Latent Tuberculosis Infection: Why It’s Important and What You Can Do About It Lynn Sosa, MD Deputy State Epidemiologist Tuberculosis Program Coordinator
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; [email protected]
TB Medical Consultation
– Global Tuberculosis Institute at Rutgers University
– 1-800- 4 TB DOCS, [email protected]
Thank you!
Thank you!