Tuberculosis
Carol Conrad, MD
Introduction
•Tuberculosis (TB) is typically caused by Mycobacterium tuberculosis and occasionally by Mycobacterium bovis.
•The lungs are the major site of M tuberculosis infection.
•M bovis infection results primarily from ingestion of unpasteurized milk or dairy products. Infection by M bovis represents about 1%–2% of TB cases and occurs most often in developing countries.
Epidemiology
•Worldwide, TB remains one of the leading causes of death from infectious disease. In 2015, there were an estimated 10.4 million new (incident) TB cases worldwide.
•Diagnosis of TB had previously been difficult, with the standard testing relying on sputum testing with acid-fast bacilli stain and culture of the primary organism, which can take <6 weeks. More effective diagnostic methods and treatments are in use today. Globally, the treatment success rate for people with newly diagnosed TB was 86% in 2013, which has been sustained since 2005.
•Multidrug-resistant (MDR; resistant to both isoniazid and rifampin) and extensively drug-resistant (resistant to isoniazid, rifampin, fluoro-quinolones, and at least 1 second-line injectable agent, such as amikacin, kanamycin, or capreomycin) TB pose the greatest threat to elimination of TB, particularly in Sub-Saharan southern Africa, China, India, and the former Soviet Union.
•Almost all cases of TB are acquired through person-to-person contact via droplet nuclei formed by sneezing, coughing, or phonating.
Primary Infection
•The initial host defense in the alveoli involves phagocytosis by the macrophages. However, a tubercle bacillus can multiply slowly within the macrophage without being killed.
•Once bacterial numbers are large enough, a cellular response is elicited by macrophage activation.
•At the slow rate of replication by M tuberculosis, this process takes about 4–8 weeks.
•The infection spreads through the lymphatic system to the hilar lymph nodes.
•The granuloma will proceed to fibrosis and calcification and produce an isolated calcification at chest radiography. This is termed a tubercle or Ghon focus.
•A Ghon focus consists of the primary focus, lymphangitis, and regional hilar lymph node inflammation associated with it. This tends to be located in the middle or lower lobes of the lungs.
Dissemination
•Bacilli can escape before a sufficient immune response has been elicited. The bacilli proliferate inside alveolar macrophages and kill the cells. Dying cells release TB bacilli into the surrounding lung parenchyma.
• Bacilli spread by erosion of the caseating lesions into the lung airways, or cavities can form. Infection is spread via droplets produced during cough.
•Bacilli spread hematogenously to other organs and can result in miliary TB.
•Symptomatic hematogenous spread occurs in immunocompromised patients.
Reactivation of Disease
•Reactivation of latent disease occurs in adolescents and adults
and results when persistent bacteria in a host suddenly proliferate. Immunosuppression is associated with reactivation of TB (Box 58-1). This reactivated form of TB is the classic upper-lobe, cavitary disease.
•In contrast to primary disease, reactivated TB tends to be localized, and there is little regional lymph node involvement.
•Reactivation of disease may occur in 50%–60% of patients who do not receive appropriate antibiotic therapy.
Clinical Features
Primary Pulmonary Disease
•Latent tuberculous infection is different from active disease. Most initial infections are asymptomatic and controlled by cell-mediated immunity. When infection is present, the child yields a positive tuberculin skin test (TST) result, but there is no clinical evidence of organ involvement.
•Approximately 10% of children who become infected develop disease, with infants and postpubertal adolescents at highest risk.
•Pulmonary disease is the most common presentation of TB in children. Symptoms include fever most commonly, cough, weight loss or poor weight gain, night sweats, and chills.
Box 58-1. Immunosuppressive Conditions Associated With Reactivated Tuberculosis
•HIV infection and AIDS
•Solid organ transplant recipient
•Diabetes mellitus
•Lymphoma
•Corticosteroid use
•Diminution in cell-mediated immunity
•Chronic renal disease
•Treatment with tumor necrosis factor–α inhibitors
•A positive skin test result directs the diagnosis toward TB. However, a negative test result for TB infection (skin test or blood-based test) does not rule out TB, particularly if the child was infected within 12 weeks.
•Radiographs may demonstrate lymphadenopathy, lymphohematogenous spread, and calcified nodules (Ghon foci), often with calcified nodes (Ghon complex). Approximately one-third of patients develop a pleural effusion. Lymphadenopathy can cause bronchial compression with resultant atelectasis (Figure 58-1).
•Infants <1 year of age are at highest risk for developing disseminated TB (10%–20%), as well as pulmonary TB (30%–40%), because they have reduced microbial killing capacity. The risk for dissemination decreases with increasing age, but it increases again in adolescents (Table 58-1).
•The most common sites of extrapulmonary disease in children are the superficial lymph nodes and the central nervous system. Infants have the highest risk of progression of TB disease with meningeal involvement.
TB, tuberculosis. Adapted with permission from Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intrathoracic tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis. 2004;8:392–402.
•Approximately 15% of patients with active TB also present with TB disease in an extrapulmonary site. The risk is increased in immunocompromised patients, as well as children <2 years of age.
•The most commonly involved sites include, in order of frequency, lymph nodes, pleural space, meninges, pericardium, skin, genitourinary tract, bone and joint sites, and peritoneum–gastrointestinal tract.
Diagnostic Considerations
Skin Testing
•The TST (Figure 58-2) is the primary screening tool used in the United States. The American Academy of Pediatrics (AAP) recommends that a TST be performed to determine latent TB infection if any of the following conditions are true:
—A patient has had contact with people with confirmed or suspected contagious TB (contact investigation).
—Children have radiographic or clinical findings suggestive of active TB disease.
—Children emigrated from countries with endemic infection (eg, Asia, the Middle East, Africa, Latin America, or countries of the former Soviet Union).
—Children have travel histories to countries with endemic infection and have had substantial contact with people from such countries.
—Annual skin testing is indicated in children with HIV infection and in incarcerated adolescents.
—An initial skin test should be performed before initiation of immunosuppressive therapy, including prolonged steroid administration, use of tumor necrosis factor–α antagonists, and other immunosuppressive therapy.
•The preferred skin test is the Mantoux test, the results of which should be interpreted within 48–72 hours of placement. See Box 58-2 for guidelines in interpreting induration in low- and high-risk populations.
•The sensitivity of TST tests ranges from 80% to 96%.
•Causes of false-negative TST findings are listed in Box 58-3.
•For children >5 years of age, interferon-γ release assays (IGRAs) are now available for diagnosis (see the Improving Immunologic Diagnosis section in this chapter).
Interpreting Skin Test Results
Figure 58-3 provides a flowchart for the evaluation of a child exposed to a person with contagious TB.
Effect of BCG Vaccine
•False-positive reactions may occur in children who have received the bacille Calmette-Guérin (BCG) vaccine.
•Nonetheless, receipt of the BCG vaccine is not a contraindication to TST administration, and interpretation of TST results is not affected by receipt of the BCG vaccine.
•Interpretation of the TST results depends on the child’s risk factors.
Box 58-2. Definition of Positive Tuberculin Skin Test Results in Infants, Children, and Adolescents
Induration of 5 mm and Larger
Children in close contact with people with active tuberculosis (TB) disease who are known or suspected to be contagious
Children suspected to have active TB disease
•Findings on chest radiographs consistent with active or previously active TB disease
•Clinical evidence of active TB diseasea
•Children undergoing immunosuppressive therapyb or those with immunosuppressive conditions, including HIV infection
Induration of 10 mm and Larger
Children at increased risk of disseminated TB disease
•Children <4 years of age
•Children with other medical conditions, including Hodgkin disease, lymphoma, diabetes mellitus, chronic renal failure, and malnutrition
•Children with a likelihood of increased exposure to TB disease
•Children born in regions of the world with high TB prevalence
•Children frequently exposed to adults who are HIV infected, homeless, users of illicit drugs, residents of nursing homes, incarcerated or institutionalized, or migrant farm workers
•Children who travel to regions of the world with high TB prevalence
Induration of 15 mm and Larger
•Children ≥4 years of age without any risk factors
These definitions apply, regardless of previous bacille Calmette-Guérin immunization; erythema alone at the tuberculin skin test site does not indicate a positive test result. Test results should be interpreted 48–72 hours after intradermal antigen placement. From American Academy of Pediatrics. Tuberculosis. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015:805
a Evidence at physical examination or laboratory assessment that would include TB in the working differential diagnosis (eg, meningitis).
b Including immunosuppressive doses of corticosteroids.
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