TB Surveillance Using TB Surveillance Using QuantiFERONQuantiFERON® ® -TB Gold-TB Gold

Is it measuring up?Is it measuring up?

Dr. David Marder, MD, MPHDr. David Marder, MD, MPH

Medical Director of University Health ServiceMedical Director of University Health Service

University of Illinois Medical Center Chicago University of Illinois Medical Center Chicago

Areas of Concern

•Estimated 10-15 million persons in U.S. infected

with M. tuberculosis (60-90 M worldwide)

Roughly 2-3 million deaths per year (worldwide)

•Drug-resistant cases reported in almost every state

- Without intervention, about 10% will develop

TB disease at some point in life

Problems with TST…Problems with TST…Poor inter-reader reliabilityPoor inter-reader reliability

9 mm (negative) vs. 10mm (positive)?9 mm (negative) vs. 10mm (positive)?False-positives/specificityFalse-positives/specificity

NTM infectionNTM infection Prior BCGPrior BCG

Poor positive-predictive value in low prevalencePoor positive-predictive value in low prevalence populations (like US)populations (like US)

Cost/time of patient visitsCost/time of patient visits Unread testsUnread tests

Sensitivity?Sensitivity? Reaction wanes over timeReaction wanes over time Lack of gold standardLack of gold standard

TB and the 21st Century; Introducing QuantiFERON® TB Gold ‘‘In-Tube’”

In the field:• TB specific antigen, Nil &Mitogen tubes• Blood collected directly into tubes

In the lab:

• ELISA for detection of IFN gamma IFN-

TB-Specific antigens TB-Specific antigens (ESAT-6, CFP-10, TB7.7) (ESAT-6, CFP-10, TB7.7)

Absent from BCGAbsent from BCG

Absent from most NTMAbsent from most NTM

Produced as synthetic peptidesProduced as synthetic peptides

Only stimulate T-cells in infected Only stimulate T-cells in infected

peoplepeople

Species specificity of QFTTM TB Antigens

Tuberculosis ComplexESAT-6 CFP-10 TB7.7 Environmental strains

ESAT-6 CFP-10 TB7.7

M tuberculosis + + + M abcessus - - - M africanum + + + M avium - - - M bovis + + + M branderi - - -

M celatum - - -BCG substrain M chelonae - - - gothenburg - - - M fortuitum - - - moreau - - - M gordonii - - - tice - - - M intracellulare - - - tokyo - - - M kansasii + + - danish - - - M malmoense - - - glaxo - - - M marinum + + - montreal - - - M oenavense - - - pasteur - - - M scrofulaceum - - -

M smegmatis - - - M szulgai + + - M terrae - - - M vaccae - - - M xenopi - - -

QuantiQuantiFERONFERON®®-TB GOLD-TB GOLD

Offers fundamental advantages over the TST:Offers fundamental advantages over the TST: Single Patient VisitSingle Patient Visit

• 100% results, No need to follow up on 100% results, No need to follow up on negativesnegatives

• Contacts, Homeless, Jail inmatesContacts, Homeless, Jail inmates Unaffected by BCG and NTMUnaffected by BCG and NTM

• Highly specific testHighly specific test• Reduces false positivesReduces false positives

Better detection of active TBBetter detection of active TB• Increased sensitivity for active TBIncreased sensitivity for active TB

QuantiQuantiFERONFERON®®-TB GOLD-TB GOLDAlso:Also: Objective and controlled testObjective and controlled test

• Reduces subjectivity in TB diagnosisReduces subjectivity in TB diagnosis Simple diagnostic cut-offSimple diagnostic cut-off

• Straight forward positive/negative interpretation Straight forward positive/negative interpretation Eliminates 2 step testingEliminates 2 step testing No ‘booster’ effectsNo ‘booster’ effects Faster turn-around, results in 24 - 48 hoursFaster turn-around, results in 24 - 48 hours Results are electronic (computer generated Results are electronic (computer generated

reports)reports)

QuantiQuantiFERONFERON®®-TB GOLD-TB GOLDAdvantages (cont.)Advantages (cont.)

Reduces unnecessary CXR and prophylaxisReduces unnecessary CXR and prophylaxis

Reliable detection of post exposure LTBIReliable detection of post exposure LTBI

Not subject to reader biasNot subject to reader bias

QuantiFERONQuantiFERON ® ® TB-Gold TB-Gold Implementation at UICMCImplementation at UICMC

First Brought up at TB Sub-First Brought up at TB Sub-Committee MeetingCommittee Meeting

Multidisciplinary approach involving Multidisciplinary approach involving Pulmonary, Infection Control, Pulmonary, Infection Control, Employee Health, Infection Disease, Employee Health, Infection Disease, Laboratory and Environmental Health Laboratory and Environmental Health and Safety Departmentand Safety Department

Review of the LiteratureReview of the Literature

University Health Service at University Health Service at UICMC QuantiFERONUICMC QuantiFERON ® ® TB- TB-

GOLD Pilot ProgramGOLD Pilot Program

University Health Services (UHS) began exploring University Health Services (UHS) began exploring the new gamma-interferon assay in June 2005 as the new gamma-interferon assay in June 2005 as an alternative to the PPD skin test for screening an alternative to the PPD skin test for screening Health Care Workers.Health Care Workers.

With the University of Illinois Medical Center With the University of Illinois Medical Center Chicago (UIMCC) laboratory, a pilot project began Chicago (UIMCC) laboratory, a pilot project began in August 2005.in August 2005.

Full implementation of the Quantiferon surveillance Full implementation of the Quantiferon surveillance program in January 2006.program in January 2006.

Moving forward w/ Pilot StudyMoving forward w/ Pilot Study

Support from Hospital AdministrationSupport from Hospital Administration Support from the Lab and Support from the Lab and

Phlebotomy staff to assist w/ blood Phlebotomy staff to assist w/ blood collection and turn around time on collection and turn around time on resultsresults

Recruitment of employee’sRecruitment of employee’s• Positive PPD groupPositive PPD group• Negative PPD groupNegative PPD group

PILOT SUBJECTSPILOT SUBJECTS

79 health care workers were 79 health care workers were recruited for the pilot program from recruited for the pilot program from the following 3 groups:the following 3 groups:• TST negativeTST negative• TST positive/BCG negativeTST positive/BCG negative• TST positive/BCG positiveTST positive/BCG positive

PILOT RESULTSPILOT RESULTS

25 out of 37 (68%) of previous TST 25 out of 37 (68%) of previous TST positive were Quantiferon negative. positive were Quantiferon negative. • In the BCG group alone, 11 (65%) were TST In the BCG group alone, 11 (65%) were TST

positive and Quantiferon negative.positive and Quantiferon negative.

The decrease in positive TB tests will The decrease in positive TB tests will increase the number of employees who increase the number of employees who can affectively be screened for TB in the can affectively be screened for TB in the future with Quantiferon as opposed to future with Quantiferon as opposed to the monitoring of symptoms by the monitoring of symptoms by questionnaire as done in the past. questionnaire as done in the past.

PILOT RESULTSPILOT RESULTS

TST - TST + TST +/BCG

QFT + 0 6 6

QFT - 42 14 11

We Did It!We Did It!

The Illinois Department of Public Health changes The Illinois Department of Public Health changes

Tuberculosis screening law Tuberculosis screening law   Control of Tuberculosis CodeControl of Tuberculosis Code

(77 Ill. Adm. Code 696) (77 Ill. Adm. Code 696)

  

Illinois Register Citation: 32 Ill. Reg. 4010 Illinois Register Citation: 32 Ill. Reg. 4010

  

Date Published: March 14, 2008Date Published: March 14, 2008

  

Effective Date: February 29, 2008 Effective Date: February 29, 2008

The current rules on tuberculosis (TB) cover the screening, treatment, testing, management The current rules on tuberculosis (TB) cover the screening, treatment, testing, management and reporting requirements for persons with active or suspected of TB, having TB and reporting requirements for persons with active or suspected of TB, having TB disease or latent TB infection (LTBI). The rules previously required the use of the disease or latent TB infection (LTBI). The rules previously required the use of the Mantoux tuberculin skin test (TST) as the only test approved for screening for LTBI. The Mantoux tuberculin skin test (TST) as the only test approved for screening for LTBI. The amendment allows the use of a newly developed FDA-approved blood test for the amendment allows the use of a newly developed FDA-approved blood test for the detection of patients with active TB disease or LTBI. The amendment only adds the use detection of patients with active TB disease or LTBI. The amendment only adds the use of the new FDA approved blood test as an approved test for screening patients and does of the new FDA approved blood test as an approved test for screening patients and does not remove the TST as an approved test for screening.not remove the TST as an approved test for screening.

UIMCC TB Control PlanUIMCC TB Control Plan IDPH - Tuberculosis Prevention and Exposure IDPH - Tuberculosis Prevention and Exposure

Control Plan, Section 7, Employee Surveillance: Control Plan, Section 7, Employee Surveillance: Previously only TST approved. Previously only TST approved.

IC Committee approved changes to the policy to IC Committee approved changes to the policy to include “…the current screening methodology include “…the current screening methodology which may include PPD, QuantiFERON-TB Gold, which may include PPD, QuantiFERON-TB Gold, and any other approved /newly developed and any other approved /newly developed test…” November 2005.test…” November 2005.

At this time QuantiFERON TB-Gold is the At this time QuantiFERON TB-Gold is the recommended form of testing for all Medical recommended form of testing for all Medical Center employees.Center employees.

Pre-Employment ScreeningPre-Employment Screening

At the time of employment, all At the time of employment, all UIMCC employees including those UIMCC employees including those with a history for BCG vaccine shall with a history for BCG vaccine shall receive a receive a tuberculosis screening tuberculosis screening testtest, such as QuantiFERON, such as QuantiFERON® ® -TB -TB Gold (QFT-G), or any other Gold (QFT-G), or any other approved test.approved test.

Pre-Employment Cont.Pre-Employment Cont.

All employees that have a positive All employees that have a positive tuberculosis screening testtuberculosis screening test will be referred will be referred for a chest x-ray and medical evaluation. for a chest x-ray and medical evaluation. The employee shall be provided with The employee shall be provided with documentation of his/her test results and documentation of his/her test results and instructed to consult with a personal instructed to consult with a personal physician regarding prophylactic therapy. physician regarding prophylactic therapy. A positive A positive tuberculosis screening testtuberculosis screening test will will not affect employment status unless not affect employment status unless active TB disease is present active TB disease is present

Annual Surveillance Annual Surveillance

All employees employed by UIC All employees employed by UIC Medical Center and all those Medical Center and all those employed elsewhere that have employed elsewhere that have patient contact shall have repeat patient contact shall have repeat tuberculosis screening testtuberculosis screening test (annually (annually or semi-annually in accordance with or semi-annually in accordance with their unit or department schedule).their unit or department schedule).

An overview of An overview of UIMCC’s first year of UIMCC’s first year of

QuantiFERONQuantiFERON®® testingtesting

2006 RESULTS2006 RESULTS

A total of A total of 46434643 QuantiFERON tests QuantiFERON tests were completed in were completed in 2006.2006.• 4313 Negative 4313 Negative

(92.9%)(92.9%)• 140 Positive (3.0%)140 Positive (3.0%)• 190 Indeterminate 190 Indeterminate

(4.1%)(4.1%)NegativePositiveIndeterminate

2006 RESULTS2006 RESULTS

Positive Rate

0.00%

5.00%

10.00%

15.00%

20.00%

2005 (TST) 2006 (QFT) 0

1000

2000

3000

4000

5000

6000

2005 (TST) 2006 (QFT)

Negative

Positive

A subset of the previous TST positive A subset of the previous TST positive received QFT. 365 of the 505 were QFT received QFT. 365 of the 505 were QFT negative (72%).negative (72%).

Cost Evaluation ConsiderationsCost Evaluation ConsiderationsIs QFT Cost Effective?Is QFT Cost Effective?

Amount of collection timeAmount of collection time SuppliesSupplies Cost of testCost of test Laboratory support, time and costLaboratory support, time and cost Nurse timeNurse time

Other Possible Cost Evaluation Other Possible Cost Evaluation ConsiderationsConsiderations

Cost of medication and associated Cost of medication and associated side effectsside effects

Convenience for employeesConvenience for employees Employee time away from workEmployee time away from work # of visits to employee health# of visits to employee health Failure of ppd readsFailure of ppd reads

PROGRAM REVIEW ANALYSISPROGRAM REVIEW ANALYSIS

A cost benefit analysis was A cost benefit analysis was done in September.done in September.• It showed considerable It showed considerable

savings to the Medical savings to the Medical Center, especially when Center, especially when the outreach lab did the outreach lab did several thousand tests.several thousand tests.

• This analysis did not This analysis did not take into account the take into account the lost time Health Care lost time Health Care Workers incur when Workers incur when utilizing the TST.utilizing the TST.

• In 2006, there were In 2006, there were 2,000 2,000 lessless visits to UHS visits to UHS since the program since the program transitioned to the transitioned to the Quantiferon testing.Quantiferon testing.

0

1000

2000

3000

4000

5000

6000

7000

2005 2006

Number of Visits

PPD vs. QFT Cost AnalysisPPD vs. QFT Cost AnalysisLow end pricingLow end pricing

YearYear Number of skin tests Number of skin tests low end price low end price Annual costAnnual cost

Year 1Year 1 50005000 $41 $41             $205,000.00 $205,000.00        

Number of QFTs Number of QFTs                              

Year 1Year 1 5000 5000 $25       $25       $125,000.00 $125,000.00

Cost SavingsCost Savings $ 80,000.00/yr.$ 80,000.00/yr.

* Statistics are extracted from the CDC Lambert Paper. All numbers are on the * Statistics are extracted from the CDC Lambert Paper. All numbers are on the conservative side. conservative side.

                          

PPD vs. QFT Cost AnalysisPPD vs. QFT Cost AnalysisNational AverageNational Average

YearYear Number of skin tests Nat'l avg. price Number of skin tests Nat'l avg. price     AnnualAnnual

Year 1Year 1 5000 5000 $100$100             $500,000.00 $500,000.00

Number of QFTs Number of QFTs       

Year 1Year 1 5000 5000 $25$25             $125,000.00$125,000.00

Cost SavingsCost Savings $ 375,000.00/yr.$ 375,000.00/yr.

CONVERSIONS & REVERSIONSCONVERSIONS & REVERSIONS

Wobble effect – results may wobble Wobble effect – results may wobble around the 0.35 cutoff when tested around the 0.35 cutoff when tested serially. This can give results of serially. This can give results of positive one time and then negative positive one time and then negative next or visa versa.next or visa versa.

This variation occurs more with This variation occurs more with positive results than negative. positive results than negative.

QuantiFERON®® TB-Gold “In Tube” Test Validation

IN TUBEEVOLIS

QFTB-G TOTAL

  POS IND NEG  

POS 23 2 22 47

IND 0 0 1 1

NEG 2 8 340 350

TOTAL 25 10 363 398

QFT - IT tests done at QFT - IT tests done at UIC 8/08 to 8/09UIC 8/08 to 8/09

Total number of QTBGI tests done at Total number of QTBGI tests done at UIC - UIC - 7,6887,688

Total number of positives Total number of positives - 612- 612

Total number of indeterminates - Total number of indeterminates - 155155

Total number of Negatives - Total number of Negatives - 6,9216,921

Discordant results Discordant results with QFT - Goldwith QFT - Gold

Total number of new positives that are on raw Total number of new positives that are on raw data sheet during this time: data sheet during this time: 8888

47 of the 88 cases had a positive PPD 47 of the 88 cases had a positive PPD history, negative QTBG gold history and history, negative QTBG gold history and presently are positive In-tube at initial and presently are positive In-tube at initial and repeat testing.repeat testing.

Total from this number that went from 1st time Total from this number that went from 1st time positive and then negative at repeat testing: positive and then negative at repeat testing: 2424

13 from this number had a positive PPD 13 from this number had a positive PPD historyhistory

11 from this number had a negative PPD 11 from this number had a negative PPD historyhistory

Higher sensitivity seen with Higher sensitivity seen with QuantiFERONQuantiFERON®® TB-Gold “In Tube” TB-Gold “In Tube”

A.R. PPD positive in past. QFT-2G: ESAT-6 CFP-10 Neg 3/6/07 0.03 0.1 Pos 9/14/07 0.38 0.29 Neg 3/21/08 0.22 0.18 QTBG IN-TUBE TB-Ag Pos 9/4/08 1.69 Pos 10/30/08 2.55

Interpreting ResultsInterpreting Results

A general overview of the guidelines used A general overview of the guidelines used at UICMCat UICMC

Must recognize some results (very small Must recognize some results (very small number, <1% at UICMC) must be reviewed number, <1% at UICMC) must be reviewed in more detail on case by case basisin more detail on case by case basis

Successful interpretation may involve Successful interpretation may involve collaboration between Employee Health collaboration between Employee Health Services, Laboratory, Infection Control, Services, Laboratory, Infection Control, and/or Cellesitis; as well as, detail history and/or Cellesitis; as well as, detail history from the employeefrom the employee

Interpreting ResultsInterpreting Results Negative – exposure to Negative – exposure to M. M.

tuberculosistuberculosis is unlikely is unlikely

Positive – exposure to Positive – exposure to M. M. tuberculosistuberculosis is likely is likely

Indeterminate – results are Indeterminate – results are inconclusive. Not a positive test. inconclusive. Not a positive test.

QFT negative regardless of PPD historyQFT negative regardless of PPD history

Cleared for employmentCleared for employment

QFTQFT positive w/ negative PPD positive w/ negative PPD

Repeat the QFT immediately and do TB QuestionnaireRepeat the QFT immediately and do TB QuestionnairePositive Positive

Chest X-rayChest X-ray Referral to PCP for evaluationReferral to PCP for evaluation Future testing to be determinedFuture testing to be determined

Negative – Annual or semi-annual Surveillance depending Negative – Annual or semi-annual Surveillance depending on departmenton department

Notify lab to get raw dataNotify lab to get raw data

Indeterminate Results at Pre-Indeterminate Results at Pre-Employment ScreeningEmployment Screening

Repeat QFT at time of annual or Repeat QFT at time of annual or semi-annual testingsemi-annual testing

Certain percentage of the population Certain percentage of the population (very small number) are repeatedly (very small number) are repeatedly IndeterminateIndeterminate• Continue Surveillance on these Continue Surveillance on these

employeesemployees Remember Indeterminate results are Remember Indeterminate results are

NOT positive resultsNOT positive results

Final ThoughtFinal Thought

Cut the Cord!Cut the Cord!

REFERENCESREFERENCES

http://www.cdc.gov/nchstp/tb/default.htm

Guidelines for Using QuantiFERON-TB Guidelines for Using QuantiFERON-TB Gold Test for detecting Mycobacterium Gold Test for detecting Mycobacterium tuberculosis Infection, United States, tuberculosis Infection, United States, MMWR December 16, 2005; 54.MMWR December 16, 2005; 54.

Guidelines for the Preventing the Guidelines for the Preventing the Transmission of Mycobacterium Transmission of Mycobacterium tuberculosis in Health-Care Settings, tuberculosis in Health-Care Settings, 2005, MMWR December 30, 2005;54.2005, MMWR December 30, 2005;54.

QUESTIONSQUESTIONS