• See Also
  1. Tuberculosis Screening in Children
  2. Tuberculosis Risk Factors (Tuberculosis Screening Indications)
  3. Tuberculosis Risk Factors for progression from Latent to Active Disease (Latent Tb treatment indications)
  4. Tuberculosis Related Chest XRay Changes
  5. Extrapulmonary Tuberculosis
  6. Tuberculin Skin Test (TST, Purified Protein Derivative, PPD)
  7. Mycobacterium Tuberculosis Antigen-Specific Interferon-Gamma Release Assay (IGRA)
  8. Latent Tuberculosis Treatment
  9. Active Tuberculosis Treatment
  10. Susceptible Tuberculosis Treatment
  11. Possibly Resistant Tuberculosis Treatment
  12. Multiple Drug Resistant Tuberculosis Treatment
  13. Tuberculosis Resources
  • Complications
  1. See Extrapulmonary Tuberculosis
  • Epidemiology
  1. Worldwide
    1. Latent TuberculosisPrevalence: 2 Billion people
      1. One third of world population has Latent Tuberculosis
      2. Over half of cases in China, India, and Southeast asia
    2. Active Tuberculosis will develop in 10% of latent cases
      1. Most frequent cause of death for young adults
      2. In 1998, 8 million Active Tb cases, 2 million deaths
      3. In 2015, 10.4 million Active Tb cases, 1.4 million deaths
        1. An additional 0.4 million deaths occurred in HIV patients with Active Tb
      4. In 2019, 10 million Active Tb cases, 1.4 million deaths
  2. United States
    1. Latent TbIncidence: 10-15 Million in U.S.
    2. Active TbIncidence has fallen
      1. 1992 cases: 26,673 (10.5 cases per 100,000)
      2. 2006 cases: 13,779 (4.6 cases per 100,000)
      3. 2014 cases: 9,421 (2.96 per 100,000)
      4. 2019 cases 9,000
    3. Active TbIncidence in U.S. born patients declined since 1992
      1. Incidence rose 74% between 1953 to 1985, before it started falling in 1992
    4. Active TbIncidence in foreign born persons Incidence increasing (4-5x U.S)
      1. Foreign borne patients represent 66% of new Tb cases in U.S.
      2. Foreign borne patient Active TbIncidence: 15.4 cases per 100,000
      3. U.S. borne patient Active TbIncidence: 1.2 cases per 100,000
      4. Latent Tb infection in 30-50% of Minnesota Refugees
      5. Drug-resistant TB is twice as likely in Refugees
    5. Active TbIncidence by ethnic groups in the United States (in 2014)
      1. Asians: 17.8 cases per 100,000
      2. Native hawaiians and others from the pacific islands: 16.9 per 100,000
      3. American indians or alaskan natives: 5.0 per 100,000
      4. Blacks: 5.1 per 100,000
      5. Hispanics: 5.0 per 100,000
      6. Whites: 0.6 per 100,000
    6. Other factors related to resurgence of Tuberculosis in the United States
      1. HIV epidemic
      2. Multidrug-Resistant Tuberculosis
    7. References
      1. (2014) CDC - Trends in Tuberculosis, accessed online 11/2/2016
        1. http://www.cdc.gov/tb/publications/factsheets/statistics/tbtrends.htm
  • History
  1. Famous people who died of Tuberculosis
    1. Eleanor Roosevelt
    2. Emily Bronte and Charlotte Bronte
    3. Anton Checkov
    4. Frederic Chopin
    5. King Henry VII
    6. James Monroe (5th U.S. president)
    7. George Orwell (1950, shortly after Nineteen Eighty four was published)
    8. Robert Louis Stevenson
    9. Henry David Thoreau
    10. Thomas Wolfe
  • Pathophysiology
  1. Mycobacterium tuberculosis Characteristics
    1. Acid Fast Bacillus
    2. Obligate aerobic Bacteria
    3. Facultative Intracellular Bacteria (initially, before cell mediated Immunity develops)
      1. Tb infiltrates Neutrophils and Macrophages after inhalation, where is suppresses lysis
      2. Tb survives within Macrophages and spreads to regional and distant lymph tissue
      3. Intracellular infection ceases after cell mediated Immunity develops
  2. Mycosides (virulence factors unique to Acid Fast Bacteria)
    1. Mycosides are Glycolipids (large Fatty Acid, mycolic acid bound to a Carbohydrate)
    2. Cord factor (unique to Tb)
      1. Composed of 2 mycolic acids bound to a Disaccharide) and leads to linear growth of Tb
      2. Inhibits Neutrophil migration and affects mitochondrial function
      3. May be associated with Tb related Cachexia (via TNF release)
    3. Sulfatides
      1. Mycosides similar to cord factor, but with sulfates bound to the Disaccharide
      2. Contributes to Tb's facultative intracellular status
        1. Inhibits Phagosome fusion with Lysosomes (with enzymatic Bacterial destruction)
    4. Wax D
      1. Adjuvant that promotes Antibody formation and cellular Immunity response to Tuberculosis
      2. May be associated with some extrapulmonary Tb findings such as Arthritis
  3. Transmission
    1. Mycobacterium tuberculosis is carried in airborne droplets (each 5 micron, and each containing ~5 Tb bacilli)
    2. Transmitted from an infected patient with respiratory Tb (laryngeal, lung) via sneeze, cough, speak, or sing
  4. Infection
    1. Latent Tuberculosis occurs when the Immune System walls off Tuberculosis infection, forming Granulomas
    2. Active Tuberculosis occurs when the Immune System can no longer contain Tb in Granulomas and the bacilli multiply
      1. See Tuberculosis Risk Factors for progression from Latent to Active Disease
      2. Latent Tuberculosis progresses to Active Tuberculosis in up to 5 to 10% of cases
      3. Risks for progression include Immunosuppression, Diabetes Mellitus, IV Drug Abuse, low body weight and age <5 years
  5. Cell-Mediated Immunity
    1. Before cell-mediated Immunity, Tb is able to survive within Macrophages by inhibiting Phagocytosis and lysosomal destruction
    2. Despite inhibition of bactericidal activity, some Macrophages successfully phagocytose and lyse some Tb cells
      1. Macrophages will present these Antigens to T helper cells at regional Lymph Nodes
      2. Sensitized T-Helper Cells target Tb cells, and on contact, release Lymphokines to attract and activate Macrophages
      3. Activated Macrophages are now able to destroy Tb cells
    3. Destruction of Tb cells by activated Macrophages results in lung collateral damage with necrosis
      1. Granulomas form in regions of lung necrosis
        1. Central caseous material (cheese-like)
        2. Surrounded by Macrophages, multinucleated giant cells, fibroblasts, Collagen
      2. Granulomas contain the Tb, walled off infection
        1. Granulomas frequently calcify, rendering them incapable of reactivation
        2. Non-calcified Granulomas may reactivate, with Active Tuberculosis during times of Immune Suppression
  6. Dissemination
    1. Active M. Tb may spread from lung alveoli to brain, Larynx, Lymph Nodes, spine, bone and Kidneys
  • Risk Factors
  1. Latent Tuberculosis
    1. See Tuberculosis Risk Factors (Tuberculosis Screening Indications)
  2. Reactivation to active Tuberculosis Risk Factors
    1. See Tuberculosis Risk Factors for progression from Latent to Active Disease (Latent Tb treatment indications)
  1. Latent Tuberculosis is asymptomatic, noninfectious and without Chest XRay findings of Tuberculosis
  2. Active Tuberculosis mimics other conditions
    1. May mimic cancer presentation (Night Sweats, weight loss)
    2. May mimic Community Acquired Pneumonia (cough, fever, mild Chest XRay infiltrate)
    3. Exercise a low index of suspicion for testing
  3. Non-specific presentation (most common)
    1. Fatigue
    2. Weight loss
    3. Cachexia
    4. Night Sweats
  4. Pulmonary Tuberculosis symptoms
    1. Productive Chronic Cough (>3 weeks)
    2. Hemoptysis (uncommon)
    3. Pleuritic Chest Pain
    4. Dyspnea
  1. Sites of Involvement
    1. Primary infection: lung involvement
  2. Disseminated Disease
    1. See Extrapulmonary Tuberculosis
  3. Findings to consider Tuberculosis Testing (e.g. undifferentiated cough in the emergency department)
    1. Mild Sinus Tachycardia
    2. Mild Hypoxia
    3. Tachypnea
    4. Low grade fever
  • Diagnosis
  1. Tuberculosis Screening Indications
    1. Asymptomatic with Tuberculosis Risk Factors
      1. See Tuberculosis Risk Factors (Tuberculosis Screening Indications)
      2. Avoid Tb screening in low risk populations (low Positive Predictive Value)
    2. Symptoms (see above)
      1. Chronic Cough >3 weeks
      2. Hemoptysis
      3. Chest Pain
      4. Fever
      5. Night Sweats
      6. Anorexia
      7. Fatigue
      8. Unexplained Weight Loss
  2. General Tuberculosis Screening Tests (latent or active disease)
    1. See Tuberculosis Screening for lab selection
    2. Tuberculin Skin Test (TST, Purified Protein Derivative, PPD)
    3. Mycobacterium Tuberculosis Antigen-Specific Interferon-Gamma Release Assay (IGRA)
      1. Cost of IGRA is approaching that of Tuberculin Skin Test
      2. IGRA tests will likely replace the Tuberculin Skin Test in longterm
        1. Some caveats (e.g. age under 5 years old)
  3. In suspected pulmonary Tuberculosis
    1. Induced Sputum samples on 3 consecutive days or
    2. Gastric aspirate may be used in young children or
    3. Bronchoscopy with bronchoalveolar lavage and biopsy
  4. In suspected Disseminated tuberculosis (Extrapulmonary Tuberculosis)
    1. Obtain specimens from infection site (e.g. urine, Lymph Nodes, Pleural Fluid, cerebrospinal fluid, Bone Marrow)
  5. Detection of organisms and drug susceptibility
    1. Acid Fast Stain (Sputum, body fluid, biopsy)
      1. Sensitive to >5000 bacilli per ml
    2. Rapid Molecular Detection
      1. Fluorescent stains and DNA probes for rapid diagnosis
    3. DNA whole genome sequencing
      1. Performed at many labs (identifies strains, mutations and predicts drug resistance)
      2. Has replaced culture in many regions of the world
    4. Mycobacterial cultures
      1. Sensitive to 10 bacilli per ml
      2. Replaced by other molecular tests above
  • Labs
  1. Diagnostic testing as above
  2. HIV Test
    1. Test every person with Tuberculosis
  1. Obtain in all positive PPD (TST) or IGRA patients
  2. See Tuberculosis Related Chest XRay Changes
  • Course
  1. Tuberculin Skin Test conversion within 2-10 weeks of exposure
    1. Household contacts of a patient with known Tuberculosis have a 30% chance of infection
  2. Latent Tuberculosis initially
    1. Tuberculin Skin Test positive without signs, symptoms
    2. Tubercle bacilli remain dormant and viable for years
  3. Active Tuberculosis (secondary or reactivation Tuberculosis)
    1. See Tuberculosis Risk Factors for progression from Latent to Active Disease (Latent Tb treatment indications)
    2. Lifetime risk of developing Active Tb from Latent Tb: 10%
      1. Active Tuberculosis occurs within 1 to 2 years in 5% of cases (highest risk time period)
      2. Remaining 5% of cases may occur years after developing Latent Tuberculosis
      3. In Immunocompromised patients (esp. HIV Infection), risk of reactivation approaches 5% per year
  • Management
  1. Report all cases of Latent and Active Tuberculosis to local or state health departments
  2. Latent Tuberculosis
    1. See Latent Tuberculosis Treatment
    2. Positive PPD or IGRA without signs of Active Tb
      1. Confirm no Active Tb (cough, Night Sweats) before starting single drug Latent Tb management
      2. Chest XRay is performed at time of Latent Tb diagnosis
    3. Treatment indicated if risk of Tb Progression from latent to active disease
      1. See Tuberculosis Risk Factors for progression from Latent to Active Disease
  3. Active Tuberculosis (Secondary or Reactivation Tuberculosis)
    1. See Active Tuberculosis Treatment
    2. Symptomatic patient (e.g. fever, weight loss, Hemoptysis)
      1. Patient isolated in negative pressure room and wears mask
      2. Healthcare workers wear N-95 Mask
      3. Obtain diagnostic testing
        1. Chest XRay
        2. Sputum acid-fast bacilli smear and culture
      4. Consult with pulmonology or infectious disease
      5. Consult public health
    3. Protocols for Active Tuberculosis management
      1. Susceptible Tuberculosis Treatment
      2. Possibly Resistant Tuberculosis Treatment
      3. Multiple Drug Resistant Tuberculosis Treatment
  4. Post-exposure Prophylaxis
    1. Indications
      1. Exposure to untreated active pulmonary or laryngeal Tuberculosis
      2. Regardless of prior BCG vaccine or prior Tuberculosis treatment
    2. Protocol: Asymptomatic contact
      1. Treatment indications based on Tuberculosis Testing at baseline AND 8-12 weeks after exposure
        1. Tuberculin Skin Test (PPD) of 5mm or greater OR
        2. Mycobacterium Tuberculosis Antigen-Specific Interferon-Gamma Release Assay positive
      2. Start treatment if positive testing
        1. Isoniazid (INH) with Vitamin B6 supplementation for 9 months
    3. Protocol: Symptomatic contact
      1. Follow Active Tuberculosis protocol as above
  • Complications
  1. See Extrapulmonary Tuberculosis
  • Prevention
  1. Bacille Calmette-Guerin Vaccine (BCG vaccine)
    1. May be indicated in high risk young children in endemic areas
    2. Routinely performed in Mexico, South America, Africa, Asia and Western Europe
  2. M72/ASO1E Vaccine
    1. Reduced progression to pulmonary Tuberculosis by 50% in HIV negative after Tb exposure and positive PPD
    2. Tait (2019) N Engl J Med 381(25):2429-39 [PubMed]
  • Resources
  1. See Tuberculosis Resources
  • References
  1. Gladwin, Trattler and Mahan (2014) Clinical Microbiology, Medmaster, Fl, p. 142-4
  2. Orman, Moran and Swaminathan in Herbert (2016) EM:Rap 16(11): 2-3
  3. Frieden (2003) Lancet 362:887-99 [PubMed]
  4. Furin (2019) Lancet 393(10181): 1642-56 [PubMed]
  5. Hartman-Adams (2022) Am Fam Physician 106(3): 308-15 [PubMed]
  6. Hartman-Adams (2014) Am Fam Physician 89(11): 889-96 [PubMed]
  7. Lewinsohn (2017) Clin Infect Dis 64(2): e1-33 [PubMed]
  8. Potter (2005) Am Fam Physician 72:2225-35 [PubMed]