Tuberculosis infection (latent tuberculosis) in children

INTRODUCTION — 

Identification and treatment of children with tuberculosis (TB), both active and inactive, is an important component of TB care and prevention efforts. Asymptomatic tuberculosis infection (TBI; formerly called latent TB infection (see 'Terminology' below)) cannot be diagnosed clinically and requires screening to identify infected individuals. The goals of TB screening programs are diagnosis and treatment of TB disease, as well as identification and treatment of TBI – to prevent development of TB disease and reduce transmission.

Most children identified with TBI have been infected relatively recently (compared with adults, who may have been infected decades previously). Young children and adolescents are at higher risk for progression from TBI to TB disease (with potential for disseminated disease) than adults [1-4]. Children under two years of age have the highest risk of progression, with development of disseminated TB and central nervous system TB [5].

Most children who progress to from TBI to TB disease do so within 2 to 12 months of initial infection [6].

Issues related to diagnosis and treatment of TBI in children will be reviewed here. Issues related to treatment of TB disease in children are discussed in detail separately. (See "Tuberculosis disease in children: Treatment and prevention".)

TERMINOLOGY — 

Tuberculosis (TB) terminology is inconsistent in the literature [7]. Relevant terms are defined in the table (table 1).

RISK FOR PROGRESSION TO TB DISEASE — 

The age-associated risk of progression from tuberculosis infection (TBI) to tuberculosis (TB) disease is outlined in the table (table 2) [2].

TBI TESTING — 

Tests for tuberculosis (TB) infection include the tuberculin skin test and interferon-gamma release assays. (See 'Test selection' below.)

Indications for testing — Evaluation for tuberculosis infection (TBI) in children should be targeted to specific groups at risk for TBI and/or progression to TB disease [8,9]. TB screening is reserved for individuals who are at increased risk of developing TB disease and would thus benefit from treatment. In general, evaluation for TBI is warranted to identify individuals in the categories outlined below (table 3) [2].

The American Academy of Pediatrics (AAP) advises that risk assessment (ie, questionnaire) for TB should be performed at first contact with a child and annually thereafter (table 4) [1]. Testing for TBI should be performed at any time TB disease is suspected, unless the child is known to be infected by prior testing.

In the absence of risk factors, testing for TBI is not indicated. There is no role for routine testing for children entering school, daycare, or camp. Very low rates of TBI and TB disease have been observed in evaluation of universal school-based screening in the United States (less than 2 percent and less than 0.02 percent, respectively), so universal testing would lead to a high rate of false-positive tests [10].

Increased risk of new infection — Children at increased risk of new infection include:

●Children born in high TB incidence settings – Children born in high TB incidence settings (including immigrants and adopted children) should undergo evaluation for TBI [11]. To determine which children warrant evaluation, some experts use a threshold TB incidence of ≥40 per 100,000 in the country of origin (table 5), although this number may vary. In addition, frequent or prolonged visits to high TB incidence regions (or frequent visits by close contacts with such exposure) should be considered in risk assessment.

●Children who are recent contacts of a person with TB disease – The most important risk factor for TBI among children is recent contact with adults who have TB disease. In a systematic review and meta-analysis including more than 137,000 children from 34 countries, the risk of developing TB disease among children <5 years of age following close exposure in the absence of TBI treatment (to reduce the risk of progression from TBI to TB disease) was 19 percent [12].

The definition of 'contact' varies among guidelines. We define a 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 used in large randomized trials [13,14].

While there are no well-defined parameters of exposure for children visiting relatives in high TB incidence settings, the frequency and character of visits should be considered when assessing risk for TBI.

In addition to interferon-gamma release assay (IGRA) or tuberculin skin test (TST), recent contacts of a patient with TB disease should be evaluated for TB disease with history, physical exam, and chest radiograph. (See 'Excluding TB disease' below.)

Increased risk of reactivation — Factors conferring increased risk of reactivation due to immunosuppression include [1,15,16]:

●HIV infection - Children living with HIV infection should undergo annual TB screening beginning at 3 through 12 months of age (in perinatally infected) or at the time HIV infection is diagnosed (in older children and adolescents).

●Solid tumor or hematologic malignancy.

●Administration of immunosuppressive agents, such as corticosteroids, tumor necrosis factor inhibitors, and other biologic agents.

When to test — The optimal timing for TBI evaluation is uncertain, since a negative IGRA or TST result may be observed in the setting of recent TB exposure. In general, we perform TBI testing (with IGRA or TST) 8 to 10 weeks following the last known exposure to TB.

For children with increased risk of new infection:

●For children born in high TB incidence settings, testing may be performed 8 to 10 weeks after immigration. However, screening immediately after immigration may be appropriate for children with significant risk of progression to TB disease (including children who are immunosuppressed, malnourished, or <2 years of age) or those who may have had ongoing exposure for months or years prior to immigration. In such cases, repeat testing should be performed 8 to 10 weeks later if the initial test is negative.

●For children who are recent contacts of a person with TB disease, evaluation should be performed as soon as the contact is identified. If initial TST or IGRA is negative, it should be repeated 8 to 10 weeks following the last known exposure to TB.

Test selection

●Available tests – Available tests to demonstrate prior TBI include IGRA and TST (table 6). These tests measure immune sensitization (type IV or delayed-type hypersensitivity) to mycobacterial protein antigens that may occur following exposure to (and infection by) mycobacteria.

●Choice of test – A clinical approach to TBI testing is summarized in the algorithm (algorithm 1).

We are in agreement with the 2024 AAP Red Book which states that either IGRA or TST may be used for children of any age [1,17,18]. However, the TST is the only test US Food & Drug Administration (FDA)-approved for children younger <2 years of age. Negative TBI test results for infants <3 months of age may not be reliable, since cell-mediated immune responsiveness may not be fully developed in this group.

In general, 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.

IGRA is especially preferred over TST for the following patient groups [1]:

•Children who have received Bacille Calmette-Guérin (BCG) vaccine [1,4]. It is not possible to distinguish between a positive TST due to infection with Mycobacterium tuberculosis from a positive TST due to previous BCG vaccination [19-21]. IGRAs are positive in those with TBI but negative in those with BCG vaccination alone [22].

•Children who are unlikely to return for TST reading.

Test interpretation — TBI is a clinical diagnosis established by demonstrating prior TBI (via either IGRA or TST) and excluding TB disease. (See 'Excluding TB disease' below.)

Interferon-gamma release assays — IGRAs are in vitro blood tests of cell-mediated immune response to relatively TB-specific antigens; such antigens are absent in the BCG vaccine and most nontuberculous mycobacteria. Numerical (quantitative) IGRA results should be reported to the provider by the laboratory. (See "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults".)

●Interpretation of test results

•Positive result – A positive IGRA result should be considered indicative of infection with M. tuberculosis or M. bovis (as TBI or TB disease).

•Negative result – A negative IGRA result cannot conclusively exclude a diagnosis of TBI (or TB disease) and should be interpreted in the context of other clinical data (algorithm 2).

•Indeterminate result – An indeterminate, borderline (for TSPOT-TB assay), or invalid IGRA result should not be used for clinical decision-making [23,24]. Such results have several possible causes that could be related to the patient or the assay.

In such cases, a repeat test should be performed (using the same IGRA assay, an alternative IGRA, or TST), with careful attention to IGRA specimen collection and processing (or TST technique and interpretation) (algorithm 1) [2].

●Sensitivity and specificity – IGRAs have sensitivity similar to the TST but greater specificity for the diagnosis of TBI. IGRAs have greater sensitivity in low TB incidence settings than in high TB incidence settings [25].

•Children ≥2 years – A number of studies and meta-analyses have demonstrated that IGRAs perform well in children ≥2 years [23,24,26-32]. In one study including more than 3500 children from 11 states in the United States with risk for TBI or progression to TB disease (most of whom were non-US-born and ≥2 years of age) screened with TST and two IGRAs (Quantiferon Gold In-Tube test [QFT-GIT] and T-SPOT), the IGRAs were found to have high specificity and high negative predictive values in comparison to the TST at two years of follow-up [23]. Specificities for TST, QFT-GIT, and T-SPOT were 73, 90, and 93 percent, respectively; negative predictive values were 99.9, 100, and 99.9, respectively. The positive predictive values were poor for both TST and the IGRAs. In addition, the sensitivity of QuantiFERON-TB Gold Plus has comparable sensitivity with that of earlier QFT-GIT assays; in a cross-sectional study involving 158 children and adolescents with confirmed TB disease, the sensitivity was 83 percent (interquartile range 77 to 89 percent) [33].

•Children <2 years – We are in agreement with the 2024 AAP Red Book which supports use of IGRAs in children <2 years [1,17].

Use of IGRAs in children <2 years has been controversial because of concerns about the sensitivity of the test in this age group (which is at increased risk for progression from TBI to TB disease). In one study including 116 children ages 7 to 23 months tested with QFT-GIT, there were 2 positive results, 3 indeterminate results, and 3 failed phlebotomies; the remaining results were negative; mitogen tube control test results were robust [34]. None of the children who were TST positive but IGRA negative and went untreated developed TB disease. In short, IGRA use was not limited by phlebotomy, indeterminate results, or the ability to produce gamma interferon.

Tuberculin skin test — The TST consists of intradermal injection of tuberculin material, which stimulates a delayed-type hypersensitivity response mediated by T lymphocytes and, in patients with immune sensitization to prior mycobacterial exposure, causes induration at the injection site within 48 to 72 hours.

Definitions for positive TST results in children are summarized in the table (table 7) [1].

Issues related to dosing, administration, and false-positive and false-negative results in children are the same as for adults; these are discussed in detail separately (table 8). (See "Use of the tuberculin skin test for diagnosis of tuberculosis infection (tuberculosis screening) in adults".)

WHOM TO TREAT — 

The decision to treat for tuberculosis infection (TBI) should be individualized.

●Positive TBI test – We administer TBI treatment for children in the risk categories outlined above who have positive interferon-gamma release assay (IGRA) or tuberculin skin test (TST). (See 'Indications for testing' above.)

●Negative TBI test – We administer TBI treatment for certain children regardless of TBI test results; the approach is outlined below and summarized in the algorithm (algorithm 1).

•Children without HIV infection who are recent contacts of a person with TB disease

-Age <5 years – For contacts <5 years of age, we administer TBI treatment regardless of IGRA or TST results (in the absence of evidence for tuberculosis [TB] disease); in children with a negative initial test, this approach is known as "window prophylaxis" [35]. It is warranted because the child's cellular immune response to TB may not have fully developed at the time of testing and because children <5 years of age with recent TB exposure are at relatively high risk for progression to TB disease (40 percent risk in infants <12 months and 25 percent in children 1 to 2 years) [15,36].

In such cases, the child should be retested at 8 to 10 weeks. If the repeat test is negative, treatment may be discontinued, at the discretion of the clinician – if there is no suspicion that this result may be a false negative (eg, due to immune incompetence, malnutrition, young age). If a false-negative second test is suspected, treatment for TBI may be continued to completion.

In resource-limited settings where TBI testing and radiography are not available, evaluation for TB disease in child contacts should be performed based on clinical assessment. In the absence of evidence of TB disease, child contacts should receive treatment for TBI [37-39]. (See 'Treatment approach' below.)

-Age ≥5 years – For contacts ≥5 years of age with negative initial IGRA or TST, no evidence of immune compromise, and negative clinical evaluation, a decision regarding TBI treatment may be deferred pending results of a second test performed 8 to 10 weeks following the last date of contact with the source patient. This approach is warranted because testing for TBI shortly following exposure may be negative, since immune reactivity to TB antigens following initial exposure to TB may take up to 10 weeks to develop.

If the repeat IGRA or TST is negative, no treatment is warranted; if the repeat test is positive, a course of TBI treatment should be completed after excluding active disease.

•Children living with HIV infection – For children living with HIV infection and negative IGRA or TST, TBI treatment is also warranted for the following individuals (since definitive diagnosis of TBI may not be feasible):

-Children who are recent contacts of a person with TB disease, regardless of age

-Children in high TB incidence settings (particularly if the CD4 cell count is <200 cells/microL, which confers greater risk for development of TB disease)

-Asymptomatic children with clinical suspicion for prior TB (eg, fibrotic disease on chest radiograph, consistent with healed TB) and no documented history of adequate TB treatment

For children in low TB incidence settings with CD4 count <200 cells/microL, and negative TBI test results, repeat TBI testing should be performed once the CD4 cell count is ≥200 cells/microL; the initial test may reflect a false-negative result in the setting of immunosuppression.

•Children with Ghon complex on chest radiography – Children with chest radiography demonstrating Ghon complex (calcified parenchymal lesion and calcification of the regional hilar lymph node) (image 1) may be treated for TBI. While this finding represents TB disease, treatment for TBI is sufficient since the number of live organisms in a Ghon complex is relatively low (as seen in TB infection rather than TB disease). In contrast, presence of enlarged hilar lymph nodes without calcification may represent TB disease, requiring a full treatment regimen. (See "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis", section on 'Chest radiography'.)

PRIOR TO TREATMENT

Excluding TB disease — Treatment for tuberculosis infection (TBI) should be initiated only after tuberculosis (TB) disease has been ruled out. (See "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

Evaluation for TB disease must be pursued in children with a positive interferon-gamma release assay (IGRA) or tuberculin skin test (TST). Evaluation should include:

●Epidemiologic history to elicit details regarding recent contact with an adult who has TB disease (if not already known), travel to or residence in a high TB incidence region, or ingestion of unpasteurized dairy products (to assess TB caused by M. bovis).

●Clinical history to assess for symptoms of TB disease.

●Physical examination.

●Chest radiograph (posterior-anterior and lateral views) – In the setting of TBI, chest radiographs are usually normal but may show dense nodules with calcifications, calcified, nonenlarged regional lymph nodes, or pleural thickening (scarring) [8]. Children with M. bovis infection may have calcified, nonenlarged mesenteric regional lymph nodes on abdominal radiographs.

Findings suggestive of TB disease should prompt further diagnostic evaluation, including further imaging (computed tomography [CT] of chest or abdomen, if necessary) and/or obtaining specimens for microbiology as outlined separately. (See "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

Baseline laboratory testing — Baseline liver enzyme testing is warranted for children with malnutrition, children with preexisting liver disease, children at risk for non-alcoholic fatty liver disease (NAFLD), and for children with additional risk factors for hepatotoxicity (such as receipt of other potentially hepatotoxic medications) [8]. For otherwise healthy children, baseline liver enzyme testing is not required. (See "Metabolic dysfunction-associated steatotic liver disease in children and adolescents", section on 'Risk factors and comorbidities'.)

Cardiac history, serum electrolytes, and electrocardiogram (EKG) may be warranted for children starting treatment with levofloxacin.

Additional issues related to monitoring are discussed below. (See 'Monitoring' below.)

TREATMENT APPROACH

Selecting a regimen — Thus far, none of the available treatment regimens has been shown to be more efficacious than any of the others. Therefore, the choice of regimen is based largely on the likelihood of adherence, the potential for adverse effects, and preference (of the patient, provider, and/or public health program).

Drug susceptibility of the source patient should guide treatment, if available. (See 'Drug-resistant TBI' below.)

The potential for drug-drug interactions should be reviewed carefully. (See 'Drug interactions' below.)

●Available regimens – For treatment of drug-susceptible tuberculosis infection (TBI) in children, regimens include (table 9):

•Isoniazid and rifapentine weekly for 12 weeks (3HP; administration via directly observed therapy preferred)

•Rifampin daily for 4 months (4R)

•Isoniazid and rifampin daily for 3 months (3HR)

•Isoniazid daily for 9 months (9H)

An alternative regimen consists of levofloxacin daily for six months; it may be used when rifamycins and isoniazid are both contraindicated, due to intolerance or drug interactions. This regimen is recommended by WHO for treatment of contacts to patients with MDR TB disease [40].

●Regimen selection – Our approach is as follows:

•Children ≥2 years of age – For children ≥2 years of age, we favor TBI treatment with either 3HP or 4R because of greater likelihood of adherence relative to other regimens [1]. Acceptable alternatives include 3HR or 9H.

For children on antiretroviral therapy (ART), regimens should be reviewed carefully for compatibility with the TBI regimen. Children on ART regimens not compatible with rifamycins should be treated with isoniazid monotherapy. (See 'Drug interactions' below and "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection", section on 'Drug interactions: ART and rifamycins'.)

•Children <2 years of age – 3HP should not be administered to children <2 years because the safety and pharmacokinetics of rifapentine (RPT) have not been established for this age group.

-Not on ART – For children <2 years of age not on ART, we favor TBI treatment with 4R because of greater likelihood of adherence relative to other regimens. Acceptable alternatives include 3HR or 9H.

-On ART – For children <2 years of age on ART, we favor TBI treatment with isoniazid (INH) monotherapy, given its favorable toxicity profile; the potential for drug-drug interactions with the rifamycin-based regimens in individuals on ART is high. In low TB incidence settings (TB incidence rate <40 per 100,000 population) we favor nine months of INH. The World Health Organization (WHO) recommends a six- to nine-month duration of INH; a six-month regimen may have higher completion rates (albeit lower efficacy) than a nine-month regimen. (See 'Isoniazid monotherapy' below.)

Other regimens (such as 4R or 3HR) may also be acceptable, with careful review of drug interactions by a clinician experienced in management of patients with TB-HIV coinfection.

In general, the American Academy of Pediatrics (AAP) and United States Centers for Disease Control and Prevention (CDC) favor 3HP (for children ≥2 years of age) and 4R (for children of all ages) as preferred regimens, given favorable tolerability and adherence [1,3].

Regimens: Administration and efficacy

Rifamycin-based regimens — The shorter rifamycin-based regimens are associated with higher adherence rates compared with isoniazid monotherapy [40-42].

Issues related to nitrosamine impurities in rifampin and rifapentine, and potential toxicity related to cumulative exposure, are discussed separately. (See "Rifamycins (rifampin, rifabutin, rifapentine)", section on 'Nitrosamine impurities'.)

Isoniazid and rifapentine (3HP)

●Administration – 3HP, a three-month regimen of weekly INH and RPT, may be used for TBI treatment in children age ≥2 years [9,43-45]. 3HP is favored by many clinicians given shorter duration of therapy and favorable treatment completion rates.

•Dosing – Dosing is summarized in the table (table 9). Potential drug interactions should be reviewed carefully. (See 'Drug interactions' below.)

•Directly observed therapy – Administration of weekly INH and RPT via directly observed therapy is preferable to maximize adherence, to review for side effects before each dose, and to withhold treatment if significant side effects are suspected. The CDC 2018 recommendations for self-administered therapy was not based on studies in children [43].

•Patient age – 3HP should not be administered to children <2 years because the safety and pharmacokinetics of RPT have not been established for this group.

●Adverse effects – Hypersensitivity (flu-like symptoms including light headedness, dizziness, headache, nausea or vomiting, syncope, rash, or angioedema) and other systemic drug reactions (eg, urticaria, hypotension) have been reported in a small percentage of adults receiving 3HP and observed anecdotally among children receiving 3HP [46]. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection", section on 'Isoniazid and rifapentine (3HP)'.)

●Efficacy – Use of 3HP is supported by a randomized trial including 7731 individuals ≥12 years of age at high risk (most recently infected) for progression from TBI to TB disease in four low TB incidence countries (Brazil, Canada, Spain, and the United States); a three-month regimen of weekly INH and RPT was shown to be noninferior to a nine-month regimen of daily INH [13].

Subsequently, a study including 1058 children ages 2 to 17 years demonstrated that directly observed treatment with 3HP was noninferior to nine months of isoniazid alone for prevention of TB at 33 months following enrollment and was associated with improved completion rate [47]. INH-RPT is generally well tolerated in children >2 years of age [48].

Rifampin (4R)

●Administration – 4R, a four-month regimen of daily rifampin (RIF), may be used for TBI treatment in children of any age. 4R is favored by many clinicians given shorter duration of therapy and favorable treatment completion rates.

Dosing is summarized in the table (table 9). Potential drug interactions should be reviewed carefully. (See 'Drug interactions' below.)

For infants and young children, the "powder" contents of the capsules can be suspended in flavored liquid (will not go into solution) or sprinkled on soft foods.

●Adverse effects – Adverse effects of rifampin are described separately. (See "Rifamycins (rifampin, rifabutin, rifapentine)", section on 'Adverse effects'.)

●Efficacy – The efficacy of 4R for reducing the incidence of TB disease is estimated to be similar to that of INH in adults and in children [14,49-51]. 4R is well tolerated, with good completion rates and a low rate of hepatotoxicity [14,40-42,49,50,52-54].

In a randomized trial including more than 800 children with TBI treated with 4R or 9H, those who received 4R had similar rates of efficacy and safety but a better adherence rate than 9H (86 versus 71 percent) [14]. TB disease was diagnosed in two children treated with 9H and no children treated with 4R (rate difference -0.37 cases per 100 person-years; 95% CI -0.88 to 0.14).

Additional considerations regarding use of RIF for treatment of TBI in children are based on studies in adults. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection", section on 'Rifampin (4R)'.)

Isoniazid and rifampin (3HR)

●Administration – 3HR, a three-month regimen of daily INH and RIF, may be used for children of any age [40]. 3HR is an alternative regimen for TBI treatment if 3HP or 4R cannot be used.

Dosing is summarized in the table (table 9). Potential drug interactions should be reviewed carefully. (See 'Drug interactions' below.)

●Adverse effects – Adverse effects of isoniazid are described below. (See 'Isoniazid monotherapy' below.)

Adverse effects of rifampin are described separately. (See "Rifamycins (rifampin, rifabutin, rifapentine)", section on 'Adverse effects'.)

●Efficacy – In a systematic review including adults and children, 3HR was found to be as efficacious and well tolerated as INH (daily for nine months) [41,55].

Isoniazid monotherapy

●Administration – INH (administered daily for nine months) may be used for TBI treatment in children at any age (table 9) [8]. The length of treatment is a major drawback of INH monotherapy.

•Dosing – Dosing is summarized in the table (table 9). Potential drug interactions should be reviewed carefully. (See 'Drug interactions' below.)

Pyridoxine supplementation (25 to 50 mg daily) should be administered together with INH for infants who are being exclusively breastfed, children and adolescents on meat- and milk-deficient diets, pregnant adolescents, and those with conditions that can predispose to neuropathy (including diabetes, uremia, malnutrition, and human immunodeficiency virus [HIV] infection), but supplementation is not necessary for children with a normal diet. Pyridoxine should also be administered to infants of breastfeeding mothers receiving INH. (See "Tuberculosis disease (active tuberculosis) in pregnancy".)

•Duration of therapy and efficacy

-Resource-abundant settings – For children in resource-abundant settings, a regimen of daily INH for nine months is preferred (efficacy 75 to 90 percent; efficacy nearly 100 percent with high adherence) [56,57]. For circumstances in which adherence is difficult, administration of INH two or three times weekly therapy under direct observation for nine months also provides substantial protection [58]. Protection from six months of INH may be adequate (60 to 70 percent efficacy) if adherence is good [56].

-Resource-limited settings – For children in resource-limited settings, the WHO recommends daily INH for six to nine months [40]. In some jurisdictions, directly observed therapy for TBI can be instituted twice weekly. This is especially useful for household contacts of a person with TB disease or other children who are at particularly high risk for progression to TB disease.

●Adverse effects – INH-induced adverse reactions include drug-induced hepatitis, gastrointestinal disturbances, peripheral neuropathy, and skin rashes. In general, adverse reactions associated with INH are relatively rare; hepatotoxicity is the most serious adverse reaction. (See "Isoniazid hepatotoxicity".)

The presentation of hepatotoxicity due to INH is variable. Asymptomatic transaminase elevation (up to two to three times the upper limit of normal) is most common, reported in 5 to 10 percent of children receiving INH for TBI; patients with slight elevations that remain stable during the course of treatment do not require cessation of therapy [59]. Other manifestations include clinical hepatitis (which resolves upon INH discontinuation) and fulminant hepatitis with liver failure [8]. Severe hepatitis requiring liver transplant or causing death has been reported [8,59,60].

Children and parents or caregivers should be advised that if unexplained abdominal pain, vomiting, and/or jaundice develop, the medication should be discontinued immediately, and prompt medical attention should be sought. (See 'Monitoring' below.)

Levofloxacin monotherapy

●Administration and dosing – Levofloxacin (daily for six months) may be used for treatment of TB infection for children of any age if rifamycins and isoniazid are both contraindicated, due to intolerance or drug interactions. It may also be used for treatment of multidrug-resistant tuberculosis (MDR-TB) infection that is fluoroquinolone-susceptible [40].

For children and adolescents up to 50 kg, levofloxacin dosing consists of 15 to 20 mg/kg (maximum 750 mg).

●Adverse Effects – In general, levofloxacin is well-tolerated; it has been associated with joint pain (mostly in adolescents), and rarely can cause neuropsychiatric symptoms. Levofloxacin can cause QTc; electrocardiogram (EKG) monitoring is recommended only for children with existing heart disease, malnutrition with associated electrolyte abnormalities, or those taking other medications that can prolong the QTc. Routine laboratory monitoring is not warranted. (See "Fluoroquinolones".)

●Efficacy – In a randomized trial (TB-CHAMP) including 922 children and adolescents in South Africa with household exposure to an adult with MDR-TB, treatment with levofloxacin reduced the risk of MDR-TB disease by 56 percent; after one year, TB disease developed among fewer children treated with levofloxacin than placebo (2.6 versus 1.1 percent) [61]. There are no comparable data evaluating levofloxacin for treatment of drug susceptible TBI in children, but by inference the efficacy of levofloxacin is expected to be comparable.

Drug interactions — Potential drug interactions are an important consideration in selecting a TBI treatment. In some cases, drug dose adjustment may be required.

●Rifamycins (rifampin or rifapentine) – Drug categories with potential rifamycin interactions include warfarin, oral contraceptives, some antihypertensives, antiarrhythmics, antidepressants, anticonvulsants, methadone, and the protease inhibitor class of antiretroviral drugs. (See "Rifamycins (rifampin, rifabutin, rifapentine)".)

●Isoniazid – Drug categories with potential isoniazid interactions include anticonvulsants, antianxiety medications, and aminophylline

Drug-resistant TBI — If TBI due to a drug-resistant organism is known or suspected (eg, contact with or likely infection by an infectious patient with drug-resistant disease), the drugs to which the organism is resistant should not be used to treat TBI [62]. Issues related to treatment of TBI among individuals with exposure to drug-resistant TB are discussed separately. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection", section on 'Drug-resistant tuberculosis infection (TBI)'.)

Patient education

●Adverse drug effects – Patients and their families should be educated about potential adverse drug effects and understand they should stop treatment and notify the provider immediately if signs or symptoms of drug toxicity are suspected. Symptoms of drug-induced liver injury may include malaise, low-grade fever, anorexia, nausea, vomiting, right upper quadrant pain, jaundice, dark urine, or acholic (clay-colored) stool.

●Adherence – Ensuring adherence to TBI treatment remains a public health challenge [63]. This is discussed further separately. (See "Adherence to tuberculosis treatment".)

Monitoring — Children on TBI treatment should be monitored by a health care worker to reinforce adherence, assess for possible drug toxicity, and to evaluate for potential progression to disease.

●Frequency of clinical monitoring – In general, clinical monitoring every four to six weeks for the first three months is appropriate, followed by every two to three months thereafter, regardless of regimen used. Use of directly observed therapy is not a substitute for this monitoring schedule.

●Laboratory monitoring – Routine laboratory monitoring (baseline serum transaminases) and periodic (eg, monthly) laboratory monitoring is warranted for children with malnutrition, children with preexisting liver disease, and for children with additional risk factors for hepatotoxicity (such as receipt of other potentially hepatotoxic medications) [2].

In addition, laboratory evaluation is warranted for children who develop clinical symptoms of liver injury that persist more than a few days (nausea, vomiting, abdominal pain, malaise).

•Indications for discontinuing treatment – We discontinue TBI treatment in patients with symptoms of hepatitis and alanine aminotransferase level (ALT) greater than three times the upper limit of normal, and in patients with ALT level greater than five times the upper limit of normal (whether or not symptoms of hepatitis are present), particularly in children whose levels are increasing during observation.

•Resuming treatment – The timing for resuming treatment and choice of regimen should be determined on an individualized basis; such decisions depend on several factors including the degree of liver dysfunction, the risk of developing TB disease, and how much treatment has been completed.

●Respiratory illness during TBI treatment – Development of breakthrough TB disease is rare among children who adhere to TBI treatment; respiratory illnesses that occur during TBI treatment are more likely to be community-acquired respiratory infections than TB [2].

Nutritional supplementation — Issues related to nutrition supplementation to reduce the risk of acquiring TBI are discussed separately. (See "Prevention of tuberculosis: BCG immunization and nutritional supplementation", section on 'Nutritional supplementation'.)

FOLLOW UP CARE

●Obtain a new baseline chest radiograph – Individuals with a history of a positive tuberculosis infection (TBI) test and ongoing potential tuberculosis (TB) exposure who have completed a course of TBI treatment should have a new baseline chest radiograph.

●Evaluation of respiratory illness following TBI treatment – Children who develop symptoms suggestive of TB disease following TBI treatment should undergo evaluation including chest radiograph and other investigations as outlined in detail separately. (See "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

●No role for repeat TST or IGRA – Patients with documented positive tuberculin skin test (TST) should never have repeat TST; once the test is positive, it will remain positive, and repeating the test has no clinical utility. Similarly, repeating an interferon-gamma release assay (IGRA) once documented to be positive is not likely to provide useful information unless a false-positive reaction is suspected (eg, low TB risk, near cut-point value). There are no additional laboratory mechanisms to evaluate subsequent TB exposure in these individuals. There is no role for repeat TST or IGRA to assess the effectiveness of treatment [1].

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

●Indications for testing – Screening for tuberculosis (TB; testing for TB infection [TBI]) is reserved for individuals who are at increased risk of developing TB disease and would thus benefit from treatment (table 4). This includes patients in the following categories (see 'Indications for testing' above):

•Children born in high TB incidence settings (table 5)

•Children who are recent contacts of a person with TB disease

•Children at increased risk of reactivation due to conditions associated with immunosuppression

●Test selection and interpretation – Diagnostic tools for TBI include the tuberculin skin test (TST) and interferon-gamma release assay (IGRA) (table 7). The approach to diagnosis of TBI in children is summarized in the algorithm (algorithm 1). (See 'Test selection' above and 'Test interpretation' above.)

●Whom to treat – The decision to treat for TBI should be individualized. In general, we recommend administering TBI treatment for children in the risk categories outlined above who have positive IGRA or TST (Grade 1B). In addition, we administer TBI treatment for certain children regardless of TBI test results, as outlined below (algorithm 1) (see 'Whom to treat' above):

•Children without HIV infection who are recent contacts of a person with TB disease

-Age <5 years – For TB contacts <5 years of age, we suggest administer TBI treatment regardless of TBI test results, rather than waiting for repeat test results 8 to 10 weeks later (Grade 2C); this approach is known as "window prophylaxis." It is warranted because the child's cellular immune response to TB may not have fully developed at the time of testing and because these children are at relatively high risk for progression to TB disease.

Repeat testing should be performed 8 to 10 weeks later. If the repeat test is positive, TBI treatment should be continued to completion. If the repeat test is negative, TBI treatment may be discontinued at the discretion of the clinician.

-Age ≥5 years – For TB contacts ≥5 years, we defer a decision regarding TBI treatment pending results of a second test performed 8 to 10 weeks after the last date of contact with the source patient. This approach is warranted because testing for TBI shortly following exposure may be negative; immune reactivity to TB antigens following initial exposure to TB may take up to 10 weeks to develop.

•Children living with HIV infection – For children living with HIV infection in the following circumstances, we recommend administer TBI treatment regardless of TBI test results (since definitive diagnosis of TBI may not be feasible) (Grade 1B):

-Children who are recent contacts of a person with TB disease

-Children in high TB incidence settings (table 5) (particularly if the CD4 cell count is <200 cells/microL, which confers greater risk for development of TB disease)

-Asymptomatic children with clinical suspicion for prior TB (eg, fibrotic disease on chest radiograph consistent with healed TB) and no documented history of adequate TB treatment

●Prior to treatment

•Excluding TB disease – Prior to initiation of treatment for TBI, children must be evaluated for TB disease (to avoid monotherapy and risk of inducing secondary drug resistance). The evaluation is described above. (See 'Excluding TB disease' above.)

•Baseline laboratory testing – Baseline liver enzyme testing is warranted for children with malnutrition, children with preexisting liver disease, and for children with additional risk factors for hepatotoxicity (such as receipt of other potentially hepatotoxic medications). Cardiac history, serum electrolytes, and electrocardiogram (EKG) may be warranted for children starting treatment with levofloxacin. (See 'Baseline laboratory testing' above.)  

●Selecting a regimen – Thus far, none of the available treatment regimens has been shown to be more efficacious than any of the others. Therefore, the choice of regimen is based largely on the likelihood of adherence, the potential for adverse effects, and preference (of the patient, provider, and/or public health program). Drug susceptibility of the source patient should guide treatment, if available. The potential for drug-drug interactions should be reviewed carefully. (See 'Selecting a regimen' above.)

Our approach to regimen selection is as follows (table 9):

•Children ≥2 years of age – For children ≥2 years of age, we suggest TBI treatment with either 3HP or 4R (Grade 2C), because of greater likelihood of adherence relative to other regimens. Acceptable alternatives include 3HR or 9H.

For children on antiretroviral therapy (ART), regimens should be reviewed carefully for compatibility with the TBI regimen. Children on ART regimens not compatible with rifamycins should be treated with isoniazid monotherapy.

•Children <2 years of age – 3HP should not be administered to children <2 years because the safety and pharmacokinetics of RPT have not been established for this age group.

-Not on ART – For children <2 years of age not on ART, we suggest TBI treatment with 4R (Grade 2C), because of greater likelihood of adherence relative to other regimens. Acceptable alternatives include 3HR or 9H.

-On ART – For children <2 years of age on ART, we suggest TBI treatment with INH monotherapy (Grade 2C), given its favorable toxicity profile; the potential for drug-drug interactions with the rifamycin-based regimens in individuals on ART is high. Other regimens (such as 4R or 3HR) may also be acceptable, with careful review of drug interactions.

●Patient education – Patients and their families should be educated about potential adverse drug effects and understand they should stop treatment and notify the provider immediately if signs or symptoms of drug toxicity are suspected. (See 'Patient education' above and "Adherence to tuberculosis treatment".)

●Monitoring – Laboratory monitoring for hepatotoxicity is advised for some patients. Children who develop symptoms of hepatotoxicity should be evaluated; in the setting of hepatotoxicity, TBI treatment should be discontinued. The timing for resuming treatment and choice of regimen should be individualized. (See 'Monitoring' above.)