IDCM CME Issue 1-11: Latent Tuberculosis Infection: What to Know About Screening and Treatment

Post Date: 
2019-07-15
Author: 
Maunank Shah, MD, PhD

Tuberculosis (TB) is the most common infectious disease cause of death in the world1, with 10 million active TB cases worldwide, and 1.6 million deaths in 2017. While incidence of active TB has declined in the US, it remains above the stated goals set forth by the Centers for Disease Control and Prevention (CDC) for TB elimination2,3. Most often, initial infection with Mycobacterium tuberculosis (MTB) is asymptomatic and not contagious. This stage of infection, referred to as latent TB (LTBI), has been called the “seedbed” of TB disease4,5 because most cases of active TB result from reactivation of latent TB.2 

Nearly one quarter of the world’s population is infected with latent TB, representing a continued reservoir for active TB. In the U.S., tuberculosis disproportionately affects vulnerable populations, including foreign-born individuals, with an estimated 13 million persons infected with LTBI living in the US today.6-9 Other groups at high-risk for latent TB infection in the U.S. include close-contacts of people with active TB; in some areas with higher local transmission, homeless individuals and individuals living in congregate facilities such as prisons may also be important target groups for LTBI. Studies suggest that achieving TB elimination is best accomplished by prioritizing prevention through latent TB treatment 6. Consequently, identifying and treating LTBI in groups at high epidemiologic risk (e.g., foreign-born individuals, homeless shelter residents, close contacts of active TB cases) or at high risk for progression to active TB if infected (e.g., HIV, immunosuppressed) is considered critical for TB elimination in the US.3,5,7 In 2016, the US preventative task force (USPTF) issued guidance formally recommending screening for LTBI in high risk populations, based on the evidence that latent TB treatment can prevent progression to active TB. 

It is important to distinguish screening for (asymptomatic) LTBI from evaluation for active TB.  Individuals with signs or symptoms of active TB, such as prolonged cough, fevers, or weight loss, require microbiological testing to identify presence of MTB. The currently recommended tests for active TB include smear-microscopy to identify acid-fast bacilli (AFB), nucleic acid amplification tests (e.g., Cepheid GeneXpert MTB/RIF), and mycobacterial culture8.  

By contrast, LTBI cannot be diagnosed through direct microbiological tests, and there is no true reference standard. Current guidelines recommend the tuberculin skin test (TST) or interferon gamma release-assays (IGRA), which evaluate immunologic responses following stimulation by mycobacterial antigens9. Each test has advantages and disadvantages, and choice of test may depend upon cost, logistical considerations, and other clinical factors. IGRAs require phlebotomy and are more costly, but have the advantage of less impact of prior BCG vaccination (i.e., antigens utilized should not cross-react with prior vaccination), and can be performed in a single visit. The commercially available IGRA tests are the T-SPOT TB and the Quantiferon-plus (which has replaced Quantiferon Gold-In-Tube).   It is important to consider that while the performance of the two IGRA tests and TST are largely similar, in the US no single test is recommended over the other on the basis of diagnostic accuracy. None of the three has perfect sensitivity (i.e., 60-90%), and sensitivity is reduced in setting of immunosuppression; the tests should therefore NOT be used as a triage test in symptomatic individuals, in whom active TB is being evaluated. Each of the three may also have false-positives (i.e., imperfect specificity). In light of these characteristics, the tests may generate discordant results when more than one test is utilized for LTBI screening (e.g., Quantiferon positive, T-SPOT negative). Test results must therefore be interpreted in the context of pre-test probability for LTBI9. In an individual patient with high risk of TB infection, a positive result on any test should prompt further evaluation and treatment for LTBI; in a low-risk individual (not currently recommended for any testing), a negative result on any of the tests is statistically most likely to represent the correct result.

Any patient with a positive IGRA or TST requires further evaluation, as these immunologic tests do not distinguish LTBI from active TB. The next step is to assess for symptoms. Individuals with LTBI are typically asymptomatic (i.e., the bacteria are in a metabolically inactive state, with good host immunological control). Any symptomatic individual requires further microbiological tests (e.g., smear, culture, NAAT) to exclude the presence of active TB disease, before consideration of LTBI treatment. Given that some individuals with active TB may have subclinical disease that is not yet apparent, current guidelines additionally recommend a chest x-ray, irrespective of the presence of symptoms.9 Individuals with latent TB typically have a normal chest x-ray (and occasionally fibrosis or calcified granulomas indicative of prior or healed TB infection). If the chest xray has any abnormality, microbiological testing should be performed to exclude active TB. Once active TB has been excluded (i.e., asymptomatic, normal CXR, +/- negative microbiological tests), treatment for latent TB should be offered.  

Treatment of LTBI reduces the risk of progression to active TB by 60-90% and is generally recommended in all individuals with LTBI, with consideration of risks and benefits. While clinicians and patients often cite concerns regarding treatment toxicity, such side-effects are generally very rare (<1%). In more recent years, newer shorter course rifamycin-based treatment regimens for latent TB have also emerged, with studies suggesting higher rates of treatment completion compared to historically longer treatment regimens (e.g., 9 months of isoniazid) and improved tolerability.10,11  These newer recommended options include four months of daily rifampin, or 3 months of once/weekly isoniazid and rifapentine (i.e., 12 doses). Given the availability of these newer, simpler treatment options, current guidelines suggest the vast majority of individuals with a diagnosis of LTBI would benefit from treatment12; in some populations, clinicians may consider delaying therapy (e.g., pregnancy), based on individual level risks and benefits. Prior to starting LTBI therapy, it is often suggested to check baseline liver function tests. Routine follow-up laboratory studies are generally reserved for individuals at higher risk of hepatotoxicity (e.g., elderly, baseline liver abnormalities, immunosuppressed individuals, pregnant women). It is worthwhile to note that there are no tests for ‘cure’ of LTBI, as there are currently no available microbiological tests that can assess the presence of latent bacteria. The current immunological assays (i.e., TST and IGRAs) most often remain positive even after LTBI treatment and should not be performed serially; test reversions to negative or persistent positivity does not correlate with any future risk of progression to active TB after treatment. It is also important to counsel patients that an individual can still be re-infected with TB after LTBI treatment, as there is not substantial protective immunity from prior infection. There are no tests currently available to assess for ‘reinfection’ with LTBI.

Latent TB Infection Treatment Regimens*

Drug(s)

Duration

Dose

Frequency

Total Doses

Isoniazid (INH) and Rifapentine (RPT)

3 months

Adults and Children aged 12 years and older:
INH: 15 mg/kg rounded up to the nearest 50 or 100 mg; 900 mg maximum

 

RPT:
10–14.0 kg 300 mg
14.1–25.0 kg 450 mg
25.1–32.0 kg 600 mg
32.1–49.9 kg 750 mg
≥50.0 kg 900 mg maximum

 

Children aged 2–11 years:
INH: 25 mg/kg; 900 mg maximum
RPT: as above

Once weekly

12

Rifampin (RIF)

4 months

Adult: 10 mg/kg

Children: 15–20 mg/kg
Maximum dose: 600 mg

Daily

120

Isoniazid (INH)

9 months

Adult: 5 mg/kg
Children: 10–20 mg/kg

Maximum dose: 300 mg

Daily

270

*Adapted from Centers for Disease Control and Prevention, Treatment of latent tuberculosis. https://www.cdc.gov/tb/topic/treatment/ltbi.htm

‡The short course regimen of once/weekly isoniazid and rifapentine was previously recommended only to be given with directly observed therapy (DOT).  Based on newer data, the guidelines have been updated to recommend that all three regimens may be given with self-administration14. In some circumstances, clinicians or health departments may consider offering DOT or video-based DOT15, to allow closer monitoring and verification of treatment completion. Examples in which DOT or video-DOT may be considered include pediatric LTBI cases, close-contacts to active TB cases, immunosuppressed individuals, or individuals requiring closer monitoring.  

 

Overall, LTBI is a treatable condition that has been prioritized by CDC and other public health agencies to aid in efforts towards TB elimination. While management of LTBI can sometimes be confusing, there are increasing options for diagnostic testing and treatment. Unfortunately, diagnosis and treatment of LTBI remains suboptimal in the US and globally. Most individuals living with LTBI in the US have not been tested. Moreover, once diagnosed, a meta-analysis of 58 studies showed that only 54% of individuals diagnosed with latent TB complete treatment.13.  Among the challenges in scaling up LTBI care is the fragmented nature of the US health system as it pertains to management of diseases of public health importance. While active TB is a reportable condition throughout the US, latent TB is reportable in only a small number of states. At the local level, health departments have significant heterogeneity in provisions for offering LTBI services. While most local public health departments offer services to test and treat close-contacts of active TB cases for LTBI, there are wide ranging differences in availability and delivery of LTBI care services for others in the community. 
 

BOTTOM LINE: It is important that all primary care clinicians consider LTBI screening and treatment of LTBI in patients at high risk for exposure or progression to active TB.

 

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References

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