Tuberculosis: Latent Tuberculosis Infection (LTBI)

Definition, Etiology, PathogenesisTop

Inhalation of Mycobacterium tuberculosis organisms is followed by a period of bacterial replication and dissemination. Thereafter, immunologic containment of viable bacilli occurs. The result of this process is latent tuberculosis infection (LTBI), which is an asymptomatic state of continuous bacterial viability, immune control, and no clinical or radiographic evidence of active tuberculosis (TB). Reactivation of LTBI leads to active TB.

Information on the pathogenesis of TB infection: see Tuberculosis: Active Disease.

DIAGNOSISTop

Currently latent M tuberculosis infection cannot be directly diagnosed in humans. As such, LTBI is diagnosed based on response to either in vitro or in vivo stimulation by M tuberculosis antigens with the use of interferon gamma release assays (IGRA) or a tuberculin skin test (TST).

1. Screening: Targeted screening is used to detect individuals with LTBI who are at the highest risk of reactivation of TB and who would therefore benefit from preventative drug therapy. The World Health Organization (WHO) 2020 guidelines recommend systematic testing and treatment for LTBI in persons with HIV infection, child and adult contacts of patients with active pulmonary TB, or in patients with the following medical risk factors: anti–tumor necrosis factor alpha treatment, receiving dialysis, preparing for an organ or hematologic transplant, silicosis. Systematic testing and treatment are to be considered for the following groups based on risks within the local and national context: prisoners, health-care workers, immigrants from high-burden countries, homeless persons, and illicit drug users.

2. Diagnostic tests:

1) TST is an intradermal injection of 0.1 mL of purified protein derivative (5 tuberculin units [TU]) into the forearm (Mantoux technique) to produce a transient wheal. It is interpreted after 48 to 72 hours by measuring the transverse diameter of palpable induration. If the TST cannot be read within 72 hours of administration, it should be repeated at a different site; there is no minimum time interval between the tests.

The interpretation of the reading depends on the size of induration, positive predictive value, and risk of progressing to active disease if the person is truly infected. The standard threshold in Canada for a positive TST result in patients without mitigating features is ≥10 mm of induration. An induration ≤4 mm is considered positive in children aged <5 years and an induration ≥5 mm, in HIV-infected individuals, contacts of an infectious individual within the last 2 years, individuals with radiologic features of fibronodular disease, transplant recipients, patients treated with TNF-alpha inhibitors or other immunosuppressants, and individuals with end-stage renal disease (details: www.canada.ca). However, other countries may use a different value to increase specificity of the test. The TST has no value in the detection of active TB. A false-positive TST result may occur in the setting of prior sensitization to nontuberculous mycobacteria (NTM) or bacillus Calmette-Guérin (BCG) vaccination at >12 months of age. However, if the BCG vaccine was received within the first year of life and a TST is performed >10 years later, the rate of false-positive results is 1%. In comparison, if the BCG vaccine was received at the age of ≥6 years, up to 40% of individuals may have a persistently positive TST result (≥25 mm). False-negative reactions can occur in the setting of systemic immunosuppression or administration of live virus immunization within 4 weeks of a TST. Typically, a steroid dose equivalent to ≥15 mg prednisone daily for 2 to 4 weeks is enough to suppress a TST reaction.

2) IGRA: The IGRA is an in-vitro blood test used for identification of latent LTBI. It is a test of cell-mediated immune response following stimulation by antigens that are more specific to M tuberculosis (ESAT-6 and CFP-10) than the purified protein derivative (PPD). These antigens are not shared with any BCG vaccine strains or most nontuberculous mycobacteria. Therefore, IGRA is the test of choice for evaluating LTBI in individuals with BCG vaccination after infancy or a history of multiple BCG vaccinations. The currently available IGRAs are the QuantiFERON-TB Gold assay and the T-SPOT.TB assay. Similarly to TST, IGRA should not be used for the assessment of active TB disease in adults.Evidence 1Strong recommendation (downsides clearly outweigh benefits; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision of specificity and indirectness to different populations. Metcalfe JZ, Everett CK, Steingart KR, et al. Interferon-γ release assays for active pulmonary tuberculosis diagnosis in adults in low- and middle-income countries: systematic review and meta-analysis. J Infect Dis. 2011 Nov 15;204 Suppl 4:S1120-9. doi: 10.1093/infdis/jir410. Review. PubMed PMID: 21996694; PubMed Central PMCID: PMC3192542. Sester M, Sotgiu G, Lange C, et al. Interferon-γ release assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis. Eur Respir J. 2011 Jan;37(1):100-11. doi: 10.1183/09031936.00114810. Review. Erratum in: Eur Respir J. 2012 Mar;39(3):793. PubMed PMID: 20847080. World Health Organization. Use of tuberculosis interferon-gamma release assays (IGRAs) in low- and middle-income countries. Policy statement. http://www.who.int/tb/features_archive/policy_statement_igra_oct2011.pdf. Published 2011. Accessed January 13, 2017.

3) Both the TST and IGRA are acceptable screening tests for LTBI, with there being no current evidence to recommend a particular test apart from late or repeat BCG vaccination, favoring the IGRA in such a scenario.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data and imprecision. Latent tuberculosis infection: updated and consolidated guidelines for programmatic management. Geneva: World Health Organization; 2018.

4) There are 2 web-based tools to assist with the interpretation TST and IGRA results:

a) An interactive algorithm, the Online TST/IGRA Interpreter, can provide a customized estimate of the positive predictive value of an individual’s TST reading: www.tstin3d.com/en/calc.html.

b) The BCG World Atlas provides information on BCG vaccination policies in different countries: www.bcgatlas.org.

Treatment Top

1. General principles of treatment:

1) Always exclude active TB before starting drug treatment for LTBI. A history, physical examination, and chest imaging are required to screen for active disease. If any clinical or radiologic features suspicious for active disease are present, further testing, including sputum for acid-fast bacilli (AFB) smear and culture, is recommended.

2) The decision to treat LTBI should be individualized, with consideration of the risks of adverse events, such as hepatotoxicity, balanced against the risk of prior TB exposure and the risk of reactivation. Clinical factors, such as comorbid diseases (kidney/liver), immunosuppression, TB exposure status, fibronodular changes on chest imaging, or risk of drug-resistant LTBI, are to be strongly considered in the risk-benefit analysis.

2. Drug regimens for LTBI: The standard regimen for LTBI treatment includes 9 months of daily self-administered isoniazid (INH) (5 mg/kg for adults; maximum dose, 300 mg) or 4 months of daily self-administered rifampin (RMP) (10 mg/kg for adults; maximum dose, 600 mg). Pyridoxine 25 mg daily may be added to INH to offset the potential adverse effect of peripheral neuropathy for patients at risk of this complication.Evidence 3Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Smieja MJ, Marchetti CA, Cook DJ, Smaill FM. Isoniazid for preventing tuberculosis in non-HIV infected persons. Cochrane Database Syst Rev. 2000;(2):CD001363. Review. PubMed PMID: 10796642. Menzies D, Alvarez G, Khan K, et al. Treatment of Latent Tuberculosis Infection. In: Menzies D, ed. Canadian Tuberculosis Standards (7th edition). Canadian Lung Association, 2013:125-52. http://www.phac-aspc.gc.ca/tbpc-latb/pubs/tb-canada-7/assets/pdf/tb-standards-tb-normes-pref-eng.pdf. Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR 2000;49(No. RR-6):1-54. https://www.cdc.gov/tb/publications/reportsarticles/mmwr/mmwr_updates.htm. Accessed January 13, 2017. RMP treatment for 4 months is noninferior in efficacy to 9 months of INH treatment and is associated with a higher rate of treatment completion and fewer drug-related adverse events.Evidence 4High Quality of Evidence (high confidence that we know true effects of the intervention). Menzies D, Adjobimey M, Ruslami R, et al. Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults. N Engl J Med. 2018 Aug 2;379(5):440-453. doi: 10.1056/NEJMoa1714283. PubMed PMID: 30067931.

Other alternative LTBI treatment regimens include INH daily for 6 months, INH/RMP daily for 3 months or INH/rifapentine once weekly for 3 months. This requires directly observed prophylaxis. In Canada, rifapentine is only available through the Special Access Program.

3. Monitoring: The goals of monitoring are to promote drug adherence and to detect and manage adverse effects. Since the evidence to guide follow-up schedules is weak, practice styles vary considerably. Many experts obtain baseline levels of transaminases and regular monthly testing. This is particularly important for those who have risk factors for liver disease. Additionally, assessing drug interactions with INH or RMP is essential. All patients on LTBI treatment are strongly advised against intake of alcohol, since this may increase the risk of hepatotoxicity.