Tuberculosis

Tuberculosis (TB) is a disease caused by the acid-fast bacillus mycobacterium tuberculosis. Over the past 25 years, the spread of HIV has lead to dramatic increases in the number of patients afflicted with TB. Children are somewhat ineffectual transmitters of TB, so they have been overlooked historically by TB control programs. Even so, a great of morbidity and mortality from TB occurs during childhood. 

The TB disease burden in children can be reduced through risk-factor based screening and implementation of appropriate chemoprophylaxis. 

Epidemiology

  • Individuals who have been in contact with a source case of TB are often classified into three groups: 1) people who have been exposed and still have an unclear TB status 2) people with a latent TB infection (LTBI), which means that they have a positive TB skin test but no symptoms, physical findings or radiologic signs 3) people with a positive TB test and physical signs or radiographic findings consistent with TB disease 
  • 5-10% of people with a LTBI will eventually develop TB disease, with higher rates in children and the immunocompromised 
  • Foreign-born individuals living in the US have TB rates almost 10 times that of US born individuals. Most cases occur in immigrants from Mexico, Vietnam, China, India and the Phillipines 
  • Risk factors for the development of TB disease in the US include: 
    -Untreated HIV infection 
    -Other immune compromising conditions
    -Latent TB Infection (LTBI)
    -IV drug use
    -Medical conditions including DM and renal failure 
  • Drug resistance is an issue throughout the world. Resistance varies widely with geographic distribution. 
    -Multi-drug resistant TB is defined as resistance to two first-line drugs (isoniazid and rifampin)
    -Extensively-drug resistant TB has been described as resistance to isoniazid, rifampin, any fluoroquinolone, and any second-line injectable (excluding streptomycin). It is extremely rare in the US. 

Pathophysiology 

  • TB is most often transmitted via airborne spread 
  • M tuberculosis often infects lymph nodes, which leads to enlargement with or without significant inflammation
  • When the bacillus is inhaled into a terminal airway, a Ghon complex forms: a focus of infection surrounded by draining lymphatics and enlarged regional nodes
  • After the initial stage, the infection may be contained, spread rapidly or reactivate later in life
  • In children, most clinical manifestations of TB occur within 1-2 years of initial infection. Different clinical manifestations follow different time frames:
    -Miliary or disseminated disease often occurs 2-6 months after infection
    -Pulmonary and lymphatic TB occur within 4-12 months 
    -Skeletal TB occurs 1-2 years after infection
    -Renal TB manifests after 5 years

Clinical Manifestations

  • Only 5-10% of children over the age of 3 years old with LTBI will progress to disease, and most will do so within 1-2 years of the initial infection
  • The most common site of infection is the lung (80% of all cases). Pulmonary TB is typified by:
    -Primary disease is typified by intrathoracic LAD and parenchymal disease. Children develop symptoms when enlarged lymph nodes compress a terminal bronchus and allow consolidations to develop. Symptoms include cough, low-grade fever, and rarely weight loss. 
    -Progressive primary disease occurs when the initial infection is poorly contained, leading to destruction of the lung tissue and cavity formation. TB cavitary disease occurs more often in immunocompromised patients. These children have more severe symptoms, including severe cough, fevers, night sweats, and weight loss.
    -Reactivation disease is most common in teens, especially in areas with high rates of HIV infection. Patients have constitutional symptoms including malaise, night sweats, fever, and weight loss. Cough with hemoptysis may occur. 
  • Other manifestations of TB are less common:
    -TB Lymphadenopathy: TB LAD is the most common extrapulmonary form of TB. TB lymph nodes may be 2-4 cm in diameter and may have overlying violet skin coloration. Systemic symptoms occur in about 50% of patients who have TB LAD. Untreated nodes can caseate, but most respond to a six-month multi-drug regimen. 
    -TB Meningitis: CNS involvement is rare and most often occurs in children under 2 years old. There are three stages: 1) nonspecific symptoms with HA 2) CN palsies and meningeal signs 3) profound changes in mental status due to increased ICP and vasculitis. Some children develop tuberculomas, 1-5 cm ring-enhancing lesions. Treatment is with a multi-drug regimen for at least 9 months. 
    -Pleural TB: Pleural TB usually occurs in older children and teens. Signs and symptoms include chest pain, fever, cough, dyspnea on exertion, and anorexia. 6 months of treatment is usually curative. 
    -Miliary TB: Miliary disease occurs when the initial infection spreads via the lymph system, and often involves multiple organs. Most children have fever and a variety of other symptoms (weight loss, anorexia, hepatomegaly, splenomegaly, and signs of CNS involvement). TST skin tests are unreliable in these patients as miliary TB can cause anergy. Miliary TB is most common in younger or immunocompromised children, and requires 9-12 months of treatment. 
    -Skeletal TB: Skeletal lesions can develop more than 10 years after the initial infection. Solitary lesions in the axial skeleton are more common in immunocompetent hosts, while the immunocompromised may develop multiple bony lesions. The most common manifestations of bony disease are osteomyelitis, spondylitis (the most common bony manifestation is Pott's disease, which impacts the thoracic and lumbar spine), dactylitis (common in infants) and arthritis. Lesions can best be seen with MRI. 
    -Congenital TB: Occurs rarely in the US. When infants are born to mothers with disseminated or endometrial TB, they may develop constitutional syptoms, difficulty breathing, and failure to thrive. Infants may have LAD, hepatomegaly, LAD, and signs of CNS involvement. Skin tests are rarely positive in very young infants. 
    -Less common forms of TB: abdominal, renal, and cutaneous 
  • Teens commonly experience TB infections in the bones, lymph nodes, and pleural spaces
  • Children with HIV and TB coinfections have similar symptoms to children who have TB without HIV. The differential diagnosis is much broader, however, because the symptoms of TB overlap with those of many other opportunistic infections. 

Diagnosis 

  • TB is often diagnosed with a positive TB skin test (TST), history of possible exposure, and correlating clinical/lab/imaging findings. 
  • Only 30-40% of children with suspected pulmonary TB have positive sputum or gastric cultures. As a result, cultures alone are rarely used to diagnose TB. 
  • The TB skin test (TST) contains antigens (purified protein derivatives) that trigger a delayed hypersensitivity reaction in patients who have come into contact with TB bacilli. The reaction is measured 48-72 hours after the PPD is placed. It is important to note that it is the size of the induration (not the erythema) that is measured. 
  • The TST usually turns positive 3 weeks to 3 months after infection and will remain positive for life. 
  • A negative TST does NOT rule out the possibility of TB infection. False negatives do exist, and may result from: improperly administered tests, age less than 6 mo, immunosuppression, viral illnesses, recent vaccination, or an overwhelming TB infection. 
  • The Interferon Gamma Release Assay (IGRA) is an in vitro blood test that assesses the cell-mediated immune response. This test is more specific than the TST. 
  • Chest radiographs (both frontal and lateral) are an important part of the work-up for any patient with suspected TB. 

Indications for Testing

  • Routine skin testing is not recommended for children in areas with low TB prevalence 
  • Immediate testing should be performed if:  
         -The patient has had contact with individuals suspected of having TB 
         -The patient has a radiograph suspicious for TB 
         -The child was born born in an endemic country (Asia, the Middle East,
         Africa, Eastern Europe, and Latin America)
         -The patient has recently traveled to a country where TB is endemic,    
         and stayed with family or friends there for more than 1 week
  • Annual Testing: indicated for HIV+ children, children who live with an HIV+ individual, and incarcerated teens
  • Testing every 2-3 years: indicated for children and teens with ongoing exposure to HIV+ individuals, migrant workers, incarcerated individuals, nursing home residents, IV drug users, and homeless individuals
  • Testing at 4-6 and 11-16 years of age: indicated for children of immigrants from an endemic area, children who travel frequently to endemic areas, children who live with immigrants from an endemic area 

Interpretation of PPD

  • The reaction is measured 48-72 hours after the PPD is placed
  • It is important to note that it is the size of the induration (not the erythema) that is measured
  • The PPD should be read by a medical professional, not a parent. Studies have shown that parents are not reliable in their assessment of the PPD site. 

Definitions of Positive TST Tests in Infants, Children and Teens

  • Induration of 5 mm or greater
  1. Children in close contact with a known or suspected person with active TB
  2. Children suspected to have TB
         -A chest radiograph consistent with active or previous disease
         -Clinical evidence of TB (neningitis, pleural effusion, TB
         pericarditis, lymphadenopathy/scrofula, Potts disease) 
  3. Immunocompromised individuals (children on immunosuppresive drugs including high doses of steroids,  HIV+ patients, or those with other immunosuppressed states)
  • Induration of 10 mm or greater
  1. Children with increased risk for disseminated TB:
         -Children less than 4 years old 
         -Children with other medical conditions, including DM, chronic
         renal disease, malnourished state, lymphoma, and
         Hodgkin's disease 
  2. Children with increased likelihood of exposure to TB: 
         -Children born in areas with high prevalence of TB
         -Children who travel to areas with high prevalence of TB
         -Children with frequent exposure to individuals who are: HIV+,
         homeless, illicit drug users, nursing home residents,
         incarcerated, or institutionalized
  • Induration of 15 mm or greater
  1. Children over 4 years old without any other risk factors 

Interpretation of PPD Following BCG Administration

  • The Bacille Calmett-Guerin Vaccine (BCG) is used in more than 100 countries and is usually given at birth or shortly after. It is derived from Mycobacterium bovis and is 50-80% protective against life threatening TB, such as miliary TB and TB meningitis. It does not prevent infection with the bacteria. 
  • Some children who are administered BCG never have a positive TST 
  • TSTs should be administered with the same indications as non-BCG recipients. 
  • If the TST is negative, no further testing or evaluation is necessary.
  • If there is greater than 10 mm of induration, a chest radiograph should be performed. If positive, then treatent for latent TB should be initiated. If the CXR is normal, an interferon gamma release assay (IGRA) should be performed in children older than 5 to confirm.

Treatment

  • In general, the treatment regimens for children with TB mirror those of adults with TB (RIPE). Dosages are, of course, adjusted by weight. 
  • Some differences in treatment exist for very young children, because these patients are at a greater risk for disseminated disease. 
     
  • TREATMENT of THE EXPOSED PATIENT: Children who have been exposed to a patient with suspected TB, but have a negative TST, normal CXR, and no signs/symptoms
         -Children who are <4 years old or otherwise immunocompromised
         should be started on medication (usually INH) pending results of a
         second skin test because these patients are at higher risk for rapid
         progression to clinical disease
         -Children who are at least 4 years old and immunocompetent can be  
         safely observed off medication until a second TST is resulted
  • TREATMENT of LATENT TB INFECTION (LTBI): children with a positive TST
         -These children should be treated to prevent progression of the disease
         later in life
         -The typical treatment is INH for 9 months. Rifampin (for 6 mo) is an
         alternative for patients who cannot tolerate INH
  • TREATMENT of ACTIVE TB DISEASE: 
         -The standard regimen is multi-drug: INH, rifampin, pyrazinamide, and
         ethambutol (RIPE). The pyrazinamide is stopped after two months, but
         the other three medications are continued for 6 months. 
         -If drug-resistance information is known, therapy should be
         appropriately tailored.
         -Children in treatment for TB disease should be monitored with monthly
         office visits to follow drug tolerance and adherence, weight gain and 
         developmental milestones. Imaging may be repeated, depending
         on the location of the child's disease. 

Prevention

  • The BCG vaccine is administered routinely in most countries (excluding the US and the Netherlands). Vaccination decreases the risk of life-threatening forms of TB in infants.
  • Children with TB may not need to be isolated in the hospital because their organism burden tends to be low, and their cough is rarely forceful enough to infect others. However, their caregivers are often the source of the infection-- so these adults should all be given CXRs and treated accordingly.
  • Children with extensive disease (cavitary or extensive pulmonary involvement, smear-confirmed TB, or laryngeal TB) should be placed in negative pressure rooms. N95 respirators should be used by their caregivers. These children should remain isolated until RIPE therapy is initiated, cough decreases, and sputum smears convert to negative. 

References

  1. Nelson LJ. Epidemiology of Childhood Tuberculosis in the United States, 1993-2001: The Need for Continued Vigilance. Pediatrics. August 2004.
  2. Lighter J. et al. Latent Tuberculosis Diagnosis in Children by Using the QuantiFERON Gold in-Tube Test. Pediatrics, Jan 2009. 
  3. Bianchi L, et al. Interferon-Gamma Release Assay Improves the Diagnosis of Tuberculosis in Children. Pediatric Infectious Disease Journal. 2009;28:510.
  4. World Health Organization Fact Sheets: Tuberculosis. http://www.who.int/mediacentre/factsheets/fs104/en/
  5. Cruz A and Starke J. Pediatric Tuberculosis. Pediatrics in Review. 2010;31:13. 
  6. MMWR Updated guidelines for Using Interferon Gamma Release Assays to Detect Mycobacterium tuberculosis. June 25, 2010.
  7. Perez-Velez CM and Marais BJ. Tuberculosis in Children. NEJM. 2012;367:4. 
  8. Zumla A. et al. Tuberculosis. NEJM. February 2013. 
  9. Pediatric Tuberculosis Cooperative Group. Targeted Tuberculin Skin Testing and Treatment of Latent Tuberculosis Infection in Children and Adolescents. Pediatrics. 2004;114:4. 

Back to Table of Contents