International TB Management Practices and their Impact on

TB in the U.S. Eric Bihler

Disclosure• BioMarck Pharmaceuticals

• Scientific advisory board

• Insmed Pharmaceutical• Speaker bureau

Outline/learning objectives• TB basics- crash course

• BCG vaccine- US recommendations

• Challenges when mothers from international countries deliver their babies in the U.S. and then return to their home country

• Testing for latent infection• Indications for and limitations of IGRA

• Assessing risks of international patients and what an ideal screening process looks like

TB basics• Genus Mycobacterium

• over 190 species• Mycobacterium avium

• Mycobacterium Tuberculosis complex• M. tuberculosis, Mycobacterium bovis, and Mycobacterium

africanum• Mycobacterium microti, Mycobacterium pinnipedii, and

Mycobacterium caprae

Factors associated with Transmission

Factors associated with Transmission

Factors associated with Transmission

How infection is established

How infection is established

Countries of Birth Among Non-U.S.–Born Persons Reported with TB, United States, 2017

Mexico 19%

Philippines 13%

India 9%

Vietnam 8%China …Guatemala 3%

Haiti 3%

Other 39%

*Percentages are rounded.

• TB basics- crash course

• BCG vaccine- US recommendations

• Challenges when mothers from international countries deliver their babies in the U.S. and then return to their home country

• Testing for latent infection• Indications for and limitation of IGRA

• Assessing risks of international patients and what an ideal screening process looks like

BCG vaccination• Bacillus of Calemette and Guerin

• Live attenuated strain on M bovis

• Derived by serial passage until less virulent• 231 times 1906- 1919

• 5 main strains account > 90%• All have different efficiency

• Most common vaccination in the world• >4 billion

BCG vaccination- cutaneous reaction

BCG vaccine – the good• Highly efficient in children• TB meningitis

• 73% protective• Milliary Tuberculosis

• 77% protective• Most effective when given at birth

• Decreased effectiveness in exposed to TB/NTM prior• Decreases all cause mortality

• 40% reduction in low birth wt• Decreased rates of sepsis/PNA• Association with scar formation

• Immunomodulary effects• Bladder cancer• Type I DM

BCG vaccine- the unknown• Efficiency in Preventing adult pulmonary TB/infection

• Highly variable• Difference in strains• Location

• Duration of protection• 10-15 years• ? Lifelong

• Interpretation of TST• Within 3 months- 3-19 mm• Less than 10 at ten years post vaccination• CDC – should not influence interpretation after 10 years• Boosting effect

BCG – the bad• Serious reactions are rare• Localized skin reaction

• Common/expected• Blue/red pustule ulceration scar

• Serious – less common• Lymphadenitis/abscess formation (1-2%)

• Can have drainage secondary to tract formation• Osteitis and osteomyelitis

• 30 per million vaccines• 4- 24 months after vaccination• Direct extension or dissemination• Treatment

• Surgical debridement – INH RIF 6-12 months• Disseminated disease

• Mostly seen in immunosuppression• HIV-infected infants ranges from 403 to 1300 per 100,000 doses

BCG the don’t s• Contraindications

• Immunosuppression• HIV infection, congenital immunodeficiency, malignancy, or

immunosuppressive drugs such as corticosteroids and tumor necrosis factor-alpha blockers

• Pregnancy

BCG the USA• Generally not recommended• Exceptions

• Children of adults with TB disease• Negative TST• Adult has lack of therapy/ineffective therapy/MDR TB

• Child can not take LTBI prophylaxis

• Healthcare workers• Work frequently with MDR TB and infection control policies have

been ineffective

BCG the WHO• Countries with high burden disease

• Top 20 countries • Accounts for 80% TB

• Vaccination at birth• Not recommended for immunosuppressed• If exposed to smear positive TB at birth

• IPT for six months followed by BCG• Health care workers optional

• MDR TB• No evidence that revaccination is protective

• Not recommended• Countries with low burden disease

• < 10 per 100,000• Consideration to BCG in high risk groups

• TB basics- crash course

• BCG vaccine- US recommendations

• Challenges when mothers from international countries deliver their babies in the U.S. and then return to their home country

• Testing for latent infection• Indications for and limitation of IGRA

• Assessing risks of international patients and what an ideal screening process looks like

• TB basics- crash course

• BCG vaccine- US recommendations

• Challenges when mothers from international countries deliver their babies in the U.S. and then return to their home country

• Testing for latent infection• Indications for and limitation of IGRA

• Assessing risks of international patients and what an ideal screening process looks like

TB elimination

Testing for latent infection• No Gold Standard

• Diagnosis is indirect and based on detecting host immune response to infection (cell-mediated immunity)– Tuberculin skin test (TST)– Interferon gamma release assays (IGRA)

• Not able to accurately predict risk of reactivation

Who to Test• Identify groups at highest risk:

– High prevalence of latent infection– More likely to reactivate or progress to disease once latently

infected

• Reduce screening groups at low risk to lessen false positives– Low risk groups likely to be exposed in future (e.g., HCW) is

one exception

• Decision to test = decision to treat

Define high risk• Close contacts of patients with TB disease

– Over half lifetime risk of reactivation occurs in 1-2 years post-conversion

• Foreign-born (recent immigrants <5 years)– In one series, 43% of foreign-born cases with TB disease had no

indication for testing by current guidelines, 65% had been in US > 5 years

• Injection drug users

• Homeless

• Prisoners

• Other epidemiologically defined high-risk groups, may vary based on area

Approved tests for LTBI• QuantiFERO

QuantiFeron goldT spot

• Inject 0.1 ml of 5 TU PPD tuberculin solution intradermal on volar surface of lower arm

• Produce a wheal 6 to 10 mm in diameter

• Measure reaction in 48 to 72 hours

• Measure induration, not erythema

• Forearm: Transversely to the long axis of the forearm

– Record in mm

• Ensure trained health care professional measures and interprets the TST

• False positive– BCG vaccination– Non-tuberculous mycobacteria infection– Improper administration or interpretation

• False negative– Very young (<6months)– Inability to mount an immune response (e.g., HIV or TB

itself)– Recent infection (<10 weeks since exposure)– Very remote infection– Recent live virus vaccination– Improper administration or interpretation

Interferon gama release assays• Approved by FDA

– QuantiFERON®-TB GOLD In Tube (QFT-GIT)

– T-SPOT ®.TB

• In vitro blood test

• Use antigens not found in BCG or most nontuberculous mycobacteria (ESAT-6, CFP-10, TB7.7)

• More specific, less cross-reaction with NTM

• Can cross-react with M. kansasii, M. marinum, M. szulgai

ELISAQuantiFERON®-TB Gold In-Tube

IFN-γNil

Negative control

IFN-γPHA

Positive control

16-24 hour incubation

ESAT-6

CFP-10

TB 7.7 IFN-γ

QuantiFERON®-TB to QFT-Plus: Evolution of QFT Technology

QuantiFERON technology: only LTBI diagnostic aid with multiple generations

1st generationQuantiFERON®-TB

2nd generationQuantiFERON®-TB Gold

(liquid antigen)

3rd generationQuantiFERON®-TB Gold

(QFT® in tube)

2001: FDA approval 2004: FDA approval 2007: FDA approval

4th generationQuantiFERON®-TB Gold Plus

(QFT®-Plus)

Q4 2014: CE-IVD 2017: FDA approved

• Measured cell-mediated immunity to tuberculin purified protein derivative (PPD)

• Breakthrough: TST becomes a blood test

• “Liquid antigen” version• Antigens specific for M.tb

with 99% specificity• New benchmark: No cross

reactivity with BCG

• Logistical advantage –remote incubation

• New benchmark: Scalable and easily automated

• >1200 peer reviewed publicatoins

• >30 million tests sold

Addition of patented CD8 antigens – potential biomarker of intracellular TB burden

QuantiFERON®-TB Gold PlusSAME test principle-procedure …..SAME technology of QFT

QFT-Plus is an improved version of QFT, :• Sensitivity of ~94% in registration trials• Maintains high specificity • NEW: Innovative CD8+ T-cell technology

– Optimized for CD4+ and CD8+ response• Improvements in test formulation and manufacturingNEW OPTIONS:• One Li-heparin tube draw approved for transfer into QFT-Plus

tubes • 53 hour extended processing time when using single tube blood draw (requires refrigeration of

specimen between 2-8 degrees C)

QFT-Plus: potential test evolution – CD8 antigens

T-SPOT®.TB

ESAT-6

ELISPOT

PHA

Positive control

Nil

Negative control

CFP-10CFP-10

ESAT-6

Overnight incubation

QFT-GIT Interpretation

Updated Guidelines for Using Interferon Gamma Release Assays to Detect Mycobacterium tuberculosis Infection — United States, 2010. MMWR Vol 59, RR-5

QFT Plus Interpretation

T-Spot®.TB Interpretation

Updated Guidelines for Using Interferon Gamma Release Assays to Detect Mycobacterium tuberculosis Infection — United States, 2010. MMWR Vol 59, RR-5

General Recommendations for Using IGRAs• May be used in place of (but not in addition to) a TST

in all situations for which CDC recommends tuberculin skin testing

• IGRA preferred• Hard to reach populations (e.g., homeless, migrant workers)

• Only one visit required

• People who have received BCG (either as vaccine or cancer therapy)

• TB specificity higher

MMWR, June 25, 2010/59

General Recommendations for Using IGRAs• Both TST and IGRA may be considered

• At high risk for infection or progression (e.g., HIV) • Suspicion for TB disease exists• Further evaluation of positive TST results in individuals at

low risk for infection and progression• Confirming questionable TST results

• Other reasons: immediate hypersensitivity to PPD, convincing high risk patient with strongly positive TST to take LTBI treatment, indeterminate/borderline IGRA

MMWR, June 25, 2010/59

General Recommendations for Using IGRAs• Use either TST or IGRA

• Contacts• Periodic screening for those with occupational

exposure, surveillance programs etc.• TST preferred

• Children < 5 yrs

MMWR, June 25, 2010/59

• 2418 HCW screened for LTBI• TST, QTF, T spot

• Baseline, 6, 12, 18 months• At baseline – only 30 positive for all three (1%)

• + QTF 3.8%• + T spot 5%• + TST 1.8%

• 50% converted to negative on subsequent testing• Converting to positive during study common

• No one converted all three test• Majority of positive conversions subsequently neg at f/u

• Wobble effect

• Take home point – a positive test in low risk population is likely false positive

• TB basics- crash course

• BCG vaccine- US recommendations

• Challenges when mothers from international countries deliver their babies in the U.S. and then return to their home country

• Testing for latent infection• Indications for and limitation of IGRA

• Assessing risks of international patients and what an ideal screening process looks like