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Tuberculosis
Carlos Atore, MD
Swati Avashia, MD, FAAP
image BASICS
DESCRIPTION
  • Active tuberculosis
    • Occurs from primary infection or reactivation of latent infection
    • Affects 10% of infected individuals without preventive therapy
    • Risk increases with immunosuppression: Highest risk is in the first 2 years after infection.
    • Well-described forms: pulmonary (85% of cases), miliary (disseminated), meningeal, abdominal
  • Usually acquired by inhalation of airborne bacilli from an individual with active tuberculosis (TB). Bacilli multiply in alveoli and spread via macrophages, lymphatics, and blood. Three possible outcomes:
    • Eradication: Tissue hypersensitivity halts infection within 10 weeks.
    • Primary infection
    • Latent infection (See “Tuberculosis, Latent [LTBI].”)
Pediatric Considerations
  • In children, there is a faster rate of progression to disease, the risk of progression to disease is higher, and severe disease is more common.
  • Most children with pulmonary TB are asymptomatic.
  • Treatment of pediatric TB should involve four drugs and be directly observed (DOT).
EPIDEMIOLOGY
Incidence
  • Worldwide (2013): 9 million (13% HIV coinfected)
  • United States (2013): 9,582 (3.0/100,000), 82 MDR, and 75 of those were foreign born (1).
Prevalence
  • Worldwide (2013): 157 cases/100,000 population (41% decrease since 1990); highest in Asia and Africa (1)
ETIOLOGY AND PATHOPHYSIOLOGY
  • Mycobacterium tuberculosis, Mycobacterium bovis, or Mycobacterium africanum are causative organisms.
  • Cell-mediated response by activated T lymphocytes and macrophages forms a granuloma that limits bacillary replication. Destruction of the macrophages produces early “solid necrosis.” In 2 to 3 weeks, “caseous necrosis” develops and latent tuberculosis infection (LTBI) ensues. In immunocompetent, granuloma undergoes “fibrosis” and calcification. In immunocompromised patients, primary progressive TB develops.
RISK FACTORS
  • For infection: homeless, ethnic minorities, close quarters (correctional facilities, nursing homes, barracks); close contact with infected individual; persons from areas with high incidence of active TB (Asia, Africa, Latin America, former Soviet Union states); health care workers; medically underserved, low income, substance abuse
  • For development of disease once infected: HIV; lymphoma; silicosis; diabetes mellitus; chronic renal failure; cancer of head, neck, or lung; children <5 years of age; malnutrition; systemic corticosteroids, immunosuppressive drugs; IV drug abuse, alcohol abuse, cigarette smokers; <2 years since infection with M. tuberculosis; history of gastrectomy or jejunal bypass; <90% of ideal body weight
GENERAL PREVENTION
  • Screening and treatment of LTBI. Active cases must be reported to health department for identification; test and treat all close contacts.
  • Bacille Calmette-Guérin (BCG) vaccine: Live attenuated M. bovis prevents 50% of pulmonary disease and 80% of meningitis and miliary disease in children. Use is more common in countries with endemic TB. In the United States, consider BCG for high-risk children with negative PPD and HIV tests or for health workers at risk for drug-resistant infection.
COMMONLY ASSOCIATED CONDITIONS
Immunosuppression; HIV-coinfection; malignancy
image DIAGNOSIS
PHYSICAL EXAM
  • Often entirely normal. Specific findings depend on organs involved: adenopathy, rales, or hepatosplenomegaly.
  • Late findings: renal, bone, or CNS disease
DIFFERENTIAL DIAGNOSIS
  • Pulmonary TB: pneumonia (bacterial fungal, atypical), malignancy, tularemia, actinomycosis
  • Extrapulmonary TB: syphilis, cat-scratch disease, leishmaniasis, leprosy; rheumatoid disease; erythema nodosum, erythema induratum, syphilis, other mycobacterial infections
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (Immunogenesis)
To determine immune response to mycobacterium
  • Tuberculin skin test (TST) (e.g., PPD): 5 U (0.1 mL) intermediate-strength intradermal injection into volar forearm. Measure induration at 48 to 72 hours:
    • PPD positive if induration
      • >5 mm and HIV infection, recent TB contact, immunosuppressed, disease on x-ray
      • >10 mm and age <4 years or other risk factors
      • >15 mm and age >4 years and no risk factors
      • Two-step test if no recent PPD, age >55 years, nursing home resident, prison inmate, or health care worker. Second test 1 to 3 weeks after initial test; interpret as usual.
    • Context of PPD results:
      • False positive: BCG (unreliable, should not affect decision to treat)
      • False negative: HIV, steroids, gastrectomy, alcoholism, renal failure, sarcoidosis, malnutrition, hematologic or lymphoreticular disorder, very recent exposure
      • If positive once, no need to repeat.
      • No need for control with Candida/other
  • Interferon-&ggr; release assays (IGRAs) measure interferon release after stimulation in vitro by M. tuberculosis antigens (2)[A]:
    • Lack of cross-reaction with BCG and most nontuberculous mycobacteria
      • IGRA is preferred (better specificity) for testing persons who have had BCG (vaccine or for cancer therapy) and for homeless persons, drug abusers and other groups with historically low rates of returning to have TST's interpreted (2)[A].
      • TST is still preferred if age <5 years (3)[A]. Either TST or IGRA may be used as periodic screening for persons in high-risk occupations and for recent contacts of persons with known or suspected active TB (2)[A].
      • Cotesting with TST and IGRA may be indicated when the initial test is negative but the risk for poor prognosis is increased (e.g., HIV-infected persons or children <5 years old) (2)[A].
Initial Tests-Active TB (lab, imaging)
  • Three consecutive sputum samples (8- to 24-hour intervals with at least one in early in the morning) for acid-fast bacilli (AFB) stain and culture by aerosol induction, gastric aspirate (children), or bronchoalveolar lavage
  • Positive AFB: Treat immediately. Culture and sensitivity ultimately guide treatment.
  • Chest radiograph
    • Primary TB: infiltrate with or without effusion, atelectasis, or adenopathy. Ghon lesion: calcified tuberculous caseating granuloma (tuberculoma); if associated with calcified ipsilateral hilar lymph node then Ghon (or Ranke) complex
    • Recrudescent TB: cavitary lesions and upper lobe disease with hilar adenopathy
    • HIV: atypical findings with primary infection, right upper lobe atelectasis
  • CT chest: good sensitivity, tree-in-bud (centrilobular nodules with branching linear opacities)
Follow-Up Tests & Special Considerations
  • Baseline CBC, creatinine, AST, ALT, bilirubin, alkaline phosphatase, visual acuity, and red-green color discrimination (regimens involving ethambutol)
  • HIV: If positive, get baseline CD4 count.
  • High risk: Check hepatitis B and C (injection drug users, Africa or Asia born, HIV infected).
  • Extrapulmonary: urine, CSF, bone marrow, and liver biopsy for culture as indicated
  • Nonspecific laboratory findings: anemia, monocytosis, thrombocytosis, hypergammaglobulinemia, SIADH, sterile pyuria
Diagnostic Procedures/Other
  • Culture: takes several weeks for definitive results
  • Xpert MTB/RIF: The World Health Organization endorses use as the initial test for diagnosis of pulmonary TB and detection of rifampicin resistance in adults and children presumed to have MDR-TB, HIV-associated TB, or TB meningitis (4)[A]
    • Results are available within 2 hours (5).
image TREATMENT
GENERAL MEASURES
  • If clinical suspicion, treat immediately. Prescribing physician is responsible for treatment completion.
  • Respiratory and droplet precautions
  • Not infectious if favorable clinical response after 2 to 3 weeks of therapy and three negative AFB smears
MEDICATION
Use ideal body weight for dosing. Directly observed therapy (DOT) strongly recommended for all, but required for children, institutionalized patients, nonadherent patients, and nondaily regimens.
P.1069

First Line
  • LTBI
    • Isoniazid (INH) for 9 months at 5 mg/kg/day (max of 300 mg) or 15 mg/kg (max of 900 mg) 2 times per week (6)[A] or
    • INH 15 mg/kg + rifapentine 300 to 900 mg weekly for 12 weeks by DOT for patients age ≥12 years (6)[A]
  • Active TB infection
    • Regimen 1 (preferred) (6)[A]
      • Initial phase:
        • INH 5 mg/kg, rifampin (RIF) 10 mg/kg (max 600 mg), pyrazinamide (PZA) 15 to 30 mg/kg, and ethambutol (EMB) 15 to 20 mg/kg daily for 8 weeks or
        • INH/RIF/PZA/EMB 5 days/week for 8 weeks
    • Continuation phase:
      • INH/RIF daily for 18 weeks; or, if DOT, INH/RIF 5 days/week for 18 weeks (recommended for HIV positive with CD4 <100 cells/mm3 due to increased risk of resistance) or
      • INH/RIF 2 to 3 times per week for 18 weeks (not used if HIV positive with CD4 <100 cells/mm3; may have increased risk of relapse) or INH/rifapentine once weekly for 18 weeks (acceptable only for HIV patients without cavitary disease, may have increased risk of relapse) (6)[A]
    • Regimen 2
      • Initial phase:
        • INH/RIF/PZA/EMB daily for 2 weeks, then twice weekly for 6 weeks or
        • INH/RIF/PZA/EMB 5 days/week for 2 weeks, then twice weekly for 6 weeks
      • Continuation phase:
        • INH/RIF 2 to 3 times per week for 18 weeks (not recommended if HIV positive with CD4 <100 cells/mm3; may have increased risk of relapse) or
        • INH/rifapentine once weekly for 18 weeks (acceptable only for HIV patients without cavitary disease; may have increased risk of relapse) (6)[A]
        • Treat TB in pregnancy with INH, RIF, and EMB; add pyridoxine 25 mg/day.
Pregnancy Considerations
  • Streptomycin: ototoxic and nephrotoxic; do not use in pregnancy. Pyrazinamide is not used in pregnant women in the United States.
  • Congenital infection: from maternal miliary or endometrial TB. PPD, CXR, lumbar puncture, and culture placenta. Start treatment promptly if suspected.
  • Breastfeeding: OK while taking TB drugs; supplement with pyridoxine 25 mg/day.
Pediatric Considerations
  • Children: Ethambutol is not used.
  • Children on medication may attend school.
ALERT
  • Maximum drug doses: RIF 600 mg all regimens, PZA 2,000 mg/day or 4,000 mg 2 times per week, EMB, 600 mg/day or 4,000 mg 2 times per week
  • If patient does not receive PZA during entire first 2 months, extend treatment to 9 months.
  • M. bovis is resistant to PZA; must be treated 9 months
  • Continue EMB until organism susceptibility to INH plus RIF is determined (6)[A].
Second Line
Fluoroquinolones and injectable aminoglycosides. Use when MDR is suspected or patient intolerance.
ISSUES FOR REFERRAL
ADDITIONAL THERAPIES
  • Pyridoxine: 50 mg may prevent INH-associated peripheral neuropathy, especially for patients who are malnourished or have comorbidities that increase risk of neuropathy (7)[A].
  • Steroids: recommended for TB meningitis (8)[A] or pericarditis (8)[B], with concomitant anti-TB therapy
SURGERY/OTHER PROCEDURES
For extrapulmonary complications (spinal cord compression, bowel obstruction, constrictive pericarditis)
COMPLEMENTARY & ALTERNATIVE MEDICINE
Vitamin D deficiency may increase susceptibility to TB and development of active TB (9)[C]. There is conflicting evidence regarding the utility of vitamin D supplementation in TB treatment.
INPATIENT CONSIDERATIONS
  • Negative pressure isolation with personal respirators and droplet precautions
  • Three consecutive negative sputum AFB smears are necessary for release from isolation.
Discharge Criteria
Once TB has been excluded or the patient has effective therapy, is clinically improving, and is not an infectious risk, arrange outpatient follow-up with a provider comfortable managing TB and coordinate case management with local public health authorities.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Monthly visits to assess treatment adherence and adverse medication effects; CXR at 3rd month
  • For HIV positive: CD4 count, CBC, and liver enzymes q3mo
  • Liver enzymes monthly if chronic liver disease, alcohol use, pregnant, or postpartum. Temporarily halt medications if asymptomatic and enzymes ≥5 times normal or if symptomatic and enzymes ≥3 times normal.
  • Visual acuity and red-green color monthly if on ethambutol >2 months or doses >20 mg/kg/day
  • If culture-positive after 2 months of therapy, reassess drug sensitivity, initiate DOT, coordinate care with public health authorities, and consider infectious disease consultation (if not already involved).
PATIENT EDUCATION
  • Emphasize medication adherence.
  • Screen and treat close contacts.
  • Alert patient that health authorities must be notified.
  • http://www.cdc.gov/tb/publications/factsheets/general/tb.htm
PROGNOSIS
Few complications and full resolution of infection if medications are taken for full course as prescribed
REFERENCES
1. World Health Organization. WHO global tuberculosis report 2014. http://www.who.int/tb/publications/global_report/en/. Accessed August 23, 2015.
2. Mazurek GH, Jereb J, Vernon A, et al. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection—United States. MMWR Recomm Rep. 2010;59(RR-5):1-25.
3. Centers for Disease Control and Prevention. National shortage of purified-protein derivative tuberculin products. MMWR Morb Mortal Wkly Rep. 2013;62(16):312.
4. World Health Organization. Tuberculosis diagnostics: Xpert MTB/RIF test. http://www.who.int/tb/publications/Xpert_factsheet.pdf. Accessed 2015.
5. Lawn, SD. Diagnosis of pulmonary tuberculosis. Curr Opin Pulm Med. 2013,19(3):280-288.
6. Hall RG, Leff RD, Gumbo T. Treatment of active pulmonary tuberculosis in adults: current standards and recent advances. Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2009;29(12):1468-1481.
7. Centers for Disease Control and Prevention. Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep. 2011;60(48):1650-1653.
8. World Health Organization. The Treatment of Tuberculosis: Guidelines. 4th ed. Geneva, Switzerland: World Health Organization; 2010.
9. Luong Kv, Nguyen LT. Impact of vitamin D in the treatment of tuberculosis. Am J Med Sci. 2011;341(6):493-498.
Additional Reading
&NA;
Centers for Disease Control and Prevention. Trends in tuberculosis—United States, 2012. MMWR Morb Mortal Wkly Rep. 2013;62(11):201-205.
See Also
&NA;
  • Tuberculosis, CNS; Tuberculosis, Latent (LTBI); Tuberculosis, Miliary
  • Algorithm: Weight Loss, Unintentional
Codes
&NA;
ICD10
  • A15.9 Respiratory tuberculosis unspecified
  • A15.0 Tuberculosis of lung
  • A19.9 Miliary tuberculosis, unspecified
Clinical Pearls
&NA;
  • Consider TB in patients with chronic cough and one additional risk factor.
  • TB is fully curable when diagnosed and treated appropriately.
  • Children and elderly clinically exhibit fewer classic features of TB.
  • Involve public health authorities early in the diagnostic and treatment process for suspected cases of TB.