*Tuberculosis: Latent Tuberculosis Infection

Chapter: Tuberculosis: Latent Tuberculosis Infection
McMaster Section Editor(s): Paul M. O’Byrne
Section Editor(s) in Interna Szczeklika: Ewa Niżankowska-Mogilnicka, Filip Mejza
McMaster Author(s): Lori Whitehead
Author(s) in Interna Szczeklika: Iwona Grzelewska-Rzymowska, Maria Korzeniewska-Koseła, Katarzyna Kruczak, Zofia Zwolska, Ewa Augustynowicz-Kopeć
Additional Information

Definition, Etiology, PathogenesisTop

Latent tuberculosis infection (LTBI) is an asymptomatic state where bacteria of the Mycobacterium tuberculosis complex may survive for years within small granulomas residing in the lung or in other sites after being seeded by lymphatic or hematologic spread. Even though tuberculosis (TB) bacteria thrive in an oxygen-rich environment, they are capable of surviving in a dormant, anaerobic state for extended periods.

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

DetectionTop

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. Screening of populations for LTBI is not justified in regions lacking the infrastructure to provide the monitoring and support required to ensure safe and complete administration of the medication. Tools used for screening include the tuberculin skin test (TST) and/or interferon gamma release assay (IGRA). A positive result should be followed by a chest radiograph. The choice of which groups are to be selected for targeted screening is usually decided by public health authorities in conjunction with health-care professionals with expertise in the area of TB. The World Health Organization 2015 guidelines recommend systematic testing and treatment for LTBI in persons with human immunodeficiency virus (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, dialysis, preparing for organ or hematologic transplantation, silicosis. Systematic testing and treatment is to be considered for the following groups: prisoners, health-care workers, immigrants from high-burden countries, homeless persons, and illicit drug users.

Screening in HIV-positive individuals: Every patient with newly diagnosed HIV infection should be assessed with regard to TB exposure history and clinical features of TB. Testing for LTBI should be done in those with no prior history of TB infection or disease. Despite a lower threshold for diagnosis of LTBI (usually TST ≥5 mm), the results of TST are often negative, results of IGRA are often indeterminate, and positive results of a direct sputum examination are less frequent. A chest radiograph and sputum for smear and culture should be performed as part of the initial screen for HIV-infected patients with LTBI.

2. Diagnostic tests:

1) TST is a diagnostic aid used for identification of LTBI. It is an intradermal tuberculin (purified protein derivate) injection administered using the Mantoux technique. The reading, based on the diameter of skin induration, is measured 48 to 72 hours after administration. The interpretation of the reading depends on size of induration, positive predictive value, and risk of progressing to active disease, if the person is truly infected. Declaration of positivity is therefore dependent on several factors with a goal to identify individuals who would benefit from treatment for LTBI. The standard threshold in Canada for patients without mitigating features is ≥10 mm, but other countries may use a different value based on demographic and socioeconomic factors. The TST has no value for active TB detection. Induration at the test site can be observed in persons with M tuberculosis infection (test does not differentiate between LTBI and clinically overt active disease), individuals after BCG vaccination, and occasionally in persons with a history of exposure to nontuberculous mycobacteria. False-positive and false-negative reactions may occur. BCG vaccination can lower the specificity of the TST and may cause a false-positive reaction, especially if administered after 12 months of age.

2) IGRAs based on interferon gamma production by T cells: The IGRA is an in-vitro blood test used for identification of latent LTBI. Like the TST, the IGRA should not be used for active TB disease detection 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. It may be reasonable to use the IGRA as a supplementary diagnostic aid for the investigation of children with suspected active TB under the age of 18 years. The assays have higher specificity than the TST, and the results are not influenced by BCG vaccination. IGRA assays are available in many countries, but access to IGRA testing in developing countries is inconsistent.

3) 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 radiograph are required to screen for active disease. If any features suspicious for active disease are detected, do further testing including sputum smear and culture. Other tests may be indicated.

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. TST cut-points for treatment of LTBI in Canada: Table 1.

2. Drug regimens for LTBI: The standard regimen of first choice is 9 months of daily self-administered isoniazid (INH) (5 mg/kg for adults, 10 mg/kg for children, with a maximum dose for all recipients of 300 mg/d).Evidence 2Strong 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. Pyridoxine 25 mg/day may be added to INH to offset the potential adverse effect of peripheral neuropathy for patients at risk of this complication. Other acceptable alternative daily self-administered regimens include 6 months INH, 3 to 4 months of INH and rifampin (INN rifampicin), or 4 months of rifampin. A summary of recommended regimens for LBTI treatment: Table 2.

3. Monitoring during LTBI treatment: The goals of monitoring are to promote drug compliance 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 in patients >35 years of age or those who have risk factors for liver disease. Patients on INH or rifampin are strongly advised against intake of alcohol, since this may increase the risk of hepatotoxicity.

TablesTop

Table 1. Tuberculin skin test cut-points for treatment of latent tuberculosis infection

TST result

Indication1

0-4 mm

– In general, this is considered negative and no treatment is indicated2

– Close contacts in children <5 years of age should be treated pending results of repeat skin test 8 weeks after exposure3

≥5 mm

– HIV infection

– Contact with infectious TB within the past 2 years

– Fibronodular disease on chest radiographs (healed TB and not previously treated)

– Organ transplantation (related to immune suppressant therapy)4

– Tumor necrosis factor alpha inhibitors

– Other immunosuppressive drugs, eg, glucocorticoids (equivalent of ≥15 mg/d of prednisone for 1 month or more; risk of TB disease increases with higher dose and longer duration)

– End-stage renal disease

≥10 mm

All others, including the following specific situations:

– TST conversion (within 2 years)

– Diabetes, malnutrition (<90% ideal body weight), cigarette smoking, daily alcohol consumption (>3 drinks/d)

– Silicosis

– Hematologic malignancies (leukemia, lymphoma) and certain carcinomas (eg, head and neck)

1 Age ≥35 years is not a contraindication to treatment of LTBI if the risk of progression to active TB disease is greater than the risk of serious adverse reactions to treatment.

2 Treatment with isoniazid of people with HIV infection who were TST negative (0-4 mm) and/or anergic was of no benefit in several randomized trials. Other authorities suggest this treatment may be considered in the presence of HIV infection or other cause of severe immunosuppression and high risk of TB infection (contact with infectious TB, from high TB-incidence country or abnormal chest radiographs consistent with prior TB infection). Hence any decision to give treatment should be individualized in consultation with a TB expert.

3 If first TST is negative, begin treatment immediately. Repeat TST 8 weeks after exposure to infectious TB case ended. Treatment can be stopped in a healthy child if repeat TST is negative (<5 mm induration). In children <6 months of age, the immune system may not be mature enough to produce a positive TST, even if the child is infected.

4 LTBI therapy is often given to people in whom transplantation is planned but before the actual transplantation.

Source: ©All Rights Reserved. Canadian Tuberculosis Standards, 7th Edition. The Public Health Agency of Canada, The Lung Association, and the Canadian Thoracic Society, 2014. Adapted and reproduced with permission from the Minister of Health, 2016.

HIV, human immunodeficiency virus; LTBI, latent tuberculosis infection; TB, tuberculosis; TST, tuberculin skin test.

Table 2. Summary of recommended regimens for LTBI treatment

Drug(s)

Duration

Schedule

Mode of administration

Level of evidence1

Standard regimen

INH

9 months

Daily

SAP

1

Acceptable alternative regimens

INH

6 months

Daily

SAP

1

INH/RMP

3 months

Daily

SAP

1

INH/RPT2

3 months

Once weekly

DOP

1

RMP

4 months

Daily

SAP

2

INH

6-9 months

Twice weekly

DOP

2

INH/RMP

3 months

Twice weekly

DOP

2

1 Level 1, multiple randomized trials. Level 2, single randomized trial and/or multiple observational (cohort) studies.

2 Use this regimen with careful monitoring for hypersensitivity reactions—these can be severe. RPT is only available in Canada through the Special Access Program.

Source: ©All Rights Reserved. Canadian Tuberculosis Standards, 7th Edition. The Public Health Agency of Canada, The Lung Association, and the Canadian Thoracic Society, 2014. Adapted and reproduced with permission from the Minister of Health, 2016.

DOP, directly observed prophylaxis; INH, isoniazid; LTBI, latent tuberculosis infection; RMP, rifampin (International Nonproprietary Name rifampicin); RPT, rifapentine; SAP, self-administered prophylaxis.

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