Tuberculosis en Niã Os-582

2017-5-30 Tuberculosis disease in children - UpToDate
Official reprint from UpToDate®
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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
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2017. | This topic last updated: May 19, 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 2014 report, the WHO estimates that, of the nine million incident cases of TB in 2013, approximately
550,000 occurred among children under age 15 [3]. Additionally, it estimated that there were 80,000 pediatric
deaths due to TB (among HIVuninfected children). Approximately 75 percent of these cases occurred in the
22 highest TBburden countries (table 1) [3]. In many developing countries, children compose more than one
half of the population, suggesting that the reported cases of childhood TB are likely underestimated.
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 [4].
It has been estimated that, of nearly one million children who developed tuberculosis disease in 2010, 32,000
had multidrugresistant TB [5]. Additional effort is needed to improve detection of drugresistant 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 [6]. In
the United States, TB among children is relatively rare. In 2012, there were 486 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 9945 cases reported that year [7,8]. However, TB in
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children and adolescents is prone to both under and overreporting 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) [6].
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 2). 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 [6].
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 [6]. 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 [7]. 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 multidrugresistant TB [6].
CLINICAL MANIFESTATIONS
Pulmonary tuberculosis — Pulmonary disease and associated intrathoracic adenopathy are the most
frequent presentations of tuberculosis (TB) in children [9,10]. Common symptoms of pulmonary TB in children
include [11]:
● Chronic, unremitting cough that is not improving and has been present for more than three weeks
● Fever of more than 38°C 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 [12]. 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 HIVuninfected 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 [13].
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 [9]. 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) [14]. Neonates have the highest risk of progression to TB
disease with miliary and meningeal involvement [14]. Some forms of TB and their common physical signs are
as follows [15]:
● 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 "Tuberculous enteritis" and "Tuberculous peritonitis")
● 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 "Renal disease in 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 lifethreatening infection; the mortality in the setting of
congenital and neonatal TB is about 50 percent [1618]:
● 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 [16,18].
Clinical manifestations of congenital TB include respiratory distress, fever, hepatomegaly, splenomegaly,
poor feeding, lethargy, irritability, and low birthweight [17]. 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
acidfast 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 [19].
In the setting of congenital or neonatal TB, the mother should be evaluated as outlined in detail separately.
(See "Diagnosis of pulmonary tuberculosis in HIVuninfected 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 [20]:
● 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 [21].
It is suggested that mycobacterial culture of respiratory specimens be performed for children suspected of
having pulmonary TB [22]. However, obtaining sputum samples from young children is challenging due to lack
of sufficient tussive force to produce adequate sputum samples by expectoration alone [23]. 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 [21].
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 acidfast bacilli (AFB) smear results [21]. 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
[9]. (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 interferongamma
release assay (IGRA), and (3) suggestive findings on chest radiograph or physical examination [15].
The approach outlined by the World Health Organization (WHO) for evaluation of a child suspected of having
TB includes [11]:
● 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 HIVprevalence 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 3) [15]. A positive TST may be falsely positive due to prior vaccination with
Bacille CalmetteGuérin (BCG), infection with nontuberculous mycobacteria, and improper administration or
interpretation (table 4).
A negative TST does NOT rule out TB disease, since falsenegative 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 livevirus
immunization, overwhelming TB infection) [15,24]. (See "Diagnosis of latent tuberculosis infection
(tuberculosis screening) in HIVuninfected adults", section on 'Falsenegative 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 [25]. Overall, up to 40 percent of immunocompetent children with culture
confirmed TB disease may have a negative TST [21,26]. 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 [2729].
Interferongamma release assays — IGRAs are in vitro blood tests of cellmediated immune response.
These assays have greater specificity than TST for diagnosis of LTBI and are most useful for evaluation of
LTBI in BCGvaccinated individuals [30]. 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 [3135]. 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 1AK) [36,37]. 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 [11]. 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 [38]. A miliary pattern of
opacification is highly suspicious for TB, as is opacification that does not improve or resolve following a
course of antibiotics [11].
Adolescents with TB generally present with typical adult disease findings of upper lobe infiltrates, pleural
effusions, and cavitations on chest radiograph [11]. (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 [39].
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 [9].
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 [9].
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 [40]. (See
"Diagnosis of pulmonary tuberculosis in HIVuninfected adults".)
Acidfast bacilli smear and culture — A respiratory specimen should be obtained for AFB smear and
mycobacterial culture for children with suspected pulmonary TB [41].
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)
[42,43]. 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 [42]. In
two studies, outpatient sputum induction yielded culture results comparable to or better than inpatient gastric
aspiration [26,42]. 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 [42].
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 [44,45]. Ideally, three early morning samples collected on different days before the child eats or
ambulates optimize specimen yield [46].
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 [47]. Smears are even less reliable, with positive results in
fewer than 10 percent of cases [47]; in addition, falsepositive smear results caused by the presence of
nontuberculous mycobacteria can occur [21]. Similar yields have been reported with nasopharyngeal
aspiration, a less invasive technique that can be performed in the outpatient setting [48].
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 HIVuninfected 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 [49,50]. 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 [49]. The initial Xpert MTB/RIF
test detected 100 percent of culturepositive 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 smearnegative 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 rifampinsensitive isolates had an "indeterminate" result. A
multicountry 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 HIVinfected children and poses a
promising alternative [51].
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 culturenegative, 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 [52]. 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 HIVuninfected 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) [53]. 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 [54].
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 [55]. 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 [56].
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 [57]. (See "Natural history, microbiology, and pathogenesis of tuberculosis", section on 'Drug
susceptibility tests'.)
Drug resistance — Mycobacterial culture with secondline drug susceptibility testing (DST) should be
performed whenever possible [58,59]. Concerted effort should be made to obtain multiple highquality
specimens from the most accessible site(s) of disease [59].
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 lineprobe 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 MDRTB
or rifampicinresistant TB who are candidates for treatment with a shortened treatment regimen [60]. The
assay may be used an initial diagnostic test; however, phenotypic culturebased drugsusceptibility 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 HIVuninfected adults".)
Pending definitive diagnostic information, in some circumstances it may be reasonable to presume presence
of drugresistant TB based on clinical criteria including signs and symptoms, radiographic findings, history of
contact with a presumed or confirmed source case with drugresistant TB, and failure to respond to firstline
TB drugs [59].
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 cultureconfirmed TB from latent TB and diseases other than TB among
children in subSaharan Africa. However, the risk score did not perform as well among children with clinically
diagnosed, culturenegative TB [61]. Moreover, in order to be a practical tool in resourcelimited 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 shortcourse multidrug regimens under directly observed therapy [15]. In general, the
pediatric treatment regimens outlined by the WHO are comparable with the adult regimens (table 5) [21,62].
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 6). 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 semisoft foods. (See "Treatment of drugsusceptible pulmonary tuberculosis in HIVuninfected
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
HIVinfected children [21,63].
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 followup radiographs beyond the termination of successful
therapy are usually not necessary unless clinical deterioration occurs [21].
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 HIVinfected 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 [64]. 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 [65,66]. 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) [65]. The most common complication was enlarging intrathoracic lymphadenopathy, often causing
airway compromise. Deterioration was more likely among children with weightforage ≤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 [66]. 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.
Drugresistant TB — In general, the approach for treatment of drugresistant 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 [67]. 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
secondline antituberculous drugs is summarized in the table (table 7). Issues related to treatment of drug
resistant TB are discussed in detail separately. (See "Treatment and prevention of drugresistant
tuberculosis", section on 'General principles'.)
In general, use of secondline antituberculous agents in children is complicated by the absence of pediatric
formulations for most of these drugs, which can lead to under or overdosing. 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
[21,60,68].
Individualized treatment in children has been associated with generally good outcomes [6971]. In a
retrospective study of 149 children under 15 years of age (median age 36 months) with documented or
suspected drugresistant 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 [69]. 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) [70].
Drug toxicity is common; in one metaanalysis of children treated for multidrugresistant TB, it was reported in
39 percent of cases [72]. Similarly, in the series from Peru, adverse effects occurred in 42 percent of cases,
although no events required suspension of therapy for >5 days [70]. Children on treatment for drugresistant
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 CalmetteGuérin (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 governmentsponsored 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 38ºC 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
interferongamma 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 3).
(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 acidfast 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 5 and table 6). Because TB in
young children can rapidly disseminate with serious sequelae, prompt initiation of therapy is critical.
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 8007 Version 49.0
GRAPHICS
The 22 highest tuberculosisburden countries
Afghanistan
Bangladesh
Brazil
Cambodia
China
Democratic Republic of the Congo
Ethiopia
India
Indonesia
Kenya
Mozambique
Myanmar
Nigeria
Pakistan
Philippines
Russian Federation
South Africa
Tanzania
Thailand
Uganda
Vietnam
Zimbabwe
Data from: World Health Organization. Global Tuberculosis Report 2014. Available at:
http://www.who.int/tb/country/en/index.html (Accessed on July 9, 2015).
Graphic 68082 Version 6.0
Countries with tuberculosis incidence >100 per 100,000*
Afghanistan Greenland Namibia
Angola Guinea Nepal
Bangladesh GuineaBissau Nigeria
Bhutan Guyana Pakistan
Bolivia Haiti Papua New Guinea
Botswana India Peru
Burundi Indonesia Philippines
Cape Verde Kenya Republic of Moldova
Cambodia Kiribati Senegal
Cameroon Kyrgyzstan Sierra Leone
Central African Republic Lao People's Democratic Republic Somalia
Chad Lesotho South Africa
Congo Liberia South Sudan
Cote d'Ivoire Madagascar Swaziland
Democratic People's Republic of Malawi Thailand

Korea
Democratic Republic of the Congo Malaysia TimorLeste
Djibouti Marshall Islands Tuvalu
Equatorial Guinea Mauritania Uganda
Ethiopia Micronesia (Federated States of) United Republic of Tanzania
Gabon Mongolia Viet Nam
Gambia Morocco Zambia
Georgia Mozambique Zimbabwe
Ghana Myanmar
* An incidence of TB of >100 per 100,000 population is associated with an annual risk of infection of approximately 1
percent.
Data from:
1. World Health Organization. TB burden estimates. Available at: http://www.who.int/tb/country/data/download/en/
(Accessed on December 16, 2016).
2. World Health Organization. Global tuberculosis report 2016. Available at:
http://www.who.int/tb/publications/global_report/en/ (Accessed on December 16, 2016).
Definitions of positive tuberculin skin test (TST) results in infants, children, and
adolescents*
Induration 5 mm or greater
Children in close contact with known or suspected contagious people with tuberculosis disease
Children suspected to have tuberculosis disease:
Findings on chest radiograph consistent with active or previous tuberculosis disease
Clinical evidence of tuberculosis disease ¶
Children receiving immunosuppressive therapy Δ or with immunosuppressive conditions, including human
immunodeficiency (HIV) infection
Children at increased risk of disseminated tuberculosis disease:
Children younger than four years of age
Children with other medical conditions, including Hodgkin disease, lymphoma, diabetes mellitus, chronic renal
failure, or malnutrition
Children with likelihood of increased exposure to tuberculosis disease:
Children born in highprevalence regions of the world
Children who travel to highprevalence regions of the world
Children frequently exposed to adults who are HIV infected, homeless, users of illicit drugs, residents of nursing
homes, incarcerated, or institutionalized
Children age four years or older without any risk factors
* These definitions apply regardless of previous Bacille CalmetteGuérin immunization; erythema alone at TST site does
not indicate a positive test result. Tests should be read at 48 to 72 hours after placement.
¶ Evidence by physical examination or laboratory assessment that would include tuberculosis in the working differential
diagnosis (eg, meningitis).
Δ Including immunosuppressive doses of corticosteroids or tumor necrosis factoralpha antagonists.
From: American Academy of Pediatrics. Tuberculosis. In: Red Book: 2012 Report of the Committee on Infectious Diseases,
29th ed, Pickering LK (Ed), American Academy of Pediatrics, Elk Grove Village, IL 2012. Used with the permission of the
American Academy of Pediatrics. Copyright © 2012. The contents of this table remain unchanged in the Red Book: 2015
Report of the Committee on Infectious Diseases, 30th ed.
Potential causes of falsenegative tuberculin tests
Technical (potentially correctable)
Tuberculin material:
Improper storage (exposure to light or heat)
Contamination, improper dilution, or chemical denaturation
Administration:
Injection of too little tuberculin or too deeply (should be intradermal)
Administration more than 20 minutes after drawing up into the syringe
Reading:
Inexperienced or biased reader
Error in recording
Biologic (not correctable)
Infections:
Active tuberculosis (especially if advanced)
Other bacterial infection (typhoid fever, brucellosis, typhus, leprosy, pertussis)
HIV infection (especially if CD4 count <200)
Other viral infection (measles, mumps, varicella)
Fungal infection (South American blastomycosis)
Recent livevirus vaccination (measles, mumps, polio)
Immunosuppressive drugs (corticosteroids, tumor necrosis factor inhibitors, and others)
Metabolic disease (chronic renal failure, severe malnutrition, stress [surgery, burns])
Diseases of lymphoid organs (lymphoma, chronic lymphocytic leukemia, sarcoidosis)
Age (infants <6 months, older adults)
Classic Ghon complex in a child infected with
Mycobacterium tuberculosis
This radiograph shows a classic Ghon complex in a child infected with
Mycobacterium tuberculosis about six months previously, based on results of a
contact investigation. There is a calcifed parenchymal lesion and calcification of
the regional hilar lymph node. Although a Ghon complex contains live
organisms, the number is small (as seen in infection rather than disease), so
management with isoniazid alone as for latent infection is sufficient.
Courtesy of Jeffrey R Starke, MD.
Expansile pneumonia caused by tuberculosis
This twoyearold toddler, infected by his mother, has an expansile pneumonia
caused by tuberculosis and, perhaps, a secondary infection. The child presented
with high fever, cough, and weight loss. The clinical symptoms improved with
conventional antibiotics, but cultures of the gastric aspirates grew
Mycobacterium tuberculosis. A subsequent computed tomography scan of the
chest revealed extensive rightsided hilar adenopathy with obstruction of the
main bronchus to the right upper lobe.
Extensive miliary pulmonary lesions in disseminated
tuberculosis
Extensive miliary pulmonary lesions in a young child with disseminated
tuberculosis. The child presented in a shocklike state with extreme respiratory
distress, weight loss, and fever. After appropriate treatment, the child had a full
recovery and a normal chest radiograph.
Extensive pulmonary tuberculosis in a preadolescent
child
Extensive pulmonary tuberculosis in a preadolescent child. There is advanced
disease in the left lung, with disease in the right lung occurring, perhaps, via
lymphatic spread.
Progressive primary tuberculosis in a toddler
Progressive primary tuberculosis in a toddler. There is extensive hilar
adenopathy with subsequent collapse consolidation in the left lung and a
miliarylike presentation in the right lung.
Cavitary tuberculosis in an adolescent male
Cavitary tuberculosis in an adolescent male. There is infiltrate and a cavity along
the horizontal fissure on the right. Note the absence of hilar adenopathy, which
is typical of socalled reactivation or adulttype tuberculosis in adolescents.
Enlarged rightsided hilar lymph nodes with local
infiltrate and atelectasis
Enlarged rightsided hilar lymph nodes with local infiltrate and atelectasis
caused by tuberculosis. This child was asymptomatic, this lesion having been
discovered during a contact investigation conducted after this child's uncle was
suspected of having pulmonary tuberculosis.
Left upper lobe infiltrate and possible cavity in
pulmonary tuberculosis
Left upper lobe infiltrate and possible cavity in an adolescent with sputum
smearpositive pulmonary tuberculosis. This patient had a one month history of
cough, eight pound weight loss, and night sweats.
Partially calcified primary tuberculous complex in a
threeyearold
This is a partially calcified primary tuberculous complex in a threeyearold girl.
There is rightsided hilar adenopathy with some atelectasis along the horizontal
fissure.
Culturepositive tuberculous pleural effusion in a nine
yearold patient
This is a culturepositive tuberculous pleural effusion in a nineyearold girl. The
source case was a school janitor. The child complained only of a mild cough and
was discovered through a contact investigation of the school case.
Extensive primary tuberculosis in a toddler
This is extensive primary tuberculosis in a toddler. There is rightsided hilar
adenopathy, narrowing of the right mainstem bronchus, and collapse
consolidation of the right lower lobe.
Treatment of tuberculosis in children
Regimen
Diagnostic category
(daily or three times weekly)*
New cases Intensive phase Continuation phase
New smearpositive pulmonary TB INH INH

New smearnegative pulmonary TB with extensive RIF RIF
parenchymal involvement PZA (4 months)
Severe forms of extrapulmonary TB (not including EMB
meningitis or osteoarticular disease)
(2 months)
Severe concomitant HIV disease
TB meningitis (see text) INH ¶ INH

RIF RIF
PZA (7 to 10 months) [1]
SM or AM or Eto
(2 months)
Osteoarticular TB INH ¶ INH

RIF RIF
PZA (7 to 10 months) [1]
EMB
(2 months)
New smearnegative pulmonary TB (other than above INH Δ INH

categories) RIF RIF
Less severe forms of extrapulmonary TB PZA (4 months)
(2 months)
Previously treated cases
Smearpositive pulmonary TB INH INH

Relapse RIF RIF
Treatment after interruption
PZA EMB
Treatment failure
EMB (5 months)
SM
(2 months)
Followed by
INH
RIF
PZA
EMB
(1 month)
Chronic and MDRTB Individualized regimens
TB: tuberculosis; INH: isoniazid; RIF: rifampin (rifampicin); PZA: pyrazinamide; EMB: ethambutol; SM: streptomycin; AM:
amikacin; Eto: ethionomide; HIV: human immunodeficiency virus; MDRTB: multidrugresistant TB.
* Direct observation of drug administration is recommended. Intermittent therapy (two or three times weekly) is not
recommended for children with HIV infection.
¶ For treatment of meningitis, EMB is replaced by SM or Am or Eto. The decision about which drug to use may be guided
by drug susceptibility data of the index case if available or countrylevel rates of specific drug resistance.
Δ EMB may be omitted during the initial phase of treatment for patients in the following categories:
Patients with noncavitary, smearnegative pulmonary TB and known to be HIV negative
Patients known to be infected with fully drugsusceptible bacilli
Reference:
1. Rapid Advice: Treatment of tuberculosis in children. World Health Organization, Geneva, 2010.
(WHO/HTM/TB/2010.13).
Reproduced with permission from: World Health Organization, Childhood TB Subgroup. Guidance for national tuberculosis
programmes on the management of tuberculosis in children, Geneva. Available at
http://whqlibdoc.who.int/hq/2006/WHO_HTM_TB_2006.371_eng.pdf. Copyright © 2006 World Health Organization.
Drug dosing for the treatment of tuberculosis in children
Twice a
Daily dose, week dose, Maximum Adverse
Drugs Dose forms
mg/kg mg/kg per dose reactions
dose
Ethambutol Tablets: 20 (15 to 25) 50 2.5 g Optic neuritis

100 mg (usually
reversible),
400 mg
decreased red
green color
discrimination,
gastrointestinal
tract disturbances,
hypersensitivity
Isoniazid* Scored tablets: 10 to 15 ¶ 20 to 30 Daily, 300 mg Mild hepatic

100 mg Twice a week, enzyme elevation,
900 mg hepatitis, ¶
300 mg
peripheral neuritis,
Syrup: hypersensitivity
10 mg/mL
Pyrazinamide* Scored tablets: 35 (30 to 40) 50 2 g Hepatotoxic

500 mg effects,
hyperuricemia,
arthralgia,
gastrointestinal
tract upset
Rifampin* Capsules: 10 to 20 10 to 20 600 mg Orange

150 mg discoloration of
secretions or urine,
300 mg
staining of contact
Syrup lenses, vomiting,
formulated hepatitis,
capsules influenzalike
reaction,
thrombocytopenia,
pruritus; oral
contraceptives may
be ineffective
* Rifamate is a capsule containing 150 mg of isoniazid and 300 mg of rifampin. Two capsules provide the usual adult (>50
kg) daily doses of each drug. Rifater, in the United States, is a capsule containing 50 mg of isoniazid, 120 mg of rifampin,
and 300 mg of pyrazinamide. Isoniazid and rifampin also are available for parenteral administration.
¶ When isoniazid in a dose exceeding 10 mg/kg per day is used in combination with rifampin, the incidence of hepatotoxic
effects may be increased.
From: American Academy of Pediatrics. Tuberculosis. In: Red Book: 2012 Report of the Committee on Infectious Diseases,
29th ed, Pickering LK, Baker CJ, Kimberlin DW, Long SS (Eds), American Academy of Pediatrics, Elk Grove Village, IL
2012. Used with the permission of the American Academy of Pediatrics. Copyright © 2012. The contents of this table
remain unchanged in the Red Book: 2015 Report of the Committee on Infectious Diseases, 30th ed.
Dosing of secondline antituberculosis drugs in children
Main and rare but
Usual maximum
Drug Daily pediatric dose serious adverse
daily dose
effects
Levofloxacin* 15 to 20 mg/kg orally or IV 750 mg* (may increase to GI toxicity, arthralgias,

in two divided doses* 1000 mg per day if tendonitis, tendon rupture,
tolerated) CNS effects (including
sleep disturbance and
headache), peripheral
neuropathy, QT
Moxifloxacin* 10 mg/kg orally or IV* 400 mg* prolongation, dysglycemia,
rash, hepatotoxicity
Amikacin ¶Δ 15 to 20 mg/kg IM or IV 1 g Ototoxicity, vestibular

adjusted according to toxicity, nephrotoxicity,
serum concentrations electrolyte disturbances,
local pain with IM
injections
Kanamycin ¶Δ 15 to 20 mg/kg IM or IV 1 g Ototoxicity, vestibular

local pain with IM
injections
Capreomycin ¶Δ 15 to 20 mg/kg IM or IV 1 g Ototoxicity, vestibular

local pain with IM
injections
Streptomycin ¶ Δ 15 to 20 mg/kg IM or IV 1 g Ototoxicity, vestibular

toxicity, nephrotoxicity,
electrolyte disturbances,
local pain with IM
injections
Ethionamide 15 to 20 mg/kg orally in 1 g GI toxicity (antiemetic

one dose or two divided premedication is often
doses helpful), hepatic toxicity,
metallic taste, endocrine
effects including
hypothyroidism (treat with
thyroid replacement),
neurotoxicity; pyridoxine
50 to 100 mg per day
(scaled to body weight)
may be useful in
preventing or reducing
peripheral neuropathy
Cycloserine ◊ 15 to 20 mg/kg orally in 1 g CNS toxicity (psychiatric

one dose or two divided symptoms, seizures usually
doses occur at peak
concentrations >35
mcg/mL but may occur in
the normal therapeutic
range), peripheral
neuropathy, dermatologic
effects
Administration of
pyridoxine 50 mg (oral
once per day scaled to
body weight) for every 250
mg of cycloserine may be
useful in preventing or
reducing neurotoxicity
Linezolid <12 years old: 20 mg kg 600 mg Myelosuppression, GI

orally or IV in two divided toxicity, neuropathy (optic
doses and peripheral); pyridoxine
≥12 years old: 600 mg 50 to 100 mg per day
orally or IV once per day (scaled to body weight)
may be useful in
preventing or reducing
peripheral neuropathy
Clofazimine (not 1 to 5 mg/kg orally 300 mg Redgrey discoloration of

commercially available in (optimal dose in children is skin, eyes, body fluids, GI
the United States; requires unknown) toxicity, photosensitivity,
application to FDA Division others
of Special Pathogen and
Immunologic Drug
Products; telephone
3017961600)
Highdose isoniazid 15 to 20 mg/kg orally, IM, 400 mg Hepatitis, peripheral

or IV neuropathy (administer
with pyridoxine),
hypersensitivity, others
Bedaquiline Not recommended for use QT prolongation, hepatitis,

in children (data lacking, GI toxicity, others
optimal dose is unknown)
Delamanid Not recommended for use GI toxicity, QT

in children (data lacking, prolongation
studies are ongoing)
Paraaminosalicylic acid 200 to 300 mg/kg orally 12 g GI toxicity, hepatotoxicity,

(usually divided 100 mg/kg hypothyroidism (treat with
in two or three divided thyroid replacement)
doses)
Imipenemcilastatin § § GI toxicity, seizures
Meropenem ￥ 60 mg/kg IV in three 3 g GI toxicity, seizures

divided doses; must be
given with oral clavulanate
(see amoxicillin
clavulanate below)
Amoxicillinclavulanate 45 mg/kg amoxicillin 2 g (amoxicillin GI toxicity

component orally in three component), 375 mg
divided doses (clavulanate component)
Thiacetazone ‡ (not 3 to 4 mg/kg orally 150 mg GI toxicity,

available in United States) myelosuppression,
hepatitis, peripheral
neuropathy, cutaneous
hypersensitivity reactions
Antituberculous agents are used in multidrug combination regimens of varying duration, which are described in
detail in a separate table (refer to the UpToDate table on regimens for treatment of drugsusceptible tuberculosis)
and in the accompanying text. The optimal dosing of many secondline drugs used to treat drugresistant
tuberculosis in children is not known.
Dosing of oral medications for treatment of multidrugresistant or extensively drugresistant tuberculosis should
be daily, not intermittent.
Doses listed in this table are for patients with normal renal function; dose adjustment of many of these agents is
needed in altered renal function.
TB: tuberculosis; IV: intravenous; GI: gastrointestinal; CNS: central nervous system; IM: intramuscular.
* According to the American Academy of Pediatrics, although fluoroquinolones are not routinely firstline therapy in
children <18 years old, their use may be justified in certain circumstances, such as multidrugresistant tuberculosis. The
optimal dose is not known.
¶ Generally given five to seven times per week (15 mg/kg or a maximum of 1 g per dose) for an initial two to four months
and then (if needed) two to three times per week (20 to 30 mg/kg or a maximum of 1.5 g per dose). Dose should be
decreased if renal function is diminished. Amikacin is preferred to kanamycin in children. Since IM injection of amikacin is
very painful, IV infusion is preferred.
Δ For patients who are overweight or obese, dose is based on adjusted dosing weight (refer to the UpToDate calculator).
When available, serum drug monitoring is advised to establish optimal dosing.
◊ When available, serum drug monitoring is advised to establish optimal dosing. Recommended peak (two to four hours
postdose) level is not higher than 30 microg/mL.
§ Experience with imipenemcilastatin in children with drugresistant TB is very limited.
￥ Dosing of meropenem in the setting of meningitis (in the absence of specific data for tuberculous meningitis) consists of
120 mg/kg in three divided doses.
‡ Should not be used in patients with HIV because of the serious risk of lifethreatening adverse effects.
Data from:
1. Seddon JA, Furn JJ, Gale M, et al. Caring for children with drugresistant tuberculosis: practicebased
recommendations. Am J Respir Crit Care Med 2012; 186:953.
2. World Health Organization. Guidelines for the programmatic management of drugresistant tuberculosis. WHO,
Geneva 2008.
3. World Health Organization. WHO treatment guidelines for drugresistant tuberculosis, 2016 update. WHO, Geneva
2016.
4. World Health Organization. Guidance for national tuberculosis programmes on the management of tuberculosis in
children, 2nd ed. WHO, Geneva 2014.
5. Treatment Guidelines from The Medical Letter. The Medical Letter 2012; 10:29.
6. Curry International Tuberculosis Center and California Department of Public Health, 2016: DrugResistant
Tuberculosis: A Survival Guide for Clinicians, Third Edition.
Contributor Disclosures
Lisa V Adams, MD Nothing to disclose Jeffrey R Starke, MD Other Financial Interest: Otsuka
Pharmaceuticals [Data safety monitoring board (delamanid)]. C Fordham von Reyn,
MD Grant/Research/Clinical Trial Support: Oxford Immunotec [Tuberculosis (vaccine)]. Morven S Edwards,
MD Grant/Research/Clinical Trial Support: Pfizer Inc. [Group B Streptococcus]. Elinor L Baron, MD,
DTMH Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

Tuberculosis en Niã Os-582

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2017-5-30 Tuberculosis disease in children - UpToDate

Afghanistan Greenland Namibia

Angola Guinea Nepal

Bangladesh Guinea­Bissau Nigeria

Bhutan Guyana Pakistan

Bolivia Haiti Papua New Guinea

Botswana India Peru

Burundi Indonesia Philippines

Cape Verde Kenya Republic of Moldova

Cambodia Kiribati Senegal

Cameroon Kyrgyzstan Sierra Leone

Central African Republic Lao People's Democratic Republic Somalia

Chad Lesotho South Africa

Congo Liberia South Sudan

Cote d'Ivoire Madagascar Swaziland

Democratic People's Republic of Malawi Thailand

Democratic Republic of the Congo Malaysia Timor­Leste

Djibouti Marshall Islands Tuvalu

Equatorial Guinea Mauritania Uganda

Ethiopia Micronesia (Federated States of) United Republic of Tanzania

Gabon Mongolia Viet Nam

Gambia Morocco Zambia

Georgia Mozambique Zimbabwe

New cases Intensive phase Continuation phase

New smear­positive pulmonary TB INH INH

TB meningitis (see text) INH ¶ INH

Osteoarticular TB INH ¶ INH

New smear­negative pulmonary TB (other than above INH Δ INH

Smear­positive pulmonary TB INH INH

Ethambutol Tablets: 20 (15 to 25) 50 2.5 g Optic neuritis

Isoniazid* Scored tablets: 10 to 15 ¶ 20 to 30 Daily, 300 mg Mild hepatic

Pyrazinamide* Scored tablets: 35 (30 to 40) 50 2 g Hepatotoxic

Rifampin* Capsules: 10 to 20 10 to 20 600 mg Orange

Levofloxacin* 15 to 20 mg/kg orally or IV 750 mg* (may increase to GI toxicity, arthralgias,

Amikacin ¶Δ 15 to 20 mg/kg IM or IV 1 g Ototoxicity, vestibular

Kanamycin ¶Δ 15 to 20 mg/kg IM or IV 1 g Ototoxicity, vestibular

Capreomycin ¶Δ 15 to 20 mg/kg IM or IV 1 g Ototoxicity, vestibular

Streptomycin ¶ Δ 15 to 20 mg/kg IM or IV 1 g Ototoxicity, vestibular

Ethionamide 15 to 20 mg/kg orally in 1 g GI toxicity (antiemetic

Cycloserine ◊ 15 to 20 mg/kg orally in 1 g CNS toxicity (psychiatric

Linezolid <12 years old: 20 mg kg 600 mg Myelosuppression, GI

Clofazimine (not 1 to 5 mg/kg orally 300 mg Red­grey discoloration of

High­dose isoniazid 15 to 20 mg/kg orally, IM, 400 mg Hepatitis, peripheral

Bedaquiline Not recommended for use QT prolongation, hepatitis,

Delamanid Not recommended for use GI toxicity, QT

Para­aminosalicylic acid 200 to 300 mg/kg orally 12 g GI toxicity, hepatotoxicity,

Meropenem ￥ 60 mg/kg IV in three 3 g GI toxicity, seizures

Amoxicillin­clavulanate 45 mg/kg amoxicillin 2 g (amoxicillin GI toxicity

Thiacetazone ‡ (not 3 to 4 mg/kg orally 150 mg GI toxicity,

Conﬂict of interest policy

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Bangladesh GuineaBissau Nigeria

Democratic Republic of the Congo Malaysia TimorLeste

New smearpositive pulmonary TB INH INH

New smearnegative pulmonary TB (other than above INH Δ INH

Smearpositive pulmonary TB INH INH

Clofazimine (not 1 to 5 mg/kg orally 300 mg Redgrey discoloration of

Highdose isoniazid 15 to 20 mg/kg orally, IM, 400 mg Hepatitis, peripheral

Paraaminosalicylic acid 200 to 300 mg/kg orally 12 g GI toxicity, hepatotoxicity,

Amoxicillinclavulanate 45 mg/kg amoxicillin 2 g (amoxicillin GI toxicity