1034, 2005

AJRCCM 174:349: 2006 CID 40: 1301, 2005AJRCCM 174:349: 2006 CID 40: 1301, 2005JID 193: 354, 2006JID 193: 354, 2006 JImmun 167: 5217, 2001JImmun 167: 5217, 2001IJTLD 9: 1034, 2005IJTLD 9: 1034, 2005





Does Does boostingboosting occur with IGRAs testing following occur with IGRAs testing following Does Does boostingboosting occur with IGRAs testing following occur with IGRAs testing following TST testing?TST testing?

Boosting of QFTBoosting of QFT--GIT is possible from serial TST GIT is possible from serial TST testing.testing.

TST testing?TST testing?

Boosting of QFTBoosting of QFT--GIT is possible from serial TST GIT is possible from serial TST testing.testing.

ERJ 29: 1212, 2007ERJ 29: 1212, 2007IUTLD 9:985, 2005IUTLD 9:985, 2005IUTLD 11: 788, 2007IUTLD 11: 788, 2007

ERJ 29: 1212, 2007ERJ 29: 1212, 2007IUTLD 9:985, 2005IUTLD 9:985, 2005IUTLD 11: 788, 2007IUTLD 11: 788, 2007

31





Does a Does a positive IGRAspositive IGRAs mean that an individual with mean that an individual with Does a Does a positive IGRAspositive IGRAs mean that an individual with mean that an individual with latent TB infection is at latent TB infection is at greater riskgreater risk of developing of developing TB disease in the future?TB disease in the future?

•• UncertainUncertain

•• Longitudinal studies pendingLongitudinal studies pending

latent TB infection is at latent TB infection is at greater riskgreater risk of developing of developing TB disease in the future?TB disease in the future?

•• UncertainUncertain

•• Longitudinal studies pendingLongitudinal studies pending•• Longitudinal studies pendingLongitudinal studies pending

•• Contacts at increased risk, relative to TST (BCG Contacts at increased risk, relative to TST (BCG exposure 46%)exposure 46%)

•• Longitudinal studies pendingLongitudinal studies pending

•• Contacts at increased risk, relative to TST (BCG Contacts at increased risk, relative to TST (BCG exposure 46%)exposure 46%)

ARJCCM 177: 1164, 2008ARJCCM 177: 1164, 2008ARJCCM 177: 1164, 2008ARJCCM 177: 1164, 2008





Is IGRAs testing Is IGRAs testing cost effectivecost effective for testing for latent TB for testing for latent TB Is IGRAs testing Is IGRAs testing cost effectivecost effective for testing for latent TB for testing for latent TB infection?infection?

•• YesYes, but depends…on local culture, but depends…on local culture

•• Single visitSingle visit

•• Higher specificity than TST (BCG, NTM)Higher specificity than TST (BCG, NTM)

infection?infection?

•• YesYes, but depends…on local culture, but depends…on local culture

•• Single visitSingle visit

•• Higher specificity than TST (BCG, NTM)Higher specificity than TST (BCG, NTM)

•• Reduce personnel cost, time awayReduce personnel cost, time away

•• Less chest xLess chest x--rays, investigation, LTBI treatmentrays, investigation, LTBI treatment

•• Direct and indirect costsDirect and indirect costs

•• Reduce personnel cost, time awayReduce personnel cost, time away

•• Less chest xLess chest x--rays, investigation, LTBI treatmentrays, investigation, LTBI treatment

•• Direct and indirect costsDirect and indirect costs

32





•• Markov modelsMarkov models•• Close contacts: Diel et al. (Western Europe)Close contacts: Diel et al. (Western Europe)•• HCW: dePerio et al. (Cincinnati VA)HCW: dePerio et al. (Cincinnati VA)

•• Both suggest that IGRAs are costBoth suggest that IGRAs are cost--effectiveeffective

•• Markov modelsMarkov models•• Close contacts: Diel et al. (Western Europe)Close contacts: Diel et al. (Western Europe)•• HCW: dePerio et al. (Cincinnati VA)HCW: dePerio et al. (Cincinnati VA)

•• Both suggest that IGRAs are costBoth suggest that IGRAs are cost--effectiveeffective

ERJ 30: 321, 2007ERJ 30: 321, 2007IUATLD Abstract N Amer 2008IUATLD Abstract N Amer 2008InfConHospEpi 24: 814, 2003InfConHospEpi 24: 814, 2003

ERJ 30: 321, 2007ERJ 30: 321, 2007IUATLD Abstract N Amer 2008IUATLD Abstract N Amer 2008InfConHospEpi 24: 814, 2003InfConHospEpi 24: 814, 2003





Can IGRAs testing be used in place of TST?Can IGRAs testing be used in place of TST?Can IGRAs testing be used in place of TST?Can IGRAs testing be used in place of TST?

•• YesYes

CDC Guidelines QFTCDC Guidelines QFT--Gold 2005:Gold 2005:

QFTQFT--Gold can be used in Gold can be used in all circumstancesall circumstances in which in which the TST is used including:the TST is used including:

•• YesYes

CDC Guidelines QFTCDC Guidelines QFT--Gold 2005:Gold 2005:

QFTQFT--Gold can be used in Gold can be used in all circumstancesall circumstances in which in which the TST is used including:the TST is used including:

•• contact investigationscontact investigations•• evaluation of recent immigrants (BCG)evaluation of recent immigrants (BCG)•• TB screening HCW, including serial screeningTB screening HCW, including serial screening

•• contact investigationscontact investigations•• evaluation of recent immigrants (BCG)evaluation of recent immigrants (BCG)•• TB screening HCW, including serial screeningTB screening HCW, including serial screening

MMWR 54: RRMMWR 54: RR--15, 2005 MMWR 54: RR15, 2005 MMWR 54: RR--17, 200517, 2005MMWR 54: RRMMWR 54: RR--15, 2005 MMWR 54: RR15, 2005 MMWR 54: RR--17, 200517, 2005

33





Should IGRAs testing always be used first for LTBI Should IGRAs testing always be used first for LTBI Should IGRAs testing always be used first for LTBI Should IGRAs testing always be used first for LTBI testing in place of TST?testing in place of TST?

•• NoNo

•• National Institute for Health and Clinical Excellence (NICE) UKNational Institute for Health and Clinical Excellence (NICE) UK

tt

testing in place of TST?testing in place of TST?

•• NoNo

•• National Institute for Health and Clinical Excellence (NICE) UKNational Institute for Health and Clinical Excellence (NICE) UK

tt•• Two step strategyTwo step strategy: 1: 1stst TST, if positive TST then TST, if positive TST then IGRAIGRA

•• If +ve TST, If +ve TST, --ve IGRAs: consider false positive TST, ve IGRAs: consider false positive TST, infection unlikelyinfection unlikely

•• Two step strategyTwo step strategy: 1: 1stst TST, if positive TST then TST, if positive TST then IGRAIGRA

•• If +ve TST, If +ve TST, --ve IGRAs: consider false positive TST, ve IGRAs: consider false positive TST, infection unlikelyinfection unlikely

HPE guideline March 2008 NICE NHS guideline March 2006HPE guideline March 2008 NICE NHS guideline March 2006HPE guideline March 2008 NICE NHS guideline March 2006HPE guideline March 2008 NICE NHS guideline March 2006





Should IGRAs testing always be used first for LTBI Should IGRAs testing always be used first for LTBI Should IGRAs testing always be used first for LTBI Should IGRAs testing always be used first for LTBI testing in place of TST?testing in place of TST?

•• NoNo

•• IGRAs as sole testingIGRAs as sole testing::th ith t ti l f l ti TSTth ith t ti l f l ti TST

testing in place of TST?testing in place of TST?

•• NoNo

•• IGRAs as sole testingIGRAs as sole testing::th ith t ti l f l ti TSTth ith t ti l f l ti TST•• those with potential false negative TST, those with potential false negative TST, immunocompromisedimmunocompromised

•• screening large numbers PHDscreening large numbers PHD•• HCW HCW

•• those with potential false negative TST, those with potential false negative TST, immunocompromisedimmunocompromised

•• screening large numbers PHDscreening large numbers PHD•• HCW HCW

HPE guideline March 2008 NICE NHS guideline March 2006HPE guideline March 2008 NICE NHS guideline March 2006HPE guideline March 2008 NICE NHS guideline March 2006HPE guideline March 2008 NICE NHS guideline March 2006

34


IFNIFN--γγ Release Assays (IGRAs)Release Assays (IGRAs)Future directionsFuture directions


IFNIFN--γγ Release Assays (IGRAs)Release Assays (IGRAs)Future directionsFuture directions

•• Predictive of TB disease in LTBI (natural history)Predictive of TB disease in LTBI (natural history)

•• Indeterminate resultsIndeterminate results

•• Cut points Cut points –– TST (5,10,15) vs. IGRAs (0.35 QFT, 8 spots TST (5,10,15) vs. IGRAs (0.35 QFT, 8 spots TT--SPOT)SPOT)

•• Predictive of TB disease in LTBI (natural history)Predictive of TB disease in LTBI (natural history)

•• Indeterminate resultsIndeterminate results

•• Cut points Cut points –– TST (5,10,15) vs. IGRAs (0.35 QFT, 8 spots TST (5,10,15) vs. IGRAs (0.35 QFT, 8 spots TT--SPOT)SPOT)

•• Specific IGRAs for specific patients Specific IGRAs for specific patients –– TNF inhibitor, TNF inhibitor, immunocompromisedimmunocompromised

•• CostCost--effectiveness for varying practiceseffectiveness for varying practices

•• Specific IGRAs for specific patients Specific IGRAs for specific patients –– TNF inhibitor, TNF inhibitor, immunocompromisedimmunocompromised

•• CostCost--effectiveness for varying practiceseffectiveness for varying practices











35

LTBI Treatment RegimensLTBI Treatment RegimensLTBI Treatment RegimensLTBI Treatment Regimens

Initiating TreatmentInitiating TreatmentInitiating TreatmentInitiating Treatment

Before initiating treatment for LTBIBefore initiating treatment for LTBI

•• Rule out TB disease (i.e., wait for culture result if Rule out TB disease (i.e., wait for culture result if

Before initiating treatment for LTBIBefore initiating treatment for LTBI

•• Rule out TB disease (i.e., wait for culture result if Rule out TB disease (i.e., wait for culture result if specimen obtained)specimen obtained)

•• Determine prior history of treatment for LTBI or TB Determine prior history of treatment for LTBI or TB diseasedisease

•• Assess risks and benefits of treatmentAssess risks and benefits of treatment

•• Determine current and previous drug therapyDetermine current and previous drug therapy

specimen obtained)specimen obtained)

•• Determine prior history of treatment for LTBI or TB Determine prior history of treatment for LTBI or TB diseasedisease

•• Assess risks and benefits of treatmentAssess risks and benefits of treatment

•• Determine current and previous drug therapyDetermine current and previous drug therapy

36

Isoniazid RegimensIsoniazid RegimensIsoniazid RegimensIsoniazid Regimens

•• 99--month regimen of isoniazid (INH) is the preferred month regimen of isoniazid (INH) is the preferred regimenregimen

•• 99--month regimen of isoniazid (INH) is the preferred month regimen of isoniazid (INH) is the preferred regimenregimengg

•• 66--month regimen is less effective but may be used if month regimen is less effective but may be used if unable to complete 9 monthsunable to complete 9 months

•• May be given daily or intermittently (twice weekly)May be given daily or intermittently (twice weekly)•• Use directly observed therapy (DOT) for Use directly observed therapy (DOT) for

intermittent regimenintermittent regimen

gg

•• 66--month regimen is less effective but may be used if month regimen is less effective but may be used if unable to complete 9 monthsunable to complete 9 months

•• May be given daily or intermittently (twice weekly)May be given daily or intermittently (twice weekly)•• Use directly observed therapy (DOT) for Use directly observed therapy (DOT) for

intermittent regimenintermittent regimen



37

IsoniazidIsoniazid RegimensRegimensIsoniazidIsoniazid RegimensRegimens

•• INH daily for 9 months INH daily for 9 months (270 doses within 12 months)(270 doses within 12 months)


•• INH twice/week for 9 months INH twice/week for 9 months (76 doses within 12 months)(76 doses within 12 months)





•• INH twice/week for 6 months INH twice/week for 6 months (52 doses within 9 months)(52 doses within 9 months)(52 doses within 9 months)(52 doses within 9 months)(52 doses within 9 months)(52 doses within 9 months)

Rifampin RegimensRifampin RegimensRifampin RegimensRifampin Regimens

•• Rifampin (RIF) given daily for 4 months is an Rifampin (RIF) given daily for 4 months is an acceptable alternative when treatment with INH is notacceptable alternative when treatment with INH is not

•• Rifampin (RIF) given daily for 4 months is an Rifampin (RIF) given daily for 4 months is an acceptable alternative when treatment with INH is notacceptable alternative when treatment with INH is notacceptable alternative when treatment with INH is not acceptable alternative when treatment with INH is not feasible.feasible.

•• In situations where RIF cannot be used In situations where RIF cannot be used (e.g., HIV(e.g., HIV--infected persons receiving protease infected persons receiving protease inhibitors), rifabutin may be substituted.inhibitors), rifabutin may be substituted.

acceptable alternative when treatment with INH is not acceptable alternative when treatment with INH is not feasible.feasible.

•• In situations where RIF cannot be used In situations where RIF cannot be used (e.g., HIV(e.g., HIV--infected persons receiving protease infected persons receiving protease inhibitors), rifabutin may be substituted.inhibitors), rifabutin may be substituted.

38

Rifampin RegimensRifampin RegimensRifampin RegimensRifampin Regimens

•• RIF daily for 4 months RIF daily for 4 months (120 d ithi 6 th )(120 d ithi 6 th )

•• RIF daily for 4 months RIF daily for 4 months (120 d ithi 6 th )(120 d ithi 6 th )(120 doses within 6 months)(120 doses within 6 months)

•• RIF and PZA for 2 months should generally not RIF and PZA for 2 months should generally not be offered due to risk of severe adverse eventsbe offered due to risk of severe adverse events66

(120 doses within 6 months)(120 doses within 6 months)

•• RIF and PZA for 2 months should generally not RIF and PZA for 2 months should generally not be offered due to risk of severe adverse eventsbe offered due to risk of severe adverse events66

__________________________________________________________________________

66MMWR MMWR August 8, 2003; 52 (31): 735August 8, 2003; 52 (31): 735--739739

__________________________________________________________________________

66MMWR MMWR August 8, 2003; 52 (31): 735August 8, 2003; 52 (31): 735--739739

Completion of TherapyCompletion of TherapyCompletion of TherapyCompletion of Therapy

Completion of therapy is based on the total Completion of therapy is based on the total number of doses administered, not on number of doses administered, not on duration alone.duration alone.

Completion of therapy is based on the total Completion of therapy is based on the total number of doses administered, not on number of doses administered, not on duration alone.duration alone.

39

Management of Patient Who Missed DosesManagement of Patient Who Missed DosesManagement of Patient Who Missed DosesManagement of Patient Who Missed Doses

•• Extend or reExtend or re--start treatment if interruptions were start treatment if interruptions were frequent or prolonged enough to precludefrequent or prolonged enough to preclude

•• Extend or reExtend or re--start treatment if interruptions were start treatment if interruptions were frequent or prolonged enough to precludefrequent or prolonged enough to precludefrequent or prolonged enough to preclude frequent or prolonged enough to preclude completioncompletion

•• When treatment has been interrupted for more When treatment has been interrupted for more than 2 months, patient should be examined to than 2 months, patient should be examined to rule out TB diseaserule out TB disease

•• Recommend and arrange for DOT as neededRecommend and arrange for DOT as needed

frequent or prolonged enough to preclude frequent or prolonged enough to preclude completioncompletion

•• When treatment has been interrupted for more When treatment has been interrupted for more than 2 months, patient should be examined to than 2 months, patient should be examined to rule out TB diseaserule out TB disease

•• Recommend and arrange for DOT as neededRecommend and arrange for DOT as needed



MMWR 52: 735, 2003MMWR 52: 735, 2003

40

Short Course Therapy with RIF plus Short Course Therapy with RIF plus INH 3 Months versus Standard INHINH 3 Months versus Standard INHShort Course Therapy with RIF plus Short Course Therapy with RIF plus INH 3 Months versus Standard INHINH 3 Months versus Standard INH

•• Not CDC approved for LTBI (as of 2000 with updates)Not CDC approved for LTBI (as of 2000 with updates)

M tM t l i LTBI t t tl i LTBI t t t

•• Not CDC approved for LTBI (as of 2000 with updates)Not CDC approved for LTBI (as of 2000 with updates)

M tM t l i LTBI t t tl i LTBI t t t•• MetaMeta--analysis LTBI treatmentanalysis LTBI treatment

•• Pooled 1926 patients (5 studies) Hong Kong, Spain, and UgandaPooled 1926 patients (5 studies) Hong Kong, Spain, and Uganda

•• Equivalent to standard therapy with INH (IR3 vs I6Equivalent to standard therapy with INH (IR3 vs I6--12) :12) :•• Efficacy (4.2% vs. 4.1%)Efficacy (4.2% vs. 4.1%)•• Severe side effects (4.9% vs. 4.8%)Severe side effects (4.9% vs. 4.8%)

M t lit (9 5% 10 4%)M t lit (9 5% 10 4%)

•• MetaMeta--analysis LTBI treatmentanalysis LTBI treatment

•• Pooled 1926 patients (5 studies) Hong Kong, Spain, and UgandaPooled 1926 patients (5 studies) Hong Kong, Spain, and Uganda

•• Equivalent to standard therapy with INH (IR3 vs I6Equivalent to standard therapy with INH (IR3 vs I6--12) :12) :•• Efficacy (4.2% vs. 4.1%)Efficacy (4.2% vs. 4.1%)•• Severe side effects (4.9% vs. 4.8%)Severe side effects (4.9% vs. 4.8%)

M t lit (9 5% 10 4%)M t lit (9 5% 10 4%)•• Mortality (9.5% vs. 10.4%)Mortality (9.5% vs. 10.4%)

•• Also equally effective in pediatric population, better completion Also equally effective in pediatric population, better completion (Greece)(Greece)

•• Mortality (9.5% vs. 10.4%)Mortality (9.5% vs. 10.4%)

•• Also equally effective in pediatric population, better completion Also equally effective in pediatric population, better completion (Greece)(Greece)

CID 40: 670CID 40: 670--676, 2005676, 2005CID 45: 715CID 45: 715--722, 2007722, 2007CID 40: 670CID 40: 670--676, 2005676, 2005CID 45: 715CID 45: 715--722, 2007722, 2007

Latent TB Infection (LTBI)Latent TB Infection (LTBI)TreatmentTreatment


•• Prospective MC treatment trial 4RIF vs 9INH Prospective MC treatment trial 4RIF vs 9INH -- LTBILTBI

•• N=847 Canada Saudi Arabia BrazilN=847 Canada Saudi Arabia Brazil


•• N=847 Canada Saudi Arabia BrazilN=847 Canada Saudi Arabia Brazil•• N=847 Canada, Saudi Arabia, BrazilN=847 Canada, Saudi Arabia, Brazil

•• Treatment completion: 78% vs. 60% (p<0.001)Treatment completion: 78% vs. 60% (p<0.001)

•• AE: 1.7% vs. 4.0%AE: 1.7% vs. 4.0%•• Grade 3Grade 3--4 hepatitis: 0.7% vs. 3.8%4 hepatitis: 0.7% vs. 3.8%

•• N=847 Canada, Saudi Arabia, BrazilN=847 Canada, Saudi Arabia, Brazil



Ann Int Med 149: 689, 2008Ann Int Med 149: 689, 2008Ann Int Med 149: 689, 2008Ann Int Med 149: 689, 2008

41




•• N=847 Canada Saudi Arabia BrazilN=847 Canada Saudi Arabia Brazil


•• N=847 Canada Saudi Arabia BrazilN=847 Canada Saudi Arabia Brazil•• N=847 Canada, Saudi Arabia, BrazilN=847 Canada, Saudi Arabia, Brazil



------------------------------------------------------------------------------------------------------------------------------

TBTC St d 26 8000 3RFP kl INH 9INHTBTC St d 26 8000 3RFP kl INH 9INH

•• N=847 Canada, Saudi Arabia, BrazilN=847 Canada, Saudi Arabia, Brazil



------------------------------------------------------------------------------------------------------------------------------

TBTC St d 26 8000 3RFP kl INH 9INHTBTC St d 26 8000 3RFP kl INH 9INH•• TBTC Study26: n=8000 3RFPweekly+INH vs. 9INHTBTC Study26: n=8000 3RFPweekly+INH vs. 9INH

•• Mouse model: 2RFPdaily+INH = 2RIF+PZAMouse model: 2RFPdaily+INH = 2RIF+PZA

•• RIF costRIF cost--saving Markov: 4RIF, 3RFP+INHdot, 9INH, 9INHdotsaving Markov: 4RIF, 3RFP+INHdot, 9INH, 9INHdot

•• TBTC Study26: n=8000 3RFPweekly+INH vs. 9INHTBTC Study26: n=8000 3RFPweekly+INH vs. 9INH

•• Mouse model: 2RFPdaily+INH = 2RIF+PZAMouse model: 2RFPdaily+INH = 2RIF+PZA

•• RIF costRIF cost--saving Markov: 4RIF, 3RFP+INHdot, 9INH, 9INHdotsaving Markov: 4RIF, 3RFP+INHdot, 9INH, 9INHdot

Ann Int Med 149: 689, 2008Ann Int Med 149: 689, 2008World Cong TB Wash DC Jun 2002World Cong TB Wash DC Jun 2002AJRCCM 179: A1017, 2009 AJRCCM 179: A1017, 2009 AJRCCM 179: 1055, 2009AJRCCM 179: 1055, 2009

Ann Int Med 149: 689, 2008Ann Int Med 149: 689, 2008World Cong TB Wash DC Jun 2002World Cong TB Wash DC Jun 2002AJRCCM 179: A1017, 2009 AJRCCM 179: A1017, 2009 AJRCCM 179: 1055, 2009AJRCCM 179: 1055, 2009

Class V versus LTBIClass V versus LTBIClass V versus LTBIClass V versus LTBI

•• Class V pulmonary TB evaluation and treatmentClass V pulmonary TB evaluation and treatment•• Class V pulmonary TB evaluation and treatmentClass V pulmonary TB evaluation and treatment

•• Start treatment for culture negative disease Start treatment for culture negative disease

•• Four drugs: RIF, INH, EMB, and PZAFour drugs: RIF, INH, EMB, and PZA

•• Reassess at 2 monthsReassess at 2 months

•• If no change in radiograph noted and patient felt to If no change in radiograph noted and patient felt to have LTBI have LTBI –– receives credit for receives credit for LTBI treatmentLTBI treatment and and

di ti di ti ddi ti di ti d

•• Start treatment for culture negative disease Start treatment for culture negative disease

•• Four drugs: RIF, INH, EMB, and PZAFour drugs: RIF, INH, EMB, and PZA

•• Reassess at 2 monthsReassess at 2 months

•• If no change in radiograph noted and patient felt to If no change in radiograph noted and patient felt to have LTBI have LTBI –– receives credit for receives credit for LTBI treatmentLTBI treatment and and

di ti di ti ddi ti di ti dmedication discontinuedmedication discontinuedmedication discontinuedmedication discontinued

42

Inhibition of tumor necrosis factor and Inhibition of tumor necrosis factor and tuberculosis infectiontuberculosis infection


•• Increased incidence of tuberculosis infection (and Increased incidence of tuberculosis infection (and other infections) with FDA approved exposure to TNFother infections) with FDA approved exposure to TNF

•• Increased incidence of tuberculosis infection (and Increased incidence of tuberculosis infection (and other infections) with FDA approved exposure to TNFother infections) with FDA approved exposure to TNFother infections) with FDA approved exposure to TNF other infections) with FDA approved exposure to TNF inhibitorsinhibitors

•• Infliximab (RemicadeInfliximab (Remicade®®)) chimeric, murinechimeric, murine--human human monoclonal antibody, soluble and transmembrane monoclonal antibody, soluble and transmembrane TNFTNF

•• Etanercept (EnbrelEtanercept (Enbrel®®)) recombinant fusion protein, recombinant fusion protein, soluble TNFsoluble TNF

other infections) with FDA approved exposure to TNF other infections) with FDA approved exposure to TNF inhibitorsinhibitors

•• Infliximab (RemicadeInfliximab (Remicade®®)) chimeric, murinechimeric, murine--human human monoclonal antibody, soluble and transmembrane monoclonal antibody, soluble and transmembrane TNFTNF

•• Etanercept (EnbrelEtanercept (Enbrel®®)) recombinant fusion protein, recombinant fusion protein, soluble TNFsoluble TNFsoluble TNFsoluble TNF

•• Adalimumab (HumiraAdalimumab (Humira®®)) humanized monoclonal humanized monoclonal antibody against TNFantibody against TNF

soluble TNFsoluble TNF

•• Adalimumab (HumiraAdalimumab (Humira®®)) humanized monoclonal humanized monoclonal antibody against TNFantibody against TNF



•• Increased extrapulmonary TB disease (57%) and Increased extrapulmonary TB disease (57%) and disseminated TB disease (25%) with TNF inhibitor Rxdisseminated TB disease (25%) with TNF inhibitor Rx

•• Increased extrapulmonary TB disease (57%) and Increased extrapulmonary TB disease (57%) and disseminated TB disease (25%) with TNF inhibitor Rxdisseminated TB disease (25%) with TNF inhibitor Rxdisseminated TB disease (25%) with TNF inhibitor Rxdisseminated TB disease (25%) with TNF inhibitor Rx

•• TBI rateTBI rate inhibitor specific (?)inhibitor specific (?)•• infliximab (33infliximab (33--54/100k) > etanercept (2754/100k) > etanercept (27--28/100k)28/100k)•• ? adalimumab (27.1/100k)? adalimumab (27.1/100k)

•• OnsetOnset of TB disease inhibitor specificof TB disease inhibitor specific•• Infliximab (median 3 mo) > etanercept (median 11.5 mo)Infliximab (median 3 mo) > etanercept (median 11.5 mo)

disseminated TB disease (25%) with TNF inhibitor Rxdisseminated TB disease (25%) with TNF inhibitor Rx

•• TBI rateTBI rate inhibitor specific (?)inhibitor specific (?)•• infliximab (33infliximab (33--54/100k) > etanercept (2754/100k) > etanercept (27--28/100k)28/100k)•• ? adalimumab (27.1/100k)? adalimumab (27.1/100k)

•• OnsetOnset of TB disease inhibitor specificof TB disease inhibitor specific•• Infliximab (median 3 mo) > etanercept (median 11.5 mo)Infliximab (median 3 mo) > etanercept (median 11.5 mo)

Nature Clinical Practice Rheum 2: 602, 2006Nature Clinical Practice Rheum 2: 602, 2006Nature Clinical Practice Rheum 2: 602, 2006Nature Clinical Practice Rheum 2: 602, 2006

43



•• Guidelines for evaluation and treatment:Guidelines for evaluation and treatment:S i i d f ll i t TNFS i i d f ll i t TNF RR

•• Guidelines for evaluation and treatment:Guidelines for evaluation and treatment:S i i d f ll i t TNFS i i d f ll i t TNF RR•• Screening required for all prior to TNFScreening required for all prior to TNF--RxRx

•• Exclude active disease prior to LTBIExclude active disease prior to LTBI•• TBI preTBI pre--test assessment, CXR, TST test assessment, CXR, TST >> 5 mm5 mm•• TwoTwo--step testing “boosting” may increase step testing “boosting” may increase

sensitivity but decrease specificitysensitivity but decrease specificity•• Consider LTBI even if TST negative if risk Consider LTBI even if TST negative if risk

sufficiently highsufficiently high

•• Screening required for all prior to TNFScreening required for all prior to TNF--RxRx•• Exclude active disease prior to LTBIExclude active disease prior to LTBI•• TBI preTBI pre--test assessment, CXR, TST test assessment, CXR, TST >> 5 mm5 mm•• TwoTwo--step testing “boosting” may increase step testing “boosting” may increase

sensitivity but decrease specificitysensitivity but decrease specificity•• Consider LTBI even if TST negative if risk Consider LTBI even if TST negative if risk

sufficiently highsufficiently highsufficiently highsufficiently high•• INH 9 months (RIF 4 months alternative)INH 9 months (RIF 4 months alternative)

sufficiently highsufficiently high•• INH 9 months (RIF 4 months alternative)INH 9 months (RIF 4 months alternative)

Nature Clinical Practice Rheum 2: 602, 2006Nature Clinical Practice Rheum 2: 602, 2006Nature Clinical Practice Rheum 2: 602, 2006Nature Clinical Practice Rheum 2: 602, 2006


TB disease despite LTBITB disease despite LTBI


TB disease despite LTBITB disease despite LTBI

•• Retrospective study of 613 patients Aristotle University, Greece Retrospective study of 613 patients Aristotle University, Greece •• Retrospective study of 613 patients Aristotle University, Greece Retrospective study of 613 patients Aristotle University, Greece p y p yp y p yreceiving TNF inhibitors for rheumatic diseasereceiving TNF inhibitors for rheumatic disease

•• All screened with TST (10mm) and CXRAll screened with TST (10mm) and CXR

•• 36 of 45 “LTBI” patients received proper LTBI therapy36 of 45 “LTBI” patients received proper LTBI therapy

•• 11 patients TB disease (211 patients TB disease (2--35 mos into TNF35 mos into TNF--Rx, 7/11 <6 mos)Rx, 7/11 <6 mos)•• 7/11 correct Rx, 2 incorrect, 1 declined, 1 neg TST and CXR7/11 correct Rx, 2 incorrect, 1 declined, 1 neg TST and CXR

•• Of correct Rx:Of correct Rx:

p y p yp y p yreceiving TNF inhibitors for rheumatic diseasereceiving TNF inhibitors for rheumatic disease

•• All screened with TST (10mm) and CXRAll screened with TST (10mm) and CXR

•• 36 of 45 “LTBI” patients received proper LTBI therapy36 of 45 “LTBI” patients received proper LTBI therapy

•• 11 patients TB disease (211 patients TB disease (2--35 mos into TNF35 mos into TNF--Rx, 7/11 <6 mos)Rx, 7/11 <6 mos)•• 7/11 correct Rx, 2 incorrect, 1 declined, 1 neg TST and CXR7/11 correct Rx, 2 incorrect, 1 declined, 1 neg TST and CXR

•• Of correct Rx:Of correct Rx:•• 3/7 while on LTBI, 4/7 after LTBI3/7 while on LTBI, 4/7 after LTBI

•• TNF inhibition stopped, +/TNF inhibition stopped, +/-- etanercept restarted after TB Rxetanercept restarted after TB Rx

•• 3/7 while on LTBI, 4/7 after LTBI3/7 while on LTBI, 4/7 after LTBI

•• TNF inhibition stopped, +/TNF inhibition stopped, +/-- etanercept restarted after TB Rxetanercept restarted after TB Rx

Int J Tuberc Lung Dis 10: 1127, 2006Int J Tuberc Lung Dis 10: 1127, 2006Int J Tuberc Lung Dis 10: 1127, 2006Int J Tuberc Lung Dis 10: 1127, 2006

44

Monitoring Monitoring Monitoring Monitoring ggDuring TreatmentDuring Treatment

ggDuring TreatmentDuring Treatment

Clinical MonitoringClinical MonitoringClinical MonitoringClinical Monitoring

Instruct patient to report signs or symptoms of Instruct patient to report signs or symptoms of adverse drug reactionsadverse drug reactionsInstruct patient to report signs or symptoms of Instruct patient to report signs or symptoms of adverse drug reactionsadverse drug reactions

•• RashRash

•• Anorexia, nausea, vomiting, or abdominal pain in Anorexia, nausea, vomiting, or abdominal pain in right upper quadrantright upper quadrant

•• Fatigue or weaknessFatigue or weakness

•• Dark urineDark urine

•• RashRash

•• Anorexia, nausea, vomiting, or abdominal pain in Anorexia, nausea, vomiting, or abdominal pain in right upper quadrantright upper quadrant

•• Fatigue or weaknessFatigue or weakness

•• Dark urineDark urine•• Dark urineDark urine

•• Persistent numbness in hands or feetPersistent numbness in hands or feet

•• Dark urineDark urine

•• Persistent numbness in hands or feetPersistent numbness in hands or feet

45


Monthly visits should include a brief physical exam Monthly visits should include a brief physical exam and a review ofand a review ofMonthly visits should include a brief physical exam Monthly visits should include a brief physical exam and a review ofand a review of

•• Rationale for treatmentRationale for treatment

•• Adherence with therapyAdherence with therapy

•• Symptoms of adverse drug reactionsSymptoms of adverse drug reactions

•• Rationale for treatmentRationale for treatment

•• Adherence with therapyAdherence with therapy

•• Symptoms of adverse drug reactionsSymptoms of adverse drug reactions

and a review ofand a review ofand a review ofand a review of

•• Plans to continue treatmentPlans to continue treatment•• Plans to continue treatmentPlans to continue treatment


•• Incidence of hepatitis in persons taking INH is Incidence of hepatitis in persons taking INH is lower than previously thought (0.1 to 0.15%)lower than previously thought (0.1 to 0.15%)

•• Incidence of hepatitis in persons taking INH is Incidence of hepatitis in persons taking INH is lower than previously thought (0.1 to 0.15%)lower than previously thought (0.1 to 0.15%)p y g ( )p y g ( )

•• Hepatitis risk increases with ageHepatitis risk increases with age•• Uncommon in persons < 20 years oldUncommon in persons < 20 years old•• Nearly 2% in persons 50 to 64 years oldNearly 2% in persons 50 to 64 years old

•• Risk increased with underlying liver disease or Risk increased with underlying liver disease or heavy alcohol consumptionheavy alcohol consumption

p y g ( )p y g ( )

•• Hepatitis risk increases with ageHepatitis risk increases with age•• Uncommon in persons < 20 years oldUncommon in persons < 20 years old•• Nearly 2% in persons 50 to 64 years oldNearly 2% in persons 50 to 64 years old

•• Risk increased with underlying liver disease or Risk increased with underlying liver disease or heavy alcohol consumptionheavy alcohol consumption

46

Laboratory MonitoringLaboratory MonitoringLaboratory MonitoringLaboratory Monitoring

Baseline liver function tests (e.g., AST, ALT, and Baseline liver function tests (e.g., AST, ALT, and bilirubin) are not necessary except for patients with bilirubin) are not necessary except for patients with th f ll i i k f tth f ll i i k f t

Baseline liver function tests (e.g., AST, ALT, and Baseline liver function tests (e.g., AST, ALT, and bilirubin) are not necessary except for patients with bilirubin) are not necessary except for patients with th f ll i i k f tth f ll i i k f tthe following risk factors:the following risk factors:the following risk factors:the following risk factors:

•• HIV infectionHIV infection

•• History of liver diseaseHistory of liver disease

•• AlcoholismAlcoholism

•• HIV infectionHIV infection

•• History of liver diseaseHistory of liver disease

•• AlcoholismAlcoholismAlcoholismAlcoholism

•• Pregnancy or in early postpartum Pregnancy or in early postpartum periodperiod

AlcoholismAlcoholism

•• Pregnancy or in early postpartum Pregnancy or in early postpartum periodperiod


Repeat laboratory monitoring if patient has Repeat laboratory monitoring if patient has

Ab l b li ltAb l b li lt

Repeat laboratory monitoring if patient has Repeat laboratory monitoring if patient has

Ab l b li ltAb l b li lt•• Abnormal baseline results Abnormal baseline results

•• Current or recent pregnancyCurrent or recent pregnancy

•• High risk for adverse reactionsHigh risk for adverse reactions

•• Symptoms of adverse reactionSymptoms of adverse reaction

•• Liver enlargement or tenderness during examinationLiver enlargement or tenderness during examination

•• Abnormal baseline results Abnormal baseline results

•• Current or recent pregnancyCurrent or recent pregnancy

•• High risk for adverse reactionsHigh risk for adverse reactions

•• Symptoms of adverse reactionSymptoms of adverse reaction

•• Liver enlargement or tenderness during examinationLiver enlargement or tenderness during examinationg gg gg gg g

47


•• Asymptomatic elevation of hepatic enzymes seen in Asymptomatic elevation of hepatic enzymes seen in 10%10%--20% of people taking INH20% of people taking INH

•• Asymptomatic elevation of hepatic enzymes seen in Asymptomatic elevation of hepatic enzymes seen in 10%10%--20% of people taking INH20% of people taking INH

•• Levels usually return to normal after completion Levels usually return to normal after completion of treatmentof treatment

•• Some experts recommend withholding INH if Some experts recommend withholding INH if transaminase level exceeds 3 times the upper limit transaminase level exceeds 3 times the upper limit of normal if patient has symptoms of hepatotoxicity, of normal if patient has symptoms of hepatotoxicity, and 5 times the upper limit of normal if patient is and 5 times the upper limit of normal if patient is asymptomaticasymptomatic77

•• Levels usually return to normal after completion Levels usually return to normal after completion of treatmentof treatment

•• Some experts recommend withholding INH if Some experts recommend withholding INH if transaminase level exceeds 3 times the upper limit transaminase level exceeds 3 times the upper limit of normal if patient has symptoms of hepatotoxicity, of normal if patient has symptoms of hepatotoxicity, and 5 times the upper limit of normal if patient is and 5 times the upper limit of normal if patient is asymptomaticasymptomatic77asymptomaticasymptomatic77asymptomaticasymptomatic77

7MMWR June 9, 2000; 49(No. RR-6): 397MMWR June 9, 2000; 49(No. RR-6): 39

Fibrotic LesionsFibrotic LesionsFibrotic LesionsFibrotic Lesions

Acceptable regimens includeAcceptable regimens include

•• 9 months of INH9 months of INH

Acceptable regimens includeAcceptable regimens include

•• 9 months of INH9 months of INH

•• 2 months RIF plus PZA2 months RIF plus PZA

•• 4 months of RIF (with or without INH)4 months of RIF (with or without INH)

•• 2 months RIF plus PZA2 months RIF plus PZA

•• 4 months of RIF (with or without INH)4 months of RIF (with or without INH)

Pregnancy and BreastPregnancy and Breast--feedingfeedingPregnancy and BreastPregnancy and Breast--feedingfeeding

•• INH daily or twice weeklyINH daily or twice weekly

•• Pyridoxine supplementationPyridoxine supplementation

•• BreastBreast--feeding not contraindicatedfeeding not contraindicated

•• INH daily or twice weeklyINH daily or twice weekly

•• Pyridoxine supplementationPyridoxine supplementation

•• BreastBreast--feeding not contraindicatedfeeding not contraindicated

48

Contacts of INHContacts of INH--Resistant TBResistant TBContacts of INHContacts of INH--Resistant TBResistant TB

•• Treatment with a rifamycin Treatment with a rifamycin and PZAand PZA

•• If unable to tolerate PZA,If unable to tolerate PZA, 44--month regimen of daily month regimen of daily RIFRIF

•• Treatment with a rifamycin Treatment with a rifamycin and PZAand PZA

•• If unable to tolerate PZA,If unable to tolerate PZA, 44--month regimen of daily month regimen of daily RIFRIF

•• HIVHIV--positive persons: 2 month regimen with a positive persons: 2 month regimen with a rifamycin and PZArifamycin and PZA

Contacts of MultidrugContacts of Multidrug--Resistant TBResistant TB

•• Use 2 drugs to which the infecting organism has Use 2 drugs to which the infecting organism has demonstrated susceptibilitydemonstrated susceptibility

•• HIVHIV--positive persons: 2 month regimen with a positive persons: 2 month regimen with a rifamycin and PZArifamycin and PZA

Contacts of MultidrugContacts of Multidrug--Resistant TBResistant TB

•• Use 2 drugs to which the infecting organism has Use 2 drugs to which the infecting organism has demonstrated susceptibilitydemonstrated susceptibility

•• Treat for 6 months or observe without treatment Treat for 6 months or observe without treatment (HIV(HIV-- negative)negative)

•• Treat HIVTreat HIV--positive persons for 12 monthspositive persons for 12 months

•• Follow for 2 years regardless of treatmentFollow for 2 years regardless of treatment

•• Treat for 6 months or observe without treatment Treat for 6 months or observe without treatment (HIV(HIV-- negative)negative)

•• Treat HIVTreat HIV--positive persons for 12 monthspositive persons for 12 months

•• Follow for 2 years regardless of treatmentFollow for 2 years regardless of treatment











49

Meeting the Challenge of Meeting the Challenge of TB PreventionTB Prevention


For every patientFor every patient

•• Assess TB risk factorsAssess TB risk factors


•• Assess TB risk factorsAssess TB risk factors•• Assess TB risk factorsAssess TB risk factors

•• If risk is present, perform TST or QFTIf risk is present, perform TST or QFT

•• If TST or QFT is positive, rule out active TB If TST or QFT is positive, rule out active TB diseasedisease

•• If active TB disease is ruled out, initiate treatment If active TB disease is ruled out, initiate treatment for LTBIfor LTBI





•• If treatment is initiated, ensure completionIf treatment is initiated, ensure completion•• If treatment is initiated, ensure completionIf treatment is initiated, ensure completion

Case StudiesCase StudiesCase StudiesCase Studies

50

Case Study ACase Study ACase Study ACase Study A

Patient historyPatient history

•• 2929--yearyear--old Africanold African--American femaleAmerican female


•• 2929--yearyear--old Africanold African--American femaleAmerican femaleyy

•• History of diabetesHistory of diabetes

•• 35 weeks pregnant35 weeks pregnant

•• TST = 20 mm of indurationTST = 20 mm of induration

•• No symptoms of TB diseaseNo symptoms of TB disease

•• CXR CBC LFTs normalCXR CBC LFTs normal

yy

•• History of diabetesHistory of diabetes

•• 35 weeks pregnant35 weeks pregnant



•• CXR CBC LFTs normalCXR CBC LFTs normal•• CXR, CBC, LFTs normalCXR, CBC, LFTs normal

•• No known contact with TB patientNo known contact with TB patient

•• CXR, CBC, LFTs normalCXR, CBC, LFTs normal

•• No known contact with TB patientNo known contact with TB patient


QuestionsQuestions

1.1. What are this patient’s risk factors for TB What are this patient’s risk factors for TB

QuestionsQuestions

1.1. What are this patient’s risk factors for TB What are this patient’s risk factors for TB infection or disease?infection or disease?

2.2. What is the appropriate management for this What is the appropriate management for this patient?patient?

infection or disease?infection or disease?


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Discussion of risk factorsDiscussion of risk factors

P ithP ith di b t llitdi b t llit 2 t 4 ti2 t 4 ti


P ithP ith di b t llitdi b t llit 2 t 4 ti2 t 4 ti•• Persons with Persons with diabetes mellitusdiabetes mellitus are 2 to 4 times are 2 to 4 times more likely to develop TB disease than those more likely to develop TB disease than those without diabetes without diabetes

•• Risk may be higher in insulinRisk may be higher in insulin--dependent dependent diabetics and those with poorly controlled diabetics and those with poorly controlled diabetesdiabetes

•• Persons with Persons with diabetes mellitusdiabetes mellitus are 2 to 4 times are 2 to 4 times more likely to develop TB disease than those more likely to develop TB disease than those without diabetes without diabetes

•• Risk may be higher in insulinRisk may be higher in insulin--dependent dependent diabetics and those with poorly controlled diabetics and those with poorly controlled diabetesdiabetes


Discussion of managementDiscussion of management•• Pregnancy has minimal influence on the Pregnancy has minimal influence on the

th i f TB th lik lih d f LTBIth i f TB th lik lih d f LTBI

Discussion of managementDiscussion of management•• Pregnancy has minimal influence on the Pregnancy has minimal influence on the

th i f TB th lik lih d f LTBIth i f TB th lik lih d f LTBIpathogenesis of TB or the likelihood of LTBI pathogenesis of TB or the likelihood of LTBI progressing to diseaseprogressing to disease

•• Pregnant women should be targeted for TB testing Pregnant women should be targeted for TB testing only if they have specific risk factors for LTBI or only if they have specific risk factors for LTBI or progression to diseaseprogression to disease

pathogenesis of TB or the likelihood of LTBI pathogenesis of TB or the likelihood of LTBI progressing to diseaseprogressing to disease

•• Pregnant women should be targeted for TB testing Pregnant women should be targeted for TB testing only if they have specific risk factors for LTBI or only if they have specific risk factors for LTBI or progression to diseaseprogression to disease

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Discussion of managementDiscussion of management

S t f t d l t t t til ftS t f t d l t t t til ft


S t f t d l t t t til ftS t f t d l t t t til ft•• Some experts prefer to delay treatment until after Some experts prefer to delay treatment until after the early postpartum period, unless the person has the early postpartum period, unless the person has recent TB infection or HIV infectionrecent TB infection or HIV infection

•• Some experts prefer to delay treatment until after Some experts prefer to delay treatment until after the early postpartum period, unless the person has the early postpartum period, unless the person has recent TB infection or HIV infectionrecent TB infection or HIV infection

Case Study BCase Study BCase Study BCase Study B


•• 4747--yearyear--old Hispanic male old Hispanic male


•• 4747--yearyear--old Hispanic male old Hispanic male

•• Moved to U.S. from Bolivia 4 years agoMoved to U.S. from Bolivia 4 years ago

•• Known contact of infectious TB caseKnown contact of infectious TB case


•• 3 months later TST = 23 mm of induration3 months later TST = 23 mm of induration


•• Moved to U.S. from Bolivia 4 years agoMoved to U.S. from Bolivia 4 years ago

•• Known contact of infectious TB caseKnown contact of infectious TB case


•• 3 months later TST = 23 mm of induration3 months later TST = 23 mm of induration

•• No symptoms of TB diseaseNo symptoms of TB diseaseNo symptoms of TB diseaseNo symptoms of TB disease

•• Normal CXR, CBC, AST, and bilirubinNormal CXR, CBC, AST, and bilirubin

No symptoms of TB diseaseNo symptoms of TB disease

•• Normal CXR, CBC, AST, and bilirubinNormal CXR, CBC, AST, and bilirubin

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QuestionsQuestions

11 What are the patient’s risk factors for TB infectionWhat are the patient’s risk factors for TB infection

QuestionsQuestions

11 What are the patient’s risk factors for TB infectionWhat are the patient’s risk factors for TB infection1.1. What are the patient s risk factors for TB infection What are the patient s risk factors for TB infection or disease?or disease?

2.2. Has the management of this patient to date been Has the management of this patient to date been appropriate?appropriate?

1.1. What are the patient s risk factors for TB infection What are the patient s risk factors for TB infection or disease?or disease?

2.2. Has the management of this patient to date been Has the management of this patient to date been appropriate?appropriate?



•• Patient is aPatient is a contact of an infectious TB casecontact of an infectious TB case


•• Patient is aPatient is a contact of an infectious TB casecontact of an infectious TB casePatient is a Patient is a contact of an infectious TB casecontact of an infectious TB case

•• Recent immigrantRecent immigrant to the U.S. from a country with a to the U.S. from a country with a high prevalence of TBhigh prevalence of TB

Patient is a Patient is a contact of an infectious TB casecontact of an infectious TB case

•• Recent immigrantRecent immigrant to the U.S. from a country with a to the U.S. from a country with a high prevalence of TBhigh prevalence of TB

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•• If the patient had not been a contact, the recency of If the patient had not been a contact, the recency of his immigration (less than 4 years) would have madehis immigration (less than 4 years) would have made


•• If the patient had not been a contact, the recency of If the patient had not been a contact, the recency of his immigration (less than 4 years) would have madehis immigration (less than 4 years) would have madehis immigration (less than 4 years) would have made his immigration (less than 4 years) would have made him a candidate for TB testing, but the 5him a candidate for TB testing, but the 5--mm reaction mm reaction would not be considered positivewould not be considered positive

•• Persons who immigrate from TBPersons who immigrate from TB--endemic countries endemic countries have increased rates of TB have increased rates of TB

his immigration (less than 4 years) would have made his immigration (less than 4 years) would have made him a candidate for TB testing, but the 5him a candidate for TB testing, but the 5--mm reaction mm reaction would not be considered positivewould not be considered positive

•• Persons who immigrate from TBPersons who immigrate from TB--endemic countries endemic countries have increased rates of TB have increased rates of TB



R t f TB h th f th i t i f i iR t f TB h th f th i t i f i i


R t f TB h th f th i t i f i iR t f TB h th f th i t i f i i•• Rates of TB approach those of their countries of origin Rates of TB approach those of their countries of origin for 5 years after arrival in the U.S.for 5 years after arrival in the U.S.

•• These increased rates most likely result from recent These increased rates most likely result from recent M. M.

tuberculosistuberculosis infection in their native countryinfection in their native country

•• Rates of TB approach those of their countries of origin Rates of TB approach those of their countries of origin for 5 years after arrival in the U.S.for 5 years after arrival in the U.S.

•• These increased rates most likely result from recent These increased rates most likely result from recent M. M.

tuberculosistuberculosis infection in their native countryinfection in their native country

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•• Should be treated for LTBI if TST reactions Should be treated for LTBI if TST reactions 10 mm 10 mm


•• Should be treated for LTBI if TST reactions Should be treated for LTBI if TST reactions 10 mm 10 mm of indurationof induration

•• As a contact of an active TB case, 5 mm of As a contact of an active TB case, 5 mm of induration is considered positiveinduration is considered positive

•• This patient should have been treated for LTBI This patient should have been treated for LTBI immediately after the first TSTimmediately after the first TST

of indurationof induration

•• As a contact of an active TB case, 5 mm of As a contact of an active TB case, 5 mm of induration is considered positiveinduration is considered positive

•• This patient should have been treated for LTBI This patient should have been treated for LTBI immediately after the first TSTimmediately after the first TST

Case Study CCase Study CCase Study CCase Study C


•• 3636--yearyear--old Asian female old Asian female


•• 3636--yearyear--old Asian female old Asian female

•• Moved to U.S. from Philippines > 15 years agoMoved to U.S. from Philippines > 15 years ago

•• Plans to work in a correctional facility Plans to work in a correctional facility

•• TST result negative 1 year ago TST result negative 1 year ago

•• TST for preTST for pre--employment physical = 26 mm of employment physical = 26 mm of induration induration

•• CXR normalCXR normal

•• Moved to U.S. from Philippines > 15 years agoMoved to U.S. from Philippines > 15 years ago

•• Plans to work in a correctional facility Plans to work in a correctional facility

•• TST result negative 1 year ago TST result negative 1 year ago

•• TST for preTST for pre--employment physical = 26 mm of employment physical = 26 mm of induration induration

•• CXR normalCXR normal•• CXR normal CXR normal


•• No known contact with a TB patientNo known contact with a TB patient

•• CXR normal CXR normal


•• No known contact with a TB patientNo known contact with a TB patient

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QuestionsQuestions

11 What are the patient’s risk factors for TBWhat are the patient’s risk factors for TB

QuestionsQuestions

11 What are the patient’s risk factors for TBWhat are the patient’s risk factors for TB1.1. What are the patient s risk factors for TB What are the patient s risk factors for TB infection or disease?infection or disease?


1.1. What are the patient s risk factors for TB What are the patient s risk factors for TB infection or disease?infection or disease?



Discussion of risk factorsDiscussion of risk factors•• Patient’sPatient’s TST convertedTST converted from negative tofrom negative to

Discussion of risk factorsDiscussion of risk factors•• Patient’sPatient’s TST convertedTST converted from negative tofrom negative to•• Patient s Patient s TST convertedTST converted from negative to from negative to

positive (within a 2positive (within a 2--year period) year period) •• TST conversion increases risk for progressing TST conversion increases risk for progressing

from LTBI to TB diseasefrom LTBI to TB disease•• ForeignForeign--born status is less of a risk factor, i.e., born status is less of a risk factor, i.e.,

she immigrated more than 5 years agoshe immigrated more than 5 years ago

•• Patient s Patient s TST convertedTST converted from negative to from negative to positive (within a 2positive (within a 2--year period) year period)

•• TST conversion increases risk for progressing TST conversion increases risk for progressing from LTBI to TB diseasefrom LTBI to TB disease

•• ForeignForeign--born status is less of a risk factor, i.e., born status is less of a risk factor, i.e., she immigrated more than 5 years agoshe immigrated more than 5 years ago

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Discussion of managementDiscussion of management•• Patient’s TST conversion indicates failure toPatient’s TST conversion indicates failure to

Discussion of managementDiscussion of management•• Patient’s TST conversion indicates failure toPatient’s TST conversion indicates failure toPatient s TST conversion indicates failure to Patient s TST conversion indicates failure to

identify this person as high risk for recent identify this person as high risk for recent exposure to TBexposure to TB

•• Patient may have had extended travel to her Patient may have had extended travel to her country of origin or other highcountry of origin or other high--prevalence parts of prevalence parts of the worldthe world

Patient s TST conversion indicates failure to Patient s TST conversion indicates failure to identify this person as high risk for recent identify this person as high risk for recent exposure to TBexposure to TB

•• Patient may have had extended travel to her Patient may have had extended travel to her country of origin or other highcountry of origin or other high--prevalence parts of prevalence parts of the worldthe world


Discussion of managementDiscussion of management•• Patient is a recent converter and, as such, is aPatient is a recent converter and, as such, is a

Discussion of managementDiscussion of management•• Patient is a recent converter and, as such, is aPatient is a recent converter and, as such, is aPatient is a recent converter and, as such, is a Patient is a recent converter and, as such, is a

candidate for treatment of LTBI with INHcandidate for treatment of LTBI with INHPatient is a recent converter and, as such, is a Patient is a recent converter and, as such, is a candidate for treatment of LTBI with INHcandidate for treatment of LTBI with INH

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•• Assess TB risk factorsAssess TB risk factors•• Assess TB risk factorsAssess TB risk factors








•• If treatment is initiated, ensure completionIf treatment is initiated, ensure completion•• If treatment is initiated, ensure completionIf treatment is initiated, ensure completion

Think and act globally!Think and act globally!Think and act globally!Think and act globally!

Think and act locally!Think and act locally!Think and act locally!Think and act locally!

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Questions?Questions?Questions?Questions?

ATS/CDC Guidelines for Treating LTBI · EXAM: Mild obese Somali male NAD VSS WNL ATS/CDC Guidelines...

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