tuberculosis disease in children

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Official reprint from UpToDatewww.uptodate.com ©2015 UpToDate

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

Tuberculosis disease in children

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jun 2015. | This topic last updated: Jun 16, 2015.

INTRODUCTION — Forma l 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 (LTBI) in children are discussed in detail separately. (See "Latent tuberculosis infection in

children".)

EPIDEMIOLOGY

Global epidemiology — E stimating the global burden of tuberculosis (TB) disease in children is challenging

due to the lack of a standard case def inition, 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's (WHO's) global TB data include age breakdowns only for smear-positive TB

cases; among children, such cases represent only a small subset of the burden of disease due to TB (about 8

percent) [3]. The WHO estimates that, of the 8.7 million incident cases of TB in 2011, approximately 500,000

occurred among children under age 15 [4]. Additionally, it is estimated that there were 64,000 pediatric deaths

due to TB (among HIV-negative children) [4]. Approximately 75 percent of these cases occurred in the 22

highest TB-burden countries (table 1) [5]. 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 [ 6].

It has been estimated that, of near ly one million children who de veloped tuberculosis disease in 2010, 32,000

had multidrug-resistant TB [7]. 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 [ 8,9]. In

the United States, TB among children is relatively rare. In 2010, there were 818 cases of TB in children and

adolescents under 18 years of age reported by the United States Centers for Disease Control and Prevention

(CDC); this number represented 7 percent of the total 11,181 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 2007 and

2010, TB annual case notifications in those under age 18 years decreased from 997 (in 2007) to 818 cases (in

2010) [8].

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Between 2008 and 2010, most children and adolescents with TB were born in the United States (69 percent). In

contrast, most adults with TB in the United States are born in areas where the disease is endemic ( table 2).

Roughly half of all non–United States–born patients under age 18 diagnosed with TB in this time period were

adolescents between the ages of 13 and 17 [8]. Among the child and adolescent TB patients who were born in

the United States, 66 percent had at least one non–United States–born parent [8]. One-quarter (25 percent) of

pediatric TB patients diagnosed in the United States had no known international connection through family or

residence history [8]. A small proportion of non–United States–born pediatric TB patients (4 percent) had

parents who were both born in the United States; these cases may arise from international adoptions, but this

could not be confirmed with available data [8].

Between 2008 and 2010, among the 2628 children and adolescents with TB with known race/ethnicity, 45

percent were Hispanic, 27 percent were black, 20 percent were Asian, 7 percent were white, and 1 percent

American Indian or Native Alaskan [8]. HIV status was only known for approximately half of the pediatric

patients reported; of these, only 1 percent was HIV-infected [8]. The isolates from 19 percent of the 918 children

and adolescents with positive cultures and drug susceptibility testing had detectable resistance to one or more

drugs, and 2 percent were multidrug-resistant TB [8].

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

[5]:

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 [13]. The only factors differentiating the groups were

history of contact with an infectious TB case and a positive tuberculin skin test (TST).

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) [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]:

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)●

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 effusions in HIV-negative patients")●

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")●

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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 [16-18]:

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-negative patients".)

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]:

DIAGNOSIS — Tuberculosis (TB) in children is often diagnosed clinically. Because pulmonary TB in childrentypically presents with paucibacillary, noncavitary pulmonary disease, bacteriologic confirmation is achievable in

only about 30 to 40 percent of cases. Obtaining sputum samples from young children is challenging because

they lack sufficient tussive force to produce adequate sputum samples by expectoration alone [21]. 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.

For diagnosis of extrapulmonary TB, specimens for culture should be collected from any site where infection is

suspected. 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 effusions in HIV-negative patients".)

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 [15].

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")●

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 birth weight [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

acid-fast bacilli [AFB] s taining culture). The TST in newborns is usually negative, but an interferon-gamma

release assay (IGRA) 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].

●

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.●




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The approach outlined by the World Health Organization (WHO) for evaluation of a child suspected of having TB

includes [5]:

All data, including thorough history, physical exam, and diagnostic test ing, 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’s 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 posit ive 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

Calmette-Guérin (BCG), infection with nontuberculous mycobacteria, and improper administration or

interpretation (table 4).

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) [15,22]. (See "Diagnosis of latent tuberculosis infection (tuberculosis

screening) in HIV-negative adults", sect ion 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 [23]. Overall, up to 40 percent of immunocompetent children with culture-

confirmed TB disease may have a negative TST [24,25]. 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 miliaryTB and TB meningitis, the TST is usually positive in only 50 percent of cases [26-28].

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 [29]. 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

[30-34]. 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) [35,36]. 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 [5]. When adenopathy advances, consolidation or a segmental lesion may

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)●



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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 [37]. A miliary pattern of

opacification is highly suspicious for TB, as is opacification that does not improve or resolve following a course

of antibiotics [5].

Adolescents with TB generally present with typical adult disease findings of upper lobe infiltrates, pleural

effusions, and cavitations on chest radiograph [5]. (See "Diagnosis of pulmonary tuberculosis in HIV-negative

patients".)

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 [38].

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 diseaseand 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 acid-fast bacilli (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 [ 39]. (See "Diagnosis of

pulmonary tuberculosis in HIV-negative patients", section on 'Diagnostic microbiology'.)

Acid-fast bacilli smear and culture

Sputum — Obtaining expectorated sputum from children for detection of AFB is difficult and its

examination of low yield (15 percent or less for microscopic examination and 30 percent or less for culture)

[40,41]. 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 [ 40]. In two

studies, outpatient sputum induction yielded culture results comparable to or better than inpatient gastric

aspiration [24,40]. 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 [40].

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

[42,43]. Ideally, three early morning samples collected on different days before the child eats or ambulates

optimize specimen yield [44].

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 [45]. Smears are even less reliable with positive results in fewer than 10percent of cases [45]; in addition, false-positive smear results caused by the presence of nontuberculous

mycobacteria can occur [25]. Similar yields have been reported with nasopharyngeal aspiration, a less invasive

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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 "Diagnosis of pulmonary tuberculosis in HIV-negative patients", sect ion on 'Pleural effusion' and "Diagnosis

of pulmonary tuberculosis in HIV-negative patients", section on 'Tissue biopsy'.)

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

Rapid testing — The GeneXpert 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 [47,48]. 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 GeneXpert MTB/RIF result [47]. The initial GeneXpert 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 GeneXpert 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 GeneXpert MTB/RIF test and 76 and 99 percent for two GeneXpert MTB/RIF tests. Test performance was

unaffected by patient HIV status. Results for GeneXpert 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.

While the GeneXpert 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 the study described above, the sensitivity

of GeneXpert 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 GeneXpert

MTB/RIF test is meant to be a rapid diagnostic test that may take the place of sputum microscopy but not

mycobacterial culture. A negative GeneXpert MTB/RIF test should be interpreted in the context of the child’s

clinical and radiolographic 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-negative patients", sect ion on 'Xpert

MTB/RIF assay'.)

Use of the GeneXpert 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) [49]. Among over 900 children in South Africa, the sensitivity of

GeneXpert MTB/RIF was similar for induced sputum and nasopharyngeal aspirate specimens (71 and 65

percent, respectively); specificity was >98 percent [50].

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 susceptibilitytesting [51]. (See "Natural history, microbiology, and pathogenesis of tuberculosis", section on 'Drug

susceptibility tests'.)

Drug resistance — New technologies including GeneXpert MTB/RIF and line probe assays can facilitate

diagnosis of drug-resistant TB among children, since these assays do not require culture. Culture and drug

susceptibility testing (DST) are recommended whenever possible [52]. For most children, the diagnosis of drug-

resistant TB is established 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 [53].

To avoid unnecessary exposure to toxic second-line agents, extensive effort should be made to obtain multiplehigh-quality specimens from the most accessible site(s) of disease [53]. All isolates with resistance to rifampin

should undergo complete second-line drug susceptibility testing and genotyping [53].

Issues related to diagnosis of drug resistance are discussed further separately. (See "Diagnosis, treatment, and

prevention of drug-resistant tuberculosis".)

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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 [54]. 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 (CDC) and the

World Health Organization (WHO) for the treatment of tuberculosis (TB) in children emphasize the use of short-

course mult idrug regimens under directly observed therapy [15]. In general, the pediatric treatment regimens

outlined by the WHO are comparable to the adult regimens (table 5) [25,55]. 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). (See "Treatment of pulmonary tuberculosis in HIV-negative patients".)

Pyridoxine supplementation is not routinely recommended for children receiving isoniazid (INH) but should be

considered for exclusively breastfed infants, malnourished children or those with diets poor in pyridoxine, andHIV-infected children [25,56].

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/available) should

guide decisions about treatment with respect to susceptibility.

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-positive 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/mm . 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 [57]. 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 [58,59]. 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)

[58]. 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 multiplesites 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

[59]. 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 — Expert consultation is important for management of drug-resistant TB. Ensuring treatment

adherence and support through a multidisciplinary care team are critical components of care.

Selection of drugs for treatment of drug-resistant TB in children should be guided by the DST results of the

child’s isolate; in the absence of such data, treatment should be guided by the DST results of the presumed

source case.

Ideally, the regimen for treatment of drug-resistant TB should include at least four drugs to which the isolate is

known to be, or presumed to be, susceptible [53]. The number of drugs and duration of therapy should be

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determined by the extent of disease, site of disease (and correlating drug penetration), and treatment response

[53]. Children with cavitary or extensive disease with resistance to only rifampin and isoniazid can achieve a

favorable outcome when treated for 18 months from the time the first negative culture is obtained [ 53].

Whenever possible, first-line TB drugs should be used since they have the most favorable efficacy and toxicity

profiles. In general, treatment of multidrug-resistant TB should include a fluoroquinolone and an injectable agent

(although there is no role for use of more than one fluoroquinolone or injectable agent) ( table 7). Subsequently, if

needed, ethionamide, cycloserine, and aminosalicylic acid may be added to complete the regimen such that it

consists of at least four active drugs. Alternative agents should be added only when the preceding drugs are notsufficient. Treatment of children with second-line agents is complicated by the absence of pediatric formulations

for most of these drugs, which can lead to under- or over-dosing.

Individualized treatment in children has been associated with generally good outcomes. 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 [60]. 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) [ 61].

Drug toxicity is common; in one meta-analysis of children treated for multidrug-resistant TB, it was reported in

39 percent of cases [62]. Similarly, in the series from Peru, adverse effects occurred in 42 percent of cases,

although no events required suspension of therapy for >5 days [ 61]. 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 "Tuberculosis transmission and

control", section on 'Contact investigation' and "Latent tuberculosis infection in children".)

The optimal treatment for prevention of TB among children with exposure to multidrug-resistant (MDR) TB cases

is uncertain. Some experts recommend using a fluoroquinolone antibiotic for treatment of MDR LTBI that is

presumed fluoroquinolone susceptible; some would give a second drug to which the organism is likely

susceptible. Further study is needed [63].

In countries where TB is endemic, routine childhood Bacille Calmette-Guérin (BCG) immunization is also an

important preventive measure. (See "BCG vaccination".)

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

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●

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●

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●

The most common chest radiograph finding in a child with TB disease is a primary complex, which

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●

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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.

●






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60. Seddon JA, Hesseling AC, Godfrey-Faussett P, Schaaf HS. High treatment success in children treated

for multidrug-resistant tuberculosis: an observational cohort study. Thorax 2014; 69:458.

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resistant tuberculosis. Pediatrics 2006; 117:2022.

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63. Seddon JA, Hesseling AC, Finlayson H, et al. Preventive therapy for child contacts of multidrug-resistant

tuberculosis: a prospective cohort study. Clin Infect Dis 2013; 57:1676.

Topic 8007 Version 34.0









GRAPHICS

The 22 highest tuberculosis-burden 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

http://www.who.int/tb/country/en/index.html





Countries with high rates of tuberculosis (TB)

Afghanistan Dominican Republic Lithuania Rwanda

Algeria Ecuador Madagascar Sao Tome and

Principe

Angola Equatorial Guinea Malawi Senegal

Azerbaijan Eritrea Malaysia Sierra Leone

Bangladesh Ethiopia Mali Solomon Islands

Belarus Fiji Marshall Islands Somalia

Benin Gabon Mauritania South Africa

Bhutan Gambia Micronesia

(Federated States

of)

South Sudan

Bolivia (Plurinational

State of)

Georgia Mongolia Sri Lanka

Botswana Ghana Morocco Sudan

Brunei Darussalam Greenland Mozambique Swaziland

Burkina Faso Guatemala Myanmar Tajikistan

Burundi Guinea Namibia Thailand

Cote d'Ivoire Guinea-Bissau Nepal Timor-Leste

Cabo Verde Guyana Nicaragua Togo

Cambodia Haiti Niger Turkmenistan

Cameroon Honduras Nigeria Tuvalu

Central African

Republic

India Northern Mariana

Islands

Uganda

Chad Indonesia Pakistan Ukraine

China Kazakhstan Papua New Guinea United Republic of

Tanzania

China, Hong Kong

SAR

Kenya Peru Uzbekistan

China, Macao SAR Kiribati Philippines Vanuatu

Congo Kyrgyzstan Republic of Korea Vietnam

Democratic People's

Republic of Korea

Lao People's

Democratic Republic

Republic of Moldova Zambia

Democratic Republic

of the Congo

Lesotho Romania Zimbabwe

Djibouti Liberia Russian Federation

Reproduced with permission from: World Health Organization, Global Tuberculosis Control: Estimated

burden of TB in 2013. http://www.who.int/tb/country/data/download/en/ Copyright © 2013 World

Health Organization.


http://www.who.int/tb/country/data/download/en/





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 w ith active or previous tuberculosis disease

Clinical evidence of tuberculosis disease

Children receiving immunosuppressive therapy 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 high-prevalence regions of the world

Children who travel to high-prevalence 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 Calmette-Guérin immunization; erythema

alone at TST site does not indicate a positive test result. Tests should be read at 48 to 72 hours

after placement.

Δ Evidence by physical examination or laboratory assessment that would include tuberculosis in

the working differential diagnosis (eg, meningitis).

◊ Including immunosuppressive doses of corticosteroids or tumor necrosis factor-alpha

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.


Δ

◊





Potential causes of false-negative 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 live virus 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 withMycobacterium 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 infect ion is sufficient.

Courtesy of Jeffrey R Starke, MD.






Expansile pneumonia caused by tuberculosis

This two-year-old 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 (CT) scan of the chest revealed

extensive right-sided hilar adenopathy with obstruction of the main

bronchus to the right upper lobe.







Extensive miliary pulmonary lesions in disseminated

TB

Extensive miliary pulmonary lesions in a young child with disseminated

tuberculosis (TB). The child presented in a shock-like 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 pre-

adolescent child

Extensive pulmonary tuberculosis in a pre-adolescent 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 miliary-like 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 so-called reactivation or adult-

type tuberculosis in adolescents.







Enlarged right-sided hilar lymph nodes with local

infiltrate and atelectasis

Enlarged right-sided hilar lymph nodes with local infiltrate and

atelectasis caused by tuberculosis. This child was asymptomatic, this

lesion having been discovered during a contact investigationconducted after this child's uncle was suspected of having pulmonary

tuberculosis.







Left upper lobe infiltrate and possible cavity in

pulmonary TB

Left upper lobe infiltrate and possible cavity in an adolescent with

sputum smear-positive 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

three-year-old

This is a partially calcified primary tuberculous complex in a three-

year-old girl. There is right-sided hilar adenopathy with some

atelectasis along the horizontal fissure.







Culture-positive tuberculous pleural effusion in a 9-

year-old patient

This is a culture-positive tuberculous pleural effusion in a nine-year-

old girl. The source case was a school janitor. The child complained

only of a mild cough and was discovered through a contactinvestigation of the school case.







Extensive primary tuberculosis in a toddler

This is extensive primary tuberculosis in a toddler. There is right-sided

hilar adenopathy, narrowing of the right mainstem bronchus, and

collapse-consolidation of the right lower lobe.







Treatment of tuberculosis in children

Diagnostic categoryRegimen

(daily or three times weekly)*

New cases Intensive phase Continuation phase

New smear-positive pulmonary TBNew smear-negative pulmonary TB with

extensive parenchymal involvement

Severe forms of extrapulmonary TB (not

including meningitis or osteoarticular

disease)

Severe concomitant HIV disease

INHRIF

PZA

EMB

(2 months)

INHRIF

(4 months)

TB meningitis (see text) INH

RIF

PZA

SM or AM or Eto

(2 months)

INH

RIF

(7 to 10 months)

Osteoarticular TB INH

RIF

PZA

EMB

(2 months)

INH

RIF

(7 to 10 months)

New smear-negative pulmonary TB

(other than above categories)

Less severe forms of extrapulmonary TB

INH

RIF

PZA

(2 months)

INH

RIF

(4 months)

Previously treated cases

Smear-positive pulmonary TB

Relapse

Treatment after interruption

Treatment failure

INH

RIF

PZA

EMB

SM

(2 months)

Followed by

INH

RIF

PZA

EMB(1 month)

INH

RIF

EMB

(5 months)

Chronic and MDR-TB Individualized regimens

Δ

[1]

Δ

[1]

◊





TB: tuberculosis; INH: isoniazid; RIF: rifampin (rifampicin); PZA: pyrazinamide; EMB: ethambutol;

SM: streptomycin; AM: amikacin; Eto: ethionomide; HIV: human immunodeficiency virus; MDR-TB:

multidrug resistant TB.

* Direct observation of drug administration is recommended. Intermittent therapy (two or three

times weekly) is not recommended for children with HIV infection.

Δ 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 country-

level rates o f specific drug resistance.

◊ EMB may be omitted during the initial phase of treatment for patients in the following

categories:

Patients with non-cavitary, smear-negative pulmonary TB and known to be HIV-negative

Patients known to be infected with fully drug-susceptible 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

DrugsDosage

forms

Daily

dosage,

mg/kg

Twice a

week

dosage,

mg/kg

perdose

Maximum

dose

Adverse

reactions

Ethambutol Tablets:

100 mg

400 mg

20 50 2.5 g Optic neuritis

(usually

reversible),

decreased red-

green color

discrimination,

gastrointestinal

tract disturbances,

hypersensitivity

Isoniazid* Scored

tablets:

100 mg

300 mg

Syrup:

10 mg/mL

10 to 15 20 to 30 Daily, 300

mg

Twice a

week, 900

mg

Mild hepatic

enzyme elevation,

hepatitis,

peripheral

neuritis,

hypersensitivity

Pyrazinamide* Scored

tablets:

500 mg

30 to 40 50 2 g Hepatotoxic

effects,

hyperuricemia,

arthralgia,

gastrointestinal

tract upset

Rifampin* Capsules:

150 mg

300 mg

Syrup

formulated

capsules

10 to 20 10 to 20 600 mg Orange

discoloration of

secretions or

urine, sta ining of

contact lenses,

vomiting,

hepatitis,

influenza-like

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 conta ining 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 dosage 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 permiss ion 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 second line antituberculosis drugs in children

Drug

Daily

pediatric

dosage

Maximum

daily dose

Main

adverse

affects

Pregnancy

Levofloxacin* Age ≥5 years:

7.5 to 10 mg/kg

orally

Age <5 years:

15 to 20 mg/kg

orally in two

divided doses*

750 mg* GI toxicity,

sleep

disturbance,

arthritis, CNS-

headache,

peripheral

neuropathy, QT

prolongation

(moxifloxacin >

levofloxacin)

Potential choice

when there are

no suitable

alternatives

Moxifloxacin* 7.5 to 10 mg/kg

orally*

400 mg*

Ofloxacin* 15 to 20 mg/kg

orally in twodivided doses*

800 mg*

Capreomycin 15 to 30 mg/kg

IM or IV

1 g Auditory and

vestibular

toxicity,

nephrotoxicity,

electrolyte

disturbances

Avoid

Kanamycin 15 to 30 mg/kg

IM or IV

1 g Ototoxicity,

nephrotoxicity

Avoid

Amikacin 15 to 22.5

mg/kg IM or IV

1 g Ototoxicity,

nephrotoxicity

Avoid

Streptomycin 15 to 30 mg/kg

IM or IV

1 g Vestibular and

ototoxicity,

neurotoxicity,

nephrotoxicity

Avoid

Ethionamide 15 to 20 mg/kg

orally in two

divided doses

1 g GI and hepatic

toxicity,

neurotoxicity,

hypothyroidism,

optic neuritis,

metallic taste.

Pyridoxine 50 to

100 mg orally

per day may be

useful in

preventing or

reducing

neurotoxicity.

Potential choice

when there are

no suitable

alternatives

Cycloserine 10 to 20 mg/kg

orally in two

divided doses

1 g Psychiatric

symptoms,

headaches,

seizures.

Potential choice

when there are

no suitable

alternatives

¶

¶Δ

¶Δ

¶Δ

◊





Pyridoxine 50

mg (oral once

per day) for

every 250 mg of

cycloserine may

be useful in

preventing or

reducing

neurotoxicity.

Para-

aminosalicylic

acid

150 mg/kg

orally in two or

three divided

doses

12 g GI toxicity,

malabsorption,

hypersensitivity,

hepatitis,

hypothyroidism

Potential choice

when there are

no suitable

alternatives

TB: tuburculosis; IM: intramuscular; IV: intravenous; GI: gastrointestinal; CNS: central nervous

system; max: maximum.

* According to the American Academy of Pediatrics, although fluoroquinolones are generally

contraindicated in children <18 years old, their use may be justified in certain circumstances,such as multidrug-resistant 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). Dosage should be decreased if renal function is diminished.

Δ For patients who are overweight or obese, dose is based on ideal body weight or dosing

weight (see 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 post-dose) level is not higher than 30 microg/mL.

Data from:

1. Seddon J, et al. Caring for children with drug-resistant tuberculosis: practice-based

recommendations. Am J Respir Crit Care Med 2012; 186:953.

2. Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva, World

Health Organization, 2008.

Adapted with special permission from: Treatment Guidelines from The Medical Letter, April 2012;

Vol. 10 (116):29. www.medicalletter.org.


http://www.medicalletter.org/




Disclosures: Lisa V Adams, MD Grant/Research/Clinical Trial Support: Oxford Immunotec [Tuberculosis (Diagnostic test for TB

infection)]. Jeffrey R Starke, MD Other Financial Interest: Otsuka Pharmaceuticals [DSMB (delamanid (anti-tuberculosis drug for MDR

TB))]. C Fordham von Reyn, MD Nothing to disclose. Morven S Edwards, MD Consultant/Advisory Boards: Novartis Vaccines[Group B streptococcus]. Elinor L Baron, MD, DTMH Nothing to disclose.

Contributor disclosures are review ed for conf licts of interest by the editorial group. When found, these are addressed by vetting

through a multi-level review process, and through requirements for ref erences 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 interes t policy

Disclosures

http://www.uptodate.com/home/conflict-interest-policy

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