November 9, 2007

Tuberculosis Screening on a Health Science Campus: Use of QuantiFERON-TB Gold Test for Students and Employees

By Veeser, Peggy Ingram Smith, Phillip Karl; Handy, Barry; Martin, Sharon R

Abstract. Detecting and managing Mycobacterium tuberculosis (TB) infection in a health-science center population is a clinical dilemma. Tuberculin skin tests are still the preferred method for detecting present or past infection of TB. The authors discuss the performance of whole blood interferon gamma release assay test commercially known as QuantiFERON-TB Gold Test (QFT-G) as an additional tool for a TB surveillance program for the students and employees at an academic medical center. QFT-G was successfully implemented as a confirmatory test for screening of TB infection. Keywords: college health, health science students, QuantiFERONTB Gold, TB screening

For many years, college health providers in the United States have relied on the tuberculin skin test (TST) to detect present or past infection with Mycobacterium tuberculosis (TB) in students and campus employees. The limitations of the TST are well-documented, including placement variability, inter-reader variability, boosting, and difficulty in interpreting results in patients previously vaccinated with Bacilli Calmette Guerin (BCG) or with nontuberculosis mycobacterium (NTM) infection.1,2 Students and employees may find the test inconvenient because they must return in 48 to 72 hours for result reading and interpretation. TST use also poses operational challenges, such as the training and retraining of numerous health-care workers in proper test performance and interpretation. Patients and providers alike may have low confidence in test results, particularly when interpreting results for patients with prior BCG vaccination.3 In addition, latent TB infection (LTBI) is not a reportable medical condition and lacks confirmatory tests, adding to the clinical dilemmas of an effective TB surveillance program.

In November 2001, the United States Food and Drug Administration (FDA) approved the first blood assay for Mycobacterium tuberculosis for use as an aid in diagnosing M. tuberculosis infection. Commercially known as the QuantiFERON-TB test (QFT; Cellestis International, Carnegie, Australia), this assay provides information about patients' cell-mediated immune response to M. tuberculosis by measuring interferon-gamma produced in whole blood after incubation with purified protein derivative (PPD) from M. tuberculosis.4 Use of this interferon-gamma release assay (IGRA) for detecting M. tuberculosis infection has been reported in several research studies and in small hospital- or laboratorybased implementations.5-9 In March 2005, a newer version of the IGRA (QuantiFERON-TB Gold [QFT- G]; Cellestis International), which uses antigens for leukocyte stimulation, became available.3

As of 2005, the FDA had approved 3 tests for detecting TB: TST, the QFT, and the QFT-G. At the time of this writing, the QFT was no longer commercially available in the United States. All 3 of these tests work by measuring the body's immune response to antigenic proteins. The TST is a measure of delayed type hypersensitivity, whereas the QuantiFERON tests measure in vitro release of interferon- gamma. The QFT differs from the QFT-G in that it measures response to purified protein derivative (PPD) whereas QFTG measures response to synthetic peptides that simulate the 2 peptides present in PPD. The QFT was approved as an aid in detecting LTBI, whereas the QFT-G is an aid in diagnosing both LBTI and active disease.10

In direct comparisons, the sensitivity of QFT-G was statistically similar to that of the TST for detecting infections in people with untreated culture-confirmed tuberculosis.11 Researchers9,11,12 have published studies assessing QFT-G with these approximation methods. Mazurek et al5 reported a specificity of 98.1% in 216 BCG- vaccinated Japanese nursing students who were entering their training and who were at low risk for M. tuberculosis infection, and a sensitivity of 89.0% in 118 patients with culture-confirmed TB. However, QFT-G results were derived slightly differently than were the methods approved by the FDA. In a group of 99 healthy, BCG- vaccinated medical students in Korea, the specificity of QFT-G was 96%, compared with 49% for the TST. Among 54 patients with pulmonary TB disease, the sensitivity of the QFT-G was 81%, compared with 78% for the TST. Ferrara et al9 compared 12 QFT-G and TST patients in a population of 318 hospitalized patients. QFT-G had greater sensitivity for TB disease (67%) than did TST (33%), but indeterminate QFT-G responses were common (21%) among patients with negative TST results, the majority of whom were thought to be immunocompromised or immunosuppressed.

Although the findings in previous studies are informative, no one knows how QFT-G will perform in health science populations. In this review, we detail how staff members of a college health service at one academic medical center developed and implemented a blood assay test as a secondary test in a TB surveillance program.

Program Description

The University of Tennessee Health Science Center (UTHSC) at Memphis is the academic medical center campus for the University of Tennessee. UTHSC has approximately 2,200 students in the colleges of allied health sciences, dentistry, graduate health sciences, medicine, nursing, pharmacy, and social work. There are approximately 6,000 employees, many of whom are involved in direct patient care. The campus is an urban, public university with approximately 600 students living on campus, and others dispersed throughout the world for clinical rotations and online education. There is a prepaid student health fee charged to students through their tuition and fees. That fee covers entry and annual TST, primary care, selected laboratory tests, and x-rays. The number of immigrant students of US presence less than 5 years at UTHSC is approximately 125, and there are an undetermined number of employees of international origin. This is germane to our discussion because international students have been shown in other college health settings to have a 4-fold higher rate of latent TB.11

A campuswide Infection Control Committee directs the university in the protection, detection, and treatment of infection and has deemed all students and employees as high risk. University Health Services (UHS) serves the students and employees of the campus and is the enforcement arm of the infection control policies that include preemployment and prematriculation requirements. As part of that program, UHS provides the mandated yearly tuberculosis screening for students, faculty, and staff. As a further requirement, all must have TB screening, including those with prior documented positive TST.

UHS employees adhere to the latest TB guidelines from Centers for Disease Control and Prevention (CDC), the American College Health Association (ACHA), and specialty organizations. In 2002, UHS instigated the 2-step TST for all new students and employees who did not have a documented negative TST within the past year. For those with a negative TST within the past year, UHS officials give 1 TST at new student orientation or employment. All people are tested annually thereafter. UHS employees routinely refer all positive cases to the Memphis/Shelby County Health Department (MSCHD) TB Clinic for x-rays, further medical evaluation, and treatment, if indicated. All past positive cases must show proof from a US county health department verifying that they are free from infectious disease. If they do not have such a document, UHS refers them to the MSCHD for evaluation, and the card must be presented to UHS for clearance.

Before the CDC recommendations for QFT-G, there were many unanswered questions about the use in college health for routine programmatic screenings. To have improved screenings for TB, UHS officials sought a contract with a local laboratory to provide the QFT-G test to UTHSC. After some discussion for need, the laboratory procured the QFTG for use beginning in June 2005.


We made a retrospective chart review on QFT-G results from patients screened from June 2005 through August 2006. Because we used data collected under routine programmatic conditions for the evaluation, health information included age, student or employee status, and TB risk factors. The Institutional Review Board approved the study as an exempt review.

In the fall of 2005, UHS began using QFT-G, substituting the QFT- G for the TST for those students and employees who met the CDC guideline criteria (see Table 1). UHSspecific criteria include: (1) past positive not documented by a county health department, (2) questionable report of past positive, (3) history of BCG immunization, or 4) UHSdocumented TST positive. We sought to evaluate the results of QFT-G testing in comparison with positive TST results as well as the acceptability and the costs of using QFT- G for the special groups. Exclusion criteria were those with contraindications for QFT-G (see Appendix 1).

Lab collection is done at UHS, and a courier transports the specimens to the reference lab by request. Blood samples must be processed within 12 hours after collection. Whole blood is required for the specimens in 2 sodium heparin 10-mL tubes; a minimum of 5 ml are needed for testing. The second tube is a precaution for lymphocyte variability to prevent the whole blood from clotting. An employee at the reference lab faxes the results to UHS within 1 week with 1 of the 3 following outcomes: a positive result suggests that M. tuberculosis infection is likely; a negative result suggests that infection is unlikely; and an indeterminate result suggests QFT-G results cannot be interpreted as a result of low mitogen response or high background response.13 An indeterminate result requires a repeat test in 1 week and initiation of evaluation for active disease, reactive or nonreactive. We kept logs on each patient receiving the QFT-G to track results.


From June 2005 through August 2006, UHS officials screened for TB using QFT-G in 109 people. Of the 109 tested, 55 were employees of UTHSC, with an average age of 44.60 years (SD = 11.98). There were 54 students tested, with an average age of 29.22 years (SD = 6.32).

Of the 55 employees tested, 25 had a history of BCG vaccination, 5 had an undocumented past positive TST, 4 had a documented positive TST, 3 were currently on steroid therapy, and 18 were uncertain of their BCG history but were from a country that traditionally uses the BCG vaccine.

Of the students tested, 37 had a history of BCG vaccination, 7 had an undocumented past positive TST, 10 students were either uncertain of BCG history or TB history, and none had a documented positive TST.

Of the total 109 participants, results showed that 94 individuals had nonreactive results, 10 were reactive, and 5 had indeterminate results of the QFT-G. Of the 10 who were reactive, 8 were students and 2 were employees. Seven of the reactive students were previous recipients of the BCG vaccine; 1 student had an undocumented past positive TST. One employee was QFT-G reactive with a documented positive TST, and 1 had an undocumented past positive TST. The remaining 3 employees with documented past positive TST had a nonreactive QFT-G result.

We considered each QFT-G result and its interpretation in conjunction with other epidemiologic, history, physical, and diagnostic findings according to CDC guidelines.14 The 5 indeterminates were all employees whose lab work was repeated in 1 week and was found to be indeterminate a second time.

To evaluate acceptability, we considered the advantages and disadvantages of the QFT-G test. Advantages of the test are the single patient visit, lack of booster phenomenon with repeat TST, and less subjectivity to reader bias and error when compared with the TST.15 QFT-G does not have cross-reactivity to the BCG vaccine, compared with >10% of BCG-vaccinated people who have a false positive with the TST.10 This is important to a university with a percentage of its staff, faculty, and students of foreign birth or vaccinated with the BCG. Disadvantages are that, as with the TST, additional tests are needed to exclude TB disease and confirm the diagnosis of LBTI. For a large group, the cost of QFT-G can also be prohibitive.

The reference lab cost for QFT-G test is $62.60. Students had been asked to pay half of this cost, and employees were charged the full amount to their respective departments. As of fiscal year 2007, UHS does not charge students but continues to charge departments for employee evaluations.

Case Study

One employee was screened with both methods. This person was a TST conversion after years of negative annual TST at our institution. The employee was referred to MSCHD and received the TB clearance form, stating no active TB. Through the advice of the MSCHD TB physician, she was placed on isoniazid prophylactically because she was a health-care worker in the high-risk category. The patient was on Lipitor, and UHS employees conducted liver function tests every 2 months at the request of her private physician. After 3 months of medication, these results were above normal. Her private physician advised her to stop the isoniazid and repeat liver function tests in 2 months. This person was a prime candidate for QFT-G as a secondary test, and the results were nonreactive. Liver function tests returned to normal after 7 months postisoniazid. She will be screened annually now with the QFT-G.


These are the first reported operational outcomes of program efforts in college health to combine TST with QFT-G for M. tuberculosis screening. Of the sample, 86% of those tested had nonreactive results, and 9% tested reactive. Indeterminate results were 5%. All of the indeterminate results were cleared without treatment by the MSCHD.

Through the use of QFT-G, there is now the opportunity for a laboratory-based surveillance system for infection with M. tuberculosis. Reliable reporting of newly detected instances of infection with M. tuberculosis among key populations, such as new immigrants and those with inadequate history of past positives and allergic reactions, is now possible. This advance in TB surveillance could allow UTHSC to target case finding and prevention activities more accurately in the future.

Phlebotomy for QFT-G proved acceptable among all patients at UHS. The more expensive RD1-based IGRA, QuantiFERON-TB Gold test implementation cost the patient, department, or UHS $62.60 per patient tested. In comparison, the Center for Medicare Services has estimated the cost of the TST to be $9.79.15 Despite this lower per- test cost for TST, several factors, such as differences in test specificity and patient time requirements, raise the possibility that the QFT-G may be the more cost-effective test. Future cost- effectiveness analysis in which researchers compare QFT-G and TST use in TB screening will be necessary and should include potential cost savings from improved patient evaluation rates and avoidance of treatment of patients with false-positive TST results.3

General comparisons of cost savings can be made for a false- positive TB skin test. We estimate the cost of a single false- positive TB skin test to be from $445 to $1,195. We obtained these figures from the following costs associated with a false positive. The average cost of an office-based chest x-ray is $105.16 We also estimate that each false-positive case who receives medication will incur at least 2 additional office visits at a cost of $120. Additional lab testing to monitor liver functions may be required. Baseline liver function tests are recommended for those with HIV, pregnancy or recent post-partum state, regular alcohol use, use of potentially hepatotoxic medications, or symptoms suggestive of liver disease. Repeat testing may be indicated if baseline tests are abnormal. Additional lab testing to monitor liver functions, when indicated, could add $84 to the cost.16 The final additional cost is that of medication. A 9-month course of isoniazid can range in cost from $31 to $850, depending on the use of name brand versus generic drugs.17 There are also hidden costs in terms of provider time ensuring compliance and office personnel time spent answering questions. Additional costs associated with potential side effects from isoniazid could also be factored into the equation. The Navy Environmental Health Center currently estimates the average cost of a single false positive TST at $600 per case.18

We noted several operational challenges during QFT-G implementation. Testing programs using the QFT-G should be implemented only if plans are in place for the necessary medical evaluation and treatment. We worked closely with our county health department to ensure that the physician at the TB clinic accepted our referrals for positive and indeterminate reactors for medical evaluation and treatment. The physician was at first reluctant to accept QFT-G because TST has long been the standard screening tool. He did, however, accept our referrals and performed a chest xray and medical evaluation before issuing the TB clearance card. All of this was done at no charge to the patient.

Our operational evaluation has several limitations. We did not randomize patients or sites to TST or QFT-G. A randomized study would yield a more accurate comparison of acceptability and testing outcomes. We had a small sample size because of the size of our campus and selection criteria for lab testing.

UHS determined some additional considerations as a result of the addition of QFT-G screening. We studied the 3 employees who were past positive TST with nonreactive QFT-G results. We can conclude only that these 3 positive TSTs, QFT-G nonreactive, were the results of a reaction to the preservative thimerosal or indurations improperly interpreted.

We created an algorithm to aid staff in assessment of follow-up (see Figure 1).

Some of the questions that were raised during this evaluation are opportunities for further discovery: (1) Do you repeat an indeterminate result and, if so, how soon? (2) On those who met UHS criteria for QFT-G testing, do you repeat the QFT-G test annually, as you would a TST? (3) If so, what are the further cost considerations? (4) In particular, what additional diagnostic evaluations should be performed before or at the time of QFT-G? (5) Will insurance carriers cover this blood test?

There are compelling advantages for the QFT-G (see Appendix 2). Some of the disadvantages for TST, such as serial testing, subjective interpretation, and lack of compliance, are not common for QFT-G. Research is still at an early stage, but the data show the QFT-G to be a useful additional diagnostic tool.

QFT-G testing was successfully implemented and wellaccepted as an addition to our campuswide TB surveillance program. Program directors who consider using TST and QFT-G may expect benefits in completion rates of TB screening, reporting of results, and surveillance capacity. With improved RD1-based QFT-G tests offering higher specificity than TST, these administrators may find that the avoidance of unnecessary testing and treatment of patients with falsepositive TST results yields additional public health benefits.3 UTHSC health-care providers found that, in conjunction with the health department, the staff at the health service center was able to implement a patient-centered strategy for detection, evaluation, and treatment of TB infection. The authors are with the University of Tennessee's Health Science Center-University Health Services, Memphis.

Copyright (c) 2007 Heldref Publications


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2. Dunlop NE, Bass J, Fujiwara P, et al. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med. 2000;161:1376-1395.

3. Dewan PK, Grinsdale J, Liska S, Wong E, Fallstad R, Kawamura LM. Feasibility, acceptability, and cost of tuberculosis testing by whole-blood interferon-gamma assay. BMC Infect Dis. 2006;6:47.

4. Mazurek GH, Villarino ME. Guidelines for using the QuantiFERON- TB test for diagnosing latent Mycobacterium tuberculosis infection. MMWR Recomm Rep. 2003:52:15-18.

5. Mazurek GH, LoBue PA, Daley CL, et al. Comparison of a whole- blood interferon gamma assay with tuberculin skin testing for detecting latent Mycobacterium tuberculosis infection. JAMA. 2001;286:1740-1747.

6. Britton WJ, Gilbert GL, Wheatley J, et al. Sensitivity of human gamma interferon assay and tuberculin skin testing for detecting infection with Mycobacterium tuberculosis in patients with culture positive tuberculosis. Tuberculosis. 2005;85:137-145.

7. Fietta A, Meloni F, Cascina A, et al. Comparison of a whole- blood interferon-gamma assay and tuberculin skin testing in patients with active tuberculosis and individuals at high or low risk of Mycobacterium tuberculosis infection. Am J Infect Control. 2003;31:347-353.

8. Taggart EW, Hill HR, Ruegner RG, Martins TB, Litwin CM. Evaluation of an in vitro assay for gamma interferon production in response to Mycobacterium tuberculosis infections. Clin Diagn Lab Immunol. 2004;11:1089-1093.

9. Ferrara G, Losi M, Meacci M, et al. Routine hospital use of a new commercial whole blood interferon-{gamma} assay for the diagnosis of tuberculosis infection. Am J Respir Crit Care Med. 2005;172:631-635.

10. Mazurek GH, Jereb J, LoBue P, Iademarco MF, Metchock B, Vernon A. Guidelines for using QuantiFERON-TB Gold test for detecting Mycobacterium tuberculosis infection, United States. MMWR Morb Mortal Wkly Rep. 2005;54:49-55.

11. Mori T, Sakatiani M, Yamagishi F, et al. Specific detection of tuberculosis infection: an interferon-g-based assay using new antigens. Am J Respir Crit Care Med. 2004;170:59-64.

12. Kang TA, Lee HW, Toon HI, et al. Discrepancy between the tuberculin skin test and the whole-blood interferon-g assay for the diagnosis of latent tuberculosis infection in an intermediate tuberculosis-burden country. JAMA. 2005;293:2756-2761.

13. Centers for Disease Control and Prevention. QuantiFERONTB Gold Test CDC Fact Sheet. Available at: tb/pubs/tbfactsheets/250103.htm. Accessed October 26, 2006.

14. Centers for Disease Control and Prevention. Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health- Care Settings, 2005. MMWR Morb Mortal Wkly Rep. 2005;54:No. RR-17). Available at: http://www.cdc. gov/mmwr/pdf/rr/rr5417.pdf. Accessed October 26, 2006.

15. Center for Medicare and Medicaid Services. Part B Extract and Summary System (BESS). Center for Medicare and Medicaid Services: Washington, DC; 2003. CPT Code 86580.

16. Atkin S, Jaker M, Reichman LB. Battling tuberculosis: a strategic update. Emerg Med [online publication]. March 15, 2003. Available at: 031503.asp. Accessed February 13, 2007.

17. Online pharmacy Web site. Accessed October 26, 2006.

18. Mitchell D. Business Case Analysis: QuantiFERON-TB Gold Costs, Benefits, & Risks. Presented at: 45th Navy Occupational Health and Preventive Medicine Conference. March 18-23, 2006; Hampton, VA.

Peggy Ingram Veeser, EdD, APRN, BC-FAANP, FACHA; Phillip Karl Smith, MD; Barry Handy, RN, BSN, COHN-S; Sharon R. Martin, BS, CMLA


For comments and further information, address correspondence to Dr Peggy Veeser, University of Tennessee Health Science Center, University Health Services, 910 Madison, Suite 922, Memphis, TN 38163 (e-mail: [email protected]).


Contraindications for QuantiFERON-TB Gold Test

1. Pregnancy

2. Children aged younger than 17 years

3. People taking immunosuppressive drugs

4. Impaired immune system



Advantages/Disadvantages of QuantiFERON-TB Gold Test (QFT-G)


1. Single visit

2. Lack of booster phenomenon

3. Decreased reaction from nontuberculous mycobacterium

4. Decreased subjectivity in interpreting results

5. Can be used in person with prior or uncertain Bacilli Calmette Guerin vaccine

6. More objective interpretation; less reader bias

7. Prevents unnecessary medical treatment for latent tuberculosis infection


1. Cost

2. Cannot be used in some patient populations

3. Requires venipuncture

4. Laboratory handling times must be adhered

5. Access to laboratory performing QFT-G

6. Sensitivity to immunocompromised patient not determined

7. Cannot differentiate infection with tuberculosis disease from latent tuberculosis infection

Source: QuantiFERON-TB Gold Test CDC Fact Sheet accessed October 26, 2006

Copyright Heldref Publications Sep/Oct 2007

(c) 2007 Journal of American College Health. Provided by ProQuest Information and Learning. All rights Reserved.