TB Latente Treatment

Official reprint from UpToDate

www.uptodate.com ©2015 UpToDate

AuthorsMadhukar Pai, MD, PhDDick Menzies, MD, MSc

Section EditorC Fordham von Reyn, MD

Deputy EditorElinor L Baron, MD, DTMH

Diagnosis of latent tuberculosis infection (tuberculosis screening) in HIV-uninfected adults

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2015. | This topic last updated: Jul 28, 2015.

INTRODUCTION — Treatment of individuals with active tuberculosis (TB) is the first priority for tuberculosis control;

an important second priority is identification and treatment of individuals with latent tuberculosis infection (LTBI).

In most individuals, Mycobacterium tuberculosis infection is contained initially by host defenses, and infection

remains latent. However, latent infection has the potential to develop into active disease at any time. Identification

and treatment of latent tuberculosis infection can reduce the risk of development of disease by as much as 90

percent [1] and so has potential to protect the health of the individuals as well as the public by reducing the number

of potential sources of infection [2,3].

There are two major tests for identification of latent tuberculosis infection: the tuberculin skin test (TST) and the

interferon gamma release assay (IGRA) [4]. Both tests evaluate cell-mediated immunity.

Use of TST for diagnosis of LTBI in HIV-uninfected patients will be reviewed here. Management of LTBI for patients

with HIV or receiving tumor necrosis factor-alpha inhibitors is discussed in detail separately, as are issues related to

TB screening in children and treatment of latent tuberculosis infection in HIV-uninfected patients. (See "Treatment of

latent tuberculosis infection in HIV-infected patients" and "Latent tuberculosis infection in children" and "Tumor

necrosis factor-alpha inhibitors and mycobacterial infections" and "Interferon-gamma release assays for diagnosis of

latent tuberculosis infection".)

INDICATIONS FOR TESTING — The goal of testing for latent tuberculosis infection (LTBI) is to identify individuals

who are at increased risk for the development of tuberculosis (TB) and therefore would benefit from treatment of

LTBI [5,6]. Only those who would benefit from treatment should be tested, so a decision to test presupposes a

decision to treat if the test is positive.

In general, testing for latent TB infection is warranted to identify individuals who are at risk of new infection and to

identify individuals at increased risk of reactivation due to associated conditions (table 1). Diagnostic tools for

diagnosis of latent TB include tuberculin skin testing (TST) and interferon gamma release assays (IGRAs). Use of

the TST for diagnosis of latent TB infection will be reviewed here; the use of IGRAs for diagnosis of latent TB

infection is discussed separately. (See "Interferon-gamma release assays for diagnosis of latent tuberculosis

infection".)

The optimal approach to screening immigrants from high-incidence countries after arrival in low-incidence countries

is uncertain. Early decision analyses suggested minimal benefit of screening for migrants [7] and that investment in

TB control within the source countries would be more cost-effective [8]. A systematic review and meta-analysis

including 45 studies with 93,249 participants found that prevalence of positive TST was significantly higher than

positive IGRA (odds ratio 1.5, 95% CI 1.1 to 2.0), and initiation of LTBI therapy occurred more often among patients

with positive TST than positive IGRA (59 versus 28 percent) [9].

In general, use of TST or IGRA for the diagnosis of active TB in adults is discouraged. (See "Diagnosis of pulmonary

tuberculosis in HIV-uninfected patients".)

Risk of new infection — Testing for latent TB should be performed in asymptomatic individuals for whom new

infection is suspected. This includes close contacts of patients with active pulmonary TB (eg, those living in the

same household), as well as casual contacts of patients with highly contagious active TB (such as healthcare

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workers). Because the risk of developing active disease is very high in the next few years following exposure, all

patients at increased risk for new TB infection should be evaluated for LTBI, regardless of age (table 1).

In general, close contacts of patients with active pulmonary TB should undergo a second test 8 to 12 weeks later if

the first test is negative. Healthcare workers should undergo baseline two step testing followed by annual testing

(see 'Repeat and serial testing' below).

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 [10]:

Increased risk of reactivation — Identifying those at risk for reactivation who warrant testing depends on age and

the degree of risk for reactivation (relative to healthy individuals) (table 1 and table 2). In general, individuals at

increased risk of reactivation require a single test only; if it is negative, no further testing is needed.

Normal healthy individuals with LTBI have an annual risk of 0.1 percent (1 per 1000) of developing active TB [11].

Annual risk of disease if infected can range from more than 10 percent (with HIV infection) to 1 to 2 percent (if on

hemodialysis or following solid organ transplant) to 0.1 percent (if healthy with a normal chest radiograph). Estimated

risks for TB relative to healthy individuals in the setting of various conditions are outlined in the Table (table 2):

Age — The risk of isoniazid-induced hepatitis and other adverse events increases with age; risk of hepatitis

increases over the age of 35 and substantially over the age of 50 [12,13]. Therefore, age is an important

consideration in the decision to test for LTBI, since testing implies that treatment will be administered if the test is

positive [12-14]. Although the annual risk of disease is relatively high, with increasing age the cumulative risk of

reactivation diminishes as does the benefit of therapy. To estimate the cumulative lifetime risk with various

conditions, a web-based algorithm can be used [15].

We favor the following age parameters for LTBI testing (with intention to treat if test is positive) (table 1):

Infants (ages ≤1): 50 percent●

Children (ages 1 to 2): 12 to 25 percent●

Children (ages 2 to 5): 5 percent●

Children (ages 5 to 10): 2 percent●

Age >10 years: 10 to 20 percent●

High risk – High risk individuals are those whose risk for reactivation is at least six times higher than normal

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 those 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 latent

TB infection, regardless of age.

●

Moderate risk – Moderate risk individuals are those whose risk for reactivation is three to six times higher than

normal healthy individuals. These include individuals with diabetes mellitus (regardless of insulin dependence)

or corticosteroid therapy. All individuals in these categories ≤65 should have a single test to evaluate for latent

TB infection.

●

Slightly increased risk – Individuals at slightly increased risk for reactivation are those whose risk is 1.5 to 3

times higher than normal healthy individuals. This includes individuals who are underweight, smoke cigarettes,

or have small granulomas on chest radiograph. All individuals ≤50 in this category should have a single test to

evaluate for latent TB infection.

●

For individuals ≥65, the risk of hepatitis is ≥5 percent, so testing and treatment are indicated only if risk of

reactivation is high [12].

●

For individuals between 50 and 65, the risk of hepatitis is 3 to 5 percent, which is sufficiently high that testing

and treatment are indicated if risk of reactivation is high or moderate.

●


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Testing and treatment are not warranted for individuals ≥50 with only slightly increased risk and individuals ≥65 with

moderate or slightly increased risk for reactivation.

TUBERCULIN SKIN TEST — The tuberculin skin test (TST) is used to identify individuals with previous sensitization

to mycobacterial antigens. It consists of intradermal injection of tuberculin material, which stimulates a delayed-type

hypersensitivity response mediated by T lymphocytes and causes induration within 48 to 72 hours.

Performing the TST — In North America, the tuberculin material is purified protein derivative (PPD); the

recommend dose is 5 tuberculin units (0.1 mL). In other regions, RT-23 may be the tuberculin material used; the

standard dose is 2 tuberculin units. These doses have been shown to be equivalent [16].

The only recommended method of tuberculin skin testing is the Mantoux technique, which consists of intradermal

injection of tuberculin material on the inner surface of the forearm [14,17]. To read the test, the transverse diameter

of the induration (not erythema) should be demarcated, measured, and recorded in millimeters. The test should be

read 48 to 72 hours following intradermal injection.

The results are less reliable if the test is read after 72 hours. Among 400 individuals with positive TST at 48 to 72

hours, about 20 percent had negative results when the TST was read seven days after placement [18]. While a

strongly positive reaction after 96 hours may be accepted, results become increasingly doubtful with longer intervals

between injection and reading; in such circumstances, it is best is to repeat the TST. If the TST is repeated after

seven days, then the boosting effect may cause a positive TST (see 'Booster response' below). However, in the

absence of a documented negative first TST, there is no way to know if the TST represents a boosted reaction.

Hence, the TST must be interpreted in the same way as a single initial TST. This potential problem reinforces the

importance of reading at the correct time.

Multipuncture methods (including the Tine test and the Heaf test) may be easier to administer but are not accurate

because it is not possible to precisely control the amount of tuberculin. Therefore, these should not be used [17].

Repeat and serial testing — If the TST is documented to be positive, it should never be repeated. Once the test is

positive, it will remain positive, and repeating the test has no clinical utility. If there is a history of a positive TST but

this is not documented, then it may be appropriate to confirm this.

If the TST is negative, there are three circumstances in which the TST should be repeated:

For individuals <50, risk of hepatitis is less than 3 percent (for individuals <35, it is less than 1 percent), so

testing and treatment are indicated if risk of reactivation is slightly increased, moderate, or high.

●

Close contacts of patients with active pulmonary tuberculosis – These individuals may have an initial negative

TST because the tuberculosis (TB) infection was so recent that delayed hypersensitivity has not yet developed.

In these individuals, the TST should be repeated eight weeks after the last exposure, since it takes three to

seven weeks for tuberculin conversion to occur after new infection [19]. The same technique and dose is used,

but the test is applied on the opposite forearm.

●

Individuals with ongoing potential exposure – In North America, ongoing potential exposure occurs in the

setting of occupational risk; healthcare workers in institutions with a substantial risk of unrecognized exposure

to tuberculosis represent the major group for which serial annual testing is warranted. Those undergoing serial

annual testing should also receive additional testing after a known episode of exposure [20].

Individuals with ongoing potential exposure who have a history of a positive test for latent TB infection (LTBI)

and have completed a course of LTBI treatment should undergo baseline chest radiograph. Reevaluation with

chest radiograph should be pursued if symptoms develop that raise the possibility of active tuberculosis. There

are no additional mechanisms to evaluate for subsequent TB exposure in these individuals.

Serial testing is NOT warranted for groups other than those with occupational risk (such as those with

increased risk of reactivation) in settings where the incidence of TB is very low (less than 1 per 1000 per year).

●


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Interpretation of repeat and serial skin testing is discussed below. (See 'Repeat TST interpretation' below.)

INTERPRETING THE TST — The tuberculin skin test (TST) reading must establish a positive or negative result in

order to determine subsequent management (figure 1 and table 3).

Sensitivity is 98 percent using the 5 mm threshold, 90 percent using the 10 mm threshold, but only 50 to 60 percent

using the 15 mm threshold [25]. As the cutoff for mm of induration is increased, the sensitivity decreases and the

specificity increases. A higher cutoff is useful for evaluation of individuals in regions with high prevalence of

nontuberculous mycobacterial exposure and low likelihood of true TB infection.

If the TST is negative, the possibility of a false-negative result must be considered, as discussed in the following

section. Repeat testing is warranted in the circumstances outlined above. (See 'Repeat and serial testing' above.).

If the test is positive, no further testing is warranted. The patient should be referred for medical evaluation to exclude

active tuberculosis (TB), followed by initiation of treatment for latent TB infection (LTBI). (See 'Positive tests' below.)

Negative tests

False-negative tests — False-negative tuberculin skin test results may occur in the setting of biological and

technical limitations (table 4). Biologic limitations include immunosuppression or natural waning of immunity.

Technical limitations include improper tuberculin handling and interpretation.

Anergy testing with control antigens such as mumps and Candida was previously thought to help determine between

true-negative and false-negative tuberculin tests. However, the role of anergy testing in the diagnosis of LTBI is not

well defined, and such testing is not recommended [14,17].

Measles vaccination may temporarily suppress tuberculin reactivity. Measles-mumps-rubella (MMR) vaccine may be

given after, or on the same day as, the TST. If MMR has been given recently, TST should be postponed until four to

six weeks after administration of MMR [26].

Treating negative tests — In the setting of recent close contact to individuals known to have infectious

tuberculosis, treatment for LTBI should be considered for adults who are severely immunocompromised (such as

HIV infected or organ transplant recipient), even with negative TST or interferon gamma release assay (IGRA).

For these patients, LTBI therapy should be initiated (following clinical evaluation to rule out active tuberculosis) and

the TST or IGRA repeated after eight weeks [19]. If the second test is positive, treatment should be continued; if the

test is negative, treatment is usually stopped, although continued therapy may be considered on an individual basis.

The approach to treatment is discussed in detail separately. (See "Treatment of latent tuberculosis infection in

HIV-negative adults".)

Positive tests — The positive predictive value (PPV) denotes the probability of true infection in the setting of a

positive test. The greater the risk of exposure (due to risk factors such as close contacts with active TB cases and

In areas where TB incidence and the annual risk of infection are high, routine serial testing is usually not

performed because of limited resources in these settings [21].

To establish a correct baseline prior to serial testing ("two-step testing") – In individuals with remote exposure to

mycobacterial antigens (eg, due to prior Bacillus Calmette-Guérin [BCG] vaccination, nontuberculous

mycobacteria exposure, or remote TB infection), the tuberculin reaction may have waned and an initial

tuberculin test may be negative [22-24]. However, placement of the initial tuberculin test stimulates anamnestic

recall of immunity, such that a second tuberculin test ("booster") will be positive. Therefore, in the setting of a

positive tuberculin test performed a year after initial screening, it may be difficult to distinguish between recent

infection and remote mycobacterial exposure. For this reason, evaluation for the "booster phenomenon" should

be performed by repeating the TST (on the opposite forearm) one to four weeks after the first test. The

induration observed with the second test is the baseline that should be used for subsequent evaluation of skin

test conversion.

●


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foreign-born status), the higher the PPV. A computer-based algorithm is available to assist in the interpretation of

TST [15].

False-positive tests — There are two important causes of false-positive tests: nontuberculous mycobacteria

infection and Bacillus Calmette-Guérin (BCG) vaccination. However, in individuals with high likelihood of LTBI and/or

high risk of development of disease if infected, potential causes of false-positive tests should not influence the

decision to administer LTBI therapy.

Treating positive tests — Patients with positive tuberculin skin test or IGRA results must undergo clinical

evaluation to rule out active tuberculosis prior to treatment for latent infection. This includes evaluation for symptoms

(eg, fever, cough, weight loss), physical examination, and radiographic examination of the chest.

A chest radiograph is considered abnormal if it demonstrates parenchymal abnormalities, particularly upper lobe

opacification. Radiographs demonstrating stable upper lobe fibro-nodular disease or calcified granulomas are

considered to have evidence of previous tuberculosis and indicate the patient is at increased risk of reactivation

(table 2). There is no role for routine radiography for patients with positive tuberculin skin test who do not complete

treatment for LTBI [29-31].

Patients with symptoms or radiographic signs suggestive of active disease should undergo evaluation with sputum

microscopy and culture and receive treatment as appropriate. Sputum induction should be performed if patients

cannot expectorate spontaneously. Symptoms related to extrapulmonary sites should also be evaluated as

appropriate. In addition, HIV testing should be considered in patients with LTBI. (See "Diagnosis of pulmonary

tuberculosis in HIV-uninfected patients" and "Treatment of pulmonary tuberculosis in HIV-uninfected patients" and

"Screening and diagnostic testing for HIV infection".).

The approach to treatment is discussed in detail separately. (See "Treatment of latent tuberculosis infection in

HIV-negative adults".)

Healthcare workers — Healthcare workers should undergo baseline two-step testing followed by annual testing.

(See 'Repeat and serial testing' above.)

The clinical approach for healthcare worker exposure to active contagious TB varies depending on TST status and

the interval since the exposure episode. In general, if primary TB infection develops following clinical exposure, TST

Nontuberculous mycobacteria – Infection with nontuberculous mycobacteria (NTM) may cause false-positive

reactions to tuberculin. Estimates of the frequency of false-positive TSTs due to NTM range from 1 to 5 percent

of positive tuberculin tests [27] to as many as 50 percent of 9 to 14 mm reactions in United States healthcare

workers [15]. Therefore, the effect is important only if prevalence of true TB infection is low (ie, less than 5

percent). This situation occurs in low incidence countries with tropical, subtropical, or temperate climates

[15,27].

●

BCG vaccination – BCG vaccination is a well known but frequently misunderstood cause of false-positive

tuberculin reactions. The effect of BCG on TST depends primarily on the age when vaccinated [27]. BCG

vaccination in the first year of life causes no discernible effect on TST after 10 years or more. Vaccination after

the first year of life (such as at entrance to primary school at age 5 to 6) causes a stronger and longer lasting

effect. As many as 20 percent of individuals remain positive 10 years or more after vaccination at this age. In

pediatric populations, the interval since vaccination is important since there is progressive waning over the first

10 years after vaccination.

Since many foreign-born persons do not know their BCG vaccination status or age at vaccination, current and

past BCG vaccination policies for most countries of the world may be reviewed online at the World Atlas of

BCG Policies and Practices [28].

TST reactivity caused by BCG sensitization can be distinguished from latent TB infection by interferon-gamma

release assays. (See "Interferon-gamma release assays for diagnosis of latent tuberculosis infection".)

●


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conversion occurs three to eight weeks later. Therefore, for TST to reflect recent TB infection, it must be performed

≥3 weeks following exposure. The clinical approach is outlined below:

The role of interferon-gamma release assay for diagnosis of latent tuberculosis infection in healthcare workers is

uncertain; further study is needed. This issue is discussed further separately. (See "Interferon-gamma release

assays for diagnosis of latent tuberculosis infection", section on 'Reproducibility'.)

Allergic reactions — Early reaction within 24 hours with absence of induration at 48 to 72 hours is considered an

allergic reaction [32]. Immediate hypersensitivity skin reactions to the TST are possible; these consist of wheal and

flare response at the testing site within 20 minutes of purified protein derivative (PPD) placement. In a case series of

3248 allergy clinic patients, immediate hypersensitivity to skin testing with PPD was observed in 2 to 3 percent of

patients, without systemic reactions [32]. Systemic allergic reactions (including urticaria, angioedema, dyspnea, and

anaphylaxis) are rarely reported [33,34]. The incidence is estimated to be 1 to 3 per million distributed doses, which

is similar to the rate of anaphylaxis with vaccines [34]. (See "Allergic reactions to vaccines".)

In our experience, a diffuse maculopapular rash can appear within 12 hours and resolve within a day or two,

although such allergic reactions to the TST are relatively uncommon. The incidence of these reactions in our clinic is

in the range of 1 reaction per 2000 to 3000 patients [35]. These allergic reactions are unrelated to the TST result at

48 to 72 hours.

Patients with immediate skin test reactions or other types of allergic reactions to the TST should not receive it again.

The best approach for individuals who require serial testing has not been studied. Our practice is to assess patients

annually for symptoms of active disease and obtain a chest radiograph if new symptoms develop.

Managing referrals — Patients may be referred after a TST is performed for expert guidance regarding initiation of

LTBI therapy. In such cases, it is imperative to review the indications for skin testing as outlined in the preceding

sections. LTBI treatment should be initiated only for patients in the categories for which treatment confers benefit.

Those who have undergone testing who fall outside these categories should not receive LTBI therapy, as risk

outweighs potential benefit. (See 'Indications for testing' above.)

REPEAT TST INTERPRETATION — The interpretation of serial or repeated tuberculin skin test (TST) depends on

the context [19]. (See 'Repeat and serial testing' above.)

Booster response — Booster response refers to a positive TST performed one to four weeks after an initial

negative TST in the absence of exposure (such as preemployment screening of healthcare workers). The booster

For individuals with prior negative tuberculin test (ideally a negative two-step TST) and low likelihood of interim

exposure, a single tuberculin test should be performed eight weeks following exposure. If positive at ≥5 mm,

this should be interpreted as a recent TST conversion.

●

For individuals without prior tuberculin testing born in a low TB-incidence country and no history of BCG

vaccination, a baseline tuberculin test could be performed immediately (ie, ≤2.5 weeks or about 18 days

following exposure). If positive, this is suggestive of prior LTBI infection. If negative, a second TST can be

performed eight weeks after the end of exposure. If positive at ≥5 mm, this should be managed as a recent

TST conversion.

●

For individuals without prior tuberculin testing born in a medium to high TB incidence country and/or who have

history of BCG vaccination, baseline two step tuberculin testing could be performed promptly so long as both

first and second steps can be completed within ≤2.5 weeks (ie, about 18 days) from the start of exposure. If

positive at ≥5 mm, this is suggestive of prior LTBI infection. If negative, a second TST can be performed eight

weeks after the end of exposure. If the second TST is positive, this should be managed as a recent TST

conversion. IGRA is not an appropriate diagnostic tool for such circumstances, as the interval between primary

TB infection and IGRA conversion is not fully understood, and there is no consensus on how to interpret IGRA

conversions and reversions. (See "Interferon-gamma release assays for diagnosis of latent tuberculosis

infection".)

●


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response is less specific for diagnosis of latent tuberculosis infection (LTBI) than the initial TST since the booster

response may be caused by prior Bacillus Calmette-Guérin (BCG) vaccination, sensitization to nontuberculous

mycobacteria, or remote tuberculosis (TB) infection. Therefore, the risk of developing active TB among individuals

with a booster response is lower than the risk of developing active TB among individuals with an initial positive TST

[12,36].

Conversion — Skin test conversion refers to one of the following:

The risk of developing active TB is much higher in the setting of skin test conversion than booster response.

Definition — For both boosting and conversion, the second TST is defined as positive if the induration measures 10

mm or greater and has increased by ≥6 mm since the previous test [19]. This definition is used because test

variability may cause increases in induration of up to 6 mm.

Criteria for boosting and conversion of 12 mm, 15 mm, or even 18 mm have been suggested; these may be more

specific but are much less sensitive. Individuals with reactions of ≥10 mm should be referred for medical evaluation

to exclude active TB prior to initiation of LTBI therapy. The reaction should be documented, and no further tuberculin

testing should be done.

INTERFERON GAMMA RELEASE ASSAYS — Issues related to interferon-gamma release assays (IGRAs) and

their use are discussed in detail separately. (See "Interferon-gamma release assays for diagnosis of latent

tuberculosis infection".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and

“Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5 to 6 grade

reading level, and they answer the four or five key questions a patient might have about a given condition. These

articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the

Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the

10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with

some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these

topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on

“patient info” and the keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS

A positive TST up to eight weeks after an initial negative TST in the setting of recent exposure (see 'Risk of

new infection' above)

●

A positive TST detected as part of serial testing with ongoing risk of exposure (such as healthcare workers), in

the setting of baseline negative TST

●

th th

th th

Beyond the Basics topics (see "Patient information: Tuberculosis (Beyond the Basics)")●

Identification and treatment of latent tuberculosis infection (LTBI) can greatly reduce the likelihood of

reactivation. Hence, this has the potential to protect both individual and public health by reducing the number of

potential sources of infection. (See 'Introduction' above.)

●

Testing for and treatment of LTBI should be pursued in patients at increased risk for tuberculosis because of

certain clinical conditions and/or in patients with recent close contact to persons known to have infectious

tuberculosis (table 1). LTBI testing is appropriate only for those who would benefit from treatment; a decision to

test implies a decision to treat if the test is positive. (See 'Indications for testing' above.)

●

Since isoniazid-induced hepatitis increases with age, we suggest the following age parameters for LTBI testing

(with intention to treat if test is positive) (table 1 and table 2) (Grade 2C):

●

For individuals ≥65, testing is indicated if risk of reactivation is high.•


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For individuals between 50 and 65, testing is indicated if risk of reactivation is moderate or high.•

For individuals <50, testing is indicated if risk of reactivation is slightly increased, moderate, or high. (See

'Age' above.)

•

The tuberculin skin test (TST) assesses the intradermal delayed-type hypersensitivity response produced by

administration of purified protein derivative (PPD) from Mycobacterium tuberculosis. The interpretation is

outlined in the Table (table 3). (See 'Tuberculin skin test' above.)

●

A period of up to eight weeks after primary tuberculosis (TB) infection may be required for tuberculin skin test

conversion to occur. Individuals with recent close contact to a known infectious case of tuberculosis, whose

initial TST is negative, should have repeat TST eight weeks after the end of exposure. (See 'Repeat and serial

testing' above.)

●

TST can be false negative because of because of biologic problems (such as immune suppression) or because

of technical problems with the TST administration, PPD material, or reading (table 4). TST can be false positive

because of nontuberculous mycobacteria or Bacillus Calmette-Guérin (BCG) vaccination. However, in

individuals with high likelihood of LTBI and/or high risk of development of disease if infected, potential causes

of false-positive tests should not influence the decision to administer LTBI therapy. (See 'Interpreting the TST'

above.)

●

For severely immunocompromised persons who have had recent close contact with known infectious cases of

tuberculosis, LTBI therapy may be started even if the initial TST is negative. These tests for LTBI should be

repeated after eight weeks. If the second test is now positive, treatment is continued. (See 'Treating negative

tests' above.)

●

Patients with positive TST or IGRA results must undergo clinical evaluation to rule out active tuberculosis and

to assess need for LTBI therapy. This includes evaluation for symptoms (eg, fever, cough, weight loss),

physical exam, and radiographic examination of the chest. (See 'Treating positive tests' above.)

●

Tuberculin boosting is defined as an increase to an induration of at least 10 mm, compared with a TST that was

previously negative (<10 mm) in the absence of any exposure (and usually within one to four weeks).

Tuberculin conversion is defined as an increase in induration of at least 10 mm, compared with a TST that was

previously negative (<10 mm) in the setting of potential exposure. (See 'Repeat TST interpretation' above.)

●


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Schwartzman K, Oxlade O, Barr RG, et al. Domestic returns from investment in the control of tuberculosis inother countries. N Engl J Med 2005; 353:1008.

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Stead WW, To T, Harrison RW, Abraham JH 3rd. Benefit-risk considerations in preventive treatment fortuberculosis in elderly persons. Ann Intern Med 1987; 107:843.

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Kopanoff DE, Snider DE Jr, Caras GJ. Isoniazid-related hepatitis: a U.S. Public Health Service cooperativesurveillance study. Am Rev Respir Dis 1978; 117:991.

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Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of theAmerican Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement ofthe American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). Thisstatement was endorsed by the Council of the Infectious Diseases Society of America. (IDSA), September1999, and the sections of this statement. Am J Respir Crit Care Med 2000; 161:S221.

14.

The Online TST/QFT Interpreter. Version 2.0. http://www.tstin3d.com/index.html (Accessed on September 24,2010).

15.

COMSTOCK GW, EDWARDS LB, PHILIP RN, WINN WA. A COMPARISON IN THE UNITED STATES OFAMERICA OF TWO TUBERCULINS, PPD-S AND RT 23. Bull World Health Organ 1964; 31:161.

16.

Menzies D, Doherty TM. Diagnosis of latent tuberculosis infection. In: Reichman and Hershfield's Tuberculosis,a comprehensive international approach, Raviglione MC (Ed), Informa Healthcare USA, New York 2006.p.215.

17.

DUBOCZY BO, BROWN BT. Multiple readings and determination of maximal intensity of tuberculin reaction.Am Rev Respir Dis 1961; 84:60.

18.

Menzies D. Interpretation of repeated tuberculin tests. Boosting, conversion, and reversion. Am J Respir CritCare Med 1999; 159:15.

19.

Jensen PA, Lambert LA, Iademarco MF, et al. Guidelines for preventing the transmission of Mycobacteriumtuberculosis in health-care settings, 2005. MMWR Recomm Rep 2005; 54:1.

20.

World Health Organization. Guidelines for the prevention of tuberculosis in health care facilities in resource-

limited settings. WHO/CDS/TB/99.269. IJTLD 1999.

21.

Menzies R, Vissandjee B, Rocher I, St Germain Y. The booster effect in two-step tuberculin testing amongyoung adults in Montreal. Ann Intern Med 1994; 120:190.

22.

Richards NM, Nelson KE, Batt MD, et al. Tuberculin test conversion during repeated skin testing, associatedwith sensitivity to nontuberculous mycobacteria. Am Rev Respir Dis 1979; 120:59.

23.

Gordin FM, Perez-Stable EJ, Flaherty D, et al. Evaluation of a third sequential tuberculin skin test in a chroniccare population. Am Rev Respir Dis 1988; 137:153.

24.

FURTHER studies of geographic variation in naturally acquired tuberculin sensitivity. Bull World Health Organ1955; 12:63.

25.

Centers for Disease Control and Prevention. Guide to Vaccine Contraindications and Precautions. Departmentof Health and Human Services. Available at: http://www.cdc.gov/vaccines/recs/vac-admin/downloads/contraindications-guide-508.pdf

26.

Farhat M, Greenaway C, Pai M, Menzies D. False-positive tuberculin skin tests: what is the absolute effect ofBCG and non-tuberculous mycobacteria? Int J Tuberc Lung Dis 2006; 10:1192.

27.

A World Atlas of BCG Vaccination Policies and Practices http://www.bcgatlas.org/ (Accessed on April 01,2009).

28.

Vinkeles Melchers NV, van Elsland SL, Lange JM, et al. State of affairs of tuberculosis in prison facilities: asystematic review of screening practices and recommendations for best TB control. PLoS One 2013;

29.


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8:e53644.

Arshad S, Bavan L, Gajari K, et al. Active screening at entry for tuberculosis among new immigrants: asystematic review and meta-analysis. Eur Respir J 2010; 35:1336.

30.

Rieder H. What is the role of case detection by periodic mass radiographic examination in tuberculosiscontrol?. In: Toman’s Tuberculosis: Case detection, treatment, and monitoring – questions and answers, 2nded, Frieden, T. (Eds), World Health Organization, Geneva 2004. p.72.

31.

Tarlo SM, Day JH, Mann P, Day MP. Immediate hypersensitivity to tuberculin. In vivo and in vitro studies. Chest1977; 71:33.

32.

Youssef E, Wooltorton E. Serious allergic reactions following tuberculin skin tests. CMAJ 2005; 173:34.33.

Froeschle JE, Ruben FL, Bloh AM. Immediate hypersensitivity reactions after use of tuberculin skin testing.Clin Infect Dis 2002; 34:E12.

34.

Richard Menzies, MD, MSc, personal communication.35.

Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. Adv Tuberc Res 1969; 17:28.36.

Topic 8005 Version 23.0


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GRAPHICS

Who should be tested for latent TB infection?*

Those with increased risk of new TB infection (all patients should be tested

regardless of age)

Close contacts of patients with active pulmonary/respiratory TB

Casual contacts of patients with highly contagious active TB

Healthcare workers and other occupations in which there is risk of exposure to patients with

untreated contagious active TB (prison facilities, homeless shelters)

Those with increased risk of reactivation

High risk (all patients should be tested regardless of age)

HIV infection (any stage of illness)

Transplant, chemotherapy, or other major immunocompromising condition

Lymphoma, leukemia, head and neck cancer

Abnormal chest radiograph with apical fibronodular changes typical of healed TB (not including

granuloma)

Silicosis

Renal failure (requiring dialysis)

Treatment with TNF-alpha inhibitors

Moderate risk (patients under age 65 should be tested)

Diabetes mellitus

Systemic glucocorticoids (≥15 mg/day for ≥1 month)

Slightly increased risk (patients under age 50 should be tested)

Underweight (<85 percent of ideal body weight); for most individuals, this is equivalent to body

mass index (BMI) ≤20

Cigarette smoker (1 pack/day)

Chest radiograph with solitary granuloma

TB: tuberculosis; TNF: tumor necrosis factor.

* Only those who would benefit from treatment should be tested, so a decision to test presupposes a

decision to treat if the test is positive.

¶ A second test is warranted if the first test is negative (refer to text).

Δ Baseline two-step testing should be performed, followed by annual testing.

◊ Generally need a single test.

§ The United States Centers for Disease Control and Prevention (CDC) recommends skin testing for all

patients in this category. However, population-based studies demonstrate that the relative risk for

development of active tuberculosis in this category is moderate (2 to 4x that of healthy individuals).

Therefore, an age cutoff of ≤65 is indicated, so that potential risks of isoniazid toxicity in older patients do

not outweigh potential benefit. (Refer to separate table summarizing relative risk for development of active

tuberculosis).

Graphic 74584 Version 5.0

¶

¶

Δ

◊

§


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Risk factors for the development of active tuberculosis among persons

infected with Mycobacterium tuberculosis

Risk factor

Estimated risk for TB relative

to persons with no known

risk factor

References

High risk

Acquired immunodeficiency syndrome

(AIDS)

110 to 170 1,2

Human immunodeficiency virus

infection (HIV)

50 to 110 3,4

Transplantation (related to immune-

suppressant therapy)

20 to 74 5 to 8

Silicosis 30 9,10

Chronic renal failure requiring

hemodialysis

10 to 25 11 to 14

Carcinoma of head and neck 16.0 15

Recent tuberculosis (TB) infection (≤2

years)

15.0 16,17

Abnormal chest radiograph with apical

fibronodular changes typical of healed

TB (not granuloma)

6 to 19 18 to 20

Tumor necrosis factor (TNF)-alpha

inhibitors

1.7 to 9 21,22,35,36

Moderate risk

Treatment with glucocorticoids 4.9 23

Diabetes mellitus (all types) 2 to 3.6 24 to 27

Young age when infected (≤4 years) 2.2 to 5 28

Slightly increased risk

Underweight (<85 percent of ideal

body weight); for most individuals

this is equivalent to body mass index

(BMI) ≤20

2 to 3 29

Cigarette smoker (1 pack/day) 2 to 3 30,31

Chest radiograph with solitary

granuloma

2 20,32

Low risk

Infected person, no known risk factor,

normal chest radiograph ("low-risk

reactor")

1 33

Very low risk


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Positive booster (two-step test) with

no other known risk factor and

normal chest radiograph)

0.5 Extrapolated

from 33 and

34

References:

Guelar A, Gatell JM, Verdejo J, et al. A prospective study of the risk of tuberculosis among

HIV-infected patients. AIDS 1993; 7:1345.

1.

Antonucci G, Girardi E, Raviglione MC, et al. Risk factors for tuberculosis in HIV-infected persons. A

prospective cohort study. JAMA 1995; 274:143.

2.

Wood R, Maartens G, Lombard CJ. Risk factors for developing tuberculosis in HIV-1 - Infected adults

from communities with low or very high incidence of tuberculosis. J Acquir Immune Defic Syndr

2000; 23:75.

3.

Selwyn PA, Hartel D, Lewis VA, et al. A prospective study of the risk of tuberculosis among

intravenous drug users with human immunodeficiency virus infection. New Engl J Med 1989;

320:545.

4.

Sakhuja V, Jha V, Varma PP, et al. The high incidence of tuberculosis among renal transplant

recipients in India. Transplantation 1996; 61:211.

5.

Aguado JM, Herrero JA, Gavalda J, et al. Clinical presentation and outcome of tuberculosis in kidney,

liver, and heart transplant recipients in Spain. Spanish Transplantation Infection Study Group,

GESITRA. Transplantation 1997; 63:1278.

6.

Miller RA, Lanza LA, Kline JN, Geist LJ. Mycobacterium tuberculosis in lung transplant recipients. Am

J Respir Crit Care Med 1995; 152:374.

7.

Meyers BR, Halpern M, Sheiner P, et al. Tuberculosis in liver transplant patients. Transplantation

1994; 58:301.

8.

Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council. A

Double-blind placebo-controlled clinical trial of three antituberculosis chemoprophylaxis regimens in

patients with silicosis in Hong Kong. Am Rev Respir Dis 1992; 145:36.

9.

Cowie RL. The epidemiology of tuberculosis in gold miners with silicosis. Am J Respir Crit Care Med

1994; 150:1460.

10.

Malhotra KK, Parashar MK, Sharma RK, et al. Tuberculosis in maintenance haemodialysis patients.

Study from an endemic area. Postgrad Med J 1981; 57:492.

11.

Lundin AP, Adler AJ, Berlyne GM, Friedman EA. Tuberculosis in patients undergoing maintenance

hemodialysis. Am J Med 1979; 67:597.

12.

Andrew OT, Schoenfeld PY, Hopewell PC, Humphreys MH. Tuberculosis in patients with end-stage

renal disease. Am J Med 1980; 68:59.

13.

Pradhan RP, Katz LA, Nidus BD, et al. Tuberculosis in dialyzed patients. JAMA 1974; 229:798.14.

Rieder HL, Cauthen GM, Comstock GW, Snider DE Jr. Epidemiology of tuberculosis in the United

States. Epidemiol Rev 1989; 11:79.

15.

Sutherland I. Recent studies in the epidemiology of tuberculosis, based on the risk of being infected

with tubercle bacilli. Adv Tuberc Res 1976; 19:1.

16.

Sutherland I. The evolution of clinical tuberculosis in adolescents. Tuberc 1966; 47:308.17.

Nolan CM, Elarth AM. Tuberculosis in a cohort of Southeast Asian refugees: A five-year surveillance

study. Am Rev Resp Dis 1988; 137:805.

18.

Grzybowksi S, McKinnon NE, Tuters L, et al. Reactivations in inactive pulmonary tuberculosis. Am

Rev Resp Dis 1966; 93:352.

19.

Grzybowski S, Fishaut H, Rowe J, Brown A. Tuberculosis among patients with various radiologic

abnormalities, followed by the chest clinic service. Am Rev Resp Dis 1971; 104:605.

20.

Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor ?

- neutralizing agent. N Engl J Med 2001; 345:1098.

21.

Brassard P, Kezouh A, Suissa S. Antirheumatic drugs and the risk of tuberculosis. Clin Infect Dis

2006; 43:717.

22.

Jick SS, Lieberman ES, Rahman MU, Choi HK. Glucocorticoid use, other associated factors, and the

risk of tuberculosis. Arthritis Rheum 2006; 55:19.

23.


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Kim SJ, Hong YP, Lew WJ, et al. Incidence of pulmonary tuberculosis among diabetics. Tuber Lung

Dis 1995; 76:529.

24.

Silwer H, Oscarsson PN. Incidence and coincidence of diabetes mellitus and pulmonary tuberculosis

in a Swedish county. Acta Med Scand 1958; 161:1.

25.

Pablos-Mendez A, Blustein J, Knirsch CA. The role of diabetes mellitus in the higher prevalence of

tuberculosis among Hispanics. Am J Public Health 1997; 87:574.

26.

Boucot KR. Diabetes mellitus and pulmonary tuberculosis. J Chronic Dis 1957; 6:256.27.

Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood

and adolescence. Am J Epidemiol 1974; 99:131.

28.

Comstock GW. Frost Revisited: The modern epidemiology of tuberculosis. Am J Epidemiol 1975;

101:263.

29.

Maurya V, Vijayan VK, Shah A. Smoking and tuberculosis: an association overlooked. Int J Tuberc

Lung Dis 2002; 6:942.

30.

Gajalakshmi V, Peto R, Kanaka T, Jha P. Smoking and mortality from tuberculosis and other diseases

in India: retrospective study of 43000 adult male deaths and 35000 controls. Lancet 2003; 362:507.

31.

Horwitz O, Wilbek E, Erickson PA. Epidemiological basis of tuberculosis eradication. Longitudinal

studies on the risk of tuberculosis in the general population of a low-prevalence area. Bull World

Health Organ 1969; 41:95.

32.

Comstock GW, Edwards LB, Livesay VT. Tuberculosis morbidity in the US Navy: its distribution and

decline. Am Rev Respir Dis 1974; 110:572.

33.

Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. Adv Tuberc Res 1969; 17:28.34.

Wolfe F, Michaud K, Anderson J, et al. Tuberculosis infection in patients with rheumatoid arthritis and

the effect of infliximab therapy. Arthritis Rheum 2004; 50:372.

35.

Carmona L, Gómez-Reino JJ, Rodríguez-Valverde V, et al. Effectiveness of recommendations to

prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor

antagonists. Arthritis Rheum 2005; 52:1766.

36.



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Measuring a reaction to the tuberculin skin test

This figure shows the correct method for measuring a reaction to the

tuberculin skin test. The size of the reaction is measured by the width of

induration, not erythema. In the example shown, the reaction measures

10 mm.

Redrawn from: Testing for Tuberculosis Infection and Disease. In: Core

Curriculum on Tuberculosis: What the Clinician Should Know, Sixth

Edition, Centers for Disease Control and Prevention, 2013. Available at:

http://www.cdc.gov/tb/education/corecurr/default.htm.



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Interpretation of tuberculin skin test

Tuberculin

skin test

reaction

size (mm)

Situation in which reaction is considered positive*

≥5 HIV infection

Close contact of active contagious case

Abnormal chest radiograph with fibrotic changes consistent with old TB

Immunosuppressed patients: TNF-alpha inhibitors, chemotherapy, organ

transplantation, glucocorticoid treatment (equivalent of ≥15 mg/day prednisone for

≥1 month)

≥10 Persons with clinical conditions that increase the risk of reactivation, including

silicosis , chronic renal failure requiring dialysis , diabetes mellitus, some

malignancies (leukemias, lymphomas, carcinoma of the head, neck, or lung),

underweight (≥10 percent ideal body weight), jejunoileal bypass, injection drug

users

Children less than 4 years of age

Foreign born from countries with incidence >25/100,000

Residents and employees in high-risk settings, such as prisons, jails, healthcare

facilities, mycobacteriology labs, and homeless shelters

≥15 Healthy individuals age 4 years and older with low likelihood of true TB infection

TB: tuberculosis; TNF: tumor necrosis factor; TST: tuberculin skin test.

* The goal of testing for latent tuberculosis infection is to identify individuals who are at increased risk for

the development of tuberculosis and therefore would benefit from treatment of latent TB infection. Only

those who would benefit from treatment should be tested, so a decision to test presupposes a decision to

treat if the test is positive (refer to text).

¶ The United States Centers for Disease Control and Prevention (CDC) recommends a 10 mm induration

definition for patients with silicosis or chronic renal failure. However, population-based studies demonstrate

that the relative risk for development of active tuberculosis in this category is high (≥10x that of healthy

individuals). For this reason, many favor a lower threshold for a positive test (≥5 mm).

Δ The CDC indicates that only those foreign-born individuals who immigrated within the past 5 years should

be tested (regardless of age), although others do not favor this practice since most recently arrived foreign

born with positive TST have old (not recent) infection.

◊ Persons with a low likelihood of true TB infection should not be tested routinely unless they are entering a

high-risk setting such as starting employment at a healthcare facility. A threshold of 15 mm is used in the

United States, and is appropriate for healthy individuals with low likelihood of true TB infection and high

likelihood of exposure to nontuberculous mycobacteria (eg, southern United States). However, Canadian

guidelines use a threshold of 10 mm for healthy individuals given the lower likelihood of exposure to

nontuberculous mycobacteria. (Refer to the topic on Epidemiology of nontuberculous mycobacterial

infections.).


¶ ¶

Δ

◊


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Potential causes of false-negative tuberculin tests

Technical (potentially correctable)

Tuberculin material:

Improper storage (exposure to light or heat)

Contamination, improper dilution, or chemical denaturation

Administration:

Injection of too little tuberculin or too deeply (should be intradermal)

Administration more than 20 minutes after drawing up into the syringe

Reading:

Inexperienced or biased reader

Error in recording

Biologic (not correctable)

Infections:

Active tuberculosis (especially if advanced)

Other bacterial infection (typhoid fever, brucellosis, typhus, leprosy, pertussis)

HIV infection (especially if CD4 count <200)

Other viral infection (measles, mumps, varicella)

Fungal infection (South American blastomycosis)

Recent live-virus vaccination (measles, mumps, polio)

Immunosuppressive drugs (corticosteroids, tumor necrosis factor inhibitors, and others)

Metabolic disease (chronic renal failure, severe malnutrition, stress [surgery, burns])

Diseases of lymphoid organs (lymphoma, chronic lymphocytic leukemia, sarcoidosis)

Age (infants <6 months, older adults)



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Disclosures: Madhukar Pai, MD, PhD Nothing to disclose. Dick Menzies, MD, MSc Nothing to disclose. C Fordham von Reyn, MD Nothingto disclose. Elinor L Baron, MD, DTMH Nothing to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through amulti-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content isrequired of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

Disclosures


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