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Prospective Comparison of the Tuberculin Skin Test and 2 Whole-Blood Interferon-γ Release Assays in Persons with Suspected Tuberculosis

  1. Gerald H. Mazurek1,2,
  2. Stephen E. Weis3,4,
  3. Patrick K. Moonan1,3,4,
  4. Charles L. Daley5,a,
  5. John Bernardo6,
  6. Alfred A. Lardizabal7,
  7. Randall R. Reves8,
  8. Sean R. Toney1,
  9. Laura J. Daniels1, and
  10. Philip A. LoBue1
  1. 1Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia
  2. 2Pulmonary and Critical Care Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
  3. 3University of North Texas Health Science Center, Fort Worth, Texas
  4. 4Tarrant County Public Health, Fort Worth, Texas
  5. 5University of California, San Francisco
  6. 6Boston University School of Medicine, Boston, Massachusetts
  7. 7New Jersey Medical School National Tuberculosis Center, Newark
  8. 8Denver Public Health Department, Denver, Colorado
  1. Reprints or correspondence: Dr. Gerald Mazurek, Centers for Disease Control and Prevention, MS E10, 1600 Clifton Rd., Atlanta, GA 30333 (gym6{at}cdc.gov).

  • ↵a Present affiliation: National Jewish Medical and Research Center, Denver, Colorado (C.L.D.).

 
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Abstract

Background. Interferon-γ release assays (IGRAs) are attractive alternatives to the tuberculin skin test (TST) for detecting Mycobacterium tuberculosis infection. However, the inability to definitively confirm the presence of most M. tuberculosis infections hampers assessment of IGRA accuracy. Although IGRAs are primarily indicated for the detection of latent tuberculosis infection, we sought to determine the sensitivity of the TST and 2 whole-blood IGRAs (QuantiFERON-TB assay [QFT] and QuantiFERON-TB Gold assay [QFT-G]) in situations in which infection is confirmed by recovery of M. tuberculosis by culture.

Methods. We conducted a prospective, multicenter, cross-sectional comparison study in which 148 persons suspected to have tuberculosis were tested simultaneously with the TST, QFT, and QFT-G.

Results. M. tuberculosis was cultured from samples from 69 (47%) of 148 persons suspected to have tuberculosis; the TST induration was ⩾5 mm for 51 (73.9%) of the 69 subjects (95% confidence interval [CI], 62.5%–82.8%). The QFT indicated tuberculosis infection for 48 (69.6%) of the 69 subjects (95% CI, 57.9%–79.2%) and was indeterminate for 7 (10.1%). The QFT-G yielded positive results for 46 (66.7%) of the 69 subjects (95% CI, 54.9%–76.7%) and indeterminate results for 9 subjects (13.0%). If subjects with indeterminate QFT-G results were excluded, 46 (76.7%) of 60 subjects (95% CI, 64.6%–85.6%) had positive TST results, and the same number of subjects had positive QFT-G results. HIV infection was associated with false-negative TST results but not with false-negative QFT-G results.

Conclusions. The TST, QFT, and QFT-G have similar sensitivity in persons with culture-confirmed infection. As with the TST, negative QFT and QFT-G results should not be used to exclude the diagnosis of tuberculosis in persons with suggestive signs or symptoms.

The tuberculin skin test (TST) has been used to support the diagnosis of tuberculosis (TB) and latent Mycobacterium tuberculosis infection for almost a century. It assesses cell-mediated hypersensitivity to M. tuberculosis antigens after intradermal injection of tuberculin PPD, a complex mixture of proteins derived from M. tuberculosis cultures. A positive TST result indicates an increased risk of currently having or subsequently developing TB [1,2–3]. However, false-positive TST responses may occur after contact with environmental mycobacteria that share common antigens with M. tuberculosis or after bacille Calmette-Guérin (BCG) vaccination [1, 4, 5]. False-negative TST results may occur in the presence of HIV infection or after recent vaccination with live-attenuated virus vaccines [6]. Errors in the placing and reading of the TST also adversely affect accuracy [6].

In vitro methods for measuring cell-mediated immune reactivity offer potential advantages and may avoid some limitations of the TST. In vitro methods are evolving rapidly, because multiple antigens and assay parameters can be evaluated simultaneously. Efforts have focused on IFN-γ as a critical cytokine for host defense against M. tuberculosis [7,8–9]. IFN-γ release assays (IGRAs) detect IFN-γ release from lymphocytes after incubation with M. tuberculosis antigens. The first IGRA approved as an alternative to the TST by the US Food and Drug Administration was the QuantiFERON-TB assay (QFT; Cellestis). The assay measures IFN-γ release when a whole blood sample is stimulated with PPD [10, 11]. Identification and characterization of M. tuberculosis proteins, such as early-secreted antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10), have led to their use as antigens in IGRAs [12]. These proteins are products of a genomic region of difference referred to as RD1, which is present in M. tuberculosis and pathogenic M. bovis strains but absent from BCG and most non-tuberculous mycobacteria (NTM). IGRAs that measure ESAT-6 and CFP-10 response, either as recombinant antigens or mixtures of overlapping peptides, appear to be highly specific [13,14,15,16,17,18,19–20]. However, sensitivity of IGRAs using these antigens has ranged from 70% to 97% [17, 20,21,22,23–24]. Because IGRA methods, interpretation criteria, and study populations varied considerably among published reports, IGRA sensitivity remains uncertain. Because ESAT-6 and CFP-10 stimulate release of less IFN-γ than does PPD, IGRAs with greater analytic sensitivity are required.

The objectives of this study were to estimate the sensitivity of the TST, the QFT, and a new whole-blood IGRA that assesses response to ESAT-6 and CFP-10 (the QuantiFERON-TB Gold assay [QFT-G]). We also looked for factors associated with false-negative test results among individuals with culture-confirmed infection. Data from this study were considered by the US Food and Drug Administration prior to the approval of the QFT-G and by the Centers for Disease Control and Prevention when the QFT-G guidelines were prepared [25, 26].

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Materials and Methods

Subjects in 6 US cities were recruited for this study after institutional review board approval by participating institutions. From June 2003 through December 2005, persons presenting with symptoms, signs, or radiographic evidence of TB were screened for participation in this study. Individuals were excluded if they were known to have received >7 days of therapy for TB or latent TB infection. If subjects were discovered after enrollment to have received treatment in the year prior to enrollment, their information was excluded from analysis, but information from subjects treated >1 year prior to enrollment was analyzed. Using a standardized questionnaire, data were collected on age, ethnicity, country of birth, foreign residence, and residence or work in health care settings, prisons, homeless shelters, drug rehabilitation units, or other group housing. The TB prevalence in the country of birth was based on 1990 data [27]. Subjects were asked about prior receipt of a TST and BCG vaccination. US-born subjects without foreign residence were classified as “not having received BCG vaccination.” Reports of chest roentgenogram findings, mycobacterial culture results, and TB-related treatment were abstracted from medical records. Subjects were categorized as having (1) “culture-confirmed TB” if M. tuberculosis was recovered from ⩾1 culture; (2) “culture-negative TB” if clinical findings were compatible with TB, treatment for TB resulted in improvement, and no cultures were positive for M. tuberculosis after 3 months of observation; or (3) “no TB” if they did not meet criteria for culture-confirmed or culture-negative TB.

Blood sample collection and IGRAs. Blood samples for IGRAs were obtained before the TST was performed. Incubation of blood samples with test antigens was initiated within 12 h after collection. Antigens (125 µL; equivalent to 3 drops), saline, or phytohemagglutinin were added simultaneously to 1-mL aliquots of heparinized blood samples in Costar 24-well microtiter plates. Saline, phytohemagglutinin, M. tuberculosis PPD, and Mycobacterium avium PPD were from QFT kits; overlapping peptides representing ESAT-6 or CFP-10 with previously described sequences [17] were manufactured by Schafer-N or Jerini Peptide Technologies, were shown to be >95% pure by high performance liquid chromatography, and were mixed in phosphate-buffered saline (pH 7.4) for a final concentration of 10 µg/mL for each peptide. Plates were incubated for 16–24 h at 37°C, and plasma was harvested. A longer incubation period (24–28 h) was allowed but was considered to be a protocol deviation. The concentration of IFN-γ in 50 µL of each plasma sample was determined by ELISA. Fresh, refrigerated (up to 14 days), or thawed plasma samples (after storage at -70°C) were tested.

For the QFT, ELISA reagents and instructions provided with QFT kits were used [28]. ELISA plates were washed 6 times with a 1.0-sec soak, using a Dynex Microplate Washer (Dynex Technologies). Optical densities were measured using a Dynex Microplate Reader with Revelation Software, version 4.21 (Dynex Technologies). Optical densities were imported into assay-specific software (QFT-TB CDC, version 1.41; Cellestis) that converted optical densities to IUs of IFN-γ on the basis of 4 IFN-γ standards of 140, 75.9, 16, and 0 IU/mL measured in duplicate in each ELISA run. QFT results were interpreted as specified in table 1.

Figure 1
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Figure 1

Study population, including 190 persons suspected to have tuberculosis (TB). TST, tuberculin skin test. aThe QuantiFERON-TB Gold assay (QFT-G) was not completed because of incubator failure, inadequate quantities of blood, and laboratory accidents.

Table 1
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Table 1

Interpretation criteria for the QuantiFERON-TB assay in persons suspected to have tuberculosis.

For the QFT-G, concentrations of IFN-γ in 50 µL of plasma stimulated with saline, ESAT-6, CFP-10, or phytohemagglutinin were determined using ELISA reagents provided in QuantiFERON-CMI kits (prototype kits for QFT-G that included no antigens). The QuantiFERON-CMI ELISA is more sensitive than the QFT ELISA (limit of detection, 0.05 IU/mL of IFN-γ vs. 1.5 IU/mL of IFN-γ) [28, 29]. QuantiFERON-CMI ELISA plates were washed and read with the same instruments and settings used for the QFT ELISA, except 8 IFN-γ standards (ranging from 0.0 IU/mL to 10.0 IU/mL) were included on each plate in duplicate; the initial ELISA incubation period was extended to 2 h; and optical densities were imported into assay-specific software (QFT-CMI CDC, version 1.51; Cellestis) and converted into IUs of IFN-γ. QFT-G results were interpreted as indicated in table 2.

Table 2
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Table 2

Interpretation criteria for the QuantiFERON-TB Gold assay.

TST. Trained individuals injected 0.1 mL (5 TU) Tubersol (Connaught Laboratories) by the Mantoux method [30]. Staff was instructed to measure TST response 48–72 h after placement. Any TST measurement obtained <48 h or >72 h after placement was considered to be a protocol deviation. TST reactions ⩾5 mm were interpreted as positive, and reactions <5 mm were interpreted as negative.

Statistical analysis. Information was entered into a database using double data entry for verification. Statistical analyses were conducted using SPSS, version 12.0 (SPSS). Sensitivity was estimated by dividing the number of positive test results by the number of subjects with culture-confirmed TB or, if specified, by the number of these subjects with valid test results. Bivariate and multivariable logistic-regression analyses were used to identify factors associated with negative TST and QFT-G results among subjects with culture-confirmed TB. Independent variables included age, ethnicity, HIV status, unintentional weight loss, time from placement to reading of the TST, time to blood sample incubation with antigens, and incubation duration. Collinearity was assessed using regression diagnostics. ORs were adjusted for confounding using stepwise backward logistic regression and for variables that, in bivariate analysis, were associated with a positive test result with P < .20. P < .05 was considered to be statistically significant.

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Results

Of 254 persons screened for this study, 190 were eligible, and 179 (94.2%) of 190 eligible subjects consented to participate in the study. Data from 31 subjects were excluded from the analysis for the reasons listed in figure 1. Characteristics of the 148 subjects included in the analysis are shown in table 3. Sixty-nine subjects had culture-confirmed TB, with the disease limited to pleural or extrapulmonary sites in 13 subjects; 27 subjects had culture-negative TB. The remaining 52 subjects were considered not to have TB after 3 months of observation.

Table 3
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Table 3

Characteristics of 148 subjects with suspected tuberculosis (TB).

Minor protocol deviations were noted for 45 subjects, and these deviations did not lead to exclusion. Treatment that occurred 5–35 years prior to enrollment was noted for 7 subjects. This included therapy for TB (1 subject) or latent TB infection (6 subjects). TST measurements were read 41–47 h after placement for 20 subjects and 76 h after placement for 1 subject. Blood samples were incubated for 24–27 h (exceeding the recommended 24 h) for 22 subjects. Subjects who experienced minor protocol deviations were statistically no different than those who experienced no deviations with regard to age, ethnicity, final diagnosis, HIV status, TST results, and QFT-G results (data not shown).

Results of the QFT-G and TST, stratified by final diagnosis, are shown in tables 4 and 5. The TST induration was ⩾5 mm for 51 (73.9%) of 69 subjects (95% CI, 62.5%–82.8%) with culture-confirmed TB; there was no significant difference in the percentage of positive results between those with pulmonary and extrapulmonary disease (75.0% vs. 69.2%; P = .67). QFT-G results were positive for 46 (66.7%) of 69 subjects (95% CI, 54.9%–76.7%) with culture-confirmed TB and indeterminate for 9 subjects (13.0%); there was no significant difference in the percentage of positive results between those with pulmonary and extra-pulmonary disease (69.6% vs. 53.8%; P = .51). The TST induration was >15 mm for 5 of 9 subjects who had indeterminate QFT-G results. If those with indeterminate QFT-G results were excluded, 46 (76.7%) of 60 subjects (95% CI, 64.6%–85.6%) had positive TST results, and the same number of subjects had positive QFT-G results. The QFT-G and TST results agreed for 48 subjects (80.0%), with both tests yielding negative results for 8 subjects (13.3%).

Table 4
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Table 4

Tuberculin skin test (TST) and QuantiFERON-TB Gold assay (QFT-G) results, stratified by final diagnosis.

Table 5
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Table 5

Tuberculin skin test (TST) results versus QuantiFERON-TB Gold assay (QFT-G) results for subjects with culture-confirmed tuberculosis (TB), subjects with culture-negative TB, and subjects without TB disease.

In bivariate analysis, HIV infection, age, white (non-Hispanic) ethnicity, and unintentional weight loss were associated with negative TST results for subjects with culture-confirmed TB (table 6). After adjustment for confounding, only HIV infection and age remained significantly associated with false-negative TST results. White (non-Hispanic) ethnicity was the only factor significantly associated with false-negative QFT-G results (table 7). Although HIV infection was strongly associated with false-negative TST results (P = .01), it did not appear to affect QFT-G results (P = .82). The TST induration was ⩾5 mm for 2 (28.6%) of 7 (95% CI, 8.2%–64.1%) HIV-infected subjects with culture-confirmed TB; the QFT-G result was indeterminate for 1 (14.1%) of these 7 subjects and positive for 4 (66.7%) of 6 (95% CI, 30.0%–90.3%) of those with interpretable results.

Table 6
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Table 6

Association of selected subject characteristics with false-negative tuberculin skin test (TST) results.

Table 7
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Table 7

Association of ethnicity with false-negative QuantiFERON-TB Gold assay (QFT-G) results.

QFT-G results were indeterminate for 13% of the subjects with culture-confirmed TB and for 4% of the subjects with culture-negative TB (P = .3). QFT-G results were indeterminate for 4 others without TB. Nine of the subjects with indeterminate QFT-G results had low mitogen responses and high nil concentrations (i.e., the IFN-γ concentration in saline-stimulated plasma), 2 had low mitogen responses only, and 3 had high nil concentrations only. None of the variables examined were associated with indeterminate QFT-G results in the entire cohort or when restricted to subjects with culture-confirmed TB.

NTM were recovered from 36 subjects, none of whom had TB. For 5 subjects, the non-tuberculous species recovered were known to have genes that encode ESAT-6 and CFP-10. Mycobacterium kansasii was recovered from 4 subjects, and TST results were positive for 3 of these subjects; QFT-G results were negative for 3 of these subjects and indeterminate for 1 subject. Mycobacterium szulgai was recovered from 1 subject who had both negative TST and negative QFT-G results. None of these subjects had HIV infection. Mycobacterium avium-intracellulare was recovered from 17 subjects, 1 of whom had positive TST and QFT-G results; the TST result alone was positive for 6 of these subjects, and the QFT-G result alone was positive for 3 of these subjects. Other NTM were recovered from 14 subjects, 1 of whom was positive for TB by both the QFT-G and TST; 1 subject had only a positive TST result, and 1 had only a positive QFT-G result.

The QFT showed M. avium reactivity for 4 of 17 subjects from whom M. avium-intracellulare was recovered, 1 of 19 subjects from whom other NTM were recovered, and none of the 69 subjects with culture-confirmed TB. The QFT results were positive for M. tuberculosis infection for 48 (77.4%) of 62 subjects (95% CI, 65.6%–86.0%) with culture-confirmed TB and valid QFT results. Seven subjects (10.1%) had indeterminate QFT results.

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Discussion

This is the first study to assess QFT-G sensitivity in a heterogeneous, geographically diverse US population. We found no significant difference between the percentage of persons with culture-confirmed TB who had positive TST results and the percentage of persons with culture-confirmed TB who had positive QFT-G results (74% vs. 67%; P = .16). If subjects with indeterminate QFT-G results were excluded, sensitivity of both the TST and QFT-G was 77%. As with the TST, the suboptimal sensitivity of the QFT-G precludes its use as the sole means of excluding a diagnosis of TB. Negative test results in this group of subjects can be accurately classified as “false-negative” results, because infection was documented by culture. HIV infection was strongly associated with false-negative TST results. After adjusting for age, HIV-infected subjects were 13.5 times more likely to have false-negative TST results than were HIV-uninfected subjects. In contrast, HIV infection did not appear to significantly affect the odds of having a false-negative or indeterminate QFT-G result. White (non-Hispanic) ethnicity was the only factor significantly associated with false-negative QFT-G results. There was no significant difference in sensitivity between the QFT-G that assesses response to 2 TB proteins and the QFT that assesses response to the multitude of TB proteins in PPD. These data show that the TST, QFT, and QFT-G have similar sensitivities for detecting M. tuberculosis infection in a diverse population with culture-confirmed TB.

Multiple factors other than test sensitivity affect the prevalence of positive test results in cohorts of subjects who receive diagnoses of culture-negative TB. A major concern is that the accuracy of this diagnosis and the presence of M. tuberculosis infection cannot be definitively confirmed. In the absence of positive culture results, clinical response is important in establishing a diagnosis. In the current study, a diagnosis of culture-negative TB was made for 27 subjects whose health improved with anti-TB therapy. Of these, 85% of the subjects had positive TST results, and 59% had positive QFT-G results. Although not a diagnostic criterion, a positive TST result likely affected a clinician's decision to treat for TB. Thus, TST results may have contributed indirectly to the diagnosis. This may explain why a larger proportion of subjects with culture-negative TB than subjects with culture-confirmed TB had positive TST results.

A substantial number of subjects who did not have TB had positive TST or QFT-G results. This was expected because the majority of subjects had substantial risk of being infected with M. tuberculosis. Even when NTM are recovered, infection with M. tuberculosis cannot be excluded. Because ESAT-6 and CFP-10 genes occur in M. kansasii and M. szulgai, positive QFT-G results may be expected in persons from whom these organisms were recovered [31]. However, 5 subjects met published criteria for disease attributable to these organisms [32], and none of them had positive QFT-G results.

Direct comparison of our results with those of prior reports is complicated by differences in interpretation criteria or antigens. Our measure of QFT-G sensitivity among a heterogeneous population is less than the 89% sensitivity reported by Mori et al. [17] among a group of 118 Japanese subjects. Both studies used similar testing methods and measured sensitivity in persons with culture-confirmed TB who were untreated or had received no more than 1 week of anti-TB therapy. However, interpretation criteria differed. In both studies, an ESAT-6 or CFP-10 response of 0.35 IU/mL of IFN-γ was used as the cutoff for separating positive and negative responses, but our evaluation included a high-background rule, which was introduced during the US Food and Drug Administration approval process. This rule states that, for positive results, in addition to an IFN-γ concentration ⩾0.35 IU/mL, ESAT-6 or CFP-10 response must be 50% greater than IFN-γ concentration in the saline-stimulated (nil) plasma. Three (21%) of our indeterminate results would have been interpreted as positive or negative without this rule. Kang et al. [21] used methods and interpretation criteria that were similar to those used by Mori et al. [17], but they found a somewhat lower QFT-G sensitivity of 81%. Ferrara et al. [23] used a different background rule, excluding test results with an IFN-γ concentration >2 IU/mL in the saline-stimulated plasma from the analysis. They reported that 8 (72.7%) of 11 subjects with culture-confirmed TB had positive QFT-G results. Using recombinant ESAT-6 and CFP-10, Ravn et al. [33] reported that 24 (86%) of 28 subjects with culture-confirmed TB responded to recombinant ESAT-6 or CFP-10 by producing an IFN-γ concentration that is at least 0.35 IU/mL above that measured in the saline-stimulated plasma.

The frequency of indeterminate QFT-G results varies considerably between studies, ranging from <1% to 21% [17, 34]. This may be because of differences in interpretation criteria, local test performance, and study populations. QFT-G results were indeterminate for 9% of our study cohort. No subject-related or test-related factors were associated with indeterminate results. Indeterminate results have been linked to immune suppression and low CD4+ T lymphocyte counts in persons with HIV infection [23, 34, 35]. Our study included few subjects with overt immunosuppression. HIV infection was documented in 11% of our subjects but was not associated with indeterminate QFT-G results. The observation that 9 indeterminate results had both high nil concentrations and low mitogen responses suggests transposition of values, and the indeterminate results were likely to have been technique related.

This study has limitations. Restricting analyses to only persons with culture-confirmed TB ensures that any negative test results are false-negative results, but this may not provide an accurate reflection of test sensitivity for latent M. tuberculosis infection or culture-negative TB. Disease severity may suppress immune responses [36, 37]. We tested a variety of assays at multiple centers using programmatic field conditions. This introduced minor protocol deviations. A few TSTs were read early on the second day or late on the third day after placement at times that were convenient for the subject. Additionally, the small sample size may have impacted the precision of our estimates, particularly measurements related to HIV-infected subjects.

In summary, we found that the TST, QFT, and QFT-G have similar sensitivities for detecting M. tuberculosis infection in persons with culture-confirmed TB. With similar sensitivities, the methodological and logistical characteristics of the QFT-G may prompt its use in place of the TST. Although all of these tests may aid in the diagnosis of M. tuberculosis infection, their sensitivities are inadequate to exclude the diagnosis of TB disease in subjects with suggestive signs or symptoms.

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Acknowledgments

We thank the volunteers who participated in this study; Jim Rothel, Chris Kozik, Cindy Merrifield, Gloria Stevens, Gerry Drewyer, Claire Murphy, Tarek Elbeik, Wei Lu, Brenda Robles, and Jenny Van Herpen, for administrative and laboratory assistance; Nong Shang, for statistical advice; and Kenneth Castro and Andrew Vernon, for editorial assistance.

Financial support. The Centers for Disease Control and Prevention.

Manuscript preparation. Cellestis provided technical assistance, QFT-CMI kits and antigens, and support for some ELISA testing.

Potential conflicts of interest. All authors: no conflicts.

  • Received December 9, 2006.
  • Accepted March 29, 2007.
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  1. Clin Infect Dis. (2007) 45 (7): 837-845. doi: 10.1086/521107
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