tuberculosis disease in children uptodate nov 2015

7/26/2019 Tuberculosis Disease in Children UPTODATE NOV 2015

1/34

4/12/2015 Tuber cul osi s di sease i n chi l dr en

http://www.uptodate.com/contents/tuberculosis- disease-i n-children?topicKey=ID%2F8007&elapsedTimeMs= 1&source=search_result&searchTerm=tubercul

Offi cial reprint from UpToDatewww.uptodate.com 2015 UpToDate

AuthorsLisa V Adams, MDJeffrey R Starke, M D

Section EditorsC Fordham von Reyn, MDMorven S Edwards, MD

Deputy EditorElinor L Baron, MD, DTMH

Tuberculosis disease in children

All topics are updated as new evidence becom es available and our peer review process is complete.Literature review current through: Nov 2015. | This topic last updated: Oct 23, 2015.

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 di agnostic 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 HIV-uninfected children). Approximately 75 percent of these cases occurred in the 22 highest TB-

burden countries (table 1) [ 3]. In many developing countries, children compose more than one-half of the

population, suggesting that the reported cases of childh ood 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

multidrug-resistant TB [ 5]. 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 [ 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 children

and adolescents is prone to both under- and over-reporting due to the difficulties related to diagnosis. Nonetheless,

in the United States, TB in children and adolescents appears to be declining. Between 2008 and 2012, TB annual

case notifications in those under age 15 years decreased from 786 (in 2008) to 486 cases (in 2012) [ 6].

In 2012, most children and adolescents with TB in the United States were born in the United States (79 percent).
http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/6http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/5http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/4http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/3http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/2http://www.uptodate.com/contents/latent-tuberculosis-infection-in-children?source=see_linkhttp://www.uptodate.com/contents/tuberculosis-disease-in-children/contributorshttp://www.uptodate.com/contents/tuberculosis-disease-in-children/contributorshttp://www.uptodate.com/contents/tuberculosis-disease-in-children/contributorshttp://www.uptodate.com/http://www.uptodate.com/http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/6http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/7,8http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/6http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/5http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/4http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/3http://www.uptodate.com/contents/image?imageKey=ID%2F68082&topicKey=ID%2F8007&rank=1%7E130&source=see_linkhttp://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/3http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/2http://www.uptodate.com/contents/latent-tuberculosis-infection-in-children?source=see_linkhttp://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/1http://www.uptodate.com/home/editorial-policyhttp://www.uptodate.com/contents/tuberculosis-disease-in-children/contributorshttp://www.uptodate.com/contents/tuberculosis-disease-in-children/contributorshttp://www.uptodate.com/contents/tuberculosis-disease-in-children/contributorshttp://www.uptodate.com/contents/tuberculosis-disease-in-children/contributorshttp://www.uptodate.com/contents/tuberculosis-disease-in-children/contributorshttp://www.uptodate.com/contents/tuberculosis-disease-in-children/contributorshttp://www.uptodate.com/contents/tuberculosis-disease-in-children/contributorshttp://www.uptodate.com/contents/tuberculosis-disease-in-children/contributorshttp://www.uptodate.com/


2/34


http://www.uptodate.com/contents/tuberculosis- disease-i n-children?topicKey=ID%2F8007&elapsedTimeMs= 1&source=search_result&searchTerm=tubercul 2

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]. [ 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 multidrug-resistant 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]:

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 HIV-

uninfected infants in South Africa, cough >2 weeks' duration (present in 17 percent) was the only diagnostic

symptom associated with severe pulmonary TB disease this symptom was twice as common in severe TB

compared with nonsevere TB [ 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 arediscussed 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 38C 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" )

Abdom inal TB Distended abdomen with ascites, abdom inal 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
http://www.uptodate.com/contents/skeletal-tuberculosis?source=see_linkhttp://www.uptodate.com/contents/skeletal-tuberculosis?source=see_linkhttp://www.uptodate.com/contents/tuberculous-lymphadenitis?source=see_linkhttp://www.uptodate.com/contents/tuberculous-peritonitis?source=see_linkhttp://www.uptodate.com/contents/tuberculous-enteritis?source=see_linkhttp://www.uptodate.com/contents/tuberculous-pericarditis?source=see_linkhttp://www.uptodate.com/contents/tuberculous-pleural-effusions-in-hiv-negative-patients?source=see_linkhttp://www.uptodate.com/contents/central-nervous-system-tuberculosis?source=see_linkhttp://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/15http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/14http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/14http://-/?-http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/9http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/13http://www.uptodate.com/contents/tuberculin-skin-test-drug-information?source=see_linkhttp://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/12http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/11http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/9,10http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/6http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/7http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/6http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/6http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/6http://www.uptodate.com/contents/image?imageKey=ID%2F93924&topicKey=ID%2F8007&rank=1%7E130&source=see_link


3/34



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-uninfected 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 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].

Obtaining sputum samples from young children is challenging due to lack of sufficient tussive force to produce

adequate sputum samples by expectoration alone [ 22]. 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


4/34



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 effusions in HIV-negative patients" .)

A diagnosis of TB (pulm onary or extrapulm onary) 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].

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

includes [ 11]:

All data, including thorough history, physical exam, and diagnostic testing, m ust 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 notyet 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 positive TST may help support a diagnosis of active disease, this findingalone 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-Gurin (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) [ 15,23]. (See "Diagnosis of latent tuberculosis infection (tuberculosis screening) in

HIV-uninfected adults", section on 'False-negative tests' .)

Because the TST cannot distinguish between TB disease, latent Mycobacterium tuberculosis infection, and

infection due to nontuberculous mycobacteria, the result must be interpreted in the context of the clinical features

and history of TB exposure [ 24]. Overall, up to 40 percent of immunocompetent children with culture-confirmed TB

disease may have a negative TST [ 21,25]. 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 miliary TB 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-

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)
http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/26-28http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/21,25http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/24http://www.uptodate.com/contents/diagnosis-of-latent-tuberculosis-infection-tuberculosis-screening-in-hiv-uninfected-adults?source=see_link&sectionName=False-negative+tests&anchor=H11#H11http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/15,23http://www.uptodate.com/contents/image?imageKey=ID%2F58908&topicKey=ID%2F8007&rank=1%7E130&source=see_linkhttp://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/15http://www.uptodate.com/contents/image?imageKey=PEDS%2F78596&topicKey=ID%2F8007&rank=1%7E130&source=see_linkhttp://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/11http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/15http://www.uptodate.com/contents/tuberculin-skin-test-drug-information?source=see_linkhttp://www.uptodate.com/contents/tuberculous-pleural-effusions-in-hiv-negative-patients?source=see_linkhttp://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/9


5/34



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 primarycomplex, 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 [ 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 [ 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

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 [ 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 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-uninfected 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 is 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 [ 25,40].
http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/25,40http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/40http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/40,41http://www.uptodate.com/contents/diagnosis-of-pulmonary-tuberculosis-in-hiv-uninfected-patients?source=see_link&sectionName=Diagnostic+microbiology&anchor=H13#H13http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/39http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/9http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/9http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/38http://www.uptodate.com/contents/diagnosis-of-pulmonary-tuberculosis-in-hiv-uninfected-patients?source=see_linkhttp://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/11http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/11http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/37http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/11http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/35,36http://www.uptodate.com/contents/image?imageKey=ID%2F67954%7EID%2F68797%7EID%2F56690%7EID%2F77006%7EID%2F56133%7EID%2F75393%7EID%2F82158%7EID%2F79049%7EID%2F63254%7EID%2F62099%7EID%2F64190&topicKey=ID%2F8007&rank=1%7E130&source=see_linkhttp://www.uptodate.com/contents/interferon-gamma-release-assays-for-diagnosis-of-latent-tuberculosis-infection?source=see_linkhttp://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/30-34http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/29


6/34



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 facilitieswhere 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 10 percent of

cases [ 45] in addition, false-positive 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 [ 46].

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-uninfected patients", section on 'Pleural effusion' and"Diagnosis of

pulmonary tuberculosis in HIV-uninfected 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 [ 49]. A negative GeneXpert MTB/RIF test should be interpreted in the context of the child's clinical and

radiographic findings. Sputum culture remains a more sensitive test and is required to detect the full drug

susceptibility profile of the infecting organism. Further study of the assay is needed in areas with high and low

prevalence of TB. (See "Diagnosis of pulmonary tuberculosis in HIV-uninfected patients", section on 'Xpert

M TB/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) [ 50]. 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 [ 51].
http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/51http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/50http://www.uptodate.com/contents/diagnosis-of-pulmonary-tuberculosis-in-hiv-uninfected-patients?source=see_link&sectionName=Xpert+MTB%2FRIF+assay&anchor=H4856396#H4856396http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/49http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/47http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/47,48http://www.uptodate.com/contents/rifampin-rifampicin-drug-information?source=see_linkhttp://www.uptodate.com/contents/screening-and-diagnostic-testing-for-hiv-infection?source=see_linkhttp://www.uptodate.com/contents/diagnosis-of-pulmonary-tuberculosis-in-hiv-uninfected-patients?source=see_link&sectionName=Tissue+biopsy&anchor=H12#H12http://www.uptodate.com/contents/diagnosis-of-pulmonary-tuberculosis-in-hiv-uninfected-patients?source=see_link&sectionName=Pleural+effusion&anchor=H11#H11http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/46http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/21http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/45http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/45http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/44http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/42,43http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/40


7/34



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 [ 52].

(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 [ 53]. 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 [ 54].

To avoid unnecessary exposure to toxic second-line agents, extensive effort should be made to obtain multiple

high-quality specimens from the most accessible site(s) of disease [ 54]. All isolates with resistance to rifampin

should undergo complete second-line drug susceptibility testing and genotyping [ 54].

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

prevention of drug-resistant tuberculosis" .)

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 [ 55].

Moreover, in order to be a practical tool in resource-limited settings, where its use would be most relevant, the

technology would require substantial modification to reduce cost and complexity.

TREATMENT

Susceptible disease Guidelines endorsed by the United States Centers for Disease Control and Prevention

(CDC) and the World Health Organization (WHO) for the treatment of tuberculosis (TB) in children emphasize the

use of short-course multidrug regimens under directly observed therapy [ 15]. In general, the pediatric treatmentregimens outlined by the WHO are comparable with the adult regimens ( table 5) [ 21,56]. 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 semi-soft foods. (See

"Treatment of pulmonary tuberculosis in HIV-uninfected adults" .)

Pyridoxine supplementation is not routinely recommended for children receiving INH but should be considered for

exclusively breastfed infants, malnourished children or those with diets poor in pyridoxine, and HIV-infected

children [ 21,57].

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

five years of age). In such cases, a presumptive diagnosis may be made based on clinical and radiographic

response to empiric treatment. If the cultures are negative, the isolates of contacts (if known or available) should

guide decisions about treatment with respect to susceptibility. During and following treatment, radiographic

abnormalities such as hilar adenopathy may persist therefore, a normal radiograph is not necessary to discontinue

treatment, and follow-up radiographs beyond the termination of successful therapy are usually not necessary

unless clinical deterioration occurs [ 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.
http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/21http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/21,57http://www.uptodate.com/contents/treatment-of-pulmonary-tuberculosis-in-hiv-uninfected-adults?source=see_linkhttp://www.uptodate.com/contents/rifampin-rifampicin-drug-information?source=see_linkhttp://www.uptodate.com/contents/isoniazid-drug-information?source=see_linkhttp://www.uptodate.com/contents/image?imageKey=ID%2F79897&topicKey=ID%2F8007&rank=1%7E130&source=see_linkhttp://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/21,56http://www.uptodate.com/contents/image?imageKey=ID%2F50271&topicKey=ID%2F8007&rank=1%7E130&source=see_linkhttp://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/15http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/55http://www.uptodate.com/contents/diagnosis-treatment-and-prevention-of-drug-resistant-tuberculosis?source=see_linkhttp://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/54http://www.uptodate.com/contents/rifampin-rifampicin-drug-information?source=see_linkhttp://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/54http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/54http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/53http://www.uptodate.com/contents/natural-history-microbiology-and-pathogenesis-of-tuberculosis?source=see_link&sectionName=Drug+susceptibility+tests&anchor=H8#H8http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/52http://www.uptodate.com/contents/isoniazid-drug-information?source=see_linkhttp://www.uptodate.com/contents/rifampin-rifampicin-drug-information?source=see_link


8/34



In HIV-infected children not on antiretroviral therapy (ART), ART should be initiated within eight weeks of starting

antituberculous therapy or within two to four weeks if t he CD4 count is 5 days [ 63]. 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.

3
http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/63http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/64http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/63http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/62http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/21,61http://www.uptodate.com/contents/bedaquiline-drug-information?source=see_linkhttp://www.uptodate.com/contents/cycloserine-drug-information?source=see_linkhttp://www.uptodate.com/contents/ethionamide-drug-information?source=see_linkhttp://www.uptodate.com/contents/image?imageKey=ID%2F88543&topicKey=ID%2F8007&rank=1%7E130&source=see_linkhttp://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/54http://www.uptodate.com/contents/isoniazid-drug-information?source=see_linkhttp://www.uptodate.com/contents/rifampin-rifampicin-drug-information?source=see_linkhttp://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/54http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/54http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/21http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/60http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/59http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/59,60http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/58


9/34



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" .)

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

tuberculosis infection in children" .)

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

preventive measure. Issues related to use of BCG in developed countries are discussed separately. (See " B C Gvaccination", section on 'Developed countries' .)

SUMMARY AND RECOMMENDATIONS

Estimating the global burden of tuberculosis (TB) disease in children is challenging due to the lack of a

standard case definition, the difficulty in establishing a definitive diagnosis, the frequency of extrapulmonary

disease in young children, and the relatively low public health priority given to TB in children relative to

adults. As a result, there is likely significant underreporting of childhood TB from high-prevalence countries.

(See 'Epidemiology' above.)

Children under the age of five years represent an important demographic group for understanding TB

epidemiology in this group, TB frequently progresses rapidly from latent infection to TB disease. Therefore,these children serve as sentinel cases, indicating recent and/or ongoing transmission in the community. (See

'Epidemiology' above.)

Common symptoms of pulmonary TB in children include cough (chronic, without improvement for more than

three weeks), fever (more than 38C for more than two weeks), and weight loss or failure to thrive. Physical

exam findings may suggest the presence of a lower respiratory infection, but there are no specific findings to

confirm that pulmonary TB is the cause. (See 'Pulmonary tuberculosis' above.)

The clinical presentation of extrapulmonary TB depends on the site of disease. The most common forms of

extrapulmonary disease in children are TB of the superficial lymph nodes and of the central nervous system.

Infants have the highest risk of progression to TB disease with dissemination (miliary TB) and meningeal

involvement. (See 'Extrapulmonary tuberculosis' above.)

Forms of perinatal TB include congenital and neonatal disease. Congenital TB is very rare and most often is

associated with maternal tuberculous endometritis or miliary TB. Neonatal TB is more common and develops

following exposure of an infant to his or her mother's aerosolized respiratory secretions. (See 'Perinatal

infection' above.)

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

(particularly among children under five years of age). Diagnosis is often based on the presence of the classic

triad: (1) recent close contact with an infectious case, (2) a positive tuberculin skin test (TST) or interferon-

gamma release assay (IGRA), and (3) suggestive findings on chest radiograph or physical examination. (See

'Diagnosis' above.)

In children, the TST or IGRA may be used as a tool for diagnosis of TB disease or latent TB infection (LTBI

although, in adults, the TST or IGRA may be used only for diagnosis of LTBI, not TB disease). The TST or

IGRA is helpful for diagnosis of TB in children only in circumstances when it is positive ( table 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 acid-fast bacilli smear and culture from
http://-/?-http://-/?-http://www.uptodate.com/contents/image?imageKey=PEDS%2F78596&topicKey=ID%2F8007&rank=1%7E130&source=see_linkhttp://-/?-http://www.uptodate.com/contents/tuberculin-skin-test-drug-information?source=see_linkhttp://-/?-http://-/?-http://-/?-http://www.uptodate.com/contents/bcg-vaccination?source=see_link&sectionName=Developed+countries&anchor=H18#H18http://www.uptodate.com/contents/latent-tuberculosis-infection-in-children?source=see_linkhttp://www.uptodate.com/contents/latent-tuberculosis-infection-in-children?source=see_linkhttp://www.uptodate.com/contents/tuberculosis-transmission-and-control?source=see_link&sectionName=CONTACT+INVESTIGATION&anchor=H17#H17


10/34


http://www.uptodate.com/contents/tuberculosis- disease-i n-children?topicKey=ID%2F8007&elapsedTimeMs= 1&source=search_result&searchTerm=tuberc 10

Use of UpToDate is subject to the Subscription and License Agreement .

REFERENCES

1. Starke JR. New concepts in childhood tuberculosis. Curr Opin Pediatr 2007 19:306.

2. Nelson LJ, Wells CD. Global epidemiology of childhood tuberculosis. Int J Tuberc Lung Dis 2004 8:636.

3. World Health Organization. Global Tuberculosis Report 2014.http://www.who.int/tb/publications/global_report/en/ (Accessed on July 07, 2015).

4. Marais BJ, Gie RP, Schaaf HS, et al. The clinical epidemiology of childhood pulmonary tuberculosis: acritical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004 8:278.

5. Jenkins HE, Tolman AW, Yuen CM, et al. Incidence of multidrug-resistant tuberculosis disease in children:systematic review and global estimates. Lancet 2014 383:1572.

6. Centers for Disease Control and Prevention. Tuberculosis: Slide Set - Epidemiology of PediatricTuberculosis in the United States, 1993-2012.http://www.cdc.gov/tb/publications/slidesets/pediatrictb/d_link_text.htm (Accessed on July 20, 2015).

7. Winston CA, Menzies HJ. Pediatric and adolescent tuberculosis in the United States, 2008-2010. Pediatrics2012 130:e1425.

8. Centers for Disease Control and Prevention (CDC). Trends in tuberculosis--United States, 2010. MMWRMorb Mortal Wkly Rep 2011 60:333.

9. Cruz AT, Starke JR. Clinical manifestations of tuberculosis in children. Paediatr Respir Rev 2007 8:107.

10. Perez-Velez CM, Marais BJ. Tuberculosis in children. N Engl J Med 2012 367:348.

11. Stop TB Partnership Childhood TB Subgroup World Health Organization. Guidance for National TuberculosisProgrammes on the management of tuberculosis in children. Chapter 1: introduction and diagnosis of tuberculosis in children. Int J Tuberc Lung Dis 2006 10:1091.

12. Schaaf HS, Beyers N, Gie RP, et al. Respiratory tuberculosis in childhood: the diagnostic value of clinicalfeatures and special investigations. Pediatr Infect Dis J 1995 14:189.

13. Mulenga H, Tameris MD, Luabeya KK, et al. The Role of Clinical Symptoms in the Diagnosis of Intrathoracic Tuberculosis in Young Children. Pediatr Infect Dis J 2015 34:1157.

14. Mandalakas AM, Starke JR. Current concepts of childhood tuberculosis. Semin Pediatr Infect Dis 200516:93.

15. World Health Organization, C hildhood TB Subgroup. Guidance for national tuberculos is programmes on themanagement of tuberculosis in children, Geneva. WHO/HTM/ TB/2006.371WHO/FCH/CAH/2006.7.

16. Starke JR. Tuberculosis in childhood and pregnancy. In: Tuberculosis: c urrent concepts and treatment, 2nded, Friedman LN (Ed), CRC Press, Boca Raton 2000.

17. Hageman J, Shulman S, Schreiber M, et al. Congenital tuberculosis: critical reappraisal of clinical findingsand diagnostic procedures. Pediatrics 1980 66:980.

18. Manji KP, Msemo G, Tamim B, Thomas E. Tuberculosis (presumed congenital) in a neonatal unit in Dar-es-Salaam, Tanzania. J Trop Pediatr 2001 47:153.

19. Laibl VR, Sheffield JS. Tuberculosis in pregnancy. Clin Perinatol 2005 32:739.

20. Cruz AT, Hwang KM, Birnbaum GD, Starke JR. Adolescents with tuberculosis: a review of 145 cases.Pediatr Infect Dis J 2013 32:937.

21. American Academy of Pediatrics. Tuberculosis. In: Red Book: 2015 Report of the Committee on Infect ious

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 andtable 6). Because TB in young

children can rapidly disseminate with serious sequelae, prompt initiation of therapy is critical.
http://www.uptodate.com/contents/image?imageKey=ID%2F79897&topicKey=ID%2F8007&rank=1%7E130&source=see_linkhttp://www.uptodate.com/contents/image?imageKey=ID%2F50271&topicKey=ID%2F8007&rank=1%7E130&source=see_linkhttp://-/?-http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/20http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/19http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/18http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/17http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/14http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/13http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/12http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/11http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/10http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/9http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/8http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/7http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/5http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/4http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/2http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/1http://www.uptodate.com/contents/license


11/34



Diseases, 30th ed, Kimberlin DW, Brady MT, Jackson MA, Long SS (Eds), American Academy of Pediatrics, Elk Grove Village, IL 2015. p.805.

22. Pereira L. Tuberculosis: role of etiologic diagnosis and tuberculin skin test. Pediatr Pulmonol Suppl 200426:240.

23. Drobac PC, Shin SS, Huamani P, et al. Risk factors for in-hospital mortality among children withtuberculosis: the 25-year experience in Peru. Pediatrics 2012 130:e373.

24. Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society.MMWR Recomm Rep 2000 49:1.

25. Hatherill M, Hawkridge T, Zar HJ, et al. Induced sputum or gastric lavage for community-based diagnosis ofchildhood pulmonary tuberculosis? Arch Dis Child 2009 94:195.

26. Steiner P, Rao M, Victoria MS, et al. Persistently negative tuberculin reactions: their presence amongchildren with culture positive for Mycobacterium tuberculosis (tuberculin-negative tuberculosis). Am J DisChild 1980 134:747.

27. van den Bos F, Terken M, Ypma L, et al. Tuberculous meningitis and miliary tuberculosis in young children.Trop Med Int Health 2004 9:309.

28. van der Weert EM, Hartgers NM, Schaaf HS, et al. Comparison of diagnostic criteria of tuberculousmeningitis in human immunodeficiency virus-infected and uninfected children. Pediatr Infect Dis J 200625:65.

29. Ge L, Ma JC, Han M, et al. Interferon- release assay for the diagnosis of latent Mycobacterium

tuberculosis infection in children younger than 5 years: a meta-analysis. Clin Pediatr (Phila) 2014 53:1255.30. Menzies D, Pai M, Comstock G. Meta-analysis: new tests for the diagnosis of latent tuberculosis infection:

areas of uncertainty and recommendations for research. Ann Intern Med 2007 146:340.

31. Pai M, Zwerling A, Menzies D. Systematic review: T-cell-based assays for the diagnosis of latenttuberculosis infection: an update. Ann Intern Med 2008 149:177.

32. Connell TG, Curtis N, Ranganathan SC, Buttery JP. Performance of a whole blood interferon gamma assayfor detecting latent infection with Mycobacterium tuberculosis in children. Thorax 2006 61:616.

33. Mazurek GH, Jereb J, Lobue P, et al. Guidelines for using the QuantiFERON-TB Gold test for detectingMycobacterium tuberculosis infection, United States. MMWR Recomm Rep 2005 54:49.

34. Starke J. Use of the new TB test in children should be limited. AAP News 2006 27:14.

35. Gie RP, Beyers N, Schaaf HS, Goussard P. The challenge of diagnosing tuberculosis in children: aperspective from a high incidence area. Paediatr Respir Rev 2004 5 Suppl A:S147.

36. Gwee A, Pantazidou A, Ritz N, et al. To x-ray or not to x-ray? Screening asymptomatic children for pulmonary TB: a retrospective audit. Arch Dis Child 2013 98:401.

37. Marais BJ, Gie RP, Hesseling AC, et al. Radiographic signs and symptoms in children treated for tuberculosis: possible implications for symptom-based screening in resource-limited settings. Pediatr InfectDis J 2006 25:237.

38. Lighter J, Rigaud M. Diagnosing childhood tuberculosis: traditional and innovative modalities. Curr ProblPediatr Adolesc Health Care 2009 39:61.

39. Centers for Disease Control and Prevention (CDC). Updated guidelines for the use of nucleic acidamplification tests in the diagnosis of tuberculosis. MMWR Morb Mortal Wkly Rep 2009 58:7.

40. Zar HJ, Hanslo D, Apolles P, et al. Induced sputum versus gastric lavage for microbiological confirmation ofpulmonary tuberculosis in infants and young children: a prospective study. Lancet 2005 365:130.

41. Marais BJ, Gie RP, Schaaf HS, et al. Childhood pulmonary tuberculosis: old wisdom and new challenges.Am J Respir Crit Care M ed 2006 173:1078.

42. Lobato MN, Loeffler AM, Furst K, et al. Detection of Mycobacterium tuberculosis in gastric aspiratescollected from children: hospitalization is not necessary. Pediatrics 1998 102:E40.

43. Mukherjee A, Singh S, Lodha R, et al. Ambulatory gastric lavages provide better yields of Mycobacteriumtuberculosis than induced sputum in children with intrathoracic tuberculosis. Pediatr Infect Dis J 201332:1313.

44. Cruz A, Revell P, Starke J. Gastric Aspirate Yield For Children With Suspected Pulmonary Tuberculosis. JPed Infect Dis 2013 2:171.
http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/44http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/43http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/42http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/41http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/40http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/39http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/38http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/37http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/36http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/35http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/34http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/33http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/32http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/31http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/30http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/29http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/28http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/27http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/26http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/25http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/24http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/23http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/22


12/34



45. Starke JR. Pediatric tuberculosis: time for a new approach. Tuberculosis (Edinb) 2003 83:208.

46. Owens S, Abdel-Rahman IE, Balyejusa S, et al. Nasopharyngeal aspiration for diagnosis of pulmonarytuberculosis. Arch Dis Child 2007 92:693.

47. Nicol MP, Workman L, Isaacs W, et al. Accuracy of the Xpert MTB/RIF test for the diagnosis of pulmonarytuberculosis in children admitted to hospital in Cape Town, South Africa: a descriptive study. Lancet InfectDis 2011 11:819.

48. Smith MS, Williams DE, Worley SD. Potential uses of combined halogen disinfectants in poultryprocessing. Poult Sci 1990 69:1590.

49. Tebruegge M, Ritz N, Curtis N, Shingadia D. Diagnostic Tests for Childhood Tuberculosis: Past Imperfect,Present Tense and Future Perfect? Pediatr Infect Dis J 2015 34:1014.

50. Bates M, O'Grady J, Maeurer M, et al. Assessment of the Xpert MTB/RIF assay for diagnosis of tuberculosis with gastric lavage aspirates in children in sub-Saharan Africa: a prospective descriptive study.Lancet Infect Dis 2013 13:36.

51. Zar HJ, Workman L, Isaacs W, et al. Rapid molecular diagnosis of pulmonary tuberculosis in children usingnasopharyngeal specimens. Clin Infect Dis 2012 55:1088.

52. Perez-Velez CM. Pediatric tuberculosis: new guidelines and recommendations. Curr Opin Pediatr 201224:319.

53. World Health Organization. Guidance for national tuberculosis programmes on the management of tuberculosis in children, Second edition. Geneva, Switzerland 2014. WHO/HTM/TB/2014.03

54. Seddon JA, Furin JJ, Gale M, et al. Caring for children with drug-resistant tuberculosis: practice-basedrecommendations. Am J Respir Crit Care Med 2012 186:953.

55. Anderson ST, Kaforou M , Brent AJ, et al. Diagnosis of childhood tuberculosis and host RNA expression inAfrica. N Engl J M ed 2014 370:1712.

56. Donald PR, Maher D, Maritz JS, Qazi S. Ethambutol dosage for the treatment of children: literature reviewand recommendations. Int J Tuberc Lung Dis 2006 10:1318.

57. Cruz AT, Starke JR. Treatment of tuberculosis in children. Expert Rev Anti Infect Ther 2008 6:939.

58. Trk ME, Yen NT, Chau TT, et al. Timing of initiation of antiretroviral therapy in human immunodeficiencyvirus (HIV)--associated tuberculous meningitis. Clin Infect Dis 2011 52:1374.

59. Thampi N, Stephens D, Rea E, Kitai I. Unexplained deterioration during antituberculous therapy in children

and adolescents: clinical presentation and risk factors. Pediatr Infect Dis J 2012 31:129.60. Olive C, Mouchet F, Toppet V, et al. Paradoxical reaction during tuberculosis treatment in immunocompetent

children: clinical spectrum and risk factors. Pediatr Infect Dis J 2013 32:446.

61. Centers for Disease Control and Prevention. Provisional CDC guidelines for the use and safety monitoringof bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis. MMWR Recomm Rep2013 62:1.

62. 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.

63. Drobac PC, Mukherjee JS, Joseph JK, et al. Community-based therapy for children with multidrug-resistanttuberculosis. Pediatrics 2006 117:2022.

64. Ettehad D, Schaaf HS, Seddon JA, et al. Treatment outcomes for children with multidrug-resistant

tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 2012 12:449.

Topic 8007 Version 38.0
http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/64http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/63http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/62http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/61http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/60http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/59http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/58http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/57http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/56http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/55http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/54http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/52http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/51http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/50http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/49http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/48http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/47http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/46http://www.uptodate.com/contents/tuberculosis-disease-in-children/abstract/45


13/34



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


14/34



Countries with high rates of tuberculosis

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/


15/34



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 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-Gurin immunization erythema alone atTST 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).

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.



16/34



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


17/34



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.



18/34



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. Asubsequent computed tomography scan of the chest revealed

extensive right-sided hilar adenopathy with obstruction of the main

bronchus to the right upper lobe.




19/34



Extensive miliary pulmonary lesions in

disseminated tuberculosis

Extensive miliary pulmonary lesions in a young child with

disseminated tuberculosis. 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.




20/34



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.




21/34



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.




22/34



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.




23/34



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 investigation

conducted after this child's uncle was suspected of having pulmonarytuberculosis.




24/34



Left upper lobe infiltrate and possible cavity in

pulmonary tuberculosis

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.




25/34



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.




26/34



Culture-positive tuberculous pleural effusion in a

nine-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 contact

investigation of the school case.




27/34



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.




28/34



Treatment of tuberculosis in children

Diagnostic category Regimen

(daily or three times weekly)*

New cases Intensive phase Continuation phase

New smear-positive pulmonary TB

New smear-negative pulmonary TB with

extensive parenchymal involvement

Severe forms of extrapulmonary TB (not

including meningitis or osteoarticular disease)

Severe concomitant HIV disease

INH

RIF

PZA

EMB

(2 months)

INH

RIF

(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)

[1]

[1]


29/34



Chronic and MDR-TB Individualized regimens

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.

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 of 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 HealthOrganization.



30/34



Drug dosing for the treatment of tuberculosis in children

Drugs Dose

forms

Daily

dose,

mg/kg

Twice a

week

dose,

mg/kg

per dose

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, staining of

contact lenses,

vomiting,

hepatitis,

influenza-likereaction,

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.


31/34



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.



32/34



Dosing of second line antituberculosis drugs in children

Drug

Daily

pediatric

dose

Maximum

daily dose

Main

adverse

affects

Pregnancy

Levofloxacin* Age 5 years:

7.5 to 10 mg/kgorally

Age

levofloxacin)

Potential choice

when there areno suitable

alternatives

Moxifloxacin* 7.5 to 10 mg/kg

orally*

400 mg*

Ofloxacin* 1 5 to 20 mg/kg

orally in two

divided doses*

800 mg*

Capreomycin 15 to 30 mg/kg

IM or IV

1 g Auditory and

vestibular

toxicity,

nephrotoxicity,

electrolyte

disturbances

Avoid

Kanamycin 1 5 to 30 mg/kg

IM or IV

1 g Ototoxicity,

nephrotoxicity

Avoid

Amikacin 15 to 22.5 mg/kgIM 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 1 g Psychiatric Potential choice


33/34



orally in two

divided doses

symptoms,

headaches,

seizures

Pyridoxine 50 mg

(orally once per

day) for every

250 mg of

cycloserine may

be useful in

preventing or

reducing

neur

tuberculosis disease in children uptodate nov 2015

Documents