TUBERCULOSIS

Diagnosis

Other than culture (which yields results very slowly due to the slow growth of the Mycobacterium tuberculosis organism), there is no "gold-standard" laboratory diagnosis; usually the diagnosis is based on clinical suspicion including possibility of exposure, PLUS:

• Pulmonary infiltrate
  • In presence of HIV, radiologic appearance is more likely to include mid- or lower-lobe infiltrates, mediastinal adenopathy, and/or pleural effusions (JAMA 293:2740, 2005--abst)
• Sputum (or other body fluids, if applicable) positive for "Acid-Fast" bacilli on stain
• Sputum (or other body fluids, if applicable) positive for M. tuberculosis on culture
• Positive skin test ("PPD") for tuberculosis--see also Anergy Testing
  • May produce false-positive results in pts with h/o BCG vaccination and/or other infections
  • Criteria per American Thoracic Society & CDC (Am. J. Resp. Crit. Care Med. 161:S221, 2000, cited in JAMA 293:2776, 2005)
    • Response with 5mm or more induration is positive if:
      • HIV-positive
      • Contact with a person with active TB
      • Fibrotic changes on chest radiograph c/w prior TB
      • Immunosuppressed (e.g. on immunosuppressants, TNF-inhibitors, or corticosteroids equivalent to > 15mg/d prednisone for 1mo or more)
    • Response with 10mm or more induration is positive if:
      • Recent immigration from high-prevalence country
      • Injection drug use
      • Resident or employee (not just starting out) of a residential institution, e.g. correctional facility, nursing home, hospital, etc.
      • Employment at a mycobacteriology laboratory
      • High risk of TB due to (silicosis, DM, chronic renal failure, hemotologic disorder, malignancy, < 90% ideal body weight, s/p gastrectomy or jejunoileal bypass)
      • < 4yo
      • < 18yo exposed to an adult at high risk
    • Otherwise, response with 15mm or more induration is positive

Emerging diagnostic tests for tuberculosis:

• Nucleic acid amplification (e.g. PCR) of sputum:
  • 338 adults suspected of having pulmonary TB were given an "official" diagnosis by a panel of experts taking into account all available clinical data. Based on these dx's, sensitivity and specificity of nucleic acid amplification were 83% & 97% respectively, c/w 60% and 92% for acid-fast smear, and 90% and 99.6% for culture (JAMA 283:639, 2000--JW)
  • In a retrospective analysis of data of 2,021 pts with sputum culture positive for M. tuberculosis, nucleic acid amplification testing had sensitivity 95% and specificity of 97.3%.  For pts with a positive AFB smear, the negative predictive value of nucleic acid amplification testing was 92%. (Clin. Inf. Dis. 49:46, 2009-JW)
• Interferon-gamma testing
  • T-cells of M. tuberculosis-infected individuals, when exposed to M. tb antigens (e.g. early secreted antigenic target 6 and culture filtrate protein 10), release IFN-gamma more than those in uninfected people.
  • In a study of 318 patients with suspected tuberculosis, the "Quanti-FERON-TB Gold" IGN-gamma assay had significantly lower concordance with tuberculin skin testing in patients on immunosuppressants and patients who had previously received BCG vaccination.  Sensitivity was sig. higher than tuberculin skin testing in patients with culture-proven active tuberculosis (Am. J. Resp. Crit. Care Med. 172:631, 2005--abst)
  • IFN-gamma was 81% sensitive for confirmed active pulmonary TB in one study (JAMA 293:2756, 2005--abst)
  • In a study in 37 pts with suspected active pulmonary TB but sputum smears negative for AFB, "ELISPOT" IFN-gamma testing of cells from  bronchoalveolar lavage fluid (with cutoff of 5 reactive cells per 200,000) had sensitivity and specificity of 100% for eventual diagnosis of pulmonary TB (Am. J. Resp. Crit. Care Med. 174:1048, 2006--JW)
  • In a study of 242 pts who underwent testing with Quantiferon-TB Gold assay, taking "indeterminate" results as positive, the sensitivity was 60% and negative predictive value was 86% for eventual diagnosis of active TB. (Clin. Inf. Dis. 44:69, 2007--JW)
  • Use for diagnosis of latent TB infection:
    • In a cross-sectional study in 726 health care workers in India, there was a high degree of agreement (81%, kappa value = 0.61) between IFN-gamma testing and PPD skin testing (JAMA 293:2746, 2005--abst)
  • Results of interferon-gamma assays may be boosted by recent administration of a tuberculin skin test (Am. J. Resp. Crit. Care Med. 180:49, 2009-JW)
• Microscopic-observation drug-susceptibility (MODS) assay
  • Relies on early microscopic detection of typical cord formation in broth culture
  • Shorter time to positivity and higher sensitivity c/w traditional culture
    
    

Antitubercular drugs:

• "First Line" (per JAMA 293:2776, 2005)
  • Isoniazid
  • Rifampin
  • Rifapentine (Priftin)--Chemically similar to rifampin but longer half-life
  • Rifabutin (not FDA-approved for treatment of TB as of 2005)
  • Pyrazinamide
  • Ethambutol
• "Second Line" (per JAMA 293:2776, 2005)
  • Cycloserine
  • Ethionamide
  • Levofloxacin
  • Moxifloxacin
  • Garifloxacin
  • P-Aminosalicylic acid
  • Streptomycin
  • Amikacin/kanamycin
  • Capreomycin

Prophylaxis for "latent tuberculosis infection" (PPD-positive individuals w/negative CXR)

Note--Must exclude active TB (e.g. with chest x-ray and review of symptoms) in all pts being considered for treatment of latent TB infection!

Joint CDC/ATS/IDSA recommendations (MMWR 2003 Aug 8;52(31):735-9.)

• 1st-line: Isoniazid (5mg/kg up to 300mg)QD x 9mos (vit. B6 usually co-administered)
• 2nd-line
  • Isoniazid 2x/wk (directly-observed) x 9mos
  • Isoniazid QD x 6mos (only if not HIV-infected)
  • Isoniazid 2x/wk (directly-observed) x 6mos (only if not HIV-infected)
  • Rifampin (10mg/kg up to 600mg) QD x 4mos
    • Consider if contacts are known to have isoniazid-resistent, rfampin-susceptible TB
    • Should not be given concurrently with delavirdine or most protease inhibitors
    • Can cause hepatotoxicity, rash, thrombocytopenia, anemia, and neutropenia
    • Some have proposed as first-line based on a randomized trial c/w Isoniazid x 9mos that showed higher compliance, reduced incidence of hepatotoxicity, though effectiveness was not compared (Ann. Int. Med. 149:689, 2008-AFP)
• Not recommended
  • Rifampin + pyrazinamide x 2mos was found to be as effective for TB prophylaxis over mean 37mo f/u in 1583 HIV-positive pts with positive PPD as INH x 1y (JAMA 283:1445, 2000--JW), though death from hepatotoxicity has been observed on this regimen (MMWR 50:289, 2001--JW), and CDC et al. no longer recommend as of 2003 (see MMWR citation above)
• Routine lab monitoring (i.e. liver function testing) not indicated except if HIV-infected, pregnant, chronic liver disease, or regular alcohol use.
• Discontinue Rifampin or INH if transaminases > 5x normal (or symptomatiand > 3x normal)
• Age and prophylactic treatment of latent TB

Note--Consider testing for HIV in pts with new Dx of TB