INTRODUCTION — Identification and treatment of children with tuberculosis (TB) infection (TBI) has become an important component of TB control efforts. The goals of TB screening programs are case finding and treatment of TB disease, identification and treatment of TBI to prevent development of disease, and decreased transmission.
Most children identified with TBI have been infected relatively recently compared with adults who may have been infected decades previously. Children and adolescents are at higher risk for progression from TBI to TB disease (with potential for disseminated disease) than adults [1,2]. Children under two to four years of age have the highest risk of progression with development of disseminated and central nervous system TB .
Most cases of progression to TB disease in children occur within 2 to 12 months of initial infection . (See "Tuberculosis: Natural history, microbiology, and pathogenesis".)
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".)
Whom to test
Overview — Evaluation for TBI in children should be targeted to specific groups at risk for TBI and/or progression to TB disease [6,7]. Only children 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, evaluation for TBI 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 2) .
Among children, the major risk factor for TBI is contact with adults who have TB disease, either due to household exposure or residence in a region where TB is endemic (table 3). In a systematic review and meta-analysis that included more than 137,000 children from 34 countries, the risk of developing TB disease following close exposure in the absence of preventive therapy among children <5 years of age was 19 percent .
Transmission from other children with TB disease is possible if the index child has smear-positive disease but is highly unlikely if the index child has smear-negative disease . Identification of a child with a positive tuberculin skin test (TST) or interferon-gamma release assay (IGRA) should prompt testing of the other children in the household as well as investigation for the index source case.
TBI is a clinical diagnosis established by demonstrating prior TBI and excluding TB disease. Available tests to demonstrate prior TBI include the TST and IGRAs. These tests measure immune sensitization (type IV or delayed-type hypersensitivity) to mycobacterial protein antigens that might occur following exposure to (and infection by) mycobacteria.
There is no lower age limit for screening. The American Academy of Pediatrics advises that risk assessment (ie, questionnaire) for TB should be performed at first contact with a child and annually thereafter . Testing for TBI should be performed if TB disease is suspected at any time. However, a negative TST or IGRA result may not be reliable in infants younger than three months of age; cell-mediated immune responsiveness may not be fully developed in young children.
In the absence of risk factors, evaluation for TBI is not indicated. There is no role for routine TST placement or IGRA 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 .
Case contacts — Case contacts of a patient with TB disease must be evaluated for TB disease with a history, physical exam, chest radiograph, and TST or IGRA (table 4). 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. (See 'Excluding TB disease' below.)
Treatment for TBI should be pursued if the test is positive (TST ≥5 mm induration or IGRA positive) and there is no evidence for TB disease.
Age <5 years — For child contacts <5 years of age, treatment for TBI should be initiated if there is no evidence for TB disease, regardless of TST or IGRA results. In children with a negative test, this approach is known as "window prophylaxis" . It is warranted because the child's cellular immune response to TB may not have fully developed by 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) [13,14].
In such cases if the initial TST or IGRA is negative, 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 [15-17]. (See 'Treatment approach' below.)
Age ≥5 years — For immunocompetent child contacts ≥5 years of age with negative initial TST or IGRA and negative clinical evaluation, a decision regarding treatment may be deferred pending results of a second test, usually with the same test performed 8 to 10 weeks following the last date of contact with the source patient. This approach is warranted because testing for TBI with TST or IGRA 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.
Children born in TB-endemic regions — Children born in TB-endemic regions (including immigrants and adopted children) should undergo evaluation for TBI . Some experts favor a threshold TB incidence in the country of origin of ≥40 per 100,000 to determine which children should be evaluated (table 3). In addition, frequent or prolonged visits to TB-endemic regions (or frequent visits by close contacts to TB-endemic regions) should be considered in risk assessment.
The optimal timing for TBI evaluation is uncertain, since a negative TST or IGRA result may be observed in the setting of recent TB exposure. Therefore, it is most accurate to perform TBI screening 8 to 10 weeks after immigration. However, performing a TST or IGRA immediately after immigration may be appropriate for children with significant risk of progression to TB disease (including children who are malnourished or immunosuppressed) or those who may have had ongoing exposure for months or years prior to immigration. In such cases, repeat testing should be performed three to six months later if the initial test is negative. The second TST is defined as positive if the induration measures ≥10 mm (table 4) .
Prior Bacille Calmette-Guérin (BCG) vaccine administration can confound TST interpretation [19-21]. 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 . IGRAs are useful for making this distinction; these assays are positive in those with TBI but negative in those with BCG vaccination alone . However, data to guide IGRA interpretation in children <5 years of age are limited . (See 'Interferon-gamma release assays' below and "Prevention of tuberculosis: BCG immunization and nutritional supplementation", section on 'Interpreting TST and IGRA after BCG'.)
Immunosuppressed children — Children with solid tumors or hematologic malignancies warrant evaluation for TBI. In one systematic review and meta-analysis including two studies of South African children with a solid tumor or hematologic malignancy, the relative risk of TB was high (incidence rate ratio 16.8, 95% CI 8.8-32.1) .
In addition, children who will be receiving significant immunosuppressive therapy (particularly immunobiologic modulating agents) should be evaluated for TBI before starting therapy, since immunosuppression can lead to reactivation of TBI and result in TB disease .
Children with human immunodeficiency virus (HIV) children should undergo annual screening for TB beginning at 3 through 12 months of age (in perinatally infected) or at the time HIV infection is diagnosed (in older children and adolescents) .
For children ≥12 months of age with HIV infection and CD4 cell count <200 cells/microL in low-incidence settings and negative initial test (IGRA or TST), repeat testing should be performed once the CD4 cell count is ≥200 cells/microL (because the initial test may reflect a false-negative result in the setting of immunosuppression). Children with a positive TST or IGRA should receive treatment for TBI, irrespective of the degree of immunosuppression .
For children ≥12 months of age with HIV infection in high-incidence settings, TBI treatment should be administered regardless of test results (particularly if the CD4 cell count is <200 cells/microL, which confers greater risk for development of TB disease) once TB disease has been excluded.
For children with HIV infection in high-incidence settings where TBI testing is not available, treatment for TBI should be administered regardless of CD4 cell count. TBI therapy administered in the absence of TBI testing has been associated with a 40 to 50 percent reduction in TB disease among individuals living in areas with very high TB incidence .
How to test — Diagnostic tools for TBI include TST and IGRA. The clinical approach is summarized in the following algorithm (algorithm 1).
Tuberculin skin test — 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 6). (See "Use of the tuberculin skin test for diagnosis of tuberculosis infection (tuberculosis screening) in adults".)
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). IGRAs have sensitivity similar to the TST but greater specificity for the diagnosis of TBI. IGRAs have greater sensitivity in low-incidence settings than in high-incidence settings . (See "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults".)
For diagnosis of TBI in children ≥2 years, either IGRA or TST may be used; IGRA is preferable if available (algorithm 1) [10,28-33]. Among children ≥2 years who received BCG vaccination, IGRA is favored over TST [10,13,34].
A number of studies and meta-analyses have demonstrated that IGRAs perform well in children ≥2 years [35-43]. In one study including more than 3500 children from 11 US states with risk for TBI or progression to TB disease (most of whom were foreign born and ≥2 years of age) screened with both 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 . 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) .
The 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 of 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 . 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. Based on such findings, we are in agreement with the American Academy of Pediatrics which permits use of IGRAs in children <2 years .
A positive IGRA result should be considered indicative of infection with M. tuberculosis or Mycobacterium bovis (as TBI or TB disease). 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. An indeterminate, borderline, or invalid IGRA result should not be used for clinical decision-making [42,43]; in such cases, repeat testing should be performed (using the same or alternative IGRA assay), with extra attention to proper specimen collection and processing .
For children without TB risk factors other than foreign birth who have an unexpected low-level positive IGRA result (QFT <1.00 international units/mL, T-SPOT with 5 to 7 spots), a second diagnostic test (either an IGRA or a TST) should be performed; the child should be considered infected only if both test results are positive.
In immunocompromised children, IGRAs should be interpreted with caution. IGRAs include positive control assays for lymphocyte responsiveness; if insufficient control reactivity is documented, IGRA test results are reported as indeterminate and are considered invalid.
Issues related to dosing, administration, and false-positive and false-negative IGRA results in children are similar as for adults; these are discussed in detail separately. (See "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults".)
WHOM TO TREAT
●Children without HIV infection – For children without HIV infection, treatment of TBI is warranted for children with an established diagnosis of TBI, based on the approach described above (algorithm 1). (See 'Diagnosis' above.)
●Children with HIV infection – For children with HIV infection, TBI treatment is warranted in the following circumstances (in some cases, it may not be possible to definitively establish the presence of TBI) (see 'Immunosuppressed children' above):
•Individuals with recent contact with a person with TB disease
•Asymptomatic individuals with clinical suspicion for prior TB (eg, fibrotic disease on chest radiograph consistent with healed TB) and no documented history of adequate TB treatment
•Individuals with positive tuberculin skin test (TST) or interferon-gamma release assay (IGRA) in absence of TB disease
•Individuals living in high-incidence settings, regardless of test results (particularly if the CD4 cell count is <200 cells/microL, which confers greater risk for development of TB disease), once TB disease has been excluded
●Children with Ghon complex on chest radiography – For children with chest radiography demonstrating Ghon complex (calcified parenchymal lesion and calcification of the regional hilar lymph node) (image 1), treatment for TBI is sufficient since the number of live organisms in a Ghon complex is relatively low (as seen in infection rather than disease).
PRIOR TO TREATMENT
Excluding TB disease — Treatment for TBI should be initiated only after 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 tuberculin skin test (TST) or interferon-gamma release assay (IGRA). Evaluation should include:
●A detailed history to elicit details regarding recent contact with an adult who has TB disease (if not already known), travel to or residence in a TB-endemic region, or ingestion of unpasteurized dairy products (to assess TB caused by M. bovis)
●History to assess for symptoms of TB disease
●Chest radiograph (posterior-anterior and lateral views)
Findings suggestive of TB disease should prompt further diagnostic evaluation, including further imaging (if necessary) and/or obtaining specimens for microbiology as outlined separately. (See "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)
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) . Children infected by M. bovis may have calcified, nonenlarged mesenteric regional lymph nodes on abdominal radiographs.
Baseline laboratory testing — Baseline liver enzyme testing is warranted for children with malnutrition, preexisting liver disease, obesity, and HIV infection and for children on potentially hepatotoxic drugs [6,25].
For otherwise healthy children, baseline liver enzyme testing is not required.
Additional issues related to monitoring are discussed below. (See 'Monitoring and adherence' below.)
Selecting a treatment regimen — Thus far, none of the four treatment regimens has been shown to be superior to 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). In general, the United States Centers for Disease Control and Prevention (CDC) favors daily rifampin (RIF) for four months (for children of all ages) and weekly isoniazid (INH) and rifapentine (RPT) for three months (for children over age two) as preferred regimens, given favorable tolerability and adherence .
For treatment of TBI in children, regimens include (table 5):
●RIF daily for four months (regimen abbreviation: 4R)
●INH and RPT weekly for three months (administration via directly observed therapy preferred; regimen abbreviation: 3HP)
●INH and RIF daily for three months (regimen abbreviation: 3HR)
●INH daily for nine months (regimen abbreviation: 9H)
Our approach is as follows:
●For children ≥2 years of age, we favor treatment of TBI with either daily 4R or weekly 3HP because of greater likelihood of adherence relative to other regimens. Acceptable alternatives include 9H or 3HR.
For children ≥2 years of age 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 INH monotherapy. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection", section on 'Drug interactions: ART and rifamycins'.)
●For children <2 years of age not on ART, we favor treatment of TBI with 4R because of greater likelihood of adherence relative to other regimens; 9H and 3HR are acceptable alternatives. 3HP should not be administered to children <2 years because the safety and pharmacokinetics of RPT have not been established for this age group.
●For children <2 years of age on ART, we favor treatment of TBI with INH monotherapy, given its favorable toxicity profile; the potential for drug-drug interactions with the shorter rifamycin-based regimens in individuals taking ART is high (see 'Isoniazid' below):
•In low-incidence settings (TB incidence rate <40 per 100,000 population) we favor 9H.
•In high-incidence settings (TB incidence rate ≥40 per 100,000 population), we favor a six-month duration of INH; this approach is in agreement with the World Health Organization (WHO), given better completion rates (albeit lower efficacy) than a nine-month regimen.
Drug susceptibility of the source case should guide treatment, if available. (See 'Drug-resistant TBI' below.)
Possible drug interactions are an important consideration for use of INH (relevant drug categories include anticonvulsants, antianxiety medications, and aminophylline) and rifamycins (RIF or RPT; relevant drugs include warfarin, oral contraceptives, some antihypertensives, antiarrhythmics, antidepressants, anticonvulsants, methadone, and the protease inhibitor class of antiretroviral drugs). (See "Rifamycins (rifampin, rifabutin, rifapentine)".)
Medication doses are based on body weight, and methods of administration vary by regimen (table 5).
Rifampin — The efficacy of RIF for reducing the incidence of TB disease is estimated to be similar to that of INH in adults and in children [48-51]. RIF is well tolerated, with good completion rates and a low rate of hepatotoxicity [25,48-50,52-56].
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) . 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)'.)
RIF may be used for treatment of TBI in children of any age. For infants and young children, the contents of the capsules can be suspended in flavored liquid or sprinkled on soft foods.
RIF is the regimen of choice for treatment of TBI in children presumed to have infection with INH-resistant, rifampin-sensitive strains of TB .
Isoniazid and rifapentine — A three-month regimen of weekly INH and RPT (3HP) may be used for treatment of TBI in children age ≥2 years, particularly when circumstances make completion of nine months of daily INH (or four months of daily rifampin) difficult and/or the likelihood of developing TB is high (such as recent exposure to contagious TB) [7,58-60].
This approach 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-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 .
Subsequently, a study including 1058 children ages 2 to 17 years demonstrated that directly observed treatment with three months of INH and RPT was noninferior to nine months of isoniazid alone for prevention of TB at 33 months following enrollment and was associated with improved completion rate . INH-RPT is generally well tolerated in children >2 years of age .
INH-RPT should not be administered to children <2 years because the safety and pharmacokinetics of RPT have not been established for this group. In addition, there are no data to guide use of INH-RPT regimen in children with HIV infection.
While 3HP is emerging as the preferred regimen in many clinical practices and is generally well tolerated, flu-like symptoms 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 . Further evaluation of the clinical significance of these reactions in children is underway.
Pill burden is another potential downside to use of INH-RPT in children. RPT is available as 150 mg tablets with dose based on body weight; the RPT dose for a 25 kg child would be 450 mg (three tablets). The INH dose is based on weight and age; if the 25 kg child is between ages 2 to 11, the INH dose (25 mg/kg) would be 600 mg (two 300 mg tablets). Vitamin B6 (recommended for coadministration with INH to children) would add a sixth tablet to each dose. Tablets may be crushed and administered in a palatable base that may improve patience acceptance .
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's 2018 recommendations for using self-administered therapy for this regimen was not based on studies in children .
INH-RPT may be used for treatment of TBI among children in low or high TB incidence settings.
For children in high-income countries treated with INH, a regimen of daily INH for nine months is preferred (efficacy 75 to 90 percent; efficacy nearly 100 percent with high adherence) . 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 . Protection from six months of INH may be adequate (60 to 70 percent efficacy) if adherence is good .
For children in resource-limited settings treated with INH, we are in agreement with the WHO, which recommends daily INH for six months [15,16,25]. In some jurisdictions, directly observed therapy for TBI can be instituted twice weekly. This is especially useful for household contacts of cases or other children who are at particularly high risk for progression to TB disease.
INH has been used for decades, and its effectiveness is well documented [6,67]. Its major drawbacks include the length of treatment with monthly monitoring visits and the increasing burden of INH-resistant TB; in the United States in 2016, 9 percent of culture-positive TB cases with drug susceptibility results were resistant to at least INH .
INH is generally well tolerated. INH tablets may be crushed and mixed with a palatable food to improve adherence. In the United States, INH is available as a suspension in sorbitol (50 mg per 5 mL); however, use of this formulation may be associated with diarrhea.
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 , with slight elevations that remain stable during the course of treatment. Other manifestations include clinical hepatitis that resolves upon discontinuation of INH and fulminant hepatitis with liver failure . Severe hepatitis requiring liver transplant or causing death has been reported [6,69,70]. Children and parents or caregivers should be advised that if persisting abdominal pain, vomiting, and/or jaundice develop, the medication should be discontinued immediately, and immediate medical attention should be sought. (See 'Monitoring and adherence' 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 HIV infection). Pyridoxine should also be administered in the setting of pregnancy and to infants of breastfeeding mothers receiving INH. (See "Tuberculosis disease (active tuberculosis) in pregnancy".)
Isoniazid and rifampin — INH and RIF (daily for three months; abbreviated 3HR) may be used for treatment of TBI in children at any age . It is favored by the Canadian and United Kingdom health authorities and by the WHO as an alternative regimen for treatment of TBI in high- or upper middle-income countries.
In a systematic review including adults and children, 3HR was found to be as efficacious and well tolerated as INH (daily for nine months) [52,71]. The 3HR regimen is useful in settings where RPT is not available and in children under age 2.
MONITORING AND ADHERENCE — 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.
●Timing – 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 in the setting of abnormal baseline liver enzymes and for patients at risk for hepatotoxicity due to immunocompromise, existing liver disease including fatty liver from obesity, or current receipt of potentially hepatotoxic medications . 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).
●When to discontinue treatment – We favor discontinuing TBI treatment in patients with symptoms of hepatitis and alanine aminotransferase level (ALT) greater than three times the upper limit of normal, and among those with an ALT greater than five times the upper limit of normal (whether or not symptoms of hepatitis are present). 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. Patients and their families should be educated about potential side effects and understand they should stop treatment and notify the provider immediately if signs or symptoms of drug toxicity are suspected.
●Respiratory illness during 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 .
●Optimizing adherence – Ensuring adherence to TBI treatment remains a public health challenge . The shorter and simpler rifamycin-based regimens, which are being used more widely, are associated with higher adherence rates [25,52,53].
SUBSEQUENT MANAGEMENT — In general, individuals with ongoing potential TB exposure who have a history of a positive test for TBI and have completed a course of TBI treatment should have a new baseline chest radiograph performed.
If symptoms develop subsequently that raise the possibility of TB disease, evaluation should be pursued with chest radiograph and other investigations as outlined in detail separately. (See "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)
Patients with documented positive tuberculin skin testing (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 mechanisms to evaluate for subsequent TB exposure in these individuals. There is no role for repeat TST or IGRA to assess the effectiveness of treatment .
DRUG-RESISTANT TBI — If TBI due to a drug-resistant organism is known or suspected (eg, contact to 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 . 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 TBI'.)
NUTRITION 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'.)
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
●We perform tuberculosis (TB) infection (TBI) testing in the following circumstances (see 'Whom to test' above):
•Children at risk for new infection through contact with adults who have TB disease, either due to household exposure or residence in a region where TB is endemic
•Children at increased risk of reactivation due to associated conditions (form 1)
Only children who would benefit from treatment should be tested, so a decision to test presupposes a decision to treat if the test is positive.
●Diagnostic tools for TBI include the tuberculin skin test (TST) and interferon-gamma release assay (IGRA) (table 4). The approach to diagnosis of TBI in HIV-uninfected children is summarized in the algorithm (algorithm 1). (See 'How to test' above.)
●Our approach to TBI treatment in children is as follows (see 'Whom to treat' above):
•For all children with a positive test TST or IGRA, we recommend treatment (Grade 1A).
•For case contacts <5 years of age, we recommend initiating treatment for TBI even if the initial TST or IGRA is negative (Grade 1A). Such patients are at increased risk for progression to TB disease; this approach is known as "window prophylaxis." Repeat testing should be performed 8 to 10 weeks after the last date of contact with the index patient. 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.
•For children with HIV infection, we recommend treatment for TBI (even if the TST or IGRA result is negative) in the following circumstances:
-Recent contact with a person with TB disease (Grade 1A)
-Asymptomatic individual with clinical suspicion for prior TB (eg, fibrotic disease on chest radiograph consistent with healed TB) and no documented history of adequate TB treatment (Grade 1A)
●Prior to initiation of treatment for TBI, patients must be evaluated for TB disease to avoid monotherapy and risk of inducing secondary drug resistance. The evaluation is described above. (See 'Prior to treatment' above.)
●The choice of TBI regimen depends on whether the patient is on antiretroviral therapy (ART), their age, and other considerations such as cost, availability, capacity for monitoring, and directly observed therapy. None of the regimens has been shown to be more efficacious; adherence is superior with shorter regimens. Dosing regimens are summarized in the table (table 5). (See 'Selecting a treatment regimen' above.)
●Our approach to selecting a regimen for treatment of TBI in children as follows (see 'Selecting a treatment regimen' above):
•For children ≥2 years of age, we suggest treatment with either RIF administered daily for four months (regimen abbreviation: 4R) or INH and RPT administered weekly for three months (regimen abbreviation: 3HP) (Grade 2C), because of greater likelihood of adherence relative to other regimens. If 3HP is chosen, administration via directly observed therapy is preferred to maximize safety and treatment completion. Acceptable alternatives to 4R and 3HP include INH administered daily for nine months (regimen abbreviation: 9H) and INH and RIF administered daily for three months (regimen abbreviation: 3HR).
For children ≥2 years of age on antiretroviral therapy (ART), ART regimens should be reviewed carefully for compatibility with the TBI regimen. Children on ART regimens not compatible with rifamycins should be treated for TBI with isoniazid monotherapy.
•For children <2 years of age with HIV, not on ART, we suggest treatment with 4R (Grade 2C) because of greater likelihood of adherence relative to other regimens; 9H and 3HR are acceptable alternatives. 3HP should not be administered to children <2 years because the safety and pharmacokinetics of RPT have not been established for this age group.
•For children <2 years of age on ART, we suggest treatment with INH monotherapy (Grade 2C), given its favorable toxicity profile; the potential for drug-drug interactions with the shorter rifamycin-based regimens in individuals taking ART is high:
-In low-incidence settings (TB incidence rate <40 per 100,000 population), we suggest a nine-month duration of INH (Grade 2C).
-In high-incidence settings (TB incidence rate ≥40 per 100,000 population), we suggest a six-month duration of INH (Grade 2C); this approach is in agreement with the World Health Organization, given better completion rates (albeit lower efficacy).
●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. TBI treatment should not be resumed with that regimen, even after liver function tests have improved. (See 'Monitoring and adherence' above.)
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