INTRODUCTION — The World Health Organization published guidelines for diagnosis and treatment of tuberculosis infection (TBI) in 2020 ; in 2022 these were incorporated into the WHO Operational Handbook for Tuberculosis .
The United States Preventive Services Task Force (USPSTF) published recommendations for TBI screening of populations with increased prevalence of TBI in 2023 . The USPSTF recommendations for TBI diagnosis aligns with guidance issued by the American Thoracic Society (ATS) and United States Centers for Disease Control and Prevention (CDC) in 2017 , and for treatment of TBI aligns with guidance by the CDC in 2020 .
•Tuberculosis infection (TBI; newer term for latent tuberculosis)
•Tuberculosis disease (newer term for active tuberculosis)
The distinction between TB infection and TB disease is important [1,4]. In most individuals, Mycobacterium tuberculosis infection is either cleared or contained (via innate and acquired immune defense mechanisms). Individuals whose immune system initially contains the organism are asymptomatic and noninfectious though likely harbor potentially viable organisms . This situation is referred to as TB infection; the older term "latent TB" may be misleading since such individuals are infected with viable mycobacteria in various stages of containment by the host immune system .
Containment of TB infection is a dynamic process; organisms have the potential to overcome immune defenses and subsequently cause symptomatic disease. Treatment of TBI prior to development of TB disease kills contained organisms, thereby reducing the risk of developing TB disease (termed reactivation TB) by as much as 90 percent . Treatment of TBI has the potential to protect the health of the infected individual as well as the public by reducing the number of potential future sources of infection to others [9,10].
The approach to diagnosis of TBI in adults will be reviewed here; issues related to interpretation of the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) are discussed separately. (See "Use of the tuberculin skin test for diagnosis of tuberculosis infection (tuberculosis screening) in adults" and "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults".)
Issues related to treatment of TBI in adults are discussed separately. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection".)
Issues related to TBI in patients with human immunodeficiency virus (HIV), patients receiving tumor necrosis factor-alpha inhibitors, and patients undergoing solid organ transplant are discussed separately. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection" and "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors" and "Tuberculosis in solid organ transplant candidates and recipients".)
Issues related to TBI in children and pregnant patients are discussed separately. (See "Tuberculosis infection (latent tuberculosis) in children" and "Tuberculosis infection (latent tuberculosis) in pregnancy".)
INDICATIONS FOR TBI TESTING — Screening for TB (testing for TB infection) is reserved for individuals who are at increased risk of developing TB disease and would thus benefit from treatment (table 2) . This includes patients in the following categories [1,3]:
●Individuals at risk for new infection (close contacts of persons with untreated TB disease; selected health care workers who may have occupational TB exposure)
●Individuals at high risk of reactivation (ie, progression to TB disease) if infected due to underlying conditions (eg, immunocompromised individuals)
For individuals who have undergone testing but fall outside the above categories, the decision to treat for TB infection should be individualized, as risk may outweigh potential benefit.
In general, repeat TBI testing among individuals with prior negative test results should be performed only in the setting of new exposure since the last assessment (such as new contact with a case of untreated respiratory TB disease, occupational exposure, or extended travel in regions where TB is endemic). (See "Use of the tuberculin skin test for diagnosis of tuberculosis infection (tuberculosis screening) in adults", section on 'Repeat and serial testing' and "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults", section on 'Serial testing, conversion, and reversion'.)
Increased risk of new infection
Individuals with recent exposure (close and casual contacts) — Testing for TB infection should be performed in asymptomatic individuals for whom new infection is suspected (algorithm 1). High-priority groups for evaluation include close and casual contacts of patients with untreated respiratory TB disease (table 2).
The definition of 'close contact' varies between guidelines; however, all emphasize that the approach to contact identification should be tailored to the specific circumstances (infectiousness of index TB patient, environment within which the exposure occurred, and susceptibility of those exposed) [11,12]. We define a 'close contact' as an individual who shares an enclosed space with a patient with untreated respiratory TB disease for ≥4 hours per week; this definition has been in large randomized trials [13-15]. In addition, another study suggested that defining high-priority close contacts as individuals sharing an enclosed space for ≥4 hours per week may be used as a measure of risk . This includes those living in the same household or frequent visitors to the house; it may also include contacts at work or school. Because the risk of developing TB disease is very high in the first few years following exposure and new infection, all close contacts should be evaluated for TBI regardless of age (table 2).
Most public health TB programs evaluate close contacts first and expand the contact investigation to casual contacts if evidence of transmission is found. Casual contacts may be defined as individuals with less than four hours of contact per week. This may include health care workers (HCWs) and/or contacts at work or school. Evidence of transmission is defined by detection of TB disease among contacts (secondary TB disease) or observing prevalence of positive tuberculin skin tests (TSTs) or interferon-gamma release assays (IGRAs) that is greater than expected. In general, source TB patients with positive sputum smear are more contagious; casual contacts of smear-negative patients are usually not evaluated unless they are immunocompromised.
If the first test is negative, close contacts of patients with pulmonary TB disease should undergo a second test 8 to 10 weeks later. Many TB programs test casual contacts only once at eight to ten weeks after last exposure. (See "Use of the tuberculin skin test for diagnosis of tuberculosis infection (tuberculosis screening) in adults", section on 'Repeat and serial testing' and "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults", section on 'Serial testing, conversion, and reversion'.)
The risk of disease in the first two years following infection is age dependent. The decline of risk with increasing age reflects greater innate and acquired immunity :
●Infants (ages ≤1 year): 50 percent
●Children (ages 1 to 2 years): 12 to 25 percent
●Children (ages 2 to 5 years): 5 percent
●Children (ages 5 to 10 years): 2 percent
●Age >10 years: 1 to 2 percent
Homeless shelters and correctional facilities — Annual screening is warranted for residents and employees of homeless shelters and correctional facilities, given the risk of TB exposure in congregate settings . (See "Epidemiology of tuberculosis", section on 'Community settings'.)
The approach to annual screening is discussed below. (See 'Approach to serial testing' below.)
Health care workers in some settings — In regions with low TB incidence rate, most HCWs in facilities with low TST conversion rate need not undergo routine serial TB screening. In such settings, HCWs should undergo initial TB screening with individual risk assessment and symptom evaluation. For individuals without documented prior TB disease or TBI, baseline TB testing with an IGRA or a TST should be performed. Thereafter, in the absence of a known exposure or ongoing transmission, no routine serial TB testing at any interval after baseline is warranted . TST interpretation thresholds are summarized in the table (table 5). (See "Use of the tuberculin skin test for diagnosis of tuberculosis infection (tuberculosis screening) in adults", section on 'Serial testing' and "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults", section on 'Serial testing, conversion, and reversion'.)
Serial TB screening may be reasonable for HCWs at increased risk for occupational exposure to TB (such as pulmonologists or respiratory therapists) or for HCWs in certain settings (such as emergency departments). Such policies should be individualized based on factors such as the regional and institutional incidence of pulmonary TB, whether delays in initiating airborne isolation have occurred, or whether prior serial screening has demonstrated ongoing transmission; such determinations may be made in consultation with local or state health departments . The approach to serial testing is described below. (See 'Approach to serial testing' below.)
In the setting of a recognized exposure, HCWs with a baseline negative TBI test and no prior TB disease or TBI should undergo testing (IGRA or TST) when the exposure is identified; if IGRA is newly positive, or TST is newly positive at ≥5 mm, this should be interpreted as evidence of new TB infection. If the test is negative, another test should be performed 8 to 10 weeks after the last exposure . In this case, we define TST conversion if the induration of the repeat TST measures ≥10 mm and has increased by ≥6 mm over the previous test (ie, the initial negative TST) . Alternatively, one test may be performed 8 to 10 weeks following the end of exposure.
For HCWs with untreated new TBI, treatment is encouraged unless medically contraindicated . HCWs with new TBI who do not complete treatment should be monitored annually with symptom evaluation to detect early evidence of TB disease and to re-evaluate the risks and benefits of TBI treatment . In addition, these HCWs should be educated about the signs and symptoms of TB disease that should prompt immediate evaluation between screenings.
The above approach reflects guidelines issued by the United States Centers for Disease Control and Prevention and National Tuberculosis Controllers Association in 2019 , which serves as an update to the prior 2005 guidelines (table 6) . This approach is supported by a number of factors. TB incidence rates in the United States declined by 42 percent between 2005 and 2017 (from 4.8 to 2.8 per 100,000 population) . In addition, the 2019 guideline statement refers to an unpublished systematic review of eight studies including more than 63,000 HCWs; there was no disease occurrence among these individuals . Furthermore, the use of TSTs and IGRAs for serial testing of HCWs has been associated with a number of limitations .
The role of IGRA for serial testing in HCWs is uncertain, in large part due to high rates of false conversions in most studies in HCWs undergoing serial testing with IGRA. This issue is discussed further separately. (See "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults", section on 'Reproducibility'.)
Increased risk of reactivation
General principles — Identifying individuals who warrant TBI testing and treatment depends on the risk for reactivation due to underlying conditions (relative to healthy individuals) (table 2 and table 3 and algorithm 1). In general, individuals with TBI who are otherwise healthy have an annual risk of at most 0.1 percent (1 per 1000) of developing TB disease ; one review noted a much lower rate of 0.03 percent (0.3 per 1000) among otherwise healthy individuals with a positive TST (table 7 and table 8) .
The relative likelihood of a true-positive versus false-positive test result should be considered carefully. A web-based algorithm can be used to estimate the likelihood that an individual with a positive TST or IGRA has a true-positive test, and the cumulative lifetime risk of developing TB disease in that individual, taking into consideration various conditions that increase risk of reactivation; it also factors in the age-related risks of isoniazid . This algorithm has been validated in a cohort of including more than 37,000 foreign-born individuals in Canada; however, risks may be overestimated in the highest risk groups .
False-positive tests occur more commonly with TST but also can occur with IGRA. True-positive tests are more likely in individuals with relevant epidemiologic exposure (such as close contact with a case of contagious TB or residence in a high-incidence country). True-positive tests are very uncommon in individuals born in the United States (or other low-incidence countries) after 1960 who have no other risk of exposure.
In general, individuals at increased risk of reactivation require a single test for diagnosis of TBI; if the result is negative, no further testing is needed. Given that the likelihood of TB infection is very low in most individuals born in the United States since 1960, the likelihood of a false-positive test result must be considered carefully. Dual testing (with IGRA as well as TST) can be useful in certain circumstances. (See 'Role of dual testing' below.)
Balancing risk of disease and risk of treatment — The approach to balancing the risk of disease and the risk of treatment depends in part on the treatment regimen utilized. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection" and "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection".)
The relationship between the risk of adverse events and increasing age is well documented for isoniazid; the risk of serious hepatotoxicity in individuals >65 years, 50 to 65 years, and 35 to 50 years is >5 percent, 2 to 5 percent, and <2 percent, respectively [27-29]. The risk of hospitalization for liver toxicity associated with isoniazid therapy is also related to older age, and presence of comorbid conditions . In individuals with conditions conferring moderate or slightly increased risk who would be treated with isoniazid, we carefully assess the balance of risks and harms in individuals >50 years of age (especially individuals >65 years of age). Guidelines in the United States [4,29] and Canada  do not set any upper age limit for testing for and treatment of TBI; guidelines in the United Kingdom set an upper age limit of 65 years .
For other TBI regimens, such as daily rifampin for four months (4R) or weekly isoniazid-rifapentine for three months (3HP), the relationship between the risk of adverse events and increasing age is less clear. In secondary analysis of two trials in adults, the risk of hepatotoxicity (grade 3 to 4) likely attributable to 4R was significantly lower than the risk attributable to daily isoniazid for nine months, and was not age related . These findings suggest that 4R is likely to be safe for older patients; therefore, if 4R is available, older age is not a contraindication for testing. However, use of concomitant medications may be more likely among older patients, increasing risk of drug-drug interactions. In a randomized trial evaluating 3HP for treatment of TBI, serious adverse reactions including hypersensitivity were significantly more common with older age . (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection".)
●High risk − We consider individuals with high risk for reactivation of TB to be those with the risk of reactivation is at least six times higher than the risk in healthy individuals. These include individuals with major immunocompromising conditions (eg, lymphoma, leukemia, head and neck cancer, chemotherapy, solid organ transplant, HIV infection, tumor necrosis factor [TNF]-alpha inhibitors), and individuals with chest radiograph demonstrating fibronodular changes typical of healed TB (so-called "inactive TB") . All individuals in these categories should have a single test to evaluate for TBI.
●Moderate risk − We consider individuals with moderate risk for reactivation of TB to be those with risk of reactivation that is three to six times higher than the risk in healthy individuals. These include individuals with diabetes mellitus (regardless of insulin dependence) or those on corticosteroid therapy. For individuals with moderate risk for reactivation, TB testing should be restricted to those from groups with increased prevalence of TBI (these include homeless individuals, injection drug users, contacts of TB disease cases, and foreign-born individuals who immigrated as adults from countries with TB incidence >100/100,000 (table 4)).
●Slightly increased risk − We consider individuals with slightly increased risk for reactivation of TB to be those with risk of reactivation that is 1.5 to 3 times higher than the risk in healthy individuals. These include individuals who are underweight, smoke cigarettes, or have small granulomas on chest radiograph. For individuals with slightly increased risk for reactivation, TB testing should be individualized; we favor testing for such individuals from groups with increased prevalence of TBI (these include homeless individuals, injection drug users, contacts of TB disease cases, and foreign-born individuals who immigrated as adults from countries with TB incidence >100/100,000 (table 4)).
Risk groups — Patients at increased risk of reactivation include individuals with HIV infection or malignancy. In such groups, exclusion of TB disease is especially important. (See 'Excluding TB disease' below.)
HIV infection — All newly diagnosed patients with HIV infection should be screened for TB infection with TST or IGRA (algorithm 1) [35,36]. Subsequently, for those who tested negative, annual screening is warranted when there are ongoing risk factors for TB (eg, incarceration, living in communal settings, active drug use). (See "Primary care of adults with HIV", section on 'Tuberculosis'.)
In addition, for patients with HIV infection who initially tested negative in the setting of a CD4 cell count <200 cells/microL, repeat testing should be performed once the CD4 cell count has increased above this threshold, because of the possibility of false-negative results in the setting of immunosuppression [35,37-39]. Testing should not be repeated in patients who have previously had a positive test.
For patients with HIV infection in high TB prevalence settings (particularly those with CD4 cell count <200, which confers greater risk for development of TB disease), TBI treatment may be reasonable regardless of test results, once TB disease has been excluded [29,31,35]. (See 'Excluding TB disease' below and "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection".)
For patients with HIV infection in high TB prevalence settings where TBI testing is not available, all patients should receive treatment for TBI regardless of CD4 cell count [40,41]. TBI therapy administered in the absence of TBI testing has been associated with a 40 to 50 percent reduction in TB disease among persons living in areas with very high TB incidence . (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection".)
Malignancy — Routine TBI testing is warranted for patients with hematologic malignancies, head and neck cancer, and lung cancer, given substantially increased risk for reactivation in these groups. In patients with solid tumors, a risk-stratified approach is reasonable, since the risk for reactivation appears to be lower. Among patients at low risk for hepatotoxicity (based on age, other comorbid illnesses, and chemotherapy regimen), we perform TBI testing for individuals with an expected five-year survival >25 percent. Among patients at increased risk for hepatotoxicity, we perform TBI testing for individuals with an expected five-year survival >50 percent.
These issues have been evaluated in systematic reviews [34,43]. One review included 13 studies with more than 920,000 patients; it reported incidence rate ratio (IRR) for TB disease of 3.5 (95% CI 1.5-7.6) for adults with hematologic malignancies and IRR of 2.3 (95% CI 2.0-2.6) for adults with solid tumors . Another review included 23 studies with more than 300,000 patients; in the six studies in the United States published after 1980, the IRR was 26 for hematologic malignancies, 16 for head and neck tumors, 9 for lung cancers, and 4 for breast and other solid tumors .
Individuals from high-incidence settings — The prevalence of TBI is increased among individuals who were born in (or are former residents of) high-incidence countries (table 4) . Testing and treatment of individuals from high-incidence countries may be beneficial, particularly if they also have risk factors for reactivation of disease (eg, fibronodular scarring on chest radiograph, immunosuppression from diabetes, HIV infection, chronic kidney disease, or other causes) (table 2).
Testing and treatment of individuals from high-incidence countries who do not have additional risk factors for reactivation is more controversial. In the United States and United Kingdom, guidelines favor TBI testing for such individuals ; in Canada, guidelines favor TBI testing only for those with additional risk factors for progression to TB disease . (See 'Guidelines vary by country' below.)
The increased incidence of TB among individuals from high-incidence countries is related principally to the increased prevalence of TBI in this group, not to an increased risk of TBI reactivation . One modeling study concluded that treatment of TBI in individuals from high-incidence countries who had resided in the United States for more than five years was moderately cost-effective, but the individual benefit was very small .
DIAGNOSTIC APPROACH — There is no test that definitively establishes a diagnosis of TBI. TBI is a clinical diagnosis established by demonstrating an immune response to M. tuberculosis antigens and excluding active TB disease. Available tests to assess the immune response to TB antigens include the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs).
Specific antigen skin tests that use protein antigens employed by IGRAs have been endorsed by the World Health Organization (WHO); these tests are not available in the United States . These measure immune sensitization (type IV or delayed-type hypersensitivity) to mycobacterial protein antigens that occurs following exposure to (and infection by) mycobacteria.
General principles — There are two major types of tests for identification of TB infection: the tuberculin skin test (TST) and the interferon-gamma release assay (IGRA) blood test (table 5 and table 9 and algorithm 1) [46,47]. Both test types evaluate cell-mediated immunity. There is no clear advantage of the IGRA or the TST to predict future risk of TB disease. The decision to select a test should be based on the setting, cost and availability. (See 'Predictive value of IGRA versus TST' below.)
Guidelines for use of TST versus IGRA vary by country. (See 'Guidelines vary by country' below.)
Guidelines for the diagnosis of TB infection and TB disease were published in 2017 by the American Thoracic Society (ATS), United States Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) . The guidelines state the following:
●For individuals with low-to-intermediate risk of progression to TB disease (table 3), the IGRA is preferred over TST for diagnosis of TBI. IGRA is especially useful for patients who are unlikely to return to have the TST read and for patients with a history of Bacille Calmette-Guérin (BCG) vaccination (administered at birth in most TB-endemic countries) . The TST is an acceptable alternative to IGRA, especially in situations where IGRA is not available or is too costly (even though it is less specific than the IGRA).
●For individuals with high risk of progression to TB disease (table 3), either the IGRA or TST may be used; in such cases, the higher false-positive rate of the TST is acceptable. A dual testing strategy (perform one test and, if negative, perform the other) may be used, in which case a positive result from either test would be considered positive.
The National Tuberculosis Controllers Association (NTCA) issued guidance for screening, diagnosis, and treatment of TB infection in 2021 . In this guidance, IGRAs are preferred for most non-United States-born patients who received (or may have received) BCG vaccination; for other individuals, either a TST or IGRA may be used, depending on availability and cost. The NTCA advises against routine use of dual testing (with both TST and IGRA), but that this approach may be considered for patients at risk for a poor immune response to these tests, for patients at risk of severe forms of TB disease, and for patients in whom TB infection is strongly suspected. The NTCA also suggests that if patients at low risk for TB infection required testing, either an IGRA or TST should be used; if the result is positive, a second test (with the same or a different method) should be performed to confirm the test result and enhance specificity.
Updated guidelines for the diagnosis and treatment of TB infection were published by the World Health Organization in 2020 ; these have been incorporated in an Operational Handbook for Tuberculosis, published in 2022 [2,49].
WHO guidelines state that either TST or IGRA may be used to test for TBI, and neither test is preferable over the other for predicting progression to TB disease [1,2,49]. Performing TSTs may require fewer resources than IGRAs and may be more familiar to practitioners in resource-constrained settings; however, global TST shortages have reduced use of TST in scaling up programmatic management of TBI. The WHO operational Handbook provides guidance for implementation of testing for TB infection, including the newer tuberculosis antigen-based skin tests (TBST) [2,49]. (See "Use of the tuberculin skin test for diagnosis of tuberculosis infection (tuberculosis screening) in adults", section on 'Tuberculin skin testing materials'.)
Predictive value of IGRA versus TST — There is no clear advantage of the IGRA or the TST for predicting future risk of TB disease; the decision to select a test should be based on the setting, cost and availability. In very high-risk populations, there may be an advantage of performing both TST and IGRA, to enhance sensitivity if a first test is negative. In general, among individuals with a given risk factor, those with positive IGRAs have higher rates of TB disease than those with positive TST, likely reflecting greater specificity of IGRA (table 7).
The key value of a test for TBI is the accuracy of the test in predicting future TB disease, since this risk determines the need for TBI treatment. There have been many longitudinal studies evaluating the risk of TB disease in untreated individuals with a positive TST and/or IGRA. In many of these studies, participants underwent more than one test at the outset, allowing comparison of the predictive accuracy of different tests. Several systematic reviews of these studies have been performed.
Reviews have focused on studies performing TST and at least one IGRA in specific populations that are frequently candidates for TBI testing: children, immunocompromised individuals, and migrants from high- to low-TB incidence countries. In one review including 17 studies, children with positive IGRA had higher risk of TB in two studies but not three others, there was no difference between TST and IGRA in pooled risk of TB among immunocompromised individuals, and three studies including migrants demonstrated inconsistent results . Subsequently, the same authors found that sensitivity to predict future incident TB was greatest with the TST if a cut-point of 5 mm was used (in migrants and children), while the QFT had highest sensitivity in immunocompromised individuals. In all three populations, the highest specificity was observed using a TST of 15 mm as criteria for a positive test .
Meta-analyses have estimated the risk of disease in persons with positive and negative TST or IGRAs [24,52,53]. In one study including data from 18 studies and more than 80,000 individuals tested for TB infection, TB disease occurred in 4.0 percent (95% CI 2.6-6.3 percent) of untreated individuals with positive TB infection tests compared with 0.2 percent (95% CI 0.1-0.4 percent) of all untreated individuals with negative TB infection tests .
Findings of earlier reviews differed from one another; one concluded there were no significant differences between TST or IGRA , and another concluded that IGRA had significantly higher positive predictive values . These disparate findings reflected differences in inclusion criteria, quality assessments, and meta-analysis methods. However, in both reviews the pooled risk of TB disease among individuals with a positive IGRA was 2.1 percent; emphasizing that the great majority of individuals with a positive IGRA do not develop TB disease. Therefore, the decision to treat also must be based on clinical and epidemiologic assessment of risk for progression to TB disease, not just the test result. These studies also emphasize that while no test can completely exclude the possibility of developing TB disease, a negative TST or IGRA is useful to identify individuals at much lower risk of TB disease.
Role of dual testing
Use of IGRA to confirm TST — Use of IGRA as a confirmatory test for TST has been shown to be effective in contact tracing. In this approach, individuals with positive TST undergo subsequent IGRA testing; TBI treatment is offered only to those with positive IGRA (algorithm 1). In one study including more than 1800 contacts in school-based outbreaks in Korea, one-third of TST-positive schoolchildren were also IGRA positive; this strategy identified all TST-positive schoolchildren who later developed TB disease . In another study including more than 870 household contacts in Spain, this sequential testing strategy was found to be noninferior to tuberculin testing alone for TB prevention . These studies suggest that this strategy may be reasonably used to identify those at highest risk of developing TB disease.
If an IGRA test is needed to confirm a TST result, it has been suggested that blood be drawn for IGRA within three days of TST placement (ie, at the time of the TST reading), due to a potential concern that prior TST may boost subsequent IGRA results. However, in a systematic review including five studies and more than 200 individuals persons, no significant boosting effect from prior TST on subsequent IGRA results was observed . In theory, TST boosts IGRA results only in individuals with prior exposure to M. tuberculosis antigens; it is well established that the TST itself does not induce a cell-mediated immune response to M. tuberculosis. However, the studies that described boosting of IGRA by TST were not designed to distinguish whether this occurred only in those with true TBI. Regardless of remaining uncertainties regarding potential boosting, a positive IGRA result obtained after prior TST should be interpreted as a positive test for TBI.
Use of IGRA and TST to assess TB risk — Use of both IGRA and TST can be useful in certain circumstances . If a first test is positive, but the risk of TBI treatment is high or the pretest likelihood of TBI is very low, a positive second test (with an assay of the alternative type, eg, using TST for the second test if IGRA was used for the first test, or vice versa) increases the risk of TB disease. Similarly, if a first test is negative, but the likelihood of TBI is high, or, if infected, the risk of disease is high (eg, in a patient with immunosuppression), then results of a second test (with an assay of the alternative type) may be useful; in such a case, a discordant result on the second test implies a higher risk of disease than concordant negative tests. The risk of TB disease is highest with concordant positive results, lowest with concordant negative results, and intermediate with discordant results .
COVID-19 vaccination and TBI testing — There is no biologic reason to suspect that inactivated vaccines affect TST or IGRA results; however, unless testing for TBI is considered urgent, the NTCA 2021 guidance recommends deferral of testing until four weeks after administration of the last coronavirus disease 2019 (COVID-19) vaccine dose. Further guidance may be found online .
Patients with history of NTM infection — For individuals with known prior history of nontuberculous mycobacterial (NTM) infection, the IGRA is preferred over TST since NTM infection may be associated with a false-positive TST result. Exceptions include Mycobacterium kansasii, Mycobacterium szulgai, and Mycobacterium marinum, which affect both the TST and IGRA.
Low-risk settings — In low-risk situations where TBI testing is not medically indicated (eg, individuals at low risk for progression to TB disease if TB infection is present) but required by law or credentialing bodies, an initial positive test result (IGRA or TST) warrants confirmatory testing (TST if the first test was an IGRA or vice versa); the person should be considered to have TBI only if both tests are positive .
Test interpretation — Issues related to interpretation of the TST and IGRAs are discussed separately. (See "Use of the tuberculin skin test for diagnosis of tuberculosis infection (tuberculosis screening) in adults" and "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults".)
Guidelines vary by country — The approach to TBI testing varies by country. Some guidelines favor use of the TST over IGRA, some favor use of either assay interchangeably, and some favor a two-step approach (TST followed by IGRA) in certain circumstances (table 9). Many guidelines favor more than one approach, depending on the risk group tested.
United States — In May 2023 the United States Preventive Services Task Force (USPSTF) recommended TBI screening for all adults at increased risk for TB infection, regardless of other risk factors for development of TB disease . This recommendation was based on evidence review demonstrating that available diagnostic tests for TBI (TST and IGRA) are moderately sensitive (≥80 percent) and highly specific (≥95 percent), and that available TBI treatment confers moderate net benefit in such cases .
Canada — Guidelines on IGRAs were published in the eighth edition of the Canadian TB Standards in 2022 . According to the guidelines, both TST and IGRA are acceptable alternatives for TBI diagnosis. Either test can be used for TBI screening in any of the situations in which testing is indicated, with preferences and exceptions noted below.
●Testing for TB infection is not recommended (neither a TST nor IGRA should be used) in the following situations:
•In persons who have a low risk of infection and a low risk of progressing to TB disease if infected
•For routine mass screening outside of outbreak investigations or occupational screening programs
●An IGRA is the preferred test in the following circumstances:
•Evaluation of children >2 years of age and <10 years of age who previously who received BCG vaccine
•Evaluation of individuals ≥10 years of age who received BCG vaccine after infancy (>12 months of age), received BCG vaccine more than once, and/or are uncertain about when they received a BCG vaccine
•Settings where adequate training and quality control are not available for TST administration and/or reading but facilities and personnel are available to perform IGRAs
•Evaluation of individuals who are unable or unlikely to return to have their tuberculin skin test read
•TST is contraindicated
●TST should be used (and IGRA should not be used) for serial testing to assess risk of new infection (ie, conversion). This includes serial testing in contact investigations as well as serial testing for health care workers or other individuals with potential for ongoing TB exposure (such as corrections staff or prison inmates).
●Either IGRA or TST may be used sequentially in the following situations:
•If either the TST or IGRA is negative, the other test may be used to increase sensitivity if the risk for TB infection is high, the risk for progression to TB disease is elevated (table 3), the risk for a poor outcome from TB disease is high.
•If an IGRA result is indeterminate, borderline, or invalid, a TST may be performed.
•If a TST is positive but the likelihood of TB infection is low, or the risk of a false-positive result due to BCG is high, then an IGRA may be used to increase specificity.
General recommendations include the following:
●TBI testing should be offered to close contacts of patients with pulmonary or laryngeal TB, individuals who are immunocompromised and at high risk of TB, and new entrants from high-incidence countries presenting for health care.
●The upper age limit for offering to test and treat TB infection is 65 years.
●In any patient, TST is considered positive if skin induration is ≥5 mm, regardless of BCG history.
●Patients should be assessed for TB disease if any test for TB infection is positive; if TB disease is excluded, treatment for TB infection should be offered.
Specific recommendations include:
●TST is recommended for adult contacts (aged 18 to 65 years) of people with pulmonary or laryngeal TB. If the TST is positive (induration ≥5 mm, regardless of BCG history) treatment for TB infection should be initiated once TB disease has been ruled out.
●Both TST and IGRA are recommended for immunocompromised adults (although intended to increase sensitivity in this high-risk group, there is no specific evidence to support this practice); TBI treatment is warranted if either test is positive. Immunocompromised children should be referred to a specialist.
●TST is recommended for new entrants from high-incidence countries who present to health care services; an IGRA can be offered if TST not available.
●IGRA alone may be used for outbreak situations and other circumstances in which follow-up for TST interpretation may be difficult.
Europe — The European Centre for Disease Prevention and Control guidelines on IGRAs were published in March 2011 . The main recommendations are:
●IGRAs should not replace the existing standard diagnostic methods for the diagnosis of TB disease, and a negative IGRA result does not exclude TB disease.
●For TBI diagnosis, IGRAs may be used as part of the overall risk assessment to identify individuals for preventive treatment (eg, immunocompromised persons, children, close contacts, and recently exposed individuals).
●In high TB incidence countries, there is no added value in using IGRAs to diagnose TBI, as the focus of prevention and control is to identify and treat active cases. In low TB incidence countries, given the evidence available, IGRAs could be used in contact-tracing algorithms applying the two-step approach (following TST, in TST-positive subjects).
●In immunocompromised individuals, as it is essential to maximize sensitivity, the simultaneous use of TST and IGRAs could be beneficial in identifying TBI. However, in immune-compromised individuals, IGRAs should not be used to exclude TBI and/or TB disease.
Other countries — World Health Organization guidelines published in 2020 recommend that either TST or IGRA may be used, but noted that IGRAs are more costly and more technically complex to perform than the TST . Hence, the decision to use TST or IGRA should be based on operational considerations including the availability of trained personnel, laboratory facilities, and adequate resources to pay for the tests [2,49].
Approach to serial testing — Serial testing (eg, annual screening) is warranted for residents and employees of homeless shelters and correctional facilities, given the risk of TB exposure in these settings. In addition, serial testing may be reasonable in some health care facilities for HCWs at increased risk for occupational exposure to TB (such as pulmonologists or respiratory therapists) or for HCWs in certain settings (such as emergency departments) . (See 'Homeless shelters and correctional facilities' above and 'Health care workers in some settings' above.)
Approximately half of the lifetime risk of reactivation occurs in the first one to two years following infection, so it is important to target those who convert their TST or IGRA for treatment. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection".)
United States guidelines recommend use of either TST or IGRA for serial testing screening (algorithm 2) . Conversion of a TST or IGRA from negative to positive indicates new infection. Given the difficulties of interpretation of serial IGRA testing, we favor use of TST for TBI screening in individuals who are tested on a regular basis.
If the TST is used, a two-step TST protocol should be followed (ie, if the first TST is negative, then a second TST is performed within one to four weeks). For the TST, conversion is defined as a new positive test (with an increase of ≥10 mm) in the size of the TST reaction compared with the previous two years. (See "Use of the tuberculin skin test for diagnosis of tuberculosis infection (tuberculosis screening) in adults", section on 'Serial testing'.)
For the IGRA, conversion is defined as a change from a negative to a positive result as determined by the cut point of the assay used; however, the use of a simple IGRA conversion cut point may be problematic due to inherent variability of these tests [22,65]. (See "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults", section on 'Serial testing, conversion, and reversion'.)
NEXT GENERATION TOOLS — In April 2022, the World Health Organization recommended use of three new skin tests for diagnosis of TBI: C-TB, C-TST, and Diaskintest; all include the same M. tuberculosis-specific antigens present in the commercially available IGRAs (ESAT-6 and CFP-10) [2,66]. These tests hold the promise of the simplicity and accessibility of the tuberculin skin test (TST), with the improved specificity of the IGRAs. However thus far they are not available in North America or western Europe.
EXCLUDING TB DISEASE — All individuals with a positive test for TB infection (positive tuberculin skin test or interferon-gamma release assay result) warrant evaluation to exclude TB disease prior to initiation of treatment for TBI. Such evaluation is important to minimize the risk of drug resistance associated with inadvertent monotherapy of TB disease.
The evaluation includes clinical history, physical examination, and chest radiograph. TB disease may be asymptomatic in patients with HIV infection [67,68].
Patients with relevant clinical manifestations (cough >2 weeks' duration, fevers, night sweats, weight loss) and/or abnormal chest radiograph should submit three sputum specimens (obtained via cough or induction at least eight hours apart and including at least one early-morning specimen) for acid-fast bacilli smear, mycobacterial culture, and nucleic acid amplification testing . Symptoms related to extrapulmonary sites should also be evaluated as appropriate. (See "Diagnosis of pulmonary tuberculosis in adults".)
For specimens collected in a health care setting, standard respiratory precautions should be used (negative pressure room and N95 mask for health care workers). For inpatients (who should be in a respiratory isolation room), sputum collection should be performed within the room. For outpatients, sputum should be collected with care to minimize exposure to others. (See "Tuberculosis transmission and control in health care settings".)
The chest radiograph is normal in 85 percent of patients with TB infection . A chest radiograph is considered abnormal if it demonstrates parenchymal abnormalities, particularly opacification of the upper lobe or superior segment of the lower lobe. Radiographs demonstrating stable upper lobe fibro-nodular disease or calcified granulomas are considered to demonstrate evidence of previous TB disease and indicate the patient is at increased risk of reactivation (table 3). In a systematic review including 25 studies of patients with TBI, 15 percent (95% CI 12-18 percent) had findings on chest radiograph suggestive of prior TB infection (such as calcified nodules, noncalcified nodules, pleural thickening, and fibrotic scarring) . These lesions may be difficult to distinguish TBI from lesions of TB disease; therefore, in the setting of any radiographic abnormality, we have a low threshold for obtaining sputum mycobacterial cultures.
In resource-limited settings (where chest radiography and laboratory sputum evaluation may be less readily available), patients with HIV infection who are not on antiretroviral therapy (ART) and have none of the four symptoms may proceed with initiation of TBI treatment [40,71]. This approach is based on a meta-analysis including more than 9000 patients with HIV infection who were not on ART (among whom the prevalence of TB disease among patients with HIV infection was 5 percent) in which absence of these clinical manifestations had a negative predictive value of 98 percent . However, in children without HIV infection ≥5 years, adults without HIV infection, and individuals with HIV infection who are on ART, the sensitivity of symptom screen alone is less than 50 percent, and chest radiography is warranted .
For people living with HIV infection (PLHIV) and CD4 <200 (and especially if CD4 <50) in high TB incidence settings, a urine lipoarabinomannan (LAM) test may be a useful adjunctive tool; however, the implications and optimal management of PLHIV with positive urinary LAM test warrants further study. In a retrospective study including 563 PLHIV with CD4 <50 (including 28 with a positive urine LAM test and 535 with a negative urine LAM test), the rate of TB disease was 18 versus 3 percent, respectively . (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Patients with HIV infection'.)
Patients with TBI warrant HIV testing. (See "Screening and diagnostic testing for HIV infection".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of tuberculosis".)
SUMMARY AND RECOMMENDATIONS
•Tuberculosis infection (TBI; newer term for latent tuberculosis)
•Tuberculosis disease (newer term for active tuberculosis)
●Indications for testing – Screening for TB (testing for TB infection) is reserved for individuals who are at increased risk of developing TB disease and would thus benefit from treatment (table 2). This includes patients in the following categories (see 'Indications for TBI testing' above):
•Individuals at increased risk of new infection (eg, close contacts of persons with untreated TB disease; selected health care workers) (see 'Increased risk of new infection' above)
•Individuals at risk of reactivation (eg, immunocompromised individuals) (see 'Increased risk of reactivation' above)
•Individuals from high incidence settings (table 4): the approach varies by country.
-US guidelines recommend screening all adults with high TB incidence settings
-Canadian guidelines recommend screening only such individuals with additional risk (moderate or slightly increased risk) of reactivation (table 3)
●Individuals at increased risk of new infection include (see 'Increased risk of new infection' above):
•Contacts of patients with untreated respiratory TB disease (algorithm 1).
•Health care workers (HCWs).
-In regions with high TB incidence rate, HCWs at risk of exposure should undergo pre-employment baseline testing prior to exposure, followed by subsequent annual testing (algorithm 2).
-In regions with low TB incidence rate, HCWs need not undergo routine serial TB testing, in the absence of a known exposure or ongoing transmission. Routine serial TB testing may be reasonable for HCWs at increased risk for occupational exposure to TB (such as pulmonologists or respiratory therapists) or for HCWs in certain settings (such as emergency departments); such institutional policies should be individualized. (See 'Health care workers in some settings' above.)
•Homeless shelter and correctional facility residents and employees (algorithm 2).
•We favor use of the tuberculin skin test (TST) for serial testing, given the difficulties of interpretation of serial interferon-gamma release assay (IGRA) testing. If the TST is used, a two-step protocol should be followed (ie, if the first TST is negative, then a second TST is performed within one to four weeks) (algorithm 2). (See 'Approach to serial testing' above.)
●Individuals at risk of reactivation (see 'Increased risk of reactivation' above):
•For diagnosis of TBI in adults with low-to-intermediate risk of progression to TB disease, IGRA is preferred over TST, particularly for patients who are unlikely to return to have the TST read and for patients with a history of Bacille Calmette-Guérin vaccination.
•For diagnosis of TBI in adults with high risk of progression to TB disease, either IGRA or TST is acceptable. A dual testing strategy may be used, in which a positive result from either test is considered positive.
●Balancing risk of disease and risk of treatment
•For all individuals who have undergone testing, the decision to treat for TB infection should be individualized, as risk may outweigh potential benefit.
•The approach to balancing the risk of disease and the risk of treatment depends in part on the treatment regimen utilized. The relationship between the risk of adverse events and increasing age is well documented for isoniazid. In individuals with conditions conferring moderate or slightly increased risk who would be treated with isoniazid, we carefully assess the balance of risks and harms in individuals >50 years of age (especially individuals >65 years of age). For other TBI regimens, such as isoniazid-rifapentine for three months or rifampin for four months, the relationship between the risk of adverse events and increasing age is less clear. Until further data on the age-related risks of adverse events with these regimens are available, it is reasonable to adhere to the same cautions as for isoniazid. (See 'Balancing risk of disease and risk of treatment' above.)
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