Purpose: To review the evidence on benefits and harms of screening for and treatment of latent tuberculosis infection (LTBI) for adult populations and settings relevant to primary care in the United States.
Data Sources: PubMed/MEDLINE, the Cochrane Library, and trial registries through December 3, 2021; reference lists of retrieved articles; outside experts; and reviewers, with surveillance of the literature through January 20, 2023.
Study Selection: English-language controlled studies evaluating (1) screening for LTBI with the tuberculin skin test (TST) using the Mantoux method or commercial interferon-gamma release assays (IGRAs) or (2) treatment of LTBI with pharmacotherapy regimens that are currently recommended by the Centers for Disease Control and Prevention. We excluded studies of close contacts of persons with active tuberculosis (TB) because testing and treatment of such populations is considered part of contact tracing for public health as opposed to a primary care function. We excluded studies of persons with underlying immunosuppression and for whom LTBI testing is considered part of standard disease management (e.g., persons with the human immunodeficiency virus, planned or active use of targeted immune modulators).
Data Extraction: One investigator extracted data and a second checked accuracy. Two reviewers independently rated quality for all included studies using predefined criteria.
Data Synthesis: This review included 113 publications (69,009 participants); 101 of those assessed screening test accuracy or reliability. No studies evaluated benefits and harms of screening compared with no screening. Pooled estimates for sensitivity of the TST at the 5-mm and 10-mm induration thresholds for positivity were 0.80 (95% confidence interval [CI], 0.74 to 0.87) and 0.81 (95% CI, 0.76 to 0.87), respectively. The pooled estimate at the 15-mm threshold was 0.60 (95% CI, 0.46 to 0.74). Pooled estimates for sensitivity of IGRA tests ranged from 0.81 (95% CI, 0.79 to 0.84) for the QuantiFERON-TB Gold-In-Tube® test (3rd-generation test) to 0.90 (95% CI, 0.87 to 0.92) for T-SPOT.TB. Pooled estimates for specificity of screening tests ranged from 0.95 to 0.99. For treatment of LTBI, a large (N=27,830) good-quality randomized, controlled trial (RCT) found a relative risk (RR) for progression to active TB at 5 years of 0.35 (95% CI, 0.24 to 0.52) for 24 weeks of isoniazid compared with placebo (N=13,955; number needed to treat, 112). Our sensitivity analyses adding four RCTs that did not meet all of our eligibility criteria (e.g., using a longer duration of treatment than currently recommended) found an RR of 0.31 (95% CI, 0.24 to 0.41; 5 RCTs; N=36,823). A previously published network metaanalysis reported that multiple regimens were efficacious compared with placebo or no treatment, including isoniazid regimens of 6 months (odds ratio [OR], 0.65 [95% credible interval [CrI], 0.50 to 0.83] vs. placebo) or longer, rifampin plus isoniazid regimens of 3 to 4 months (OR, 0.53 [CrI, 0.36 to 0.78] vs. placebo), and weekly rifapentine plus isoniazid regimens (OR, 0.36 [CrI, 0.18 to 0.73] vs. no treatment). For harms, a large (N=27,830) good-quality RCT reported an RR for hepatotoxicity of 4.59 (95% CI, 2.03 to 10.39; number needed to harm, 279) for 24 weeks of isoniazid compared with placebo. Our sensitivity analyses adding three RCTs that did not meet all of our eligibility criteria (e.g., longer duration of isoniazid) yielded a similar result (pooled RR, 5.04 [95% CI, 2.50 to 10.15]; 4 RCTs; N=35,161). Our meta-analyses found greater risk for hepatotoxicity with isoniazid than with rifampin (pooled RR, 4.22 [95% CI, 2.21 to 8.06], N=7,339).
Limitations: Tests for the direct diagnosis of LTBI are not available. Thus, studies estimated accuracy using patients with confirmed active TB to establish sensitivity and healthy, low-risk persons to establish specificity. The applicability to other populations is somewhat uncertain. The single placebo-controlled trial meeting all eligibility criteria that established the effectiveness of isoniazid for preventing active TB was published more than 40 years ago and was conducted among subjects with pulmonary fibrotic lesions; it may overestimate the benefits of treatment for populations with lower risk for progression. Contemporary treatment studies have not included placebo arms; benefits and harms of newer treatments were estimated from comparative studies.
Conclusions: No studies evaluated the benefits and harms of screening for LTBI compared with no screening. TST and IGRAs are moderately sensitive and highly specific. Treatment of LTBI with recommended regimens reduces the risk of progression to active TB. Isoniazid is associated with higher rates of hepatotoxicity than placebo or rifampin.