in progress

Final Research Plan

Screening for Latent Tuberculosis Infection in Adults

June 17, 2021

Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Figure 1 depicts the key questions within the context of the eligible populations, screenings/interventions, comparisons, outcomes, and settings. On the left, the population of interest is asymptomatic adults belonging to populations with increased risk for latent tuberculosis infection (LTBI). Moving from left to right, the figure illustrates the overarching question: Does targeted screening for LTBI in primary care settings in asymptomatic adults at increased risk for developing active tuberculosis disease (TB) improve quality of life or reduce active TB disease incidence, transmission of TB, or disease-specific or overall mortality (KQ1)? The figure depicts the pathway from screening to reduction in the development of active TB, transmission, quality of life and mortality of LTBI to illustrate the questions: What is the accuracy and reliability of the tuberculin skin test (TST) or interferon gamma release assay (IGRA) for screening asymptomatic adults at increased risk for developing active TB and what is the accuracy and reliability of sequential screening strategies that use TST and IGRA (KQ2a/KQ2b)? Screening may result in harms (KQ4). After detection of LTBI, the figure illustrates the following questions: Does treatment of LTBI with Centers for Disease Control and Prevention recommended pharmacotherapy regimens improve quality of life or reduce progression to active TB disease, transmission of TB, or disease-specific or overall mortality (KQ3)? Treatment may result in harms (KQ5).

Abbreviations: IGRA=interferon gamma release assay; LTBI=latent tuberculosis infection; TB=tuberculosis; TST=tuberculin skin test.

1. What are the benefits of targeted screening for latent tuberculosis infection (LTBI) in primary care settings in asymptomatic adults who are at increased risk for developing active tuberculosis (TB), including among specific populations of interest?
2a. What are the accuracy and reliability of the tuberculin skin test (TST) or interferon gamma release assay (IGRA) for screening in asymptomatic adults who are at increased risk for developing active TB disease, including among specific populations of interest?
2b. What are the accuracy and reliability of sequential screening strategies that use TST and IGRA in asymptomatic adults who are at increased risk for developing active TB disease, including among specific populations of interest?
3. What are the benefits of treatment of LTBI with Centers for Disease Control and Prevention (CDC)–recommended pharmacotherapy regimens, including among specific populations of interest?
4. Are harms associated with screening for LTBI, including among specific populations of interest?
4a. Do these harms differ by screening method or strategy?
4b. Do these harms differ by population?
5. What are the harms associated with treatment of LTBI with CDC-recommended pharmacotherapy regimens, including among specific populations of interest?

The contextual question will not be systematically reviewed and is not shown in the Analytic Framework.

  1. What risk assessment tools are available for use in primary care to identify adults to screen for LTBI? How do the tools incorporate race and ethnicity?

The Research Approach identifies the study characteristics and criteria that the Evidence-based Practice Center will use to search for publications and to determine whether identified studies should be included or excluded from the evidence review. Criteria are overarching as well as specific to each of the key questions (KQs).

Criteria Included Excluded
Populations All KQs: A priori subgroups of interest include those defined by age, sex, race/ethnicity, pregnancy, and higher risk for developing TB.* For each KQ, we will look for evidence to inform whether results differ by subgroups.

KQs 1, 4: Asymptomatic adults belonging to populations at increased risk for LTBI.* Studies that combine eligible and ineligible populations can be included if results are stratified for the eligible portion of the study population or the ineligible portion does not exceed 25% of the study population.

KQ 2: For sensitivity outcome: Patients with bacteriologically confirmed active TB who have not yet received treatment or who had received no more than a few weeks of treatment. For specificity outcome: Healthy persons with no history of TB exposure or risks. Studies that combine children and adults or studies with both HIV-negative and HIV-positive persons (sensitivity outcome only) can be included if results are stratified for the eligible portion of the study population or the ineligible portion does not exceed 25% of the study population.

KQs 3, 5: Asymptomatic adults with confirmed LTBI (e.g., with a positive TST and without symptoms or chest x-ray findings indicative of active TB disease); otherwise, same criteria as for KQ 1 except that close contacts of active TB patients are eligible if LTBI is confirmed.
KQs 1, 4: Children, symptomatic adults, close contacts of active TB patients, and populations at highest risk for progression from LTBI to active TB disease because of underlying immunosuppression or for whom LTBI screening and treatment would be part of standard disease management by specialty care providers. This includes persons with HIV, head and neck cancer, leukemia or lymphoma, silicosis, history of or planned organ transplant, dialysis, planned or active use of TNF-α inhibitors, and planned or active use of chemotherapy.

KQ 2: For sensitivity outcome: Persons with TB infection not confirmed by culture, AFB smear, or molecular tests. For specificity outcome: Persons with known history of TB or TB exposure, persons with HIV, and acutely ill persons.
Intervention and Comparator  KQs 1, 4: Screening with TST, IGRA, or both compared with no screening.

KQs 2, 4: TST using Mantoux method with intermediate strength dose of PPD and standard thresholds for positive test (i.e., 5 mm, 10 mm, or 15 mm). Commercially available, FDA-approved IGRA tests: T-SPOT.TB, QFT-Gold in tube (QFT-GIT 3rd generation), and QFT-Gold Plus (4th generation).

KQs 3, 5: Treatment with CDC-recommended regimen (INH daily for 6 or 9 months, INH twice weekly by directly observed therapy for 6 or 9 months, RIF daily for 4 months, or INH plus RPT weekly by directly observed therapy for 3 months) compared with placebo, no treatment, delayed treatment, or another eligible treatment.
KQs 1, 4: Studies with no comparator group.

KQs 2, 4: Other tests, such as nucleic acid amplification and two-step TST.

KQs 3, 5: Studies comparing other treatments or combinations (i.e., regimens that are not recommended by CDC).
Outcomes   KQs 1, 3: Active TB disease, TB transmission, quality of life, and mortality (disease-specific and overall).

KQ 2: Sensitivity, specificity, and reliability (i.e., test-retest).

KQ 4: False-positive results leading to unnecessary testing or treatment, labeling, stigma, anxiety, and cellulitis.

KQ 5: Hepatotoxicity, mortality from hepatotoxicity, nausea, vomiting, peripheral neuropathy, development of drug-resistant TB, and other specific adverse effects of medications.
KQ 2: Concordance rates among tests and other outcomes.
Study Designs   KQ 1: RCTs and prospective cohort studies.

KQ 2: RCTs, cohort studies, and cross-sectional studies.

KQ 3: Systematic reviews and meta-analyses (including network meta-analyses), and RCTs. 

KQ 4: Systematic reviews, RCTs, and prospective cohort studies

KQ 5: Systematic reviews and meta-analyses (including network meta-analyses), RCTs, prospective cohort studies, and case-control studies.
All other study designs not already indicated.
Setting   KQ 1:  Study settings considered to be applicable to primary care, including primary care practices, homeless shelters, correctional facilities, college health settings, long-term care facilities, and public health clinics.

KQ 2: Any setting.

KQs 3, 5: Same as KQ 1, except that workplace settings are also eligible.

KQ 4: Studies eligible for KQ 1 or 2.
KQs 1: HIV and subspecialty care settings and workplace settings that screen for LTBI as part of a formal surveillance program for occupational exposure.

KQs 3, 5: Same as KQ 1, except that workplace settings are eligible.

Country KQs 1, 3, 5: Countries categorized as “High” or “Very High” using the Human Development Index, as defined by the United Nations Development Programme.

KQ 2: For sensitivity outcome: Studies in any country. For specificity outcome: Studies in low-TB–burden countries.

KQ 4: Studies eligible for KQs 1 or 2
KQs 1, 3, 5: Countries not categorized as “Very High” on the Human Development Index, as defined by the United Nations Development Programme.

KQ 2: For specificity outcome: Studies in high-TB–burden countries.
Quality Studies rated good or fair quality Studies rated poor quality
Language  Full text published in English  Not English language 

* Adult population subgroups at increased risk for developing active TB include 1) persons who have immigrated from TB-endemic countries; 2) persons who work or reside in facilities or institutions with high-risk individuals, such as homeless shelters, correctional facilities, nursing homes, and residential facilities; and 3) persons with increased risk for progression from LTBI to active TB because of underlying illness or use of medications, injection drug use, or radiographic evidence of prior healed TB.1
High TB-burden countries include the following: Angola, Bangladesh, Brazil, Cambodia, Central African Republic, China, Congo, the Democratic Republic of the Congo, Democratic People's Republic of Korea, Ethiopia, India, Indonesia, Kenya, Lesotho, Liberia, Mozambique, Myanmar, Namibia, Nigeria, Pakistan, Papua New Guinea, Peru, the Philippines, the Russian Federation, Somalia, South Africa, Thailand, the United Republic of Tanzania, Vietnam, and Zimbabwe. This list is not exhaustive but represents the countries with the highest absolute burden (high rates and high population).2
We will focus on the best evidence to address this KQ on treatment, focusing on the most recent high-quality meta-analysis rather than re-reviewing and synthesizing the primary RCTs that were summarized in the prior review on this topic (e.g., those comparing INH vs. placebo that were published in the 1960s and 1970s).

Abbreviations: AFB=acid fast bacilli; CDC=Centers for Disease Control and Prevention; FDA=Food and Drug Administration; HIV=human immunodeficiency virus; IGRA=interferon gamma release assay; INH=isoniazid; KQ=key question; LTBI=latent tuberculosis infection; PPD=purified protein derivative; QFT=QuantiFERON; RCT=randomized, controlled trial; RIF=rifampin; RPT=rifapentine; TB=tuberculosis; TNF-α=tumor necrosis factor-α; T-SPOT. TB=commercial IGRA assay; TST=tuberculin skin test.

The draft Research Plan was posted on the USPSTF website for public comment from March 11 to April 7, 2021. Most of the comments did not affect the scope of the review. In response to public comments, the USPSTF revised the KQs to clarify intentions and expanded the eligibility criteria to include countries categorized as both “high” and “very high” on the Human Development Index.

  1. Centers for Disease Control and Prevention. Latent Tuberculosis Infection: A Guide for Primary Health Care Providers. Published 2020. Accessed May 24, 2021. http://www.cdc.gov/tb/publications/LTBI/default.htm
  2. World Health Organization. Tuberculosis Data. Published 2020. Accessed May 24, 2021. https://www.who.int/teams/global-tuberculosis-programme/data