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A. Epidemiology [2]navigator

  1. Caused by Mycobacterium tuberculosis (Tubercle bacillus, TB)
  2. About 14,500 new cases in 2004 in USA
  3. Worldwide, 8.9 million new cases and 1.7 million deaths in 2004
  4. Worldwide, ~35% of world's population is infected
  5. Clinical TB
    1. In majority of persons exposed to TB, immune response contains infection
    2. ~10% of immunocompetent persons exposed to TB develop clinical disease
    3. However, once a person is exposed, organism is rarely completely eradicated
    4. TB is more aggressive and devastating in HIV+ persons
  6. TB in immigrants to USA is often resistant to isoniazid (INH) and testing is critical [10]
  7. TB transmission can now be "molecularly" tracked through rapid genotyping [13]

B. Etiologynavigator

  1. TB is spread by airborne droplet nuclei (1-5µm particles) of MTB
    1. Remain airborne for minutes to hours
    2. Inhaled and enter alveoli
    3. Taken up by alveolar macrophages
    4. MTB replicates slowly but continuously in these macrophages
  2. TB and the Immune System
    1. Mycolic acid, major component of surface coat, is highly inflammatory
    2. Directly stimulates immune responses through dendritic cells and macrophages
    3. These macrophages normally stimulate CD4+ helper T cells
    4. Cell immunity generally develops over 2-8 weeks and contains infection
    5. Granulomas (caseating) develop over time to contain the infection
    6. Complete eradication generally does not occur; MTB remains dormant in granulomas
  3. Role of Cellular Immunity [27]
    1. Adequate control depends on cell mediated immunity, primarily T helper cells
    2. Usual helper T cells with alpha-beta as well as gamma-delta bearing T cells involved
    3. Immunosuppression in infected persons increases risk of clinical TB
    4. Clinical TB in immunosuppressed patients is often systemic (rather than localized)
    5. Disseminated mycobacteremia is not uncommon in AIDS patients
    6. Many genes are implicated in susceptibility to and/or severity of TB infection [2]
  4. Pathology
    1. T cells and macrophages are prominant and mediate granuloma formation
    2. Multinucleated giant cells derived from macrophages are found
    3. Macrophages appear to be required for containing infections
    4. Formation of granulomas depends on Interferon (IFN) gamma and probably Interleukin 12
    5. Most TB lesions are necrotizing (caseating) granulomas containing dead cells
    6. Occasionally, noncaseating granulomas are found
  5. Drugs Associated with Increased Risk for TB
    1. Many chronic immunosuppressive agents associated with increased risk of clinical TB
    2. Glucocorticoids
    3. Methotrexate
    4. Anti-tumor necrosis factor alpha (TNFa) antibody infliximab increases risk of TB [5]
    5. Risk factors for TB associated with infliximab include concomitant immunosuppressant use, history of latent or active TB, or spending time in TB endemic area [3]
    6. Of 100 case reports of infliximab associated TB, 34 had a negative TB skin test before initiating therapy [3]
    7. Soluble TNFa receptor (etanercept) does not appear to increase risk of TB [5]
  6. Genetic Contributions to Controlling MTB Infection
    1. TNF alpha production appears to be important to containing TB
    2. IFN gamma receptor 1 mutations are associated with increased susceptibility
    3. Increased risk for clinical disease in persons with HLA-DQB1*0503 allele
    4. Human NRAMP1 gene polymorphism is associated with suscpetibility to TB in Africa [34]
    5. These mutations, in an intron and 3' untranslated region, have 4 fold increased risk [34]
    6. These data strongly suggest a genetic component to containing TB infections
    7. Similar findings have been reported for leprosy (M. leprae) infections

B. Symptoms navigator

  1. Pulmonary Disease
    1. Shortness of breath
    2. Sputum production, often with (transient) hemoptysis [8]
    3. Fatigue, malaise
    4. Fever
  2. Systemic Symptoms [8]
    1. Fever (and fever of unknown origin)
    2. Lethargy, severe malaise
    3. Weight loss [20]
  3. Disseminated Disease [31]
    1. Miliary pattern on chest radiograph
    2. Pancyotpenia due to bone marrow involvement
    3. Respiratory failure may occur
  4. Other Sites Affected
    1. Osteomyelitis [21] - any location; spinal osteomyelitis is called "Pott's Disease"
    2. Liver disease
    3. "Tuberculoma"
    4. Brain or Meninges
    5. Kidneys / Genital / Peritoneum (ascites) [32]
    6. Lymph Nodes (scrofula) - can cause highly inflamed lymphadenitis [6]
    7. Pleura / Pericardium [7]
    8. Gastrointestinal Tract
    9. Skin - erythema nodosum [51]
    10. Pancreatic mass
    11. Virtually any other organ
  5. Asymptomatic in large number of persons (~90% of all infected)

C. Conditions Associated with Increased Risk of Active TB [12,38]navigator

  1. Overall, ~20% of normal persons exposed to TB (endemic areas) develop clinical disease
    1. Risk for clinical TB increased in persons with HLA-DQB1*0503 allele
    2. Clinical disease risk also increased in persons with IFN gamma receptor mutations [6,7]
    3. These IFN gamma mutations likely reduce ability to generate Th1 type immune responses
  2. HIV / AIDS [38]
    1. Increased risk especially CD4<500/µL
    2. Very high risk associated with CD4<200/µL
    3. Very high risk associated with positive PPD reaction (see below)
    4. Increased risk associated with anergy to mumps antigen
    5. More aggressive and devastating infection in HIV+ persons
  3. Diabetes Mellitus
  4. Immunosuppressive Therapy
    1. Especially glucocorticoids
    2. Cancer chemotherapy
    3. Infliximab anti-TNFa antibody [3]
  5. Hematologic Disease
  6. Chronic Renal Disease
  7. Cancer of upper gastrointestinal tract
  8. Malnutrition
    1. Chronic Malabsorption Syndromes
    2. Intestinal Bypass
    3. Gastrectomy
    4. Starvation
  9. Body weight <10% below ideal
  10. Silicosis
  11. Chronic Alcoholism may be a risk factor for contraction
  12. Indigent urban populations
  13. Travel to Endemic Areas
    1. Concerning in any region with epidemic or endemic tuberculosis
    2. Africa, Central America, South America, South Asia and Pacific, former Soviet states
    3. Overall incidence on visits to epidemic area is 2.8-3.5/1000 person-months of travel
    4. BCG vaccination or post-travel tuberculin skin testing should be considered
  14. Erythema Induratum [53]
    1. Lobular panniculitis associated with vasculitis
    2. Usually in young women
    3. Subcutaneous, tender, possibly ulcerating nodules, usually on legs
    4. MTB found in >75% of lesions using polymerase chain reaction
    5. Likely due to hypersensitivity vasculitis affecting primarily fat tissue
    6. Treatment with anti-TB agents usually ameliorates symptoms

D. Evaluation [1,2]navigator

  1. General screening
    1. Immigrants, especially from endemic areas
    2. Chronic alcoholics, Intravenous drug abuse
    3. Before initiation of immunosuppressive therapy
    4. Nursing Home and Chronic Care patients
    5. Healthcare workers
    6. HIV+
  2. Screening Methods
    1. Whole blood tests based on the detection of interferon gamma (IFNg) production by T cells in response to MTB antigens ex vivo are superior to skin testing [24,25]
    2. IFNg-stimulation test should replace skin testing as it requires only asingle visit [24]
    3. Skin Test - purified protein derivative (PPD), derived from mycobacteria
    4. Chest Radiography
    5. Nucleic acid detection tests for analysis within 24 hours of repiratory tract specimens
    6. Rapid polymerase chain reaction (PCR) based test for TB (Amplicor MTB®) is available
  3. IFNg-Stimulation Tests [15,23,24,25]
    1. Quantification of IFNg in MTB (PPD)-stimulated whole blood
    2. As sensitive and more specific than skin test evaluation
    3. Requires only single visit for blood sample, and less susceptible to false positives
    4. These tests are rarely positive after BCG vaccination [23,24]
    5. Cannot distinguish between active TB and latent TB [25]
    6. Quantiferon TB Gold® test for MTB stimulated IFNg is FDA approved
  4. Skin Test Evaluation [4,11,12]
    1. 0.1ml of PPD (5U) should be placed intradermally to form a small wheal
    2. The test should be read (measured) for true induration (not erythema) in 48-72 hours
    3. Previous BCG vaccination does not alter PPD interpretation
    4. However, previous BCG vaccination reduces predictive value of serial PPD testing [41]
    5. BCG related delayed hypersensitivity responses correlate with protective markers of mycobacterial immunity [41]
    6. Skin test does not distinguish various mycobacterial species
    7. Skin test usually administered with common antigens to provide positive control
    8. These antigens include mumps or candida antigens and should show a positive response
    9. However, use of these "anergy" tests is not clearly beneficial in TB evaluation [44]
  5. Skin Test Induration of 5mm or greater is positive in following patients:
    1. with recent close contact with a person with active TB
    2. with fibrotic lesions on CXR consistent with past healed TB
    3. with known or suspected HIV infection
    4. who have received solid organ transplants
    5. who are receiving TNFa inhibitor (infliximab, etanercept, adalimumab)
    6. who are receiving >15mg/d prednisone or equivalent for >1 month
  6. Induration of 10mm or greater is positive in following hosts:
    1. Patients with high risk comorbid conditions (see above)
    2. Persons from endemic areas
    3. Injection (intravenous and other) drug abusers (IVDA)
    4. Residents or employee of long-term (chronic) care facilities, prison or jail
    5. High risk persons (see below)
    6. Recent immigrant from high-prevalence country
    7. Workers in mycobacteriology laboratory
    8. Children <4 years, or infant, child, or adolescent exposed to high risk adult
  7. Induration >15mm required for positivity in normal hosts (not mentioned above)
  8. High Risk Persons [4]
    1. Chronic Renal Failure
    2. Diabetes Mellitus
    3. Lung or Head and Neck Carcinoma
    4. Weight loss >10% of ideal body weight
    5. Gastrectomy
    6. Jejunoileal bypass
    7. Silicosis
  9. Chest Radiograph (CXR)
    1. Usually upper lobe consolidation
    2. Can have lesion on a diagonal to the first lesion in opposite lung
    3. Calcified nodules ("granulomas") and/or lymph nodes (Ghon focus) may be seen in old TB
    4. Healed fibrotic or cavitary Lesions (may become superinfected)
    5. TB pleural effusion is exudative with very high LDH
    6. Multiple small nodules may occur in miliary (disseminated) TB
    7. HIV infection alters CXR appearance in TB due to altered host immune system [20]
    8. Atypical CXR with adenopathy, effusion or mid/lower lung zone infiltrates or none of the above features were found in 20% of TB infection in HIV+ persons [20]
  10. Latent TB Infection [4,16]
    1. Positive PPD test as defined above without evidence of clinical disease
    2. Normal CXR
    3. Peripheral T Cell Interferon gamma (IFNg) TB specific tests now available
    4. These include QuantiFERON-TB Gold (FDA approved) and T SPOT-TB (approved in Europe)
    5. These tests may be helpful for confirming or detecting latent TB infection
    6. INH alone x 9 months is usually adequate for treatment of latent TB infection
  11. Other Laboratory Findings
    1. Sedimentation rate may be highly elevated, often >100mm/hr
    2. Elevated serum alkaline phosphatase often found in AIDS with mycobacteremia
    3. Urine may show eosinophils
    4. Peripheral eosinophilia may occur, especially with disseminated disease
    5. Interferon gamma (IFNg) >3.7 IU/mL in pleural fluid strongly suggests TB [57]
  12. TB (Miliary) Versus Sarcoidosis [42]
    1. Nonreactive PPD test: 25% of miliary TB and 95% of sarcoidosis
    2. Noncaseating Granulomas: 20% of miliary TB and 100% of sarcoidosis
    3. Normal ACE Level: 95% of miliary TB and 20-50% of sarcoidosis
    4. TB specific IFNg assay is more sensitive and specific than skin testing [22,24,25]

E. Definitive Diagnosisnavigator

  1. In most cases, tissue or sputum with positive acid-fast bacilli (AFB) smear required
  2. TB may also be cultured under special conditions for growth
    1. Induced sputum is typically used in adults and is safe and accurate in infants/children [60]
    2. Gastric lavage has been used in the past in children but sputum induction is sufficient [60]
    3. Typical solid or specialized cultures require 13-26 days for positivity [28]
  3. Polymerase chain reaction (PCR) or other amplification may be used to identify TB
  4. Microscopic-Observation Drug-Susceptibility Assay [28]
    1. Allows detection of TB directly from sputum
    2. Growth of TB in liquid medium, allows characteristic cord formation
    3. Drugs added to medium can determine susceptibility early
    4. ~98% sensitivity (versus standard culture), medium time to culture positive 7 days
    5. Excellent drug susceptibility results compared with standard methods
  5. TB specific T lymphocyte activation assay (ELISpot) [22,36]
    1. Can be used to distinguish TB from most other disorders and from BCG vaccination skin test responses
    2. ELISpot-Plus assay is more sensitive than ELISpot
    3. ELISPpot-Plus with TB skin testing can rapidly exclude active TB infection in patients with moderate to high probability of TB [62]
  6. Tissue Histology
    1. Tissue usually shows caseating (necrotizing) granulomas
    2. However, noncaseating granulomas can occur in 10-20% of cases
    3. Histoplasmosis, coccidiomycosis and sarcoidosis may have similar findings
    4. However, sarcoidosis has noncaseating granulomas only

F. Prophylaxis [1,2,12,38]navigator

  1. For PPD+ patients, obtain a chest radiograph and evaluate for signs of active disease
  2. If radiograph is negative, then chemoprophylaxis should be considered
  3. Candidates for prophylaxis regardless of Age:
    1. Persons with known or suspected HIV Infection (PPD >5mm) [30]
    2. Close contacts of infectious cases with positive PPD
    3. Note: a negative PPD is one which is read >3 months after the last contact with case
    4. Recent PPD positve converters <35 years old with >9mm of induration
    5. Fibrotic changes on radiograph (suggesting past healed disease) and PPD >5mm
    6. IVDA patients with >10mm induration (HIV negative)
    7. Persons with high risk medical conditions (above) and PPD >10mm
  4. Candidates for Prophylaxis Age <35 years and PPD >9mm
    1. Persons from endemic areas either in another country or USA
    2. Residents of long term care facilities
    3. Medically underserved low-income populations
  5. Overview of Treatment of Latent TB (Prophylaxis)
    1. Isoniazid (INH) is preferred agent for 6-12 months
    2. This may be combined with rifampin (RIF) and pyrazinamide (PZA) for 2 months
    3. For PZA intolerance, use RIF for 4 months
    4. Rifabutin may be substituted in RIF intolerance
    5. RIF 10m/kg (max 600mg) qd or twice weekly
    6. PZA 15-20mg/kg qd (max 2gm)
    7. PZA can also be given twice weekly: 2.5gm/3.0gm/3.5gm for weight <50/50-75/>75kg
    8. For persons from Vietnam, Haiti, Phillipines, INH resistance common and RIF containing regimen is recommended [10]
    9. Susceptibility testing is generally recommended in most patients
  6. INH
    1. INH duration is 6 months for normal hosts
    2. INH duration is 9-12 months in HIV (? other immunosuppression)
    3. INH is always be given with pyridoxine (vitamin B6), 50mg po qd
    4. INH dose is typically 300mg po qd or 15mg/kg (900mg maximum) twice weekly
    5. Drug is hepatically metabolized and renally excreted
    6. Main side effect is drug-induced hepatitis, with increased occurrence >35 years old
    7. INH is not recommended to anergic patients with HIV unless exposed to active TB [29]
    8. No benefit to adding rifampin or pyrazinamide for prophylaxis in HIV+ persons [30]
  7. INH Hepatitis
    1. Incidence of INH hepatitis in prophylactic setting is very low (<0.15%) [40]
    2. The CDC recommends monthly liver function monitoring, especially in >35 years old
    3. INH is contraindicated in patients with known hepatic disease and chronic alcoholics
    4. Whether to stop INH if hepatitis occurs is controversial
    5. If symptoms (abdominal pain, jaundice) develop, the INH should be stopped
    6. If AST or ALT >5X normal, some authorities recommend stopping the drug
    7. In persons <35 years of age, hepatitis occurs due to mutations in NAT2 acetylase gene
  8. Prophylaxis in Drug Resistant Areas [10,12]
    1. No good studies evaluating any drug combination
    2. If suspected INH (only) resistance, give RIF 600mg qd x 6 months [52]
    3. If suspected INH and RIF resistance, CDC recommends ethambutol 12-25mg/kg qd with PZA 25-30mg/kg po qd
    4. An alternative is PZA + a fluoroquinolone
    5. Either ciprofloxacin 750mg po bid or ofloxacin 400mg po bid may be used
  9. Therapy Compliance
    1. Incomplete or delayed treatments are independent risks for death from TB
    2. In patients with HIV, delay of therapy by 1 month had >75% mortality
    3. Multidrug resistant (MDR) strains, even in HIV negative persons, had nearly 50% mortality
    4. Directly observed therapy is very effective at reducing spread in indigent populations
  10. Drug Interactions [38]
    1. Protease inhibitors and NNRTIs cannot be used with rifampin
    2. Rifabutin (but not RIF) can be used with indinavir, nelfinavir
    3. Rifabutin cannot be used with saquinavir, ritonavir, or nonnucleoside RT inhibitors
    4. Antiretroviral agents can be used with INH, PZA, ethambutol
    5. Cytochrome P450 enzyme inhibition is basis for the drug interactions

G. Treatment [4]navigator

  1. General Overview [4]
    1. Drug susceptible TB is usually treated for 6 months
    2. Induction for 2 months followed by continuation phase for 4 months
    3. Certain populations should be treated up to 9 months for lifelong
    4. Initiate induction therapy with 4 drugs in most cases for 2 months (see below)
    5. Repeat sputum for AFB after 2 months induction
    6. Continue maintenance therapy for additional minimum of 4 months
    7. If cavitation initially present on CXR, check cultures at 2 months
    8. If cultures positive 2 months after maintenance initiated, continue mainenance for 7 months
    9. HIV- patients with negative AFB after induction can switch to rifapentine+INH
    10. Initial drug resistance by TB associated with substantially worse outcomes [63]
  2. World Health Organization (WHO) Treatment Category I (Table 1 in Ref [1])
    1. New cases of smear positive pulmonary TB or severe extrapulmonary TB or
    2. Severe smear negative pullmonary TB or severe severe concomitant HIV disease
    3. Induction: INH+RIF+PZA+EMB or INH+RIF+PZA+STR 3 times/week (tiw) or daily for 2 months
    4. Daily INH+RIF+PZA+EMB leads to more rapid culture negativity than tiw regimen [17]
    5. Continuation: INH+RIF tiw or daily (qd) for 4 months, or INH+EMB qd for 6 months
    6. Continuation with INH+RIF for 4 months was superior to INH+EMB for 6 months [17]
  3. Treatment Category II (Table 1 in Ref [1])
    1. Previously treated smear positive pulmonary TB, relapse, or treatment failure
    2. Drug susceptibility testing recommended in any treatment failuree
    3. Induction: INH+RIF+PZA+EMB+STR tiw or qd x 2months, then 1 month INH+RIF+PZA+EMB
    4. Continuation: INH+RIF+EMB tiw or qd for 5 months
  4. Treatment Category III (Table 1 in Ref [1])
    1. New cases of smear negative pulmonary TB or less severe forms extrapulmonary TB
    2. Induction: INH+RIF+PZA+EMB tiw or qd for 2 months
    3. EMB may be removed from induction phase if known susceptible TB or noncavitary disease
    4. Continuation: INH+RIF tiw or qd for 4 months, or INH+EMB qd for 6 months
  5. Standard Drugs and Dosages [4,38,52]
    1. Isoniazid (INH) - 300mg (given with pyridoxine 25-50mg po qd)
    2. Rifampin (RIF) - 600mg (rifabutin or rifapentine can be substituted
    3. Pyrazinamide (PZA) - 20mg/kg/day, maximum 2gm qd
    4. Ethambutol (EMB) - 15-25mg/kg; stop this agent if organism is sensitive to the others
    5. Streptomycin (STR) may be substituted for EMB, especially in children, noncompliance
    6. STR - 15-30mg/kg IM or IV; maximum 1gm qd
    7. Rifamate® is 300mg RIF and 150mg INH - dose is usually 2 tabs
    8. Rifater® is 120mg RIF and 50mg INH - 4-6 tabs depending on weight
  6. Rifampin Substitutes
    1. Note important drug interactions with RIF, rifabutin, rifapentine (see above)
    2. Rifabutin may be substituted for RIF in HIV+ persons
    3. Rifabutin: children 10-20mg/kg, adults 5mg/kg, maximum 300mg
    4. Rifapentine (Priftin®) - long acting RIF analog 600mg one or twice weekly [39,55]
    5. Rifapentine 600mg + INH 900mg once weekly effective in HIV- TB [55]
    6. Rifapentine is reserved for compliant, HIV- persons, AFB smear negative [4]
  7. Monitor Liver Function Tests (LFTs)
    1. For INH treatment alone, monitor LFTs only if symptomatic
    2. Consider switching or discontinuing offending agent if >3X elevation in AST, ALT
    3. May substitute INH or RIF with another drug such as ciprofloxacin
    4. RIF + PZA for 2 months associated with 8% grade 3 or 4 hepatotoxicity [56]
    5. Therefore, RIF+PZA must be monitored closely and alcohol not used
  8. TB Meningitis
    1. Highest at risk group is indigent urban population
    2. Fever, abnormal mental status and headache most common
    3. Presentation unaltered in HIV+ persons including CSF findings
    4. Treatment should include glucocorticoids to reduce cerebral inflammation
    5. Dexamethasone (0.4mg/kg/d week 1, 0.3mg/kg/d week 2, 0.2mg/kg/d week 3, and
  9. 1mg/kg/d week 4) improved survival in moderate and severe TB meningitis [61]
    1. Treatment should be initiated with four (or 3) agents in non-MDR areas
    2. Course is generally >12 months
  10. Treatment is >12 months for disseminated TB or TB osteomyelitis
  11. In patients with HIV or known malabsorption, assess serum levels of RIF and PZA [29]

H. Multidrug Resistant (MDR) TB [1] navigator

  1. Defined as resistance to INH and RIF
  2. Risk Factors
    1. HIV Infection
    2. Intravenous drug abuse (IVDA)
    3. Malnourishment is also a risk factor
    4. Partial treatment of susceptible infections appears to be major contributor
    5. Healthcare workers at increased risk for contraction
  3. Prevalance
    1. Up to 33% of isolates in New York City in hospitals, >90% nosocomially transmitted
    2. Rate of 1-2% of total TB cases in 1994-2003 surveys in California [19]
    3. Overall worldwide rate of MDR TB was ~2% [36] but up to 14% in some areas [48]
    4. High levels of MDR TB (>6.5% of new cases) in former Soviet Union, areas of China [26]
    5. Hong Kong and USA with reduced levels of MDR TB [26]
    6. Single drug resistances to isoniazid and streptomycin is more common (~10%) [36]
  4. Mean time from diagnosis until death 4-8 months in HIV
  5. Response to Anti-TB Therapy [49,58]
    1. Within 3 months of therapy, ~50% converted sputum cultures to negative [58]
    2. Overall, ~75% of patients with MDR TB converted sputum cultures to negative [58]
    3. High colony count in initial sputum, bilateral cavitary lesions, history of treatment for MDR TB all predicted delay in conversion of sputum culture to negative [58]
    4. Treatment must be continued 12-18 months after culture negativity documented [1]
    5. At least 3 active drugs are used
    6. HIV negative patients with MDR TB respond well to appropriate therapy
    7. About 10% of patients were treatment failures
    8. Surgical resection may improve outcomes, particularly with bilateral cavitary lesions
  6. "Reserve" Agents [1,52]
    1. Capreomycin (IV, IM): children 15-30mg/kg; adults 15mg/kg; maximum 1000mg
    2. Ciprofloxacin (PO, IV): 750mg bid
    3. Cycloserine (PO): children 15-20mg/kg; adults 500-1000mg; divided doses
    4. Ethionamide (PO): children 7.5-10mg/kg bid; adults 250mg bid or tid
    5. Kanamycin / Amikacin (IM, IV): chilren 15-30mg/kg, adults 15mg/kg; maximum 1000mg
    6. Levofloxacin (PO, IV): adults 500-1000mg
    7. Moxifloxacin (PO, IV): 400mg
    8. Ofloxacin 400mg bid
    9. Para-Aminosalicylic acid (PO): children 150mg/kg; adults 4gm q12 hour; maximum 12 gm
  7. INH Resistance [38]
    1. HIV- persons receive RIF+PZA+ETH for 6 months
    2. HIV+ persons receive same (or rifabutin for RIF) for 6-9 months
    3. Note drug interactions between RIF and rifabutin (see above)
  8. RIF Resistance [38]
    1. HIV- persons receive INH+PZA+ETH for 18-24 months
    2. HIV+ persons receive INH+PZA+ETH for 18-24 months OR
    3. HIV+ persons receive INH+PZA+ETH+Streptomycin for 2 months, then INH+PZA+ Streptomycin for 7-10 months
  9. Aerosolized interferon gamma can suppress local disease [9]
    1. Dose was 500µg three times a week for one month
    2. Reduction in sputum smear TB counts, reduction in cavitary lesion size
    3. Disease recurred when drug was stopped, but it was well tolerated
    4. Reasonable investigational agent which stimulates macrophage killing of TB

I. Prevention [11]navigator

  1. Persons Exposed to TB
    1. Treat contacts (with INH or other) of confirmed TB cases regardless of PPD status
    2. May discontinue treating contacts of TB+ patients if PPD negative after 3 months
    3. Previous BCG vaccination of children appears to reduce TB infection from close contacts [22]
  2. Yearly PPD testing of individuals at high risk for exposure
  3. Vaccination with BCG [18,33]
    1. Purified derivatives of Mycobacterium bovis (Bacillus Calmette-Guerin, BCG) are used
    2. BCG vaccination has consistently shown ~50% reduction in MTB [18,50]
    3. BCG related delayed hypersensitivity responses correlate with protective markers of mycobacterial immunity [41]
    4. BCG induction of interferon gamma (measured in ELISpot T cell assay) likely provides future protection against TB [54]
    5. BCG revaccination to children ages 7-14 years does not provide additional protection [59]
    6. Children with BCG vaccination have 40% lower risk of contracting TB from infected household contacts than children without vaccination [22]
    7. BCG vaccination is highly cost effective and clearly reduces meningitis, miliary TB [33]
    8. Novel vaccines are being developed as BCG vaccine use has not reduced prevalence [27]
  4. INH Prophylaxis
    1. Prophylaxis for 6-12 months is extremely effective for prevention
    2. INH usually given as 300mg qd for 6 months to persons in contact with active TB
    3. INH is not recommended to anergic patients with HIV unless exposed to active TB
    4. It is clear that HIV+ persons with positive PPD benefit from INH prophylaxis [35]
    5. HIV+ patients may be given 600-800mg/day INH
    6. HIV+ patients with one episode of TB should receive INH prophylaxis for 1 year following completion of their initial treatment [47]
    7. Pyridoxine 25mg po qd should be given to all patients taking INH
  5. RIF Alone
    1. 600mg po qd x 4 months
    2. May be effective in both HIV+ and HIV- persons
  6. PZA with either Rifampicin or RIF
    1. May be given for 2 months for prevention in exposed patients
    2. As effective as INH for prevention of TB in HIV+ patients [35,43]
    3. Equally effective for prevention in HIV+ when dosed daily or twice weekly [37]
    4. Most cost effective and best tolerated regimen for prophylaxis in HIV+ persons [37]
    5. Incidence of grade 3 or 4 hepatotoxicity with 2 month course is 8% [56]
    6. Stongly consider RIF + pyrazinamide over INH in HIV+ patients [43]
    7. Frequent LFT monitoring is required with this combination
  7. Exposure to Resistant TB [52]
    1. RIF 600mg/d ± ethambutol or
    2. Fluoroquinolone (such as ofloxacin) may be effective
  8. Maintain high index of suspicion and isolate suspected cases

References navigator

  1. Frieden TR, Sterling TR, Munsiff SS, et al. 2003. Lancet. 362(9387):887 abstract
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