Basics
Description
- Pediatric tuberculosis (TB) is the disease state caused by Mycobacterium tuberculosis, an acid-fast bacillus (AFB). Pediatric TB should be regarded as a spectrum of exposure through infection to disease because progression from an infected person (exposure) to infection and disease can occur much faster (within 3 " 6 months) in children <2 years of age (occurring within the incubation of the disease stated below).
- Progression through this spectrum depends on age; such disease progression being 40 " 50% for children up to 2 years old, ’ Ό20% for those 2 " 4 years old, and 10 " 15% for those ≥5 years old. 5 " 10-year-old children are the most protected age group. Adolescence is another vulnerable age group.
Epidemiology
- Most common route of infection is via the respiratory tract. TB is spread from a person with disease by droplet nuclei that are inhaled by other people. Infection occurs after close and prolonged contact with an adult or adolescent who has active untreated infectious disease, usually pulmonary TB, in a poorly ventilated space. However, there are people who develop TB without knowledge of an infectious contact.
- Congenital infection occurs, although rarely, in the setting of an untreated mother in the last trimester of pregnancy.
- Infection with the tubercle bacillus needs to be differentiated from disease (i.e., TB).
- The interval between onset of infection and disease is usually 10 " 12 weeks.
- The greatest chance of disease occurring (i.e., of developing a positive result in tests using purified protein derivative [PPD], now renamed tuberculin skin test [TST]) is within the 1st 2 years after infection. However, for infants and children <5 years of age, progression through the spectrum of pediatric TB (exposure " infection " disease) is age dependent (see "Description " ).
- Postpubertal adolescents and immunosuppressed people including people with diabetes, with chronic renal failure, the malnourished, and those taking steroids for any reason have higher risks for progression of infection to disease.
General Prevention
- There are now several treatment regimens available for the treatment of latent TB infection. The reader is referred to the Centers for Disease Control and Prevention (CDC) Web site in the "Additional Reading " section.
- Preferred regimen is isoniazid (isonicotinic acid hydrazide-INH), 10 " 20 mg/kg/day PO for 9 months or, if compliance is not anticipated, 2 times a week as direct observed therapy at 20 " 30 mg/kg, with a maximum dose of 900 mg usually administered by a school nurse, child care worker, or the local TB control program, ideally without breaks in treatment, although the patient has 12 months to complete the course. If a break occurs near the end of treatment, it need not be restarted because such treatment is ’ Ό90% effective against development of active TB for 20 years in nonimmunosuppressed children. This recommendation prevents disease in the treated patient and, as a public health measure, interrupts transmission to contacts of that infected person with 90% efficacy.
- Other drugs for latent TB when INH cannot be tolerated or case-patient has INH-resistant but rifampicin-susceptible TB include 6 months of INH 10 " 20 mg/kg by direct observed therapy (for a total of 72 doses).
- For adults and children 12 years and older, a once-weekly 3-month course of INH and rifapentine can be considered via direct observed therapy (12 doses total).
- Bacille Calmette-Guerin (BCG) vaccine is recommended in the United States only for infants and children who test negative to PPD and who are continually exposed to contagious adults or to adults with TB that is resistant to both INH and rifampin and who cannot be kept away from the contagious adult.
Commonly Associated Conditions
- HIV infection
- Lymphoma
- Diabetes
- Chronic renal failure
- Malnutrition
- Immunosuppression, including chronic daily steroid use, high-dose steroid use or tumor necrosis factor-α (TNF-α) agonists, cancer chemotherapy
- Social issues: incarcerated adolescents, infants, and children in homeless shelters
Diagnosis
History
- Exposure: family member with TB or positive skin test
- Migrant farm workers
- Immigration from a TB-endemic geographic area (e.g., Haiti, Southeast Asia, Africa, South and Central America, Russia, and elsewhere in Eastern Europe, where greater concern about drug-resistant strains ought to be exercised); visit by individuals from those countries; or visited the above countries
- Higher incidence in Native Americans
- Contact with adults who have active TB
- HIV-positive people
- Immunosuppressed state
- Incarcerated adolescents and their relatives who visit
- Homeless people
- Poor people in urban areas
- Exposure to milk from untested herds
- Malnutrition
- Long-term steroid usage
Physical Exam
- Cervical and/or axillary adenopathy
- May reflect underlying disease or state (e.g., HIV, malnutrition, long-term steroid use)
- Pulmonary rales or clear chest
- Enlarged liver or spleen
- Site-specific findings (e.g., gibbus [vertebral TB]) or focal neurologic signs (TB meningitis)
- Signs and symptoms:
- Failure to thrive
- Cervical or axillary lymphadenopathy without any other cause or that is prolonged
- Cough >2 weeks
- Weight loss
- Change in sensorium
- Fever in infants and adolescents, rarely in children 5 " 10 years of age
- Decreased energy levels/playfulness >2 weeks
Diagnostic Tests & Interpretation
Lab
- Culture for TB: sputum, 3 gastric washings (early morning), pleural fluid, CSF, urine
- Culture may take 2 " 3 weeks by the radiometric method.
- Positive cultures are found in <50% of children.
Imaging
Chest radiographs may show hilar adenopathy with or without atelectasis. However, any infiltrate or pleural effusion in a child with a positive TST result and a risk factor for TB should be considered a TB suspect until proven otherwise. Infiltrates from bacterial or viral pathogens generally clear within 6 " 8 weeks; TB infiltrates tend not to clear so rapidly.
Diagnostic Procedures/Other
- Skin testing: TST
- The Mantoux test comprises 5 tuberculin units with PPD administered intradermally. Details may be found at http://www.cdc.gov/tb.
- The CDC does not recommend routine skin testing in low-risk groups in communities with low prevalence of TB.
- Children at high risk should be tested annually:
- Those in contact with adults from regions with high TB prevalence
- Children who spend time in homeless shelters
- Those in contact with adults with TB, HIV, and other disease-producing immunosuppressed states: A skin test result may become positive 3 " 6 weeks after exposure; however, most commonly, it does not turn positive for 2 " 3 months " hence the rationale for treating an exposed child with INH and retesting with a PPD in 3 months.
- A positive TST is a SENTINEL public health event indicating TB transmission in a community even if all other tests and examinations are negative.
- Interferon gamma release assays (IGRA) are being used with more frequency to diagnose TB exposure in children. These tests can be used as an alternative to TST in screening high-risk children; they are most helpful in children who have received BCG vaccine in the past, as these tests are more specific for TB. There are limited data on the use of these tests in children younger than 4 years of age.
- A promising new molecular diagnostic test, Xpert MTB/RIF, is both simple and accurate but performs less well in children compared to adults.
Differential Diagnosis
- Malignancy
- Cervical or axillary adenopathy
- Pulmonary infiltrate: other chronic organisms, disorders, and conditions (e.g., Nocardia, histoplasmosis). Infiltrates owing to bacterial or viral pathogens resolve faster than TB; thus, reevaluation of a suspect in 8 " 12 weeks clarifies this differential.
- Hilar adenopathy: In TB is usually unilateral, but Epstein-Barr virus, adenovirus, pertussis, and malignancy may possibly mimic symptoms.
- GI disease: Most common differential diagnosis is Crohn disease.
- Meningitis: fungal meningitis, partially treated bacterial meningitis (rarely)
Treatment
Medication
- Initial treatment in areas with multidrug-resistant TB >4%: Until sensitivities are known, a 4-drug regimen should be started: INH, 10 " 15 mg/kg/day; rifampin, 10 " 20 mg/kg/day; pyrazinamide (PZA), 15 " 30 mg/kg/day; and either ethambutol, 15 " 20 mg/kg/day, or streptomycin, 20 " 40 mg/kg/day (depending on whether diagnosis is meningitis or miliary TB, for which a bactericide is desired); however, many cases in children of foreign-born parents are increasingly streptomycin resistant, making ethambutol a better choice.
- If the organism is sensitive to therapy, treatment with the initial 4 primary drugs should continue for the first 2 months; by then, all sputum specimens should have a negative result on culture, followed by 4 months of INH and rifampin. When this regimen is adhered to, prognosis and a complete cure are achieved in 97 " 98% of patients.
- If sputum specimens continue to test positive, the initiation phase is longer. For meningeal TB, the duration of treatment is always longer (12 months).
Additional Therapies
General Measures
- Hospitalization (if the patient has disease)
- In cases of extensive disease (e.g., miliary TB or meningitis), and when an adult source case is not known, aggressive attempts should be made to obtain an organism from gastric aspirates, sputum induction, bronchoalveolar lavage, CSF, pleural or joint aspirate, bone aspirate, liver or tissue biopsy, and, in some cases, blood cultures.
- Isolation policies
- Unless the clinician can verify that the parent or any adult visitors are not themselves contagious, many infection control units require isolation of the child because the family members ' state of contagion remains unknown at admission.
- Nonpulmonary TB (e.g., GI TB, meningitis, bone TB, and TB with joint involvement) does not require isolation.
- Children >8 years of age and adolescents should be isolated until they have completed 10 days of therapy. Occasionally, immunocompromised children <8 years old also have cavitary disease and hence they, too, should be isolated.
Ongoing Care
Follow-up Recommendations
Patient Monitoring
Follow-up and contact tracing are key to making TB preventable.
Prognosis
- Mortality for untreated TB is 40% over 4 years.
- For miliary TB and meningeal TB, prognosis depends on the stage of presentation as already discussed.
- For outbreaks of multidrug-resistant TB, death rates range from 70 to 90% within 4 months of diagnosis.
Complications
- Missed diagnosis: failure to consider TB in a child who is failing to thrive and whose TST is negative
- TB meningitis: Outcome depends on the stage at which anti-TB medication starts:
- If pharmacotherapy is started at stage I, complete recovery occurs in 94%, with neurologic sequelae in 6%.
- If delayed until stage II, complete recovery occurs in 51%, with neurologic sequelae in 40% and death in 7%.
- If delayed until stage III, complete recovery occurs in 18%, with neurologic sequelae in 61% and death in 20%.
- Miliary TB: at least 2 organ systems involved
- Bone TB: most commonly spinal manifestation
- Renal TB: presents as a fever of undetermined origin (FUO), with or without urinary symptoms
- Congenital TB manifests with hepatosplenomegaly; may have CSF abnormalities and abnormalities on CSF testing and chest radiograph. Patients are too young for TST to be useful.
- Drug toxicity: Pediatric patients are much more tolerant of anti-TB medications than adults; thus, regular monitoring of liver function test results is not routinely required, although clinical monitoring for symptoms such as abdominal pain and loss of appetite on a monthly basis remains the cornerstone for identifying any toxicity.
- Hepatitis with INH, rifampin, and PZA; neurologic and hematologic complications with INH; skin rashes predominantly with rifampin and INH, but reports have occurred with all anti-TB medications; ototoxicity with streptomycin; but ocular toxicity with ethambutol in the pediatric age group has not been documented, and therefore it is a safe drug to use. Management of common side effects and drug interactions may be found in the 2006 American Thoracic Society/CDC/Infectious Disease Society of America statements (see "Additional Reading " ).
Additional Reading
- American Thoracic Society, Centers for Disease Control and Prevention, Infectious Disease Society of America. Treatment of tuberculosis recommendations. Am J Respir Crit Care Med. 2006;147:935 " 952.
- Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med. 2010;363(11):1005 " 1015. [View Abstract]
- Centers for Disease Control and Prevention. Latent tuberculosis infection: a guide for primary health care providers. www.cdc.gov/tb/publications/ltbi/treatment.htm. Accessed March 24, 2015.
- Cruz AT, Starke JR, Lobato MN. Old and new approaches to diagnosing and treating latent tuberculosis in children in low-incidence countries. Curr Opin Pediatr. 2014;26(1):106 " 113. [View Abstract]
- MMWR trends in TB 2004. Global incidence of multidrug-resistant tuberculosis. MMWR Recomm Rep. 2004;53:1 " 24.
- Perez-Velez CM, Marais BJ. Tuberculosis in children. N Engl J Med. 2012;367(4):348 " 361. [View Abstract]
- Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Recomm Rep. 2000;49(RR-6):1 " 51. [View Abstract]
Codes
ICD09
- 011.90 Pulmonary tuberculosis, unspecified, unspecified
- 771.2 Other congenital infections specific to the perinatal period
- V01.1 Contact with or exposure to tuberculosis
ICD10
- A15.9 Respiratory tuberculosis unspecified
- P37.0 Congenital tuberculosis
- A15.0 Tuberculosis of lung
- Z20.1 Contact with and (suspected) exposure to tuberculosis
SNOMED
- 56717001 Tuberculosis (disorder)
- 37260006 Congenital tuberculosis
- 154283005 Pulmonary tuberculosis (disorder)
FAQ
- Q: Should all children in close proximity to inner city areas with a prevalence of TB be screened annually with PPD?
- A: The AAP and CDC encourage targeted screening based on risk factors indicated earlier. The targeted screening questionnaire should be administered at every visit until age 2 years then annually thereafter. See tools at http://www.cdc.gov/tb.
- Q: Can the whole blood assay, IGRA (e.g. "QuantiFERON-TB Gold " ), be used instead of the TST to differentiate children who were born in other countries and had BCG?
- A: Yes. The IGRA tests can be used as an alternative to TST, although additional larger studies are needed to evaluate the test characteristics of IGRAs in children. See www.cdc.gov/mmwr/pdf/rr/rr5905.pdf and Cruz et al. in the section "Additional Reading. "