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Janice Louie, MD, MPHMedical Director

Tuberculosis Prevention and Control Program

San Francisco Department of Public Health

LTBI/TB Intensive, September 2020

Latent Tuberculosis Infection:The Basics

LTBI epidemiology

Pathophysiology

Who to target for testing: TB risk groups

References:

Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020. MMWR Recomm Rep 2020; 69(No. RR-1): 1-11.

Lewinsohn et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children, Clinical Infectious Diseases, Volume 64, Issue 2, 15 January 2017, Pages e1–e33

Latent Tuberculosis Infection (LTBI): The Basics - Overview

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TB is Global

Approx. one-quarter of the world’s population is infected with TB

10 million cases active TB/yr

1.5 million TB deaths/yr

WHO 2018 Global Tuberculosis Report (2017 data)

9105 active TB cases*(2.8 per 100,000 population)

~ 327 million people U.S. population

Estimated10-15 millionpersons withLatent TB infection(NHANES: 13 million with 4.2% prevalence )

Preventable!

Approx. 85% of active cases due to reactivation (France AM et al, Am J Epidemiol 2015)

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These can vary significantly – know your local surveillance data!

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Proportion of TB cases by country of origin, 2018

San Francisco , CA

For example:

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2.4 million Californians with latent TB infection; most are unaware and untreated

What are the most common communities that might serve as a reservoir for TB in your local jurisdiction?

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ATS/CDC LTBI Guidelines: Targeted tuberculin testing and treatment of latent tuberculosis infection (April 2000 AJRCCM)

LTBI Testing & Treatment: Summary of US Recommendations (Feb 2019 update)

LTBI epidemiology

Pathophysiology

Who to target for testing: TB risk groups

Latent Tuberculosis Infection (LTBI): The Basics - Overview

Natural History of TB

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Latent TB (LTBI)(Dormant or “sleeping”)

Active TB disease

Exposure to

infectious TB

Rapidly develop

active TB disease (~1-5%)- Children <5 years

- Immunocompromised/HIV

- Recent converters

years

Not infected

5-10% over lifetime, depending on risk factors

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TB Disease vs. (Latent) Tuberculosis Infection (LTBI)

Active TB disease Latent TB infection

Cough, fever, weight loss, night sweats

No symptoms

Abnormal chest x-ray Normal chest x-ray

Infectious Not infectious

May progress to active TB disease

Case: Is it something I said?

Mr. X is an recent immigrant with LTBI. I tell him that his positive PPD means that he has been exposed to TB and I think that he should start preventive treatment.

He explains to me that since he has only “been exposed” and doesn’t have the disease that he graciously declines.

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Rather than saying: “You have been exposed to TB…”

“We would like to give you

preventative/prophylactic treatment for TB…”

Say this:

“You are infected with TB, but it is in a dormant

state now (“sleeping TB” or what we call latent TB

infection). We would like to treat the infection

now before it has a chance to “wake-up” and

become active…

Nomenclature: “Latent TB Infection”(2)

Share your favorite words you use to explain latent TB infection to your patients

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Probably not a true binary “latent vs. active”-----> spectrum

Are the bugs truly “sleeping”…….?

Barry C et al. Nature Reviews 2010 (modified)

Infection eliminated without priming antigen-specific T cells

Sym

pto

ms

Clinical disease

Bacterial replication maintained at a subclinical

level by the immune system

Infection controlled with some bacteria persisting in

non-replicating form

Infection eliminated in association with T cell priming

Bacte

rial lo

ad?

Quiescent infection

Active infection

Disease

Acquired immune response

Innate immune response

TARGETED TESTING…..

Should we just screen everyone?

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Targeted Testing and Latent Tuberculosis Infection

Fundamental Principles: As a low incidence country, targeted testing and

treatment of LTBI is an essential component of the strategic plan towards TB elimination in the US

Focus on high risk individualsGoal: Reduce reservoir of latent TB

“A Decision to Test is a Decision to Treat.”

Risk of false positives is high in a low incidence population

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TARGETED TESTING…..

Only target if higher risk for TB

higher risk for recent infection

higher risk for progression

Screening in Primary Care

U.S. Preventive Services Task Force March 2016

(UPSTF)

Recommendation Grade

The USPSTF recommends screening for latent tuberculosis infection (LTBI) in populations that are at increased risk.

Population

Adults who are at increased risk for tuberculosis:• persons born in, or former residents of, countries with

increased tuberculosis prevalence • persons who live in, or have lived in, high-risk congregate

settings (such as homeless shelters and correctional facilities)

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ATS/CDC LTBI Guidelines: Targeted tuberculin testing and treatment of latent tuberculosis infection (April 2000 AJRCCM)

LTBI Testing & Treatment: Summary of US Recommendations (Feb 2019 update)

LTBI epidemiology

Pathophysiology

Who to target for testing: TB risk groups

Latent Tuberculosis Infection (LTBI): The Basics - Overview

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~75% of US TB cases in are non-US born. Countries of origin for most cases outside of US include: Mexico, Philippines, Vietnam, and China.

HIV patients have exceptionally high rate of reactivation (7-10% per year); screen annually

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Close contacts/converters (i.e. household) have a high risk of developing active TB in the first 2 years after conversion

Eliminated by innate immune response

Eliminated by acquired immune response- no memory

Eliminated by acquired immune response- memory

Quiescent

Subclinical

Active

In general: 5-10% lifetime risk of Active TB

LTBI: Lifetime risk for (active) TB Disease

5% first year, 2-3% second year

90% no disease~0.1% per year thereafter

Figure: Esmial and Barry Drug discovery 2012

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Note: Age not considered in this assessment, and is complicated. Because younger adults have more years of expected life, some clinicians may choose to prioritize younger non-US born persons

Lifetime risk: Age matters (non-converters)Horsburgh NEJM 2004

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Watch out! Patients with abnormal CXR and report that says “lesions consistent with old TB, no evidence of active TB”

• Risk of developing active TB is 5-fold higher compared to someone with a normal CXR

• TST or IGRA may be negative

• Check sputa and await culture results before starting LTBI treatment

• Data still unclear on what are best regimens

o At SFDPH we use INH+ RIF x 3 months or INH x 9 months

Radiographic lesions “consistent with inactive TB”

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LTBI with abnormal chest X-ray: 3 cases

A

B

C

• Non- US born

• Asymptomatic

• QFT+

• CXR report: “BUL nodules, calcified, consistent with old granulomatous disease. No active disease.”

What do you do?

Check sputa!

Sputa preliminary results:

• Smear neg x 3, geneXp neg x 1

• Await cultures (8 weeks)

Culture results

A

B

C

Yes, Active TB, pan-sensitive

No, TB 4 (old granulomatous disease, LTBI treatment with INH and rifampin)

Yes, Active TB, pan-sensitive

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Coleman. Infect Immun. 2014.

• Macaque monkey • Inoculated with TB via

bronchoscopy• Followed with PET/CT

over 6 mo.• At 6 mo., classified as LTBI

vs. TB disease - Clinical- Radiographic- Microbiologic (BAL)- Inflammatory

markers (ESR)

Pathophysiology of LTBI

Pathophysiology of TB lesions: a dynamic state

A radiographic interpretation of “old” TB on chest X-ray does NOT rule out active disease

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Risk Factors for Developing Active TB

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• Children are ”sentinel of transmission”

• Children <5 years at high risk of disseminated TB/TB meningitis

• Active TB in children is usually pauci-bacillary:

- Asymptomatic or atypical symptoms

- CXR abnormalities non-specific: look for infiltrate in lower lobes, mediastinal lymphadenopathy

- Sputum typically non-diagnostic, need gastric aspirates x 3 (geneXpoften not available)

- Exposure history important

- Infants and children <5 yrsare “sentinels of transmission”

Routine testing of persons without risk factors is not recommended and may result in unnecessary evaluation and treatment because of false positive results

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Special Populations: What are your local policies?

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Historically, U.S. HCWS were at increased risk for LTBI and TB disease from occupational exposures.

CDC recommendations for HCWs included annual screening based on the type of health care setting and assessment of risk.

In California, this was enfolded into law:

CalOSHA Annual TB testing of Health Care Personnel CodeAccording to the California Code of Regulations, Title 8, Section 5199(h)(3), “…The employer shall make an assessment for latent tuberculosis infection (LTBI) available to all employees with occupational exposure. Assessment procedures shall be in accordance with applicable public health guidelines. (A) TB tests and other forms of TB assessment shall be provided at least annually, and more frequently if applicable public

health guidelines or the local health officer recommends more frequent testing. Employees with a baseline positive TB test shall have an annual symptom screen.

(B) The employer shall refer employees who experience a TB conversion to a PLHCP knowledgeable about TB for evaluation”

Health Care Workers-New Guidelines (2019)

Surveillance data from 1995–2007 revealed that TB incidence rates among HCWS were similar to those in the general population (3-5%)

In addition, a recent retrospective cohort study of approximately 40,000 HCWS found an extremely low rate of TST conversion (0.3%) during 1998–2014.

Nearly 50% of U.S. HCP previously testing positive revert to a negative test result during serial testing

• No cases of TB disease reported among the ~64,000 U.S. HCP included in the studies reviewed

Health Care Workers-New Guidelines (2019)

Sosa et al. MMWR Weekly / May 17, 2019 / 68(19);439–443

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Licensing and Certification (L&C)

California Code of Regulation (CCR) Title 22, Div. 5, Ch.1-12CDPH Licensing & Certification enforces licensing requirements for hire & annual testing and notifies health care facilities of policy changes through All Facility Letters.

Recent updates to Health care worker annual TB screening requirements:

Acute care hospitals: Licensing and Certification suspended hospital TB screening requirements (AFL 20-26): “CDPH is temporarily waiving licensing requirements and suspending regulatory enforcement of all licensing requirements for hospitals”). This waiver is valid until March 31, 2021.

As a FYI, TB testing on hire requirements were also specifically delayed for Primary Care Clinics (https://www.cdph.ca.gov/Programs/CHCQ/LCP/Pages/AFL-20-30.aspx ): H&S code 1226.1(s)(2): “tuberculosis test requirement for primary care clinic personnel at the time of employment is suspended until 60 days after the end of the declared emergency.

Healthcare facilities can also request an exemption with the CDPH Licensing and Certification Branch: submit this form https://www.cdph.ca.gov/CDPH%20Document%20Library/ControlledForms/cdph5000.pdf

California Dept of Public Health Exemptions

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LTBI Basics: Summary

LTBI identification and treatment is fundamental to US TB elimination strategy

“Latency” may be dynamic process

Identifying target high risk groups appropriate to your local setting is key