Tuberculosis disease in children

Authors:
Lisa V Adams, MD
Jeffrey R Starke, MD
Section Editors:
C Fordham von Reyn, MD
Morven S Edwards, MD
Deputy Editor:
Elinor L Baron, MD, DTMH

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Oct 2017. | This topic last updated: Sep 26, 2017.

INTRODUCTION Formal policies and control efforts addressing tuberculosis (TB) in

children have been limited, in part due to lack of a standardized case definition and
difficulties associated with establishing a definitive diagnosis [1]. However, since diagnostic
and treatment tools for TB in children have begun to improve significantly, TB in children
has received increasing attention by researchers, clinicians, and policy makers.

Issues related to TB disease in children will be reviewed here. Issues related to diagnosis and
treatment of latent TB infection in children are discussed in detail separately. (See "Latent
tuberculosis infection in children".)

EPIDEMIOLOGY

Global epidemiology Estimating the global burden of tuberculosis (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 [2].

The World Health Organization (WHO) publishes global TB data including new and relapse
cases by age. In its 2016 report, the WHO estimates that, of the 10.4 million incident cases of
TB in 2014, approximately 1 million occurred among children under age 15 [3]. In 2017, the
WHO and colleagues estimated that there were 239,000 pediatric deaths due to TB (39,000
occurring in HIV-infected children) [4]. Approximately 80 percent of these deaths occurred
in children under age five [4].

Children under age five represent an important demographic group for understanding TB
epidemiology, since TB frequently progresses rapidly from latent infection to disease, and
severe disease manifestations, such as miliary TB and meningitis, are more common in this
age group. Therefore, these children serve as sentinel cases, indicating recent and/or ongoing
transmission in the community.

Most children are infected by household 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 [5].
It has been estimated that, of nearly one million children who developed tuberculosis disease
in 2010, 32,000 had multidrug-resistant TB [6]. Additional effort is needed to improve
detection of drug-resistant TB among children.

United States epidemiology Risk factors for pediatric TB in the United States include
being foreign born, having a parent who is foreign born, or having lived outside the United
States for more than two months [7]. In the United States, TB among children is relatively
rare. In 2013, there were 485 cases of TB in children and adolescents under 15 years of age
reported by the United States Centers for Disease Control and Prevention (CDC); this number
represented 5 percent of the total 9582 cases reported that year [8-10]. However, TB in
children and adolescents is prone to both under- and over-reporting due to the difficulties
related to diagnosis. Nonetheless, in the United States, TB in children and adolescents
appears to be declining. Between 2008 and 2012, TB annual case notifications in those under
age 15 years decreased from 786 (in 2008) to 486 cases (in 2012) [7].

In 2012, most children and adolescents with TB in the United States were born in the United
States (79 percent). In contrast, most adults with TB in the United States were born in
endemic areas (table 1). Nearly half of all patients under age 15 diagnosed with TB in 2012
(42 percent) were young children between the ages of 1 and 4 [7].

In 2012, among 471 children and adolescents with TB in the United States, 40 percent were
Hispanic, 27 percent were black, 22 percent were Asian or Pacific Islander, 8 percent were
white, and 4 percent were American Indian or Native Alaskan [7]. Between 1993 and 2011,
HIV status was known for 24 percent of the pediatric patients reported (n = 19,354); of these,
3.7 percent were HIV infected [8]. Drug susceptibility testing data from 2011 reveal that the
isolates from 17 percent of pediatric TB cases had detectable resistance to one or more drugs,
and 3 percent were multidrug-resistant TB [7].

CLINICAL MANIFESTATIONS

Pulmonary tuberculosis Pulmonary disease and associated intrathoracic adenopathy are

the most frequent presentations of tuberculosis (TB) in children [11,12]. Common symptoms
of pulmonary TB in children include [13]:

Chronic, unremitting cough that is not improving and has been present for more than three
weeks

Fever of more than 38C for at least two weeks, other common causes having been
excluded

Weight loss or failure to thrive (based on child's growth chart)

However, these symptoms are fairly nonspecific. In one study comparing symptoms of
children with culture-proven TB with children with other lung diseases, there was no
difference between the two groups with respect to weight loss, chronic cough, and duration of
symptoms [14]. The only factors differentiating the groups were history of contact with an
infectious TB case and a positive tuberculin skin test (TST). In a study of more than 1000
HIV-uninfected infants in South Africa, cough >2 weeks' duration (present in 17 percent) was
the only diagnostic symptom associated with severe pulmonary TB disease; this symptom
was twice as common in severe TB compared with nonsevere TB [15].
Physical exam findings may suggest the presence of a lower respiratory infection, but there
are no specific clinical signs or findings to confirm that pulmonary TB is the cause. Children
ages 5 to 10 may present with clinically silent (but radiographically apparent) disease,
particularly in the setting of contact investigation [11]. In contrast, infants are more likely to
present with signs and symptoms of lung disease. Common radiographic findings are
discussed below. (See 'Chest radiography' below.)

Extrapulmonary tuberculosis The clinical presentation of extrapulmonary TB depends on

the site of disease. The most common forms of extrapulmonary disease in children are TB of
the superficial lymph nodes and of the central nervous system (CNS) [16]. Neonates have the
highest risk of progression to TB disease with miliary and meningeal involvement [16]. Some
forms of TB and their common physical signs are as follows [17]:

Tuberculous meningitis meningitis not responding to antibiotic treatment, with a subacute

onset, communicating hydrocephalus, stroke, and/or elevated intracranial pressure (see
"Central nervous system tuberculosis")

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")

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

TB of the joint Nontender joint effusion (see "Skeletal tuberculosis")

Vertebral TB Back pain, gibbus deformity, especially of recent onset (rarely seen) (see
"Skeletal tuberculosis")

Skin Warty lesion(s), papulonecrotic lesions, lupus vulgaris; erythema nodosum may be a
sign of tuberculin hypersensitivity

Renal Sterile pyuria, hematuria (see "Urogenital tuberculosis")

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

In the context of exposure to TB, presence of these signs should prompt further investigation
of extrapulmonary TB.

Perinatal infection Perinatal TB can be a life-threatening infection; the mortality in the

setting of congenital and neonatal TB is about 50 percent [18-20]:

Congenital TB is rare and most often is associated with tuberculous endometritis or

disseminated TB in the mother. It can be acquired hematogenously via the placenta and
umbilical vein or by fetal aspiration (or ingestion) of infected amniotic fluid [18,20].
Clinical manifestations of congenital TB include respiratory distress, fever, hepatomegaly,
splenomegaly, poor feeding, lethargy, irritability, and low birthweight [19]. Clinical
evaluation of the infant in the setting of suspected congenital TB should include TST, HIV
testing, chest radiograph, lumbar puncture, cultures (blood and respiratory specimens), and
evaluation of the placenta with histologic examination (including acid-fast bacilli [AFB]
staining culture). The TST in newborns is usually negative, but an interferon-gamma release
assay test may be positive in some cases.

Neonatal TB develops following exposure of an infant to his or her mother's aerosolized

respiratory secretions. This is more common than congenital TB, and diagnosis of neonatal
TB can lead to identification of previously unrecognized diagnosis of TB in the mother [21].

In the setting of congenital or neonatal TB, the mother should be evaluated as outlined in
detail separately. (See "Diagnosis of pulmonary tuberculosis in HIV-uninfected adults".)

Adolescent infection Adolescents with TB can present with features common in children
or adults. In one review including 145 cases of adolescent TB, the following features were
noted [22]:

Most adolescents presented with clinical symptoms.

Rates of extrathoracic TB were high, including six immunocompetent adolescents with TB

meningitis.

Most cases were AFB sputum smear negative.

Only half of patients with intrathoracic TB had positive cultures.

Antituberculous medications were generally well tolerated.

DIAGNOSIS Tuberculosis (TB) in children is often diagnosed clinically. Because

pulmonary TB in children typically presents with paucibacillary, noncavitary pulmonary
disease, bacteriologic confirmation is achievable in less than 50 percent of children and 75
percent of infants; in such cases, pulmonary TB is diagnosed by other clinical criteria [23].

It is suggested that mycobacterial culture of respiratory specimens be performed for children

suspected of having pulmonary TB [24]. However, obtaining sputum samples from young
children is challenging due to lack of sufficient tussive force to produce adequate sputum
samples by expectoration alone [25]. For these reasons, gastric aspiration is the principal
means of obtaining material for culture from young children; induced sputum may also be
collected if feasible. In addition, most experts recommend that children <12 months who are
suspected of having pulmonary or extrapulmonary TB undergo lumbar puncture, regardless
of whether neurological symptoms are present [23].

For diagnosis of extrapulmonary TB, specimens for culture should be collected from any site
where infection is suspected. Each specimen should be cultured regardless of acid-fast bacilli
(AFB) smear results [23]. The most common extrapulmonary specimens include whole
blood, bone marrow, tissue specimens (such as lymph node or bone), cerebrospinal fluid,
urine, and pleural fluid. Diagnostic yield is variable. In pleural TB, adenosine deaminase
(ADA) levels over 40 units/L in the pleural fluid are observed in the majority of patients [11].
(See "Tuberculous pleural effusion".)

A diagnosis of TB (pulmonary or extrapulmonary) in a child is often based on the presence of

the classic triad: (1) recent close contact with an infectious case, (2) a positive tuberculin skin
test (TST) or interferon-gamma release assay (IGRA), and (3) suggestive findings on chest
radiograph or physical examination [17].

The approach outlined by the World Health Organization (WHO) for evaluation of a child
suspected of having TB includes [13]:

Careful history (including history of TB contact and symptoms consistent with TB)

Clinical examination (including growth assessment)

TST and/or IGRA (both tests, if available, to increase sensitivity)

Bacteriological confirmation whenever possible

Investigations relevant for suspected pulmonary and extrapulmonary TB

HIV testing (eg, in high HIV-prevalence areas)

All data, including thorough history, physical exam, and diagnostic testing, must be
considered carefully. A history of recent close contact with an infectious (sputum smear
positive) case of TB is a critical factor in making the diagnosis of TB in children, especially
for those under the age of five years. However, the ill adult may have not yet been diagnosed,
so asking about ill contacts and facilitating evaluation for ill adults can also expedite
diagnosis for children.

In many cases of TB in children, laboratory confirmation is never established (particularly

among children under five years of age). In such cases, a presumptive diagnosis may be made
based on clinical and radiographic response to empiric treatment. Treatment is often guided
by the culture and drug susceptibility results from the index case (eg, the adult TB contact).

Screening tests

Tuberculin skin test A positive TST may be present in both contained latent TB infection
(LTBI) and in active TB disease. Thus, although a positive TST may help support a diagnosis
of active disease, this finding alone is not diagnostic of active disease; it must be considered
together with other diagnostic criteria. 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 2) [17]. A positive TST may be falsely positive due to prior vaccination with Bacille
Calmette-Gurin (BCG), infection with nontuberculous mycobacteria, and improper
administration or interpretation (table 3).

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 of the TST, age less
than six months, immunosuppression by HIV, other disease or medication, certain viral
illnesses or recent live-virus immunization, overwhelming TB infection) [17,26]. (See
"Diagnosis of latent tuberculosis infection (tuberculosis screening) in HIV-uninfected adults",
section on 'False-negative tests'.)

Because the TST cannot distinguish between TB disease, latent Mycobacterium tuberculosis
infection, and infection due to nontuberculous mycobacteria, the result must be interpreted in
the context of the clinical features and history of TB exposure [27]. Overall, up to 40 percent
of immunocompetent children with culture-confirmed TB disease may have a negative TST
[23,28]. 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 usually positive in only 50 percent of cases [29-31].

Interferon-gamma release assays IGRAs are in vitro blood tests of cell-mediated immune
response. These assays have greater specificity than TST for diagnosis of LTBI and are most
useful for evaluation of LTBI in BCG-vaccinated individuals [32]. As with the TST, IGRAs
cannot distinguish LTBI from active disease. IGRAs may prove a useful tool to improve the
diagnosis of TB, although evidence for use of IGRAs in children is limited [33-37]. Use of
both TST and IGRA may increase sensitivity for evaluation of children with suspected TB.
Additional issues related to use of IGRAs are discussed further separately. (See "Interferon-
gamma release assays for diagnosis of latent tuberculosis infection".)

Imaging

Chest radiography Frontal and lateral chest radiography can be a very useful tool for
diagnosis of TB in children (image 1A-K) [38,39]. The most common chest radiograph
finding in a child with TB disease is a primary complex, which consists of opacification with
hilar or subcarinal lymphadenopathy, in the absence of notable parenchymal involvement
[13]. When adenopathy advances, consolidation or a segmental lesion may occur, leading to
collapse in the setting of infiltrate and atelectasis.

In a study of 326 traced contacts under five years of age, 9 percent of children diagnosed with
intrathoracic TB were asymptomatic and had radiographic findings only of the primary
complex [40]. A miliary pattern of opacification is highly suspicious for TB, as is
opacification that does not improve or resolve following a course of antibiotics [13].

Adolescents with TB generally present with typical adult disease findings of upper lobe
infiltrates, pleural effusions, and cavitations on chest radiograph [13]. (See "Diagnosis of
pulmonary tuberculosis in HIV-uninfected adults".)

Computed tomography scan 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, bronchiectasis, and cavitations may be more readily visualized
on CT scans than chest radiographs [41]. However, there is no role for routine use of CT
scans in the evaluation of an asymptomatic child since treatment regimens are based on chest
radiography findings [11].

In the setting of tuberculous meningitis, CT scan of the head is useful. Hydrocephalus and
basilar meningeal enhancement are observed in 80 and 90 percent of cases, respectively;
chest radiography may be normal [11].
Laboratory studies The likelihood of achieving bacteriological confirmation depends on
the extent of disease and the type of specimen. The initial approach for diagnosis of TB in
children consists of sputum examination: expectorated (for adolescents), swallowed and
collected as gastric contents (young children), or induced. Gastric aspiration is the primary
method of obtaining material for AFB smear and culture from young children.

Sputum specimens should be sent for examination by smear microscopy and mycobacterial
culture. Nucleic acid amplification (NAA) testing can be used for rapid diagnosis of an
organism belonging to the M. tuberculosis complex (24 to 48 hours) in patients for whom the
suspicion for TB is moderate to high [42]. (See "Diagnosis of pulmonary tuberculosis in
HIV-uninfected adults".)

Acid-fast bacilli smear and culture A respiratory specimen should be obtained for AFB
smear and mycobacterial culture for children with suspected pulmonary TB [43].

Sputum Obtaining expectorated sputum from children for detection of AFB is difficult and
its examination is of low yield (15 percent or less for microscopic examination and 30
percent or less for culture) [44,45]. However, most adolescents can produce expectorated
sputum spontaneously.

Sputum induction has higher yield than expectorated sputum in children, and the use of
sputum induction for obtaining TB diagnostic specimens in children is increasing. Sputum
induction is performed via administration of aerosolized heated saline combined with
salbuterol (or similar drug to minimize wheezing), followed by suctioning to capture the
expectorated sputum. In a study of 250 children (median age 13 months), sputum induction
was found to be a safe and effective procedure in children as young as one month of age [44].
In two studies, outpatient sputum induction yielded culture results comparable to or better
than inpatient gastric aspiration [28,44]. Minimal adverse effects associated with the
procedure included coughing, epistaxis, vomiting, and wheezing. Children with underlying
reactive airways disease should receive pretreatment with a bronchodilator to prevent
bronchospasm during or following the procedure [44].

Gastric aspirate Early morning gastric contents collected from a fasting child contain
sputum swallowed during the night. Gastric aspiration specimens may be obtained in the
inpatient or outpatient setting [46,47]. Ideally, three early morning samples collected on
different days before the child eats or ambulates optimize specimen yield [48].

Gastric aspiration remains the most common method for obtaining respiratory samples from
children (in facilities where this procedure may be performed). In general, cultures of gastric
aspirate specimens are positive for TB in only 30 to 40 percent of cases [49]. Smears are even
less reliable, with positive results in fewer than 10 percent of cases [49]; in addition, false-
positive smear results caused by the presence of nontuberculous mycobacteria can occur [23].
Similar yields have been reported with nasopharyngeal aspiration, a less invasive technique
that can be performed in the outpatient setting [50].

Other specimens Other body fluid and/or tissue samples may be necessary in some
circumstances, depending on suspicion for extrapulmonary TB. The approach to these
diagnostic tools is outlined separately. (See "Clinical manifestations, diagnosis, and treatment
of miliary tuberculosis" and "Tuberculous lymphadenitis" and "Diagnosis of pulmonary
tuberculosis in HIV-uninfected adults".)
Diagnosis of TB should prompt HIV testing. (See "Screening and diagnostic testing for HIV
infection".)

Xpert MTB/RIF and other rapid tests The Xpert MTB/RIF assay is an automated nucleic
acid amplification test that can simultaneously identify M. tuberculosis and detect rifampin
resistance. This test performs substantially better than smear microscopy [51,52]. In a
randomized trial including 452 children in South Africa with suspected pulmonary TB, 6
percent had a positive sputum smear, 16 percent had a positive sputum culture, and 13
percent had a positive sputum Xpert MTB/RIF result [51]. The initial Xpert MTB/RIF test
detected 100 percent of culture-positive cases that were smear positive but only 33 percent of
those that were smear negative; a second Xpert MTB/RIF test improved the detection of
smear-negative cases to 61 percent. Overall, with induced sputum specimens, the sensitivity
and specificity were 59 and 99 percent, respectively, for one Xpert MTB/RIF test and 76 and
99 percent for two Xpert MTB/RIF tests. Test performance was unaffected by patient HIV
status. Results for Xpert MTB/RIF were available within a median of one day (versus 12 days
for culture). Detection of rifampin resistance was less promising: 1 of 3 rifampin-resistant
isolates was not detected, and 4 of 74 rifampin-sensitive isolates had an "indeterminate"
result. A multi-country study found that Xpert MTB/RIF testing of both a nasopharyngeal
aspirate and stool sample had a high yield (sensitivity of 75 percent and specificity >97
percent) in HIV-infected children and poses a promising alternative [53].

While the Xpert MTB/RIF test appears to be highly specific, its sensitivity for sputum smear
negative TB in children remains low. Since culture was used as the gold standard in both
studies described above, the sensitivity of Xpert MTB/RIF is expected to be even lower in
sputum culture-negative, clinically confirmed cases. Therefore, it cannot replace current
methods used to suspect and diagnose TB in infants and children. Most children in the study
presented with symptomatic pulmonary TB and extensive disease. The Xpert MTB/RIF test
is meant to be a rapid diagnostic test that may take the place of sputum microscopy but not
mycobacterial culture [54]. A negative Xpert MTB/RIF test should be interpreted in the
context of the child's clinical and radiographic findings. Sputum culture remains a more
sensitive test and is required to detect the full drug susceptibility profile of the infecting
organism. Further study of the assay is needed in areas with high and low prevalence of TB.
(See "Diagnosis of pulmonary tuberculosis in HIV-uninfected adults".)

Use of the Xpert MTB/RIF test on gastric lavage and nasopharyngeal specimens may be
beneficial in settings where induced sputum and mycobacterial culture are not feasible. In one
study in Zambia, sensitivity and specificity were found to be similar for sputum and gastric
lavage aspirates (sensitivity 90 and 69 percent, respectively; specificity 99 percent for both)
[55]. Among over 900 children in South Africa, the sensitivity of Xpert MTB/RIF was
similar for induced sputum and nasopharyngeal aspirate specimens (71 and 65 percent,
respectively); specificity was >98 percent [56].

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 [57]. 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 [58].
Molecular line probe assays are rapid tests that can be used to detect the presence of M.
tuberculosis as well as genetic mutations that confer rifampin resistance alone or in
combination with isoniazid resistance. These assays have high sensitivity (90 to 97 percent)
and specificity (99 percent) compared with drug susceptibility testing [59]. (See "Natural
history, microbiology, and pathogenesis of tuberculosis", section on 'Drug susceptibility
tests'.)

Drug resistance Mycobacterial culture with second-line drug susceptibility testing (DST)
should be performed whenever possible [60,61]. Concerted effort should be made to obtain
multiple high-quality specimens from the most accessible site(s) of disease [61].

Rapid molecular tests are useful for providing some information regarding susceptibility in
the absence of culture data. These include Xpert MTB/RIF (an automated nucleic acid
amplification test that provides information regarding susceptibility to rifampin) and
MTBDRsl (a line-probe assay that provides information regarding susceptibility to
fluoroquinolones and injectable antituberculous agents).

In 2016, the World Health Organization recommended use of MTBDRsl for identifying
patients with MDR-TB or rifampicin-resistant TB who are candidates for treatment with a
shortened treatment regimen [62]. The assay may be used an initial diagnostic test; however,
phenotypic culture-based drug-susceptibility testing is required to detect resistance to other
drugs and to monitor for emergence of additional resistance during treatment. Issues related
to diagnosis of drug resistance are discussed further separately. (See "Diagnosis of pulmonary
tuberculosis in HIV-uninfected adults".)

Pending definitive diagnostic information, in some circumstances it may be reasonable to

presume presence of drug-resistant TB based on clinical criteria including signs and
symptoms, radiographic findings, history of contact with a presumed or confirmed source
case with drug-resistant TB, and failure to respond to first-line TB drugs [61].

Investigational diagnostic methods Because of the difficulty in achieving microbiologic

confirmation of clinically suspected TB in children, interest has grown in alternate methods
of laboratory diagnosis. One candidate method is microarray analysis of blood samples to
identify a pattern of RNA expression that is associated with active TB infection. One study
identified an RNA expression risk score that distinguished with high sensitivity and
specificity culture-confirmed TB from latent TB and diseases other than TB among children
in sub-Saharan Africa. However, the risk score did not perform as well among children with
clinically diagnosed, culture-negative TB [63]. Moreover, in order to be a practical tool in
resource-limited settings, where its use would be most relevant, the technology would require
substantial modification to reduce cost and complexity.

TREATMENT

Susceptible disease Guidelines endorsed by the United States Centers for Disease Control
and Prevention (CDC) and the World Health Organization (WHO) for the treatment of
tuberculosis (TB) in children emphasize the use of short-course multidrug regimens under
directly observed therapy [17]. In general, the pediatric treatment regimens outlined by the
WHO are comparable with the adult regimens (table 4) [23,64]. Because TB in young
children can rapidly disseminate with serious sequelae, prompt initiation of therapy is critical.
Appropriate dosing is outlined in the table (table 5). For infants and young children, isoniazid
(INH) tablets and can be pulverized, and the contents of rifampin capsules can be suspended
in a flavored liquid or sprinkled on semi-soft foods. (See "Treatment of drug-susceptible
pulmonary tuberculosis in HIV-uninfected adults".)

Pyridoxine supplementation is not routinely recommended for children receiving INH but
should be considered for exclusively breastfed infants, malnourished children or those with
diets poor in pyridoxine, and HIV-infected children [23,65].

In many cases of TB in children, laboratory confirmation is never established (particularly

among children under five years of age). In such cases, a presumptive diagnosis may be made
based on clinical and radiographic response to empiric treatment. If the cultures are negative,
the isolates of contacts (if known or available) should guide decisions about treatment with
respect to susceptibility. During and following treatment, radiographic abnormalities such as
hilar adenopathy may persist; therefore, a normal radiograph is not necessary to discontinue
treatment, and follow-up radiographs beyond the termination of successful therapy are
usually not necessary unless clinical deterioration occurs [23].

Drug susceptibility testing (DST) should be performed on initial isolates from each site of
disease. Susceptibility testing should be repeated if the patient remains culture positive after
three months of therapy or positive cultures are detected after negative cultures have been
documented.

In HIV-infected children not on antiretroviral therapy (ART), ART should be initiated within
eight weeks of starting antituberculous therapy or within two to four weeks if the CD4 count
is <50 cells/mm3. Children with TB meningitis may be the only exception. Emerging
evidence suggests that there is no survival benefit to starting ART before two months of
antituberculous therapy, and, in fact, delaying ART until that time may reduce adverse events
[66]. Selection of an optimal ART regimen should be made in consultation with a pediatric
HIV specialist.

Unexplained deterioration among immunocompetent children receiving appropriate therapy

for pulmonary and/or extrapulmonary TB has been described [67,68]. In one study of 110
children, clinical or radiographic deterioration was observed in 14 percent of cases after
initiating therapy (range 10 to 181 days; mean 80 days) [67]. The most common complication
was enlarging intrathoracic lymphadenopathy, often causing airway compromise.
Deterioration was more likely among children with weight-for-age 25th percentile and
multiple sites of disease. All children achieved clinical or radiographic cure; corticosteroids
were administered in 60 percent of cases. In another study of 115 immunocompetent
children, 12 developed paradoxical worsening within 15 to 75 days (median 39 days) of
starting TB therapy; children with paradoxical reactions tended to be younger (median age at
diagnosis of 26 months versus 66 months) and had never received BCG vaccination [68]. The
most common manifestation was worsening of preexisting pulmonary lesions, observed in 75
percent, while 25 percent had new disease present in new anatomic locations.

Drug-resistant TB In general, the approach for treatment of drug-resistant TB in children

is similar to the approach for adults. Children may be treated with a conventional regimen or,
if they meet appropriate criteria, a shortened regimen [69]. However, the approach to
selection of antituberculous agents for children may differ from that of adults in some
circumstances; this is discussed further below, and pediatric dosing of second-line
antituberculous drugs is summarized in the table (table 6). Issues related to treatment of drug-
resistant TB are discussed in detail separately. (See "Treatment of drug-resistant pulmonary
tuberculosis in adults", section on 'General principles'.)

In general, use of second-line antituberculous agents in children is complicated by the

absence of pediatric formulations for most of these drugs, which can lead to under- or over-
dosing. Children with nonsevere disease should not be treated with injectable agents, since
the harm of these drugs class outweighs the potential benefits. In addition, although the
relatively new agents bedaquiline and delamanid have been approved for use in adults, there
are no safety, tolerability, efficacy, or pharmacokinetic data for children [23,62,70].

Individualized treatment in children has been associated with generally good outcomes [71-
73]. In a retrospective study of 149 children under 15 years of age (median age 36 months)
with documented or suspected drug-resistant TB in South Africa, treatment regimens
included at least four active drugs, included an injectable agent in 66 percent of patients, and
were given for a median of 13 months [71]. Cure or probable cure was achieved in 92
percent. Similar outcomes were reported in a series of 38 children in Peru who received 18 to
24 months of a supervised individualized treatment regimen (five to seven drugs) based on
susceptibility results of their M. tuberculosis isolate or the source case's isolate (usually a
household contact) [72].

Drug toxicity is common; in one meta-analysis of children treated for multidrug-resistant TB,
it was reported in 39 percent of cases [74]. Similarly, in the series from Peru, adverse effects
occurred in 42 percent of cases, although no events required suspension of therapy for >5
days [72]. Children on treatment for drug-resistant TB should be monitored at least monthly
for adherence, response to treatment (eg, sputum analysis for those with pulmonary TB), and
potential adverse events.

PREVENTION Measures for prevention of tuberculosis (TB) include infection control

interventions and prompt identification and treatment of latent TB infection (LTBI).
Suspicion of TB disease in a child should be reported to the health department so that an
investigation can be started right away. (See "Latent tuberculosis infection in children" and
"Tuberculosis transmission and control", section on 'Contact investigation'.)

Issues related to treatment of LTBI following contact with a source case are discussed
separately. (See "Latent tuberculosis infection in children".)

In countries where TB is endemic, routine childhood Bacille Calmette-Gurin (BCG)

immunization is an important preventive measure. Issues related to use of BCG in developed
countries are discussed separately. (See "BCG vaccination", section on 'Developed
countries'.)

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

Estimating the global burden of tuberculosis (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. As a result, there is likely significant
underreporting of childhood TB from high-prevalence countries. (See 'Epidemiology' above.)

Children under the age of five years represent an important demographic group for
understanding TB epidemiology; in this group, TB frequently progresses rapidly from latent
infection to TB disease. Therefore, these children serve as sentinel cases, indicating recent
and/or ongoing transmission in the community. (See 'Epidemiology' above.)

Common symptoms of pulmonary TB in children include cough (chronic, without

improvement for more than three weeks), fever (more than 38C for more than two weeks),
and weight loss or failure to thrive. Physical exam findings may suggest the presence of a
lower respiratory infection, but there are no specific findings to confirm that pulmonary TB is
the cause. (See 'Pulmonary tuberculosis' above.)

The clinical presentation of extrapulmonary TB depends on the site of disease. The most
common forms of extrapulmonary disease in children are TB of the superficial lymph nodes
and of the central nervous system. Infants have the highest risk of progression to TB disease
with dissemination (miliary TB) and meningeal involvement. (See 'Extrapulmonary
tuberculosis' above.)

Forms of perinatal TB include congenital and neonatal disease. Congenital TB is very rare
and most often is associated with maternal tuberculous endometritis or miliary TB. Neonatal
TB is more common and develops following exposure of an infant to his or her mother's
aerosolized respiratory secretions. (See 'Perinatal infection' above.)

TB in children is often diagnosed clinically; in many cases, laboratory confirmation is never

established (particularly among children under five years of age). Diagnosis is often based on
the presence of the classic triad: (1) recent close contact with an infectious case, (2) a positive
tuberculin skin test (TST) or interferon-gamma release assay (IGRA), and (3) suggestive
findings on chest radiograph or physical examination. (See 'Diagnosis' above.)

In children, the TST or IGRA may be used as a tool for diagnosis of TB disease or latent TB
infection (LTBI; although, in adults, the TST or IGRA may be used only for diagnosis of
LTBI, not TB disease). The TST or IGRA is helpful for diagnosis of TB in children only in
circumstances when it is positive (table 2). (See 'Tuberculin skin test' above.)

The most common chest radiograph finding in a child with TB disease is a primary
complex, which consists of opacification with hilar or subcarinal lymphadenopathy, in the
absence of notable parenchymal involvement. (See 'Imaging' above.)

Gastric aspiration is the primary method of obtaining material for acid-fast bacilli smear 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 or expectoration (for older children). For diagnosis of extrapulmonary TB,
specimens for culture should be collected from any site where infection is suspected.
Diagnosis of TB should also prompt HIV testing. (See 'Laboratory studies' above.)

The pediatric treatment regimens for TB are outlined in the tables (table 4 and table 5).
Because TB in young children can rapidly disseminate with serious sequelae, prompt
initiation of therapy is critical.
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