Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis

INTRODUCTION — Issues related to epidemiology, clinical manifestations, and diagnosis of tuberculosis (TB) disease (active TB) in children will be reviewed here [1-5].

Issues related to treatment of TB disease in children are discussed separately. (See "Tuberculosis disease in children: Treatment and prevention".)

Issues related to diagnosis and treatment of TB infection in children are discussed in detail separately. (See "Tuberculosis infection (latent tuberculosis) in children".)

TERMINOLOGY — TB terminology is inconsistent in the literature [6]. Relevant terms are defined in the table (table 1).

EPIDEMIOLOGY

Worldwide — Estimating the global burden of TB disease in children is challenging due to the lack of a standard case definition, the difficulty in establishing a definitive diagnosis, the frequency of extrapulmonary disease in young children, and the relatively low public health priority given to TB in children relative to adults [5].

The World Health Organization (WHO) publishes global TB data, including new and relapse cases by age. In its 2022 report, the WHO estimated that of the estimated 10.6 million incident cases of TB in 2021, approximately 1.2 million (11 percent) occurred among children <15 years of age [7]. In addition, the WHO estimated that there were 216,570 deaths due to TB among children <15 years of age (20,570 occurring in children with human immunodeficiency virus [HIV] infection) in 2021 [7]. These deaths represent 15.5 percent of all TB deaths (which is higher than the estimated proportion of cases in children), suggesting a higher mortality rate in this age group [7].

Most children diagnosed with TB had been infected by household or other close contacts with TB disease, particularly parents or other caretakers. Even in circumstances when adult index cases are sputum smear negative, transmission to children has been documented in 30 to 40 percent of households [8].

It has been estimated that each year, between 25,000 and 32,000 children have multidrug-resistant (MDR)-TB, representing 3 percent of all children who develop TB disease each year [9]. Only 3 to 4 percent of these children are diagnosed and treated, and an estimated 21 percent of children who develop MDR-TB die [9]. Additional effort is needed to improve detection and treatment of drug-resistant TB among children.

United States — Risk factors for pediatric TB disease in the United States include being born outside of the United States, having a parent who is non-United States-born, or residence outside the United States for more than two months [10,11].

In the United States in 2021, 317 cases of TB were reported among children and adolescents <15 years of age, accounting for 4 percent of all TB cases in that year [11]. Among children and adolescents <15 years of age (more than half of whom were one to four years of age), 80 percent were born in the United States [11]. Among the 675 adolescents and young adults ages 15 to 24 years, 35 percent were born in the United States [11]. Overall, the incidence of TB was 15.6 times higher among patients born outside the United States [11].

CLINICAL MANIFESTATIONS

By age group

●Age <1 month

•Congenital TB – Congenital TB is relatively rare in that it occurs most often in the setting of maternal TB endometritis or disseminated TB. It can be acquired hematogenously via the placenta and umbilical vein or via fetal aspiration (or ingestion) of infected amniotic fluid.

Clinical manifestations of congenital TB include respiratory distress, fever, hepatomegaly, splenomegaly, poor feeding, lethargy, irritability, and low birthweight [12]. The primary location of congenital TB may be the liver, with relative absence of pulmonary findings. Congenital TB can mimic neonatal sepsis [3].

•Neonatal TB – Neonatal TB develops following postnatal exposure to the aerosolized respiratory secretions of a contagious person, often the infant’s mother. Diagnosis of neonatal TB can lead to identification of previously unrecognized TB in the mother (or other close contact).

●Age 1 to <12 months – Infants are more likely than older children to progress from TB infection to TB disease, and they are more likely than older children to present with signs and symptoms of lung disease. Infants may develop both pulmonary and extrapulmonary TB and are at increased risk for TB meningitis and disseminated TB [13]. Fever, fatigue, weight loss, and failure to thrive are more likely to occur when there is Ghon focus cavitation or thoracic lymph node caseation [13].

In one study including more than 1000 infants without HIV infection in South Africa who underwent evaluation for TB, 64 percent had symptomatic illness; the most common symptom was failure to thrive (50 percent of cases). Other symptoms included persistent cough (17 percent), wheezing (13 percent), weight loss (3 percent), fever (2 percent), and lethargy (1 percent) [14].

●Age 1 to <5 years – In this age group, progression from TB infection to disease occurs less commonly than among children <12 months; when it does occur, it predominantly results in bronchial or lymph node disease [13]. Airway irritation can cause persistent cough; with further progression, airway irritation can lead to wheezing and eventually stridor [13]. Extrapulmonary disease is relatively uncommon in this age group.

●Age 5 to <10 years – This age group has the lowest risk for progression from TB infection to disease [13]. Children ages five to nine years may present with clinically silent (but radiographically apparent) disease [15]. Pleural effusions are more commonly seen in children ≥5 years [13].

●Age 10 to 17 years – Adolescents with TB can present with features common to children or adults. In one review including 145 cases of adolescent TB, symptoms were present in 79 percent of cases; the most common symptoms were fever, cough, and weight loss (63, 60, and 30 percent, respectively) [16]. Extrathoracic TB was observed in 19 percent of cases; the most common sites were peripheral lymphadenopathy and meningitis.

Forms of illness

Pulmonary tuberculosis — Pulmonary TB in children typically presents with paucibacillary (often acid-fast bacilli [AFB] smear negative), noncavitary disease.

●Signs and symptoms – TB disease in children most commonly presents with pulmonary disease and/or intrathoracic adenopathy [15,17,18]. Clinical manifestations of pulmonary TB include:

•Prolonged cough (>1 to 2 weeks)

•Fever >38°C

•Weight loss or failure to thrive

Many children are asymptomatic; signs and symptoms occur most commonly among infants. (See 'By age group' above.)

●Physical findings – Physical findings of pulmonary TB are nonspecific; this is discussed further separately. (See "Pulmonary tuberculosis: Clinical manifestations and complications", section on 'Physical findings'.)

Extrapulmonary tuberculosis — Extrapulmonary manifestations occur more commonly in children <5 years of age than in adults; sites of involvement include lymph nodes, central nervous system (CNS), abdomen, and bone/joint [5]. The risk of progression to extrapulmonary TB, especially disseminated TB (including TB meningitis and miliary TB), is highest among neonates and infants [13,19]. (See 'By age group' above.)

The clinical presentation of extrapulmonary TB depends on the site of disease. Some forms of extrapulmonary TB and associated manifestations are outlined below; in the context of TB exposure, these findings should prompt further evaluation:

●CNS TB – Altered mental status, cranial nerve palsies, headache, vomiting, or seizures (see "Tuberculous meningitis: Clinical manifestations and diagnosis" and "Central nervous system tuberculosis: An overview", section on 'Forms of disease')

●TB adenitis – Painless, fixed, enlarged lymph nodes, especially in the cervical region, with or without fistula formation (see "Tuberculous lymphadenitis")

●Pleural TB – Pleural effusion (see "Tuberculous pleural effusion")

●Pericardial TB – Pericardial effusion (see "Tuberculous pericarditis")

●Abdominal TB – Distended abdomen with ascites, abdominal pain, jaundice, or unexplained chronic diarrhea (see "Abdominal tuberculosis")

●Urogenital TB – Sterile pyuria, hematuria; maternal tuberculous endometritis (see "Urogenital tuberculosis")

●Tuberculous arthritis – Nontender joint effusion (see "Bone and joint tuberculosis")

●Vertebral TB – Back pain, gibbus deformity, especially of recent onset (rarely seen) (see "Bone and joint tuberculosis")

●Skin – Warty lesion(s), papulonecrotic lesions, lupus vulgaris; erythema nodosum may be a sign of tuberculin hypersensitivity (see "Cutaneous manifestations of tuberculosis")

●Eye – Iritis, optic neuritis, phlyctenular conjunctivitis (see "Tuberculosis and the eye")

●Miliary TB – Hematogenous dissemination of M. tuberculosis (see "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis")

DIAGNOSIS

Overview

●When to suspect TB – The diagnosis of TB should be suspected in children with relevant clinical manifestations (which may include cough >2 to 3 weeks' duration, fevers, weight loss, failure to thrive) and relevant epidemiologic factors (recent close contact with an infectious case, and/or past or present residence in or travel ≥1 month to an area where TB is endemic). However, many children with TB are asymptomatic.

Inpatients with suspected TB should be placed on airborne infection isolation; this and other aspects of infection control are discussed further separately. (See "Tuberculosis transmission and control in health care settings".)

●Definitive diagnosis – The diagnosis of TB is definitively established by culture isolation of M. tuberculosis from a bodily secretion or fluid or tissue [4]. Additional diagnostic tools include respiratory specimen acid-fast bacilli (AFB) smear and nucleic acid amplification (NAA) testing such as Xpert MTB/RIF or Xpert MTB/RIF Ultra; a positive sputum NAA test (with or without AFB smear positivity) in a person at risk for TB (who has no prior history of treatment for pulmonary TB) is considered sufficient to confirm the diagnosis of TB.

Definitive diagnosis of TB disease in children can be achieved in up to 75 percent of infants but fewer than 50 percent of children with pulmonary TB diagnosed by clinical criteria [3,20].

●Clinical diagnosis – TB disease in children is often diagnosed clinically, given the challenges of definitive diagnosis; in addition, some children with TB disease are asymptomatic.

A presumptive diagnosis of TB may be made in the following circumstances [1]:

•Recent close contact with an infectious case – A history of recent close contact is a critical factor in making the diagnosis of TB in children (especially those <5 years of age). However, the ill adult contact may not yet be diagnosed with TB; therefore, asking about ill contacts (such as family members or visitors) and facilitating their evaluation can expedite diagnosis for children.

•Suggestive chest radiograph findings. (See 'Radiographic imaging' below.)

•A positive interferon-gamma release assay (IGRA) or tuberculin skin test (TST). (See 'Immunologic tools: IGRA and TST' below.)

A clinical diagnosis of TB is strengthened in the setting of clinical and radiographic response to empiric treatment. (See "Tuberculosis disease in children: Treatment and prevention", section on 'Administrative logistics and follow-up monitoring'.)

●Use of algorithms and scoring systems – A number of algorithms and scoring systems (with weighted point value assigned to clinical features and risk factors) have been developed for use in resource-limited settings [2,21-25]:

•In 2021, the World Health Organization (WHO) published two treatment decision algorithms to guide the clinical diagnosis of children with suspected pulmonary TB, for settings with and without access to chest radiography [2]. These are being used as interim guidance in resource-limited settings until 2024 while multicountry validation studies are underway.

•In a 2021 report, an algorithm used clinical data initially and, if inconclusive, reflexed to chest radiography and Xpert MTB/RIF; among 478 children <13 years of age without HIV infection (including 176 children <2 years of age and 197 children with low weight for age) in South Africa, sensitivity and specificity were 91 and 52 percent, respectively [25].

•In a 2019 report, an algorithm applied to 438 children <14 years of age with HIV infection in Burkina Faso, Cambodia, Cameroon, and Vietnam had a sensitivity and specificity of 89 and 61 percent, respectively [24].

While these findings are promising, further validation is needed before broad implementation; the efficacy is likely to be dependent upon the population and setting in which they are used [22].

Approach to diagnostic evaluation

●Suspected pulmonary TB – Patients with suspected pulmonary TB should undergo diagnostic evaluation as follows [3,18]:

•Careful history (including history of TB contacts and symptoms consistent with TB)

•Clinical examination (including growth assessment)

•Chest radiography (see 'Radiographic imaging' below)

•Respiratory specimens for AFB smear and mycobacterial culture (at least three sputum specimens or gastric aspirates) and NAA testing (at least one specimen) (see 'Obtaining laboratory specimens' below and 'Acid-fast bacilli smear and culture' below)

•IGRA and/or TST (see 'Immunologic tools: IGRA and TST' below)

•For infants <12 months of age: lumbar puncture (regardless of whether neurologic symptoms are present)

•For neonates with suspected congenital TB: placenta AFB smear, mycobacterial culture, and histologic examination

•For settings with high incidence of HIV and TB, use of urine antigen detection is discussed below (see 'Urine antigen detection' below)

●Suspected extrapulmonary TB – Patients with suspected extrapulmonary TB should undergo collection of specimens from any site(s) where disease is suspected for AFB smear and mycobacterial culture (as well as NAA testing, if feasible) [3]. Examples include cerebrospinal fluid, lymph node tissue, pleural fluid, urine, whole blood, bone marrow, and joint fluid. (See related topics.)

Diagnosis of TB should prompt HIV testing. (See "Screening and diagnostic testing for HIV infection".)

Obtaining laboratory specimens — Typical specimen types obtained during evaluation of a child with presumptive TB are described below. To increase diagnostic yield, multiple specimen types are frequently obtained. Several studies have demonstrated value in obtaining specimens from different anatomic sites on the same day [26].

●Respiratory specimens – For children with suspected pulmonary TB, at least three respiratory specimens should be obtained for AFB smear and mycobacterial culture; in addition, at least one specimen should be sent for NAA testing [4,27].

•Sputum and gastric aspirate specimens – Sputum may be expectorated (>5 years of age) (table 2), swallowed and collected as gastric contents via aspiration (<7 years of age), or induced using nebulized hypertonic saline (any age) (table 3). Sputum specimens should be obtained every 8 to 24 hours, with at least one early morning specimen. Gastric aspirates should be collected on three separate mornings upon awakening [3].

-Age <5 years – Among children age <5 years, obtaining expectorated sputum is difficult due to lack of sufficient tussive force to produce adequate samples. Therefore, gastric aspiration is the principal means of obtaining material for culture; induced sputum may also be collected if feasible.

In one study including 191 culture-confirmed cases of pulmonary TB among children in South Africa, comparable diagnostic yield was observed for (i) paired induced sputum and gastric lavage specimens obtained on a single day or (ii) two gastric lavage specimens obtained on consecutive days (67 versus 66 percent, respectively) [28].

-Age 5 to <10 years – Sputum may be expectorated or induced.

-Age ≥10 years – Most adolescents ≥10 years can produce expectorated sputum, although sputum induction should be pursued if cough is not productive.

•Nasopharyngeal aspirate (<7 years) – In settings where neither gastric aspiration nor sputum induction is readily available, nasopharyngeal aspiration may be an acceptable alternative [29].

In one study including 294 Kenyan children <5 years of age, testing (via Xpert MTB/RIF and culture) of two nasopharyngeal aspirate samples, one nasopharyngeal aspirate sample and one stool sample, or one nasopharyngeal aspirate sample and one urine sample was associated with sensitivities of 74, 71, and 69 percent (compared with culture), respectively [26,30].

•Bronchoscopy – Bronchoscopy may be useful for evaluation of patients with severe disease and nondiagnostic test results with other specimens.

In a South African study including 146 children age 3 months to 13 years, diagnostic confirmation via bronchoalveolar lavage (BAL) was observed in 69 percent of cases [31].

●Other specimens

•Pleural fluid – Issues related to pleural fluid are discussed separately. (See "Tuberculous pleural effusion".)

•Stool – In children, stool culture has limited yield; stool Xpert MTB/RIF (off-label) has sensitivity of 57 to 67 percent and specificity of 98 to 99 percent [32]. Stool Xpert MTB/RIF Ultra (not US Food and Drug Administration [FDA] approved) has similar results to gastric aspirate [27]. (See 'Molecular tests' below.)

DIAGNOSTIC TOOLS

Radiographic imaging

Chest radiography — Chest radiography (frontal and lateral) is important for diagnosis of intrathoracic TB in children (image 1A-K) [33,34].

●Children – TB in young children is often primary TB disease (as opposed to reactivation TB disease, which typically occurs in adolescents and adults). Radiographic findings of primary pulmonary TB disease consist of lymphadenopathy involving the mediastinal, hilar, subcarinal, and/or paratracheal nodes; associated granulomatous parenchymal inflammation (Ghon focus; together referred to as a Ghon complex (image 1A)) may or may not be present. Children with chest radiography demonstrating Ghon complex may be treated for TB infection rather than TB disease since the number of live organisms is relatively low. (See "Tuberculosis infection (latent tuberculosis) in children", section on 'Whom to treat'.)

As adenopathy advances, obstruction of the neighboring airway may result in consolidation or a segmental lesion, leading to collapse of a lung segment or lobe in the setting of infiltrate and atelectasis.

Presence of diffuse small nodules (a "miliary" pattern) reflects hematogenous spread.

●Adolescents – Adolescents with TB generally present with radiographic findings observed in adults; these include upper lobe consolidation, cavitation, and fibrosis or scarring, as well as pleural effusion [18]. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Radiographic imaging'.)

Adolescents also can present with findings seen in younger children described above.

Computed tomography — Computed tomography (CT) scan of the chest may be used to further delineate the anatomy for cases in which radiographic findings are equivocal. Endobronchial involvement, necrosis of lymph nodes, bronchiectasis, and cavitation may be more readily visualized on CT scans than chest radiographs [35].

However, there is no role for routine use of CT scans in the evaluation of an asymptomatic child with a normal chest radiograph [15]. One review of CT scan use among adolescents with intrathoracic TB found that prompt ordering of sputum specimens for microscopy, molecular testing, and culture would avoid unnecessary CT scans [36].

In the setting of suspected tuberculous meningitis, CT scan or magnetic resonance imaging (MRI) of the head is useful. Hydrocephalus and basilar meningeal enhancement are observed in 80 and 90 percent of cases, respectively, and evidence of vasculitis or stroke is not uncommon; chest radiography may be normal [15]. (See "Tuberculous meningitis: Clinical manifestations and diagnosis", section on 'Radiographic imaging'.)

Immunologic tools: IGRA and TST

●Clinical approach – Interferon-gamma release assay (IGRA) and tuberculin skin test (TST) are tools that measure immune sensitization to TB protein antigens; they are designed for diagnosis of TB infection. Because of the challenges in making a definitive diagnosis of TB disease in children, these tests are often obtained to provide additional evidence to support a diagnosis of TB disease. A positive result supports (but cannot be used to establish) a diagnosis of TB disease, and a negative result does not rule out TB disease.

For patients >2 years of age, we use IGRA (if available). For patients <2 years of age, we use TST given limited data for accuracy of IGRA in this age group.

Use of both IGRA and TST may increase sensitivity for evaluation of children with suspected TB; this may be warranted when additional evidence in support of a diagnosis (increased test sensitivity) is sought, especially in children <5 years of age. In one study including 69 children age 5 to 18 years with TB who underwent both IGRA and TST, the sensitivity of IGRA was greater than TST (95 versus 83 percent); among children two to four years, the sensitivity was comparable (91 percent) [37].

●IGRA – IGRAs are in vitro blood tests of cell-mediated immune response to relatively TB-specific antigens (such antigens are absent in the Bacille Calmette-Guérin [BCG] vaccine and most nontuberculous mycobacteria). IGRAs should be interpreted with caution in immunocompromised children.

A positive IGRA result should be considered indicative of infection with M. tuberculosis or Mycobacterium bovis (as TB infection or TB disease). IGRAs are not affected by BCG vaccination status so are useful for evaluation of BCG-vaccinated individuals.

A negative IGRA result cannot conclusively exclude a diagnosis of TB infection (or TB disease) and should be interpreted in the context of other epidemiologic and clinical data. IGRAs can be falsely negative in children with advanced TB disease given that this condition is immunosuppressive.

An indeterminate IGRA may be repeated; if a second indeterminate result is obtained, an alternate IGRA may be used or a TST may be performed. An indeterminate IGRA result should not be used for clinical decision-making; the complete epidemiologic and clinical picture must be considered. Expert consultation may also be helpful.

Issues related to IGRA interpretation are discussed further separately. (See "Tuberculosis infection (latent tuberculosis) in children", section on 'Interferon-gamma release assays'.)

●TST – The TST is helpful for diagnosis of TB in children only in circumstances when it is positive. Criteria for positive TST are outlined in the table (table 4) [38]. A positive TST may be falsely positive due to prior BCG vaccination (especially among children <10 years of age), infection with nontuberculous mycobacteria, or improper test administration or interpretation.

A negative TST does not rule out TB disease, since false-negative results can occur in a variety of circumstances (eg, incorrect administration or interpretation, age <6 months, immunosuppression [due to HIV, other disease, or medication], certain viral illnesses or recent live-virus immunization, and overwhelming TB disease) (table 5) [38,39].

Because the TST cannot distinguish between TB disease, TB infection, and infection due to nontuberculous mycobacteria, the result must be interpreted in the clinical context and history of TB exposure [40]. Up to 40 percent of immunocompetent children with culture-confirmed TB disease may have a negative TST [3,28]. TST positivity rates vary by form of disease; in pulmonary and extrapulmonary TB, the TST is typically positive (90 and 80 percent, respectively), while in miliary TB and TB meningitis, the TST is typically positive in about 50 percent of cases [41-43].

Issues related to TST interpretation are discussed further separately. (See "Tuberculosis infection (latent tuberculosis) in children", section on 'Tuberculin skin test'.)

Laboratory studies

Acid-fast bacilli smear and culture — For patients with suspected pulmonary TB, at least three respiratory specimens should be obtained for acid-fast bacilli (AFB) smear and mycobacterial culture [4]. (See 'Obtaining laboratory specimens' above.)

Most children have smear-negative TB disease; the sensitivity of AFB smear is 7 to 29 percent; the specificity is >90 percent [5,44]. The yield of culture can be less than 40 percent, with slightly higher sensitivity and faster results in liquid mycobacterial growth in tube compared with solid culture media [45,46].

Issues related to logistics and accuracy of AFB smear and mycobacterial culture are discussed further separately. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Microbiologic testing'.)

Molecular tests — Molecular methods are available for detection of M. tuberculosis complex deoxyribonucleic acid (DNA) and common mutations associated with drug resistance [32]. These tools are useful for expediting diagnosis and providing some initial guidance for initiation of empiric treatment; however, phenotypic culture-based drug-susceptibility testing is still required for definitive clinical management.

Use of Xpert MTB/RIF in children is discussed further below; other emerging molecular tools are discussed further separately. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Molecular testing'.)

●General principles

•Xpert MTB/RIF – Xpert MTB/RIF assay is an automated nucleic acid amplification (NAA) test that can detect M. tuberculosis complex organisms as well as rifampin resistance. The Xpert MTB/RIF is the only NAA test approved by the US Food and Drug Administration (FDA) for use in the United States; it is approved only for sputum (induced or spontaneous) in individuals who have been on antituberculous therapy for less than three days.

•Xpert MTB/RIF Ultra – Xpert MTB/RIF Ultra is a newer version of Xpert MTB/RIF developed to improve sensitivity by using an updated cartridge and improved software; it is not available in the United States [47]. The World Health Organization (WHO) supports use of Xpert MTB/RIF Ultra with sputum and nasopharyngeal aspirate specimens for diagnosis of TB in children <10 years of age [22]. In addition, in 2021, the WHO endorsed use of Xpert MTB/ RIF Ultra with gastric aspirate or stool as an initial diagnostic test for TB and detection of rifampicin resistance in children age <10 years of age [22].

●Interpretation of Xpert MTB/RIF – The Xpert analytical limit of detection is reported to be 131 colony forming units (CFU)/mL of specimen; this is better than AFB smear (10³ – 10⁴ CFU/mL) but not as good as culture [48]. For clinical respiratory specimens, Xpert MTB/RIF has sensitivity of 65 to 73 percent and specificity of 97 to 100 percent [32,49].

A positive sputum Xpert MTB/RIF test should be regarded as an actionable diagnostic result; sputum mycobacterial culture is still required for full drug susceptibility data to guide clinical management. A negative Xpert MTB/RIF test should be interpreted in the context of the patient’s clinical and radiographic findings.

●Use of Xpert MTB/RIF with alternate specimens for suspected pulmonary TB − Use of the Xpert MTB/RIF test on alternate specimens may be beneficial, especially in settings where induced sputum and mycobacterial culture are not feasible. While Xpert MTB/RIF is not FDA approved in the United States for specimens other than sputum, some laboratories may offer validated, "off-label" testing for other specimen types.

The WHO endorsement of Xpert MTB/ RIF Ultra with gastric aspirate or stool is based on a systematic review and meta-analysis of six studies from nine countries (including four high-TB and five high-TB-HIV burden countries) that evaluated the sensitivity and specificity of Xpert MTB/RIF Ultra among 659 participants for gastric aspirate samples and 1278 participants for stool samples [22]. Compared with culture, the sensitivity and specificity for gastric aspirate samples were 64 and 95 percent, respectively; the sensitivity and specificity for stool samples were 53 and 98 percent, respectively [22].

In a systematic review and meta-analysis including 12 studies and 2177 children, Xpert MTB/RIF used with stool specimens and compared with bacteriologically confirmed TB with respiratory specimens, the pooled sensitivity of Xpert MTB/RIF with stool specimens was 50 percent (with a high degree of heterogeneity between studies); the pooled specificity was 99 percent [50].

In a study of 317 children in Vietnam with presumptive TB disease, combined Xpert MTB/RIF Ultra testing of a respiratory sample and stool resulted in an increase in the proportion of bacteriologically confirmed TB by 3.9 percent [51]. TB was detected more often from stool than respiratory samples (26 versus 23 percent, although this did not reach statistical significance), including one child with rifampin resistance. Collection of stool was less difficult than collection of respiratory samples, and processing was comparable for both specimen types.

●Use of Xpert MTB/RIF in setting of extrapulmonary TB − Data on the use of Xpert MTB/RIF in children with extrapulmonary tuberculosis are promising:

•In one study including 23 children in South Africa with musculoskeletal tuberculosis (confirmed by histology), the sensitivity and specificity of Xpert MTB/RIF were 74 and 100 percent, respectively; the sensitivity and specificity of culture were 61 and 100 percent, respectively [52].

•In another study including 55 children in South Africa with tuberculous meningitis, combining results from culture, GenoType MTBDRplus, and Xpert MTB/RIF yielded sensitivity and specificity of 56 and 98 percent, respectively [53].

Urine antigen detection — Urine-based detection of mycobacterial cell wall glycolipid lipoarabinomannan (urine LAM assay) is an assay for diagnosis of TB; it is not approved by the FDA for use in the United States.

For settings with high incidence of HIV and TB, we are in agreement with the WHO which favors use of urine LAM testing (in addition to routine diagnostic tests) for patients with HIV infection who have signs and symptoms of TB (pulmonary and/or extrapulmonary) and CD4 ≤100 cells/microL, and for any patient with HIV infection who is seriously ill [54].

The high specificity of LAM testing suggests this can be used as a "rule-in" test among those at highest risk for TB. In children, it has sensitivity of 28 to 73 percent and specificity of 61 to 91 percent; the accuracy is increased in the setting of HIV infection [5]. In one cohort study including 204 children in South Africa, assay specificity was 92 percent overall and 96 percent in those >2 years of age; assay sensitivity was 42 percent overall, but 60 percent among the 40 children with HIV infection and 62 percent among the 44 children who were malnourished [55,56].

The urine LAM assay may also have prognostic utility. In one study including 137 children with HIV infection in Malawi initiating antiretroviral therapy, the six-month mortality rate was 3.7-fold higher among those with a positive urine LAM assay [57].

Issues related to use of this assay are discussed further separately. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Urine antigen test in HIV infection'.)

Drug susceptibility testing — Phenotypic, culture-based drug susceptibility testing is the gold standard for diagnosis of drug-resistant TB; this information should be used to guide treatment.

Pending these results, molecular tools (if available) may provide useful preliminary information; however, these tools have reduced sensitivity and are not always predictive of phenotypic resistance.

●Xpert MTB/RIF – Xpert MTB/RIF provides rifampin susceptibility data. (See 'Molecular tests' above.)

●MTBDRsl – MTBDRsl (not approved in the United States) is a line-probe assay that provides information regarding susceptibility to fluoroquinolones and injectable antituberculous agents. The WHO recommended use of MTBDRsl in 2016 for identifying patients with multidrug-resistant (MDR)-TB who are candidates for treatment with a shortened treatment regimen [58].

●Whole genome sequencing – Whole genome sequencing with molecular determination of drug resistance is available for patients in the United States from the Centers for Disease Control and Prevention (CDC) laboratory for patients with Xpert-positive sputum specimens and for patients with positive sputum culture who are at risk for drug resistance. This service may be initiated through state public health laboratories [59].

Issues related to diagnosis of drug resistance are discussed further separately. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Microbiologic testing'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of tuberculosis includes:

●Mycobacterium bovis pulmonary disease – M. bovis is a member of the Mycobacterium tuberculosis complex (MTBC), which also includes M. tuberculosis. Risk factors for M. bovis infection include consumption of unpasteurized dairy products and contact with infected animals or humans. Pulmonary disease due to M. bovis is clinically and radiographically indistinguishable from pulmonary disease due to M. tuberculosis; these are distinguished microbiologically. (See "Mycobacterium bovis".)

●Nontuberculous mycobacterial disease (NTM) – Symptoms of NTM include fatigue, dyspnea, and occasional hemoptysis; fever and weight loss occur less frequently than in patients with tuberculosis. NTM is distinguished from tuberculosis by culture results and/or molecular diagnostic testing. (See "Overview of nontuberculous mycobacterial infections".)

●Fungal infection – Fungal pneumonia can present with a range of manifestations including pneumonia, pulmonary nodules, and cavitary lung disease. It is distinguished from tuberculosis by epidemiologic exposure and culture results. (See "Diagnosis and treatment of pulmonary histoplasmosis".)

●Lymphoma – Lymphoma typically presents with a rapidly growing mass together with fever, night sweats, and weight loss. It is distinguished from tuberculosis by histopathology. (See related topics.)

CONTACT TRACING — Close adult contacts of children with TB should be evaluated as outlined in detail separately. (See "Diagnosis of pulmonary tuberculosis in adults".)

Treatment of TB in children is often guided by the culture and drug susceptibility results from the index person, emphasizing the importance of contact tracing for optimal management.

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

●Epidemiology – Estimating the global burden of TB disease in children is challenging due to the lack of a standard case definition, the difficulty in establishing a definitive diagnosis, the frequency of extrapulmonary disease in young children, and the relatively low public health priority given to TB in children relative to adults. (See 'Epidemiology' above.)

●Clinical manifestations – Clinical manifestations of TB disease vary by age group. Infants (age 1 to <12 months) are more likely than older children to progress from TB infection to TB disease. Infants are also more likely than older children to present with signs and symptoms of lung disease; these include cough, fever, and weight loss or failure to thrive. In addition, infants are at increased risk for TB meningitis and disseminated TB. (See 'Clinical manifestations' above.)

●Diagnosis (See 'Overview' above.)

•When to suspect TB – The diagnosis of TB disease should be suspected in children with relevant clinical manifestations (which may include cough >2 to 3 weeks' duration, fevers, weight loss, failure to thrive) and relevant epidemiologic factors (recent close contact with an infectious case, and/or past or present residence in or travel ≥1 month to an area where TB is endemic). However, many children with TB are asymptomatic.

•Definitive diagnosis – The diagnosis of TB disease is definitively established by culture isolation of M. tuberculosis from a bodily secretion or fluid or tissue. A positive respiratory specimen nucleic acid amplification (NAA) test (with or without acid-fast bacilli [AFB] smear positivity) in a person at risk for TB disease (who has no prior history of treatment for pulmonary TB) is sufficient to confirm the diagnosis of TB disease.

Definitive diagnosis of TB disease in children can be achieved in up to 75 percent of infants but among fewer than 50 percent of children with pulmonary TB diagnosed by clinical criteria.

•Clinical diagnosis – TB disease in children is often diagnosed clinically, given the challenges of definitive diagnosis. A presumptive diagnosis of TB may be made in the following circumstances:

-Recent close contact with an infectious case

-Suggestive chest radiograph findings

-Positive interferon-gamma release assay (IGRA) or tuberculin skin test (TST)

•Approach to diagnostic evaluation – Patients with suspected pulmonary TB disease should undergo diagnostic evaluation as follows (see 'Approach to diagnostic evaluation' above):

-Careful history (including history of TB contacts and symptoms consistent with TB disease)

-Clinical examination (including growth assessment)

-Respiratory specimens for AFB smear and mycobacterial culture (at least three sputum specimens or gastric aspirates), and NAA testing (at least one specimen)

-Chest radiography

-IGRA and/or TST

-For infants <12 months of age: lumbar puncture (regardless of whether neurologic symptoms are present)

-For neonates with suspected congenital TB: placenta AFB smear, mycobacterial culture, and histologic examination

Patients with suspected extrapulmonary TB should undergo collection of specimens from any site(s) where disease is suspected for AFB smear and mycobacterial culture (as well as NAA testing, if feasible).

•Obtaining respiratory specimens – Gastric aspiration is the primary method of obtaining material for diagnostic testing (including AFB smear, rapid tests, and culture) from young children, since these patients lack sufficient tussive force to produce adequate sputum samples by expectoration alone. Alternative approaches include sputum induction, nasopharyngeal aspiration, or expectoration (for older children). (See 'Obtaining laboratory specimens' above.)

•Radiographic imaging – Radiographic findings of primary pulmonary TB disease consist of lymphadenopathy involving the mediastinal, hilar, subcarinal, and/or paratracheal nodes; associated granulomatous parenchymal inflammation may or may not be present. As adenopathy advances, obstruction of the neighboring airway may result in consolidation or a segmental lesion, leading to collapse of a lung segment or lobe in the setting of infiltrate and atelectasis. (See 'Radiographic imaging' above.)