QuantiFERON-TB Gold®:Practical Applications

L. Masae Kawamura M.D.Director, San Francisco TB Control

Section, Department of Public HealthFrancis J. Curry National TB Center

Diagnosis of tuberculosis infection

TB Skin Test (TST) QuantiFERON Blood Test(QFT)

“..the greatest needs in the United States are new diagnostic tools for the more accurate identification of individuals who are truly infected and who are also at risk of developing tuberculosis”

US Institute of Medicine Report,“Ending Neglect”; 2000

Problems with TST…Poor inter-reader reliability

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

NTM infection Prior BCG

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

Cost/time of patient visits Unread tests

Sensitivity? Reaction wanes over time Lack of gold standard

Program Implications of a More Specific Blood-Based TB Test

• ↓Societal costs and public safety: Elimination of unnecessary CXRs, evaluation and treatment

Program efficiency: More results means targeting efforts on “positives” instead of on retesting individuals who fail to show up for TST readings (homeless, jails, employee testing)

Public confidence : Reliable and specific results• New surveillance capabilities: laboratory-based

targeted testing

SF QFT Guidelines/Philosophy• QFT: Acceptable alternative to TST in all patients

• In contacts, use in same fashion as TST —Follow-up test needed at 8-12 weeks

• TB Suspects: Use QFT in conjunction with TST to maximize diagnostic yield in suspects and highest risk patients (especially immunocompromised patients and contacts under age 5)

• Don’t “confirm” TST unless it will change patient management

Programmatic use of QFT-G in San Francisco

• Targeted testing —Homeless and IDUs (high rates of TB, HIV

and ongoing transmission) Rationale: poor TST return rates

-New immigrants and refugees (high infection prevalence) Rationale: BCG-induced, false positive TSTs

• Contact investigation• Prioritizing TB suspects for outreach• Surveillance: Homeless shelters, Newcomers

Current implementation

• Limited use: 15 sites — public health clinics and community clinics targeting newcomers, homeless and IDUs (methadone clinics)

• Non-health department requests: must be approved by “gate keeper”

 Planned expansion: 2006-2007 • Access to all HD providers when automation is

available• Unresolved: private provider demand for QFT

Number of New Patients Evaluated Monthly by QFT-TB & QFT-G,

San Francisco, Nov. 2003 - Feb. 2006

0100200300400500600

Nov

Jan '0

4Mar

May Jul

Sept

Nov

Jan '0

5Mar

May Jul

Sept

Nov

Jan '0

6

Num

ber

QFT-TB n=4574

QFT-G n=6124

TB testing by Quantiferon-TB Gold by clinic typeSan Francisco, Mar. 2005 – Feb. 2006

Result

Homelessn=3594 (%)

TB Clinicn=693 (%)

Methadone n=546 (%)

Immigrantn= 626 (%)

HIVn=154 (%)

Positive 221 (6) 182 (26) 21 (4) 72 (12) 4 (3)

Negative 3168 (88) 463 (66) 494 (90) 490 (78) 142 (92)

Indetermin. 118 (3) 32 (5) 26 (5) 58 (9) 5 (3)

Not Tested 87 (2) 16 (2) 5 (1) 6 (1) 3 (2)

*2 clinic types not listed: refugee clinic (n=147) & community clinics (n=399)

QFT-G Test Results by Age Category March 2005 – February 2006

0%

20%

40%

60%

80%

100%

<5 5 to 14 15 to24

25 to44

45 to64

65 to84

Perc

ent

IndeterminateNegativePositive (%) (3) (1) (6) (7) (12)

(31)

TB Infection Prevalence by Testand Clinic Type

Homeless TB Clinic Methadone Immigrant

TST(2001-2003)

26% >50% 10% 37%

QFT-1 (11/04-2/05)

17 %n=1848

48 %n=292

18 %n=346

37 % n=344

QFT-Gold (3/05-2/06)

Decline in positive rate from TST

6 %n=3594

77%

26 %N=693

48%

4 %n=546

60%

12 %n=626

66%

Preliminary HIV results from SF AIDS Clinic

3/1/06 and 5/31/06Why they were anxious to switch: TST return rate <50%

# samples submitted: 44Results: 93%Results w/o indeterminates: 86%

    Indeterminate: 3 (7%)     Not Tested: 3 (7%)     Positive: 1 (2%)     Negative: 37 (84%)

Wisconsin Shelter TST Results

January 2004 – March 2005• 268 TSTs were given

– 152 people returned (56%)– 14 were positive (9%)

Data provided by the Wisconsin Division of Public Health

QFT shift:Wisconsin Shelter testing April – December 2005

• 306 QFT-TB Gold (95% initial results)– 31 positives (10%)

• 5 people previously documented negative TST• 4 people known TST positives• 12 people previously in other shelters within one

year– 259 negative (85%)

• 17 people previously documented positive TST– 17 indeterminate (5%)

• 7 people retested — 1 positive• Multiple medical and immunity problems

Data provided by the Wisconsin Division of Public Health

QFT and Contact Investigation

Expect maximum benefit:• Populations with poor return rates (homeless and hotel dwellers)• F.B. with high background prevalence of LTBI and BCG vaccination

Example: SF low-cost hotel drug-resistance investigation• Prior QFT results easy to track down in database• 9/31 converters found! (6 QFT conversions and 1 case found)

4 negative TSTs → positive QFT2 negative QFTs → positive QFT3 negative TSTs → positive TST

Example: XDR investigation involving F.B. contacts (88% FB, ½ with prior +TST)1 out of 25 contacts with positive QFT (Is QFT weeding out remote infection?)…..stay tuned!

Don’t use QFT-G to “rule out” TB!TB Suspects: 37/242 had culture-confirmed tuberculosis

(3/2/05-12/31/05)

• QFT-G sensitivity: 64% (TST sensitivity = 88%)• Very poor performance in extrapulmonary TB (14%

sensitivity 1/7 cases)

Conclusion: low sensitivity and poor correlation to published studies

Note: No cases were missed due to a negative QFT result

TST is not perfect either …

• 282 B notifications reported 3/1/05 to 4/3/06• 217 with either QFT-G or TST• QFT-G – 84/164 positive = 51.8% positive rate

73 B1 - 40 positive = 55.8%• 91 B2 - 45 positive = 49.5%• TST - 38/53 positive = 71.6% positive rate

32 B1 - 21 positive = 65.6%21 B2 - 17 positive = 81.0%

• 11 cases identified with either QFT or TSTQFT- /TST + : 2 cases potentially missed by QFT QFT+ /TST - : 2 cases potentially missed by TST

Estimated Costs in High Usage Setting

Commercial Kit

QFT-G QFT-GIn-tube

QFT-GIn-tube

T-SPOT

Assay type ELISA ELISA ELISA ELISPOT

Lab Automation

partial partial Full Partial

TOTAL ($) 29.22 26.74 25.09 57.79

Costs include facility space, equipment, consumables and staff timeTST cost estimated (Medicare) $12-14 per patient tested

Remaining issues…

• Interpretation of discordant TST and QFT results• Management of indeterminate results• QFT-G thresholds set for higher specificity… has it

sacrificed too much sensitivity?• Serial testing: no long-term data on conversions,

reversions, management of changing results and evidence-based thresholds for conversion

• Unknown dynamics of T-cell responses during and after treatment for LTBI and active treatment

Is the TST still useful? Of course!• When there is no phlebotomy expertise or

patient is a “difficult stick “E.g., very young children and some IDUs

• When TB screening opportunities are limited (e.g., contact investigation, jail screening)Until 12-hour laboratory submission time eliminated or access to blood-based testing becomes widespread and 24/7, PPD may be more practical

• When maximizing sensitivity in suspects, immunocompromised, and young children

Conclusions• QFT-G is highly specific!!! It will result in a significantly lower

number of positive results compared to QFT-TB and TST• While this is disconcerting, there is no evidence to date that

cases are being missed • Long-term studies are needed to study discordants, QFT-G

negative contacts and high-risk children• Blood-based TB testing is a superior surveillance tool with

more believable results• Training lab personnel is much easier than the training

countless providers of a whole city • QFT-G is most useful in nonadherent and BCG-vaccinated

populations • NEVER USE A QFT TO RULE OUT DISEASE… it’s a tool,

not a panacea!

QFT-Gold: Clinical Applications

• The distraught mother….Feisty 4 year-old Chinese adoptee with history of 2 BCGs and 12mm TST result.

QFT-1: conditionally positiveQFT-Gold: negative

• The BCG-vaccinated baby…MDR newborn contact to smear+ mother. BCG given X2. TST at 4 months negativeResults at 6 months QFT-1: conditionally positive QFT-Gold: negative

QFT-Gold: Clinical Applications• The nonbeliever: “I’m TST positive because of BCG!”

French-born HIV researcher with documented BCG X3 returns from a 10-day trip in Africa (worked in HIV clinic). Refuses LTBI treatment.-PPD 20mm -QFT-Gold positive

• Other potential uses: Solving disputes-Waxing and waning TST results in serial testing -Funny-looking TST results -“Well, it might be swollen and it sure is red!”-Referred patient: “I think they read my skin test wrong.”

Acknowledgments: Puneet Dewan, M.D.,

SF TB Control staff, SFDPH laboratory (Sally Liska, Ernest Wong),

SF community clinics

Tanya Oemig RM(NRM)TB Program Director

Wisconsin Division of Public Health