Latent Tuberculosis Infection: Why It’s Important and What You Can Do About It

Lynn Sosa, MD Deputy State Epidemiologist

Tuberculosis Program Coordinator

Outline Why Tuberculosis Matters

– Brief overview

– Data- Global, National, Local

Screening and Testing for Latent Tuberculosis Infection (LTBI)

– Risk assessment

– Skin test vs blood test

Treatment

– Three regimens!

– How the health department can help

But first a few questions:

I have tested a patient for tuberculosis

I have treated a patient for tuberculosis

Tuberculosis Characteristics

• Tuberculosis (TB) is an airborne disease

• Causative agent is Mycobacterium tuberculosis

• Spread by droplet nuclei

• Expelled by person with TB disease

• Can result in TB disease or latent TB infection (LTBI)

TB

LATENT TB INFECTION (LTBI)

NO SYMPTOMS

NOT CONTAGIOUS

NOT INFECTIOUS

ACTIVE TB DISEASE

COUGH,FEVER,NIGHT SWEATS

CONTAGIOUS/INFECTIOUS

TB

8-10 WEEKS

EXPOSURE

PRIMARY TB INFECTION

TB SKIN TEST OR BLOOD TEST

POSITIVE

NO INFECTION

(75%)

TB

TB

TB

TB

How is TB Spread?

Contagiousness

– Smear-positive sputum

– Cavitary disease

Exposure duration and environment – Small, enclosed space

– Limited air flow

Health status of the exposed person

Virulence of the M. tb bacteria

Transmission of M. tuberculosis

LTBI vs. TB Disease

LTBI TB Disease

Tubercle bacilli in the body

Skin test or blood test usually positive

Chest x-ray normal Chest x-ray abnormal

Bacteriology negative Bacteriology positive

No symptoms Cough, weight loss, night sweats

Not infectious, not a case Often infectious before treatment, a TB case

Who Gets Tuberculosis?

Reported TB Disease Cases United States, 1982–2017*

*As of February 12, 2018.

0

5,000

10,000

15,000

20,000

25,000

30,000

1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016

No

. of

case

s

Year

LTBI in the United States

Estimated global prevalence: 23% = 1.7 billion people

Estimated U.S. prevalence: 4.4%-4.8% = 12.4-13.6 million people

No national, unified U.S. surveillance system

– Varies by state, focus on high risk groups

Work ongoing to establish national system around 2020

Connecticut 2017 TB Disease Incidence

63 Cases

– 21% increase from 2016 (52 cases)

– Rate = 1.8/100,000

52 (83%) Foreign-Born

– 30 different nations represented (India, Haiti, Guatemala, Mexico)

37 (59%) males

Cases reported from 30 different towns

Two (3%) co-infected with HIV

Nine (14%) with diabetes

One case was multi-drug resistant

Seven cases (11%) had previous known LTBI

LTBI in Connecticut

Estimated Connecticut prevalence (based on NHANES): 161,460 people

More recent estimate from CDC based on a back-calculation method: 2.1% or 75,348 people

High Risk for Exposure

• Close contacts

• Persons who were born in or visit TB endemic areas

– Everywhere that is not US/Canada, Australia, Western Europe

• Persons who work or reside in high-risk congregate settings (e.g. prisons, LTCFs, shelters)

• HCWs who serve people at high risk for TB infection

• Local populations at high risk for infection or disease

High Risk for Progression of LTBI to TB Disease

• Recent infection, documented conversion (within the last 2 years)

• HIV infection

• Substance abuse (alcohol or drugs)

• Children under 5 years of age

• Certain medical conditions

Medical Conditions

• HIV infection

• <90% of ideal body weight

• Diabetes mellitus

• Chronic renal failure

• Solid organ transplant

• Certain cancers and / or treatment

• Steroid treatment (15mg, >4 weeks)

• Tumor necrotizing factor antagonist therapy (TNF-α antagonists)

• History of gastrectomy or jejunoileal bypass surgery

Latent Tuberculosis Infection Why Is It Important?

• 5–10% of persons with LTBI will develop TB disease if untreated

– 50% in the first two years

– 50% later in life

• >80% of TB disease in the United States is reactivation disease

– Preventable!

Think TB!

• Who should I screen?

• How do I do it?

Risk Assessment Key Points

Keep it simple!

Three easy questions

What Test Should I Choose?

Challenges of Testing for LTBI

• Limited by inability to identify Mycobacterium tuberculosis in people with latent infection

• Diagnosis is indirect and based on detecting host immune response to infection

– Tuberculin skin test (TST)

– Interferon gamma release assays (IGRA)

Testing for M. tuberculosis Infection

• Mantoux tuberculin skin test (TST)

– Produces delayed-type hypersensitivity reaction in persons with M. tuberculosis infection

• Interferon-gamma release assays (IGRA)

– Blood test that measures and compares amount of interferon-gamma (IFN-) released by blood cells in response to TB antigens

Tuberculin Skin Test (TST)

• Has been the standard method of identifying LTBI

• Delayed-type hypersensitivity reaction

• Area of induration measured

• Interpretation based on size and risk

Reading the TST

• Measure reaction in 48–72 hours

• Measure induration, not erythema

• Record reaction in millimeters

• Positive TST reactions can be measured accurately for up to 7 days

• Negative reactions can be read accurately for only 72 hours

• Training is important!

nyc.gov/health

Interpretation of TST Results

TSTs and BCG

• Vaccination with Bacille-Calmette Guerin (BCG) is NOT a contraindication to TST testing

– BCG does not protect against TB infection

– Prevents dissemination of TB in young children

– Prevents young children from dying of TB

Effect of BCG on TST reaction

• BCG in infancy (age <2 years)

– 23 studies with 78,846 vaccinees

– 6.3% positive TST due to BCG

– 1% positive TST after 10+ years

• BCG older (age 2+ years)

– 11 studies with 4,026 vaccinees

– 40% positive TST due to BCG

– 20% positive TST after 10+ years

Farhat, Menzies. Int J Tuberc Lung Dis 2006;10:1192-204

Interferon Gamma Release

Environmental strains

Antigens

ESAT CFP

M abcessus

-

-

M avium

-

-

M branderi

-

-

M celatum

-

-

M chelonae

-

-

M fortuitum

-

-

M gordonii

-

-

M intracellulare

-

-

M kansasii

+

+

M malmoense

-

-

M marinum

+

+

M oenavense

-

-

M scrofulaceum

-

-

M smegmatis

-

-

M szulgai

+

+

M terrae

-

-

M vaccae

-

-

M xenopi

-

-

Tuberculosis complex

Antigens

ESAT

CFP

M tuberculosis

+

+

M africanum

+

+

M bovis

+

+

BCG substrain

gothenburg

-

-

moreau

-

-

tice

-

-

tokyo

-

-

danish

-

-

glaxo

-

-

montreal

-

-

pasteur

-

-

Species Specificity of ESAT-6 and CFP-10

T-Spot.TB Assay

IGRA Sensitivity and Specificity

TST T.-SPOT®.TB QFT-GIT

Sensitivity† 95% 91% 84%

Specificity* 85% 88% 99%

†Pooled estimate, low incidence countries

*Pooled estimate, patients unlikely to have M. tb infection

Updated Guidelines for Using Interferon Gamma Release Assays to Detect Mycobacterium tuberculosis

Infection — United States, 2010. MMWR Vol 59, RR-5

IGRAs- Advantages

• Single patient visit

• Responses not boosted by previous testing

• Not subject to reader bias

• Not affected by prior BCG vaccination

– Antigens in the test are not in the BCG strain

IGRAs- Limitations

• Requires a blood draw

• Specimen must be incubated within 16-32 hours (can be extended)

• Cost

• Indeterminate result is a possibility

• Unexplained conversions and reversions when used serially

Which test should be used to diagnose LTBI?

Discordant Results

• Test considerations

– TST induration

– IGRA values

• Patient considerations

– Why was the test done in the first place?

– What is the TB risk of the patient?

– Risks/benefits of treating or not treating?

• Clinical decision

Indeterminate?

• Less frequent with third generation QFT; hopeful for even less with QFT-Plus

• Several possible reasons

– High background IFN-: patient illness, mitogen in wrong well, defective tubes

– Low mitogen: immune suppression, defective tubes, overfilling, inadequate shaking

• Options?

– Repeat QFT

– Place TST instead

What about Kids?

• Red Book June 2018 Updates

– IGRAs now recommended for ≥2 years old

– Some experts use down to age 1 year

– IGRA preferred in BCG-vaccinated children

– Risk factor assessment unchanged

– Caution in immunocompromised

LTBI Testing Key Points

• IGRAs are more specific (e.g. BCG vaccinated)

• IGRAs are not always better than TST

• Choose the best test for your patient but not usually both tests

• Expanded opportunity to use them in younger children

• Risk assessment is still important

LTBI Treatment

Why is there debate about treating LTBI?

Menzies et al., Indian Journal of Medical Research, 2011

Initiating Treatment for LTBI

Before initiating treatment for LTBI:

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

• Obtain an HIV test

• Consider Hepatitis testing

• Determine prior history of treatment for LTBI or TB disease

• Assess risks and benefits of treatment

• Determine current and previous drug therapy

Three regimens to Treat LTBI

NEJM, August 2, 2018

NEJM, August 2, 2018

Newest Option for LTBI Treatment

• 12 weekly doses of Isoniazid/Rifapentine (3HP) with directly observed therapy

• CDC Recommendations in 12/2011

• Based on review of randomized clinical trial and two other studies:

– As effective as Isoniazid for 9 months

– More likely to be completed

3HP Treatment Status and Outcomes

69

796

23 57 15 0

100

200

300

400

500

600

700

800

900

Currently OnTreatment

SuccessfullyCompletedTreatment

Lost to Follow-Upor Refused

StoppedTreatment due to

Adverse Event

StoppedTreatment forOther Reason

Nu

mb

er

of

Pati

en

ts

Treatment Status

Treatment outcomes for patients March 2012 - September 2018 (N=1007)

89.4% successfully

complete

What About Kids?

• Red Book consistent with CDC recommendations

– Same three regimens

– Shorter is better….

– Changes in rifampin dosing

• 15-20 mg/kg/day

• 20-30 mg/kg/day (young children)

LTBI Treatment Key Points

• Three regimens to choose from

• Shorter regimens have higher adherence rates

• Options the same for kids and adults

Health Department Resources

Get to know your local health department!

– www.portal.ct.gov/dph

Get to know your state health department!

– Lynn Sosa, MD- 860-509-7723; lynn.sosa@ct.gov

TB Medical Consultation

– Global Tuberculosis Institute at Rutgers University

– 1-800- 4 TB DOCS, mc_gtbi@njms.rutgers.edu

Thank you!

Thank you!