The Mantoux tuberculin test (TST) is likely the oldest widely used test in contemporary diagnostics. In the past, when its obvious weaknesses were considered, it always “received a pass” because of the lack of an alternative test. However, with the advent and improvement of interferon γ release assays (IGRAs), we feel it is past time to reconsider the widespread use of TSTs.
Case
An adolescent with inflammatory bowel disease refractory to steroids was tested for latent tuberculosis infection (LTBI). The TST result was read as positive by a nurse and negative by a physician who had never seen a positive TST result. The patient was not treated for LTBI, received infliximab, and 2 months later developed cavitary pulmonary tuberculosis. Contact tracing identified 2 relatives and several classmates with LTBI and a younger sibling with intrathoracic tuberculosis.
How can we do better? IGRAs, or blood tests for the diagnosis of tuberculosis infection in place of TSTs, have been licensed in the United States since 2001. IGRAs are now recommended for use for children as young as 2 years of age1 and are recommended by the Centers for Disease Control and Prevention (CDC) for adults in all situations in which a TST has been done.2 IGRAs have clear advantages over the TST: improved specificity due to absence of false-positive results from Bacillus Calmette-Guérin (BCG) vaccine and most nontuberculous mycobacteria, the need for only 1 patient encounter, and avoidance of boosting (Table 1).3
Comparison of the TST and IGRAs
| Characteristic . | TSTa . | QuantiFERONb . | T-SPOTb . |
|---|---|---|---|
| Antigens studied | Multiple | ESAT-6, CFP-10 | ESAT-6, CFP-10 |
| Test mechanics | Measurement of delayed-type hypersensitivity to proteins shared by Mycobacterium tuberculosis and multiple NTM species, including the attenuated Mycobacterium bovis used for the BCG vaccine | Detects amount of interferon γ produced by sensitized lymphocytes after exposure to M. tuberculosis antigens | Detects No. lymphocytes elaborating interferon γ after exposure to M. tuberculosis antigens |
| Cross-reactivity with BCG | Yes | No | No |
| Cross-reactivity with MAC and most NTM species | Yes | Less likelyc | Less likelyc |
| Able to differentiate between tuberculosis infection and disease | No | No | No |
| Possibility of boosting with serial testing | Yes | No | No |
| Criteria for positivity | Based on sliding scale | Tuberculosis antigen: nil ≥0.35 IU/mLd | Panels A or B ≥8 spotsd |
| <5 y old, HIV-seronegative, foreign born,e % (95% CI) | |||
| Sensitivity | 69.1 (58.5–79.7) | 71.2 (55.3–86.5) | 58.9 (42.7–76.2) |
| Specificity | 73.9 (69.6–77.9) | 98.9 (97.4–99.9) | 99.4 (98.4–99.9) |
| PPV | 10.0 (4.8–16.5) | 73.1 (41.3–95.3) | 79.2 (52.0–96.3) |
| NPV | 98.3 (96.7–99.3) | 98.8 (97.4–99.6) | 98.3 (96.5–99.4) |
| ≥5 y old, HIV-seronegative, US born,e % (95% CI) | |||
| Sensitivity | 72.6 (62.2–84.3) | 78.0 (65.0–91.0) | 68.5 (55.7–83.4) |
| Specificity | 92.1 (89.7–94.3) | 97.9 (96.0–99.4) | 99.1 (98.1–99.8) |
| PPV | 66.0 (56.5–75.4) | 88.6 (78.6–97.0) | 94.3 (87.2–98.9) |
| NPV | 93.9 (89.9–97.3) | 95.3 (91.1–98.5) | 93.5 (89.0–97.3) |
| ≥5 y old, HIV-seronegative, foreign born,e % (95% CI) | |||
| Sensitivity | 80.7 (72.6–90.5) | 78.9 (69.6–90.2) | 73.5 (63.9–86.3) |
| Specificity | 70.0 (68.3–71.5) | 98.5 (96.1–99.8) | 99.3 (98.0–99.9) |
| PPV | 57.9 (52.8–61.3) | 96.4 (90.0–99.5) | 98.2 (94.2–99.8) |
| NPV | 87.3 (79.9–95.0) | 89.9 (83.6–96.3) | 87.7 (81.1–94.9) |
| Characteristic . | TSTa . | QuantiFERONb . | T-SPOTb . |
|---|---|---|---|
| Antigens studied | Multiple | ESAT-6, CFP-10 | ESAT-6, CFP-10 |
| Test mechanics | Measurement of delayed-type hypersensitivity to proteins shared by Mycobacterium tuberculosis and multiple NTM species, including the attenuated Mycobacterium bovis used for the BCG vaccine | Detects amount of interferon γ produced by sensitized lymphocytes after exposure to M. tuberculosis antigens | Detects No. lymphocytes elaborating interferon γ after exposure to M. tuberculosis antigens |
| Cross-reactivity with BCG | Yes | No | No |
| Cross-reactivity with MAC and most NTM species | Yes | Less likelyc | Less likelyc |
| Able to differentiate between tuberculosis infection and disease | No | No | No |
| Possibility of boosting with serial testing | Yes | No | No |
| Criteria for positivity | Based on sliding scale | Tuberculosis antigen: nil ≥0.35 IU/mLd | Panels A or B ≥8 spotsd |
| <5 y old, HIV-seronegative, foreign born,e % (95% CI) | |||
| Sensitivity | 69.1 (58.5–79.7) | 71.2 (55.3–86.5) | 58.9 (42.7–76.2) |
| Specificity | 73.9 (69.6–77.9) | 98.9 (97.4–99.9) | 99.4 (98.4–99.9) |
| PPV | 10.0 (4.8–16.5) | 73.1 (41.3–95.3) | 79.2 (52.0–96.3) |
| NPV | 98.3 (96.7–99.3) | 98.8 (97.4–99.6) | 98.3 (96.5–99.4) |
| ≥5 y old, HIV-seronegative, US born,e % (95% CI) | |||
| Sensitivity | 72.6 (62.2–84.3) | 78.0 (65.0–91.0) | 68.5 (55.7–83.4) |
| Specificity | 92.1 (89.7–94.3) | 97.9 (96.0–99.4) | 99.1 (98.1–99.8) |
| PPV | 66.0 (56.5–75.4) | 88.6 (78.6–97.0) | 94.3 (87.2–98.9) |
| NPV | 93.9 (89.9–97.3) | 95.3 (91.1–98.5) | 93.5 (89.0–97.3) |
| ≥5 y old, HIV-seronegative, foreign born,e % (95% CI) | |||
| Sensitivity | 80.7 (72.6–90.5) | 78.9 (69.6–90.2) | 73.5 (63.9–86.3) |
| Specificity | 70.0 (68.3–71.5) | 98.5 (96.1–99.8) | 99.3 (98.0–99.9) |
| PPV | 57.9 (52.8–61.3) | 96.4 (90.0–99.5) | 98.2 (94.2–99.8) |
| NPV | 87.3 (79.9–95.0) | 89.9 (83.6–96.3) | 87.7 (81.1–94.9) |
CI, confidence interval; MAC, Mycobacterium avium complex; NPV, negative predictive value; NTM, nontuberculous mycobacteria; PPV, positive predictive value.
Although IGRAs offer similar sensitivity and enhanced specificity compared with the TST, there continue to be circumstances under which TSTs should be considered. These include (1) in children <2 y of age, for whom TSTs remain the test of choice given the relative paucity of data for this age group compared with older children; (2) in children in whom IGRAs are not interpretable (eg, results are borderline or indeterminate); (3) in children with suspected tuberculosis disease, in whom any positive test result is of clinical utility; and (4) in children at high-risk for progression from infection to disease (eg, children receiving tumor necrosis factor antagonists), in whom any positive test result would prompt initiation of therapy for tuberculosis infection.
The 2 commercially available IGRAs are QuantiFERON (Qiagen, Germantown, MD) and the T-SPOT.TB (Oxford Immunotec USA, Marlborough, MA).
IGRA results can be positive in patients infected with the following mycobacterial species: Mycobacterium kansasii, Mycobacterium marinum, and Mycobacterium szulgai.
Assuming appropriate performance of positive and negative controls.
In the absence of a reference standard for tuberculosis infection, latent class analysis has been used to assess test performance when no single reference standard exists. The recent study by Stout et al3 did not report test performance for US-born children <5 y of age; however, the other age and birth cohorts are presented. The study included 464 foreign-born HIV-seronegative children <5 y of age, 7931 patients aged ≥5 y who were foreign born and HIV-seronegative, and 775 US-born HIV-seronegative persons ≥5 y old. The QuantiFERON version used in these analyses was the QuantiFERON Gold In-Tube, which included a third antigen (TB7.7); in 2018, a newer version (QuantiFERON-TB Gold Plus) was released that does not include this antigen but does include CD8+ T-cell responses. Because the older versions are no longer being produced, the antigens listed at the top of the table only include those for currently available assays.
What is not sufficiently emphasized is the advantage of a laboratory-based test over a clinical test that is infrequently performed by many physicians and nurses and is even less frequently interpreted by these same providers (it is estimated that up to 20% of children do not return for TST interpretation).4 Those interpreting the TST are required to differentiate erythema from induration, measure the induration down to the millimeter, and use a sliding scale to interpret the results on the basis of epidemiologic risk factors that patients and their families may or may not report accurately (or even know about). And all of these interventions are usually conducted without any meaningful quality control or validation. What other test that we perform clinically is subject to this degree of variation at so many stages in the process?
It may be germane to ask why, then, do we continue to widely use the TST? Pre-IGRA, the answer was easy: there was no other test for tuberculosis infection. But now, with almost 2 decades of mounting data on IGRA use, justifying the widespread use of the TST is more problematic. Let us explore the 4 commonly stated arguments in favor of TST use: cost, availability, paucity of data in some populations, and lack of knowledge and comfort in using IGRAs.
Cost
TSTs are less expensive than IGRAs if only direct reagent, testing, and reading costs are included. However, other costs, including time for patients to return for TST interpretation, false-positive TST results (unnecessary clinical evaluation, chest radiographs, baseline hepatic transaminases [particularly in adults], medication, time out of work and/or school for return visits), and drug side effects and toxicity, are high and unquantified. Such TST cost considerations have led to IGRA adoption in many occupational health settings.5 In addition, a recent US Preventive Services Task Force B rating for either test6 ensures payment from third-party insurance sources, which should contribute to increased IGRA use.
Availability
The lack of laboratory availability is clearly a limitation for IGRAs in some resource-scarce settings. However, it is difficult to extrapolate this scenario to most countries in which testing for and treatment of LTBI occurs. More widespread IGRA availability in commercial laboratories and advancements in IGRA technology, which allow for samples to be stored for longer periods before processing, have vastly expanded IGRA availability and utility.
Limitations of Data
Early recommendations to avoid using IGRAs in preschool-aged children were based on the lack of data on sensitivity and the high percentage of indeterminate test results in preschool-aged children. More recent pediatric data demonstrate that IGRAs are as sensitive as TSTs even in young children (≥2 years old)3,7 and that uninterpretable results are far less common than the percent of children who fail to return for TST interpretation.4 Current CDC guidelines2 state that either a TST or IGRA can be used, but IGRAs are preferred in persons less likely to return for interpretation and for BCG recipients. Furthermore, the CDC has revised the Tuberculosis Technical Instructions for immigration, notifying all civil surgeons that beginning in October 2018, the TST will not be allowed for testing purposes and that all persons requiring a test of infection (including <5-year-old children) must have an IGRA performed.8
Provider Comfort
Health care workers who infrequently order LTBI testing are less cognizant of IGRAs. The comfort surrounding TSTs may well reflect that they learned about TSTs during training rather than a philosophical belief that TSTs are superior to IGRAs. Moreover, the comfort that providers have in many cases is perceived comfort. There are decades of data documenting the consistently low accuracy of TST interpretation, with 1 study finding that >90% of all positive TST results were read as negative.9 Finally, declining rates of tuberculosis disease (and, presumably, tuberculosis infection) will almost certainly be paralleled by declining provider comfort with and expertise in TST placement and interpretation.
In the era of targeted testing for tuberculosis infection, providers’ pretest probability should be higher than when universal testing was recommended. Thus, the importance of “getting it right,” with the correct test being ordered and accurately interpreted, is potentially more essential now than it was 2 decades ago. Reduced testing does not mean inferior testing. There is still a role for TSTs, such as in areas where laboratory-based diagnostics may be unavailable, in cases of disseminated tuberculosis disease (in which any test result being positive would warrant therapy), or for the few patients in whom IGRA results are uninterpretable. What we question is the wisdom of using TSTs as first-line tests when a quality controlled, more specific test is easily available.
Still, providers have been slow to give up the TST, fearing the patient with a positive TST and a negative IGRA result may progress to active tuberculosis. At the recent 2018 annual meeting of the North American Region of the International Union Against Tuberculosis and Lung Disease, a distinguished international panel of pediatric tuberculosis authorities was asked from the floor if any had ever seen a patient who had a positive TST result in the presence of a negative IGRA result and progressed to active tuberculosis. All of the 4 panelists stated that they had never seen such a case but warned that it could occur. In an era when more specific laboratory tests for tuberculosis infection are readily available, we question the wisdom of continuing to use a test that, at its core, entails subjectively measuring a bump on the arm.
Dr Cruz conceptualized the article, drafted the initial manuscript, and reviewed and revised the manuscript; Dr Reichman conceptualized the article and critically reviewed and revised the manuscript; and both authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: No external funding.
References
Competing Interests
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
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