Whats an IGRA and how do I use it

1
Whats an IGRA and how do I use it?

• Jae Yang
• Medical Director of the TB Program
• St. Michaels Hospital
• December 14, 2007

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DECLARATION

• I have nothing to disclose and no conflicts of
  interest.

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IGRA
Oxford Immunotec T-SPOT.TB
Cellestis QuantiFERON-TB Gold In-Tube
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CASE 1

• 44 year old immunocompetent man, born in Canada,
  is a household contact of his mother who was
  diagnosed with active pulmonary TB.
  Should an IGRA be used to see if he has
  been infected?

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CASE 2

• A 30 year old man born in China is being
  considered for a TNF-alpha inhibitor for his IBD.
  He is currently on other immunosuppressants.
  Should an IGRA be done instead of a TST?

6
CASE 3

• A 40 year old woman born in the Phillipines but
  in Canada for 20 years is going to become a
  personal support worker. She had the BCG during
  grade school. Should an IGRA be done if she is
  TST positive?

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IGRA

• Interferon
• Gamma
• Release
• Assay
• THEORY A persons T-cells that previously were
  sensitized to TB antigen produce high levels of
  IFN-gamma when re-exposed to the same
  mycobacterial antigen.

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IGRA

• Two currently available in Canada
• T-SPOT.TB
• QuantiFERON-TB Gold In-Tube
• No antigens in the above tests are found in BCG.
  Therefore, no false positives from BCG!!
• Only M. leprae, M. kansasii, M. marinum, M.
  szulgai and M. flavescens cross react with above.

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IGRA
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IGRA

• Why do we get indeterminate results?
• Poor patient immune function
• Incorrect sample collection, handling, incubation
  or delay in processing
• Other technical factors.

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IGRA

• T-SPOT.TB
• Uses TB specific antigens ESAT-6 and CFP-10
• 8 cc of blood is collected and the peripheral
  blood mononuclear cells (PBMC) are washed,
  isolated and exposed to the above antigens.
  Incubate overnight and the number of T-cells
  producing IFN-gamma are counted
• Not many indeterminates more laboratory
  intensive

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IGRA

• QuantiFERON-TB Gold In-Tube
• 3 cc of blood is collected and exposed to ESAT-6,
  CFP-10 and TB7.7 antigens.
• Incubated overnight and plasma removed and
  assayed for IFN-gamma levels using ELISA.
• Arbitrary cutoff for level of positives and more
  indeterminate results.

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IGRA

• CDC in 2005 Guidelines for the Investigation of
  Contacts of Persons with Infectious Tuberculosis
  recommended the QFT-G assay MAY be used in place
  of the TST for all indications. (Dr. Vernon)

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IGRA

• UK 2006 National Institute for Health and
  Clinical Excellence TB guidelines recommended an
  initial screen with TST and subsequent IGRA
  testing (if available) to those who are TST
  positive (or if TST may be unreliable) to confirm
  the TST results.

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IGRA

• Swiss recommendations for screening for TB before
  initiation of anti-TNF-alpha therapy
• Swiss Med Wkly 2007 137621-622. (November 3,
  2007) (Official journal of the Swiis ID, GIM and
  Resp Societies.)
• Recommend screening using history, CXR and IGRA
  instead of TST.
• Indeterminates means using only the history and
  CXR with a conservative approach.

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IGRA

• 2007 Canadian TB Committee Interferon Gamma
  Release Assays for Latent TB Infection
  guidelines released November 1, 2007.
• Based on review of the literature and expert
  opinion as of October 2006.
• http//www.phac-aspc.gc.ca/publicat/ccdr-rmtc/07vo
  l33/acs-10/index-eng.html
• Yangj_at_smh.toronto.on.ca

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2007 Canadian Guidelines

• Precise indication for use and interpretation of
  the results of IGRAs is uncertain at this time.
• 1. SERIAL TESTING
• Insufficient published evidence to recommend
  serial IGRA testing in populations exposed to TB
  (ie. Health care workers). Serial screening for
  LTBI should continue with TST.

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2007 Canadian Guidelines

• 2. DIAGNOSIS OF LTBI IN CHILDREN
• After literature review, unclear if IGRAs are
  equivalent, better of worse than TST.
• Therefore, IGRAs are not recommended in children
  until published evidence is consistently
  demonstrating the utility and accuracy of these
  tests in pediatric populations.

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2007 Canadian Guidelines

• 3. IMMIGRANT SCREENING
• CTS does not recommend mass screening of
  immigrants with TST since not cost-effective
  since there is substantial non-adherance to
  screening, follow-up and LTBI treatment.
• However, foreign born have a higher prevalence of
  LTBI and they should be targeted for LTBI
  screening if they have a clinical condition that
  increases their risk of reactivation.

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2007 Canadian Guidelines

• Clinical conditions that increase risk of
  reactivation
• HIV
• Transplant
• Silicosis
• Renal failure requiring dialysis
• Carcinoma of head and neck
• Recent TB infection (lt 2 years)
• Abnormal CXR
• Steroid treatment
• TNF-alpha treatment

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2007 Canadian Guidelines

• Diabetes
• Underweight (BMI lt 20)
• Cigarette smoker
• Children lt 15 who have lived in a country with
  high TB incidence and have immigrated within the
  last 2 years.
• People gt 15 who have lived in a country with high
  TB incidence, have immigrated within the last 2
  years and have been living with or in known
  contact with a TB case or are at high risk of
  development of active TB.

High TB incidence is WHO (sputum smear pos) gt
15/100 000
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2007 Canadian Guidelines

• 3. IMMIGRANT SCREENING (cont.)
• Routine or mass screening for LTBI of all
  immigrants, with either TST or IGRA is NOT
  recommended. However, targeted screening is
  recommended for foreign born individuals with
  clinical conditions that increase their risk of
  reactivation and the TST should be used.

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2007 Canadian Guidelines

• 4. CONTACTS OF A CASE OF ACTIVE
  
  
  INFECTIOUS TB
• Several studies compared the 2 IGRAs to TSTs in
  the context of contact investigation.
• The majority of these studies showed that the
  sensitivity of positives were similar for TSTs
  and IGRAs in non-BCG vaccinated individuals but
  in BCG vaccinated individuals, there were fewer
  positive IGRA results in the low-exposure groups.

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2007 Canadian Guidelines

• When the pretest probability of infection is high
  (ie. household) or the person has an increased
  risk of progression to active disease if
  infected, it is important to identify these
  individuals so a TST (or both TST and IGRA)
  should be used and if either if positive, the
  contact should be considered to have LTBI.

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2007 Canadian Guidelines

• If the pretest probability is low and the person
  has no risk for progression to active disease if
  infected, IGRA testing may be used as a
  confirmatory test for a positive TST (especially
  in BCG vaccinated individuals) to reduce the
  likelihood of administering treatment for LTBI to
  persons with false positive TSTs.

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2007 Canadian Guidelines

• IF both TST and IGRA testing will be used, it is
  recommended that blood be drawn for IGRA before
  or on the same days as placing the TST since some
  animal studies have shown that TST might boost
  subsequent measurements of IFN-gamma.

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2007 Canadian Guidelines

• 5. IMMUNOCOMPROMISED INDIVIDUALS
• Very limited published data
• TST should be the initial test used in
  immunocompromised people and if TST positive,
  should be considered to have LTBI.
• However, due to high TST negativity in
  immunocompromised, an IGRA could be done if the
  initial TST is negative.

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2007 Canadian Guidelines

• If IGRA positive, consider as LTBI.
• If IGRA indeterminate, repeat and if
  indeterminate again, use clinical history to make
  a decision concerning likelihood of LTBI
• If IGRA negative, no LTBI.
• By accepting either positive TST or IGRA,
  sensitivity of detecting LTBI in
  immunocompromised populations is achieved.

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2007 Canadian Guidelines

• However, a meta-analysis of 5 studies showed that
  INH was of no benefit in TST-negative HIV
  patients from a high incidence area.
• Therefore, by finding more IGRA positive
  immunocompromised patients, it is unclear whether
  they will benefit from INH therapy of their LTBI

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2007 Canadian Guidelines

• 6. LOW RISK PERSONS WITH A POSITIVE TST RESULT
• Confounders BCG and Non-tuberculous mycobacteria
• IF TST , immunocompetent, low risk of LTBI and
  no risks for reactivation, an IGRA may be
  performed and no treatment offered if IGRA
  negative.

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2007 Canadian Guidelines

• 7. DIAGNOSIS OF ACTIVE TB DISEASE
• IGRA sensitivity in active TB has been found to
  be comparable to the sensitivity of TST (up to
  30 negative). This reflects the diminished
  immune response in patients with active TB
  particularly in those with more advanced disease,
  malnutrition or older age.
• Therefore, IGRAs are NOT recommended for the
  diagnosis of active TB.

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2007 Canadian Guidelines

• SPECIAL SITUATIONS
• IGRA indeterminate results
• Repeat and if still indeterminate, base on TST or
  clinical situation

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2007 Canadian Guidelines

• SUMMARY
• IGRAs not recommended for
• 1. Serial testing
• 2. Children
• 3. Immigrant screening
• 7. Diagnosing active TB

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2007 Canadian Guidelines

• SUMMARY
• IGRAs are recommended for
• 4. Contacts of active TB
• Close contacts (HIGH RISK) can get both TST and
  IGRA and if either is positive, be treated for
  LTBI
• Casual contacts (LOW RISK) can have IGRA
  confirmation if TST positive to verify infection
  vs BCG or MOTT
• 5. Immunocompromised
• TST first, if negative do IGRA and if IGRA
  positive treat as LTBI
• 6. Low risk people who are TST positive
• Do an IGRA, if positive consider as LTBI

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2007 Canadian Guidelines

• Costs
• TST costs approximately 14 in public health
  settings
• IGRAs are considerably more expensive and some
  IGRAs (TspotTB) require more lab and technical
  time and also they need blood drawn
• Thus, most cost-effective in populations with
  high BCG vaccinations after infancy.

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CASE 1

• 44 year old immunocompetent man, born in Canada,
  is a household contact of his mother who was
  diagnosed with active pulmonary TB.
  
• Should an IGRA be used to see if he has been
  infected?

• Start with TST. If negative, consider doing an
  IGRA. If IGRA positive, treat as infected.

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CASE 2

• A 30 year old man born in China is being
  considered for a TNF-alpha inhibitor for his IBD.
  He is currently on other immunosuppressants.
  Should an IGRA be done instead of a TST?

• Do TST if TST, no need for IGRA. If TST-, do
  an IGRA and if IGRA consider as having LTBI.

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CASE 3

• A 40 year old woman born in the Phillipines but
  in Canada for 20 years is going to become a
  personal support worker. She had the BCG during
  grade school. Should an IGRA be done if she is
  TST positive?

• YES