LA LaTENT TUBERCULOSIS INFECTION LTBI: Diagnosis and Treatment

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LALaTENT TUBERCULOSIS INFECTION
(LTBI)Diagnosis and Treatment

• Allen Radner, M.D.

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OUTLINE

• 1. Epidemiology and Pathophysiology
• 2. Who should be tested for LTBI?
• 3. How should we test for LTBI?
• 4. How should we treat LTBI?
• American Thoracic Society and Centers for Disease
  Control and Prevention. Targeted Tuberculin
  Testing and Treatment of Latent Tuberculosis
  infection. American Thoracic Society. MMWR
  Recomm Rep 2000 49 (RR-6) 1-51CDC.
• Update Adverse Event Data and Revised ATS/CDC
  Recommendations Against the Use of Rifampin and
  Pyrazinamide for treatment of latent tuberculosis
  United States, 2003. MMWR Wkly Rep 2003
  52735-9.

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TUBERCULOSIS

• 1. Caused by Mycobacterium tuberculosis.
• 2. Common worldwide
• 1.7 billion (1/3 of Worlds population)
  infected
• 8 million new cases/yr 2 million deaths
• 11 million people in the U.S. infected

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PATHOPHYSIOLOGY

• 1. Transmission
• Inhalation of respiratory droplets ? bacillus
  deposited in alveolus. Engulfed by macrophages.
• 2. Infection, Proliferation, and Dissemination
• Bacilli may survive and proliferate, kill
  macrophages ? replicates at primary focus and in
  lymphohematogenous metastatic foci
• 3. Host Response (Cell-Mediated Immunity)
• Macrophages present antigens to T-cells (CD4
  lymphocytes) ? lymphs proliferate, activate
  macrophages , secrete regulatory factors (TNF-?
  , interferon-? )? microbicidal (cellular
  immunity) get involution of primary lesion /
  granuloma formation (epitheliod cells/Langerhans
  giant cells are highly stimulated macrophages)
  (3-9 wks?)
• 4. Liquefaction and Proliferation
• Reactivation with cavity formation.
• Three major outcomes
• CXR Findings

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KEY POINTS

• 1. Contained infection known as LTBI
• Positive PPD patient
• 2. 10 of those infected develop active
  disease
• Risk of developing active disease a function of ?
  time from acquisition and certain co-existent
  illnesses
• 3. Important to distinguish infection from
  active disease!

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WHO SHOULD WE TEST FOR LTBI?
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WHO SHOULD WE TEST FOR LTBI?
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Who Should be Tested for LTBI?

• 1. Test those at high risk for developing
  active disease.
• 2. Why? - Good evidence that treatment of LTBI
  reduces likelihood of developing active disease
  (and reducing transmission)
• However given risks of treatment and limited
  resources current recommendation is Targeted
  Testing

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PERSONS AT RISK FOR DEVELOPING ACTIVE TB

• Target those recently infected and those at
  greatest risk of developing active disease.
• Of those who develop active disease 50 in 1st
  yr, 80 with 2 yrs (Adv Tuberc Res 1980
  201-63)
• Multiple co-existent conditions increase the
  risk of developing active disease

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LTBI TESTING

• 1. Annual Screening - HIV, ongoing contact with
  cases of active TB (health care workers, prison
  guards) , medical conditions increasing the risk
  of TB, underserved, low income population (e.g.
  homeless, IVDU) and residence in long-term care
  facilities.
• 2. Single Test a single exposure to TB,
  incidentally discovered fibrotic lung lesion,
  immigrants from countries with high TB prevalence
  (Latin America, Asia, Africa)
• Test those with recent TB exposures and/or at
  risk of developing active TB. Do not test if low
  risk of exposure or development of active disease.

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LTBI TESTINGMethodology and Interpretation

• PPD
• 1. Cutaneous (CMI) reaction to concentrated M.
  tuberculosis antigens
• 2. Takes 2-12 wks to develop
• 3. Interpretation based on desire to maximize
  sensitivity and specificity. Different criteria
  based on prior probability of true TB infection.
• - Three measurement groups

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PPD (TST) TESTING METHODOLGY
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PPD INTERPETATION NEJM 20023471860-6
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ISSUES RELATED TO TST

• Placement and interpretative variability
• 2 step process
• New positive?
• Boosting
• DTH wanes with time.
• False positive TST with MOTT/NTMB including BCG
• History of BCG should be ignored.
• 8 of infants given BCG had PPD 15 yrs later
  (Am Rev Respir Dis 1992 145621-5)
• Limited utility of Controls

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IGRA Testing

• Test of interferon-gamma release from
  T-lymphocytes after stimulation to M.
  tuberculosis antigens
• Advantages
• Does not cross react with MOTT
• 1 stop testing
• Less subjective
• Predictive of developing active disease

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IGRA Testing Key Points

• Like TST test individuals at increased risk for
  developing active TB (who will benefit from
  treatment)
• QFT-G can be used in all circumstances in which
  the TST is used

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WHO SHOULD BE TREATED FOR LTBI?
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LTBI TREATMENT

• Who Should be Treated?
• Risk of active disease vs. side effects, costs,
  efficacy
• Treat infected persons at high risk of developing
  disease regardless of age
• Non- urgent - Exclude Active Disease!!!! (Hx,
  PE, CXR)

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MEDICATIONS
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LTBI TREATMENT

• Isoniazid (INH)
• Preferred
• 60 effective (25-92) (Bibl Tuberc
  19702628-106)
• 6 mo course inferior to 12 mo. Subgroup
  analysis max benefit by 9 mo. (Bull World Health
  Organ 1982 60555)
• Compliance 3-60 (20-30) with 6 mo
  self-administered course
• Hepatotoxicity
• Interference with pyridoxine metabolism (Vit B6
  if risk of neuropathy - alcoholic, pregnant, DM,
  malnourished)

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LTBI TREATMENT

• Rifampin
• Daily dose x 4 mo
• Hepatotoxicity / Drug interactions
• INH/Rifampin
• Daily dose x 3 mo
• Rifampin/PZA
• 2 mo course similar to 12 mo INH in HIV
• In general pop sig increased risk of
  hepatoxicity/death
• NOT RECOMMENDED

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LTBI TREATMENT

• Other issues
• DOT (2x/wk)
• Infection with drug-resistant TB
• Pregnancy
• Incomplete course of therapy
• Intolerance/contraindications to medications

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MONITORING

• Emphasis on clinical rather than routine
  laboratory monitoring recommended.

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DRUG MONITORING

• Clinical Monitoring
• Education about the signs/symptoms of liver
  dysfunction.
• Follow-up monthly to question about problems and
  do physical exam
• Documentation

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DRUG MONITORING

• Laboratory Monitoring
• Liver disease, HIV, pregnant, post-partum,
  regular use of ETOH
• Baseline and Follow-up LFTS

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SUMMARY

• Screen (only) those at risk of getting active
  disease
• PPD interpretation (and decision to treat) based
  on risk of getting active disease
• Consider IGRA testing
• Before beginning therapy - differentiate LTBI
  from active disease
• Treat with INH x 9 months.
• Monitor clinically

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REFERENCES

• American Thoracic Society and Centers for Disease
  Control and Prevention. Targeted Tuberculin
  Testing and Treatment of Latent Tuberculosis
  infection. American Thoracic Society. MMWR
  Recomm Rep 2000 49 (RR-6) 1-51CDC.
• Update Adverse Event Data and Revised ATS/CDC
  Recommendations Against the Use of Rifampin and
  Pyrazinamide for treatment of latent tuberculosis
  United States, 2003. MMWR Wkly Rep 2003
  52735-9.
• CR Horsburgh Jr. Priorities for the Treatment of
  Latent Tuberculosis in the United States. NEJM
  2004 3502060-7
• Cohn DL. Treatment of Latent Tuberculosis
  Infection Renewed Opportunity for Tuberculosis
  Control. Clinical Infectious Diseases 2000
  31120-4.
• Jasmer RM. Nahid P, Hopewell PC. Latent
  Tuberculosis Infection. NEJM 20023471860-6.