Final Research Plan
Latent Tuberculosis Infection: Screening
September 25, 2014
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.
The final Research Plan will be used to guide a systematic review of the evidence by researchers at an Evidence-based Practice Center. The resulting Evidence Review will form the basis of the USPSTF Recommendation Statement on this topic.
The draft Research Plan was available for comment from June 5 until July 2, 2014 at 5:00 p.m., ET.
Abbreviations: IGRA = interferon-γ release assay; KQ = key question; LTBI = latent tuberculosis infection; QOL = quality of life; TB = tuberculosis; TST = tuberculin skin test.
This figure is the analytic framework depicting the five key questions and the research approach that will guide the evidence review outlined in this research plan. In general, the figure illustrates the overarching question of whether targeted screening for latent tuberculosis infection in asymptomatic adults at increased risk for developing active tuberculosis leads to improved health outcomes (key question 1) or potential harms. The framework starts on the left with the patient population of interest, asymptomatic adults at increased risk. Moving from left to right, the figure depicts the accuracy and reliability of two specific screening tests, the tuberculin skin test and the interferon-gamma release assay (key question 2a), and the accuracy and reliability of sequential screening strategies (key question 2b). Screening may result in harms (key question 4). For adults with latent tuberculosis infection, treatment may improve health outcomes, such as quality of life, or reduce mortality, progression to active tuberculosis, or its transmission (key question 3). Treatment may result in harms (key question 5).
1. Is there direct evidence that targeted screening for latent tuberculosis infection (LTBI) in primary care settings in asymptomatic adults at increased risk for developing active tuberculosis (TB) disease (e.g., persons in populations with a high prevalence of active TB disease or with documented increased risk for progression from LTBI to active TB disease) improves quality of life, reduces active TB disease incidence, reduces transmission of TB, or reduces disease-specific or overall mortality?
2a. What is the accuracy and reliability of the tuberculin skin test (TST) or the interferon-γ release assay (IGRA) for screening asymptomatic adults at increased risk for developing active TB disease?
2b. What is the accuracy and reliability of sequential screening strategies that include both TST and IGRA testing in asymptomatic adults at increased risk for developing active TB disease?
3. Does treatment of LTBI with Centers for Disease Control and Prevention (CDC)–recommended pharmacotherapy regimens improve quality of life or reduce progression to active TB disease, reduce transmission of TB, or reduce disease-specific or overall mortality?
4. Are there harms associated with screening for LTBI?
- Do these harms differ by screening method or strategy?
- Do these harms differ by population?
5. Are there harms associated with treatment of LTBI with CDC-recommended pharmacotherapy regimens?
Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.
1. What are the estimated prevalence rates of LTBI and active TB disease in adult populations at increased risk for TB receiving care in U.S. primary care settings? What are the limitations or uncertainties regarding these estimates? Do these rates differ by geographic region of the United States?
2a. What proportion of U.S. adults receiving care in primary care settings belong to a population at increased risk?
2b. What proportion of U.S. adults belonging to a population at increased risk are seen in primary care settings, and what proportion are screened for LTBI in primary care settings?
3. What proportion of active TB disease cases in U.S. adults originate in populations at increased risk?
4. Is there an incremental net benefit of more or less frequent screening for LTBI in adults at increased risk for TB receiving care in primary care settings?
5. What is the reported frequency of screening for LTBI in adults in U.S. primary care settings, both overall and in populations at increased risk?
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).
| Include | Exclude | |
|---|---|---|
| Populations | Asymptomatic adults belonging to populations at increased risk* |
|
| Setting | Studies conducted in primary care settings in countries categorized as “Very High” on the Human Development Index (as defined by the United Nations Development Programme); for this topic, study settings considered to be applicable to primary care will also include homeless shelters, correctional facilities, college health settings, long-term care facilities, public health clinics, and workplaces |
|
| Screening | Screening using TST or IGRA; studies using a single screening test or multiple tests in series | Any other tests, such as nucleic acid amplification tests |
| Treatment/management interventions | CDC-recommended pharmacotherapy regimens (such as isoniazid, rifampin, or isoniazid plus rifapentine), self-administered at home or by directly observed therapy‡ | Other treatments or combinations |
| Comparisons |
KQs 1, 4: Screened vs. nonscreened groups
KQ 2: Studies on screening accuracy assessing the sensitivity of TST or IGRA in a sample of persons with microbiologically confirmed active TB or assessing specificity in a sample of healthy persons with low risk for TB and without known exposure to TB; studies on screening reliability must include measures of reproducibility (e.g., test-retest, comparisons between different laboratories or readers) KQ 3: Primary studies comparing treatment with placebo, no treatment, delayed screening/treatment, or another eligible treatment KQ 5: Primary studies comparing treatment with placebo, no treatment, or another eligible treatment |
KQs 1, 3–5: No comparison; nonconcordant historical controls; comparisons with screening tests or treatments not being evaluated in this review
KQ 2: No referent standard defined |
| Outcomes |
KQs 1, 3: Active TB disease (i.e., progression to active TB disease); reduction in transmission; quality of life; reduction in mortality (disease-specific and overall)
KQ 2: Sensitivity and specificity; reliability (i.e., test-retest) KQ 4: False-positive results leading to unnecessary testing (e.g., chest x-ray) or treatment, labeling, stigma, anxiety, cellulitis KQ 5: Hepatotoxicity (e.g., isoniazid-induced hepatitis), mortality from hepatotoxicity, nausea, vomiting, peripheral neuropathy, development of drug-resistant TB, other specific adverse effects of medications |
All other outcomes not specified in inclusion criteria |
| Study designs |
KQ 1: RCTs§
KQ 2: Systematic reviews; RCTs, cross-sectional studies, and cohort studies published after the time period covered by included systematic reviews KQ 3: RCTs KQ 4: Systematic reviews; RCTs and prospective cohort studies published after the time period covered by included systematic reviews KQ 5: RCTs, prospective cohort studies, and case-control studies |
KQs 1, 3, 5: All other designs
KQs 2, 4: Primary studies of any design published during the time period covered by included systematic reviews |
| Language | English | Non-English |
* Adult population subgroups at increased risk for developing active TB receiving care in U.S. primary care settings will be defined based on an initial scan of the published literature, but may include persons with diabetes, persons who have previously received the Bacillus Calmette–Guérin (BCG) vaccination, injection drug users, persons who are homeless or residing in homeless shelters, former prisoners, persons born in or former residents of countries with high TB prevalence, persons who work with such individuals, and persons with a documented increased risk for progression from LTBI to active TB. Persons who have previously received the BCG vaccination will be examined separately for KQ 2.
† Workplace settings that screen employees for LTBI as part of a formal surveillance program for occupational exposure under Occupational Safety and Health Administration directive. This includes employees of health care facilities, correctional institutions, long-term care facilities for the elderly, homeless shelters, and drug treatment centers. Because the CDC recommends different criteria for positive LTBI test results for mycobacteriology laboratory personnel, we will exclude studies enrolling employees of mycobacteriology laboratories.
‡ Current CDC-recommended LTBI treatment regimens include the following: isoniazid daily for 6 or 9 months, isoniazid twice weekly by directly observed therapy for 6 or 9 months, rifampin daily for 4 months, or isoniazid plus rifapentine weekly by directly observed therapy for 3 months. Because of reports of severe liver injury and death, the CDC recommends that rifapentine and pyrazinamide in combination generally should not be used to treat LTBI.
§ A best evidence approach will be taken and if no RCTs are identified upon initial search, inclusion of other study designs, such as observational or operational studies, will be considered.
Abbreviations: CDC = Centers for Disease Control and Prevention; HIV = human immunodeficiency virus; IGRA = interferon-γ release assay; LTBI = latent tuberculosis infection; RCT = randomized, controlled trial; TB = tuberculosis; TNF-α = tumor necrosis factor-α; TST = tuberculin skin test.
The draft Research Plan was posted for public comment on the U.S. Preventive Services Task Force (USPSTF) Web site from June 5 to July 2, 2014. The USPSTF received many comments requesting it broaden the scope of the review to include public health and nonprimary care settings and other populations. As a result, the USPSTF included additional settings providing primary care services in the research plan. The USPSTF removed restrictions on the amount of time in the United States for persons who were born in or former residents of countries with high TB prevalence (previously limited to 5 years or less). The USPSTF also removed any indication of a preferential order of sequential testing or of TST as a reference standard, as there is no gold standard test for LTBI. Finally, the USPSTF clarified the language to make outcomes and disease terminology clearer and more consistent with the field.