Tuberculosis disease in children
Estimating the global burden of tuberculosis (TB) disease in children is challenging due to the lack of a standard case definition, the difficulty in establishing a definitive diagnosis, the frequency of extrapulmonary disease in young children, and the relatively low public health priority given to TB in children relative to adults. As a result, there is likely significant underreporting of childhood TB from high-prevalence countries. (See 'Epidemiology'above.)
●Children under the age of five years represent an important demographic group for understanding TB epidemiology; in this group, TB frequently progresses rapidly from latent infection to TB disease. Therefore, these children serve as sentinel cases, indicating recent and/or ongoing transmission in the community. (See 'Epidemiology' above.)
●Common symptoms of pulmonary TB in children include cough (chronic, without improvement for more than three weeks), fever (more than 38ºC for more than two weeks), and weight loss or failure to thrive. Physical exam findings may suggest the presence of a lower respiratory infection, but there are no specific findings to confirm that pulmonary TB is the cause. (See 'Pulmonary tuberculosis' above.)
●The clinical presentation of extrapulmonary TB depends on the site of disease. The most common forms of extrapulmonary disease in children are TB of the superficial lymph nodes and of the central nervous system. Infants have the highest risk of progression to TB disease with dissemination (miliary TB) and meningeal involvement. (See 'Extrapulmonary tuberculosis' above.)
●Forms of perinatal TB include congenital and neonatal disease. Congenital TB is very rare and most often is associated with maternal tuberculous endometritis or miliary TB. Neonatal TB is more common and develops following exposure of an infant to his or her mother's aerosolized respiratory secretions. (See 'Perinatal infection' above.)
●TB in children is often diagnosed clinically; in many cases, laboratory confirmation is never established (particularly among children under five years of age). Diagnosis is often based on the presence of the classic triad: (1) recent close contact with an infectious case, (2) a positive tuberculin skin test (TST) or 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 young children, since these patients lack sufficient tussive force to produce adequate sputum samples by expectoration alone. Alternative approaches include sputum induction or expectoration (for older children). For diagnosis of extrapulmonary TB, specimens for culture should be collected from any site where infection is suspected. Diagnosis of TB should also prompt HIV testing. (See 'Laboratory studies' above.)
●The pediatric treatment regimens for TB are outlined in the Tables (table 5 and table 6). Because TB in young children can rapidly disseminate with serious sequelae, prompt initiation of therapy is critical.
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).
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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.
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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:
|
| Children receiving immunosuppressive therapyΔ or with immunosuppressive conditions, including human immunodeficiency (HIV) infection |
| Induration 10 mm or greater |
Children at increased risk of disseminated tuberculosis disease:
|
Children with likelihood of increased exposure to tuberculosis disease:
|
| Induration 15 mm or greater |
| 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.
¶ Evidence by physical examination or laboratory assessment that would include tuberculosis in the working differential diagnosis (eg, meningitis).
Δ Including immunosuppressive doses of corticosteroids or tumor necrosis factor-alpha antagonists.
¶ Evidence by physical examination or laboratory assessment that would include tuberculosis in the working differential diagnosis (eg, meningitis).
Δ Including immunosuppressive doses of corticosteroids or tumor necrosis 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.
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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) |
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Classic Ghon complex in a child infected withMycobacterium 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 infection is sufficient.
Courtesy of Jeffrey R Starke, MD.
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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 scan of the chest revealed extensive right-sided hilar adenopathy with obstruction of the main bronchus to the right upper lobe.
Courtesy of Jeffrey R Starke, MD.
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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.
Courtesy of Jeffrey R Starke, MD.
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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.
Courtesy of Jeffrey R Starke, MD.
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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.
Courtesy of Jeffrey R Starke, MD.
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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.
Courtesy of Jeffrey R Starke, MD.
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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 pulmonary tuberculosis.
Courtesy of Jeffrey R Starke, MD.
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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.
Courtesy of Jeffrey R Starke, MD.
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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.
Courtesy of Jeffrey R Starke, MD.
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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.
Courtesy of Jeffrey R Starke, MD.
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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.
Courtesy of Jeffrey R Starke, MD.
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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)[1] |
| Osteoarticular TB |
INH¶
RIF
PZA
EMB
(2 months) |
INH
RIF
(7 to 10 months)[1] |
New smear-negative pulmonary TB (other than above categories)
Less severe forms of extrapulmonary TB |
INHΔ
RIF
PZA
(2 months) |
INH
RIF
(4 months) |
| Previously treated cases | ||
Smear-positive pulmonary TB
|
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 | |
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.
Δ EMB may be omitted during the initial phase of treatment for patients in the following categories:
* 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.
Δ 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:
- Rapid Advice: Treatment of tuberculosis in children. World Health Organization, Geneva, 2010. (WHO/HTM/TB/2010.13).
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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-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 containing 50 mg of isoniazid, 120 mg of rifampin, and 300 mg of pyrazinamide. Isoniazid and rifampin also are available for parenteral administration.
¶ When isoniazid in a dose exceeding 10 mg/kg per day is used in combination with rifampin, the incidence of hepatotoxic effects may be increased.
¶ 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.
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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/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 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¶Δ | 15 to 30 mg/kg IM or IV | 1 g | Ototoxicity, nephrotoxicity | Avoid |
| Amikacin¶Δ | 15 to 22.5 mg/kg IM or IV | 1 g | Ototoxicity, nephrotoxicity | Avoid |
| Streptomycin¶Δ | 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
Pyridoxine 50 mg (orally once per day) for every 250 mg of cycloserine may be useful in preventing or reducing neurotoxicity | Potential choice when there are no suitable alternatives |
| 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). Dose 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.
* 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). Dose 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:
- Seddon J, et al. Caring for children with drug-resistant tuberculosis: practice-based recommendations. Am J Respir Crit Care Med 2012; 186:953.
- Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva, World Health Organization, 2008.
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