Replacing the tuberculin skin test with a specific blood test

For almost 100 years has the tuberculin skin test (TST) been used for the support the diagnosis of active and latent TB infection. The TST test has, however, a number of limitations most notable low specificity in BCG vaccinated individuals due to cross-reactive components in PPD and the M. bovis BCG vaccine strain and an intensive search for new and more specific diagnostic antigens has therefore be ongoing. In this review we describe the discovery process leading to the identification of the M. tuberculosis specific antigens ESAT6 and CFP10; two low molecular weight proteins which are highly sensitive and specific for detection of a M. tuberculosis infection.     

Diagnosis of tuberculosis infection using interferon-γ-based assays

Interferon-γ-based assays, collectively known as IFN-γ release assays (IGRAs), have emerged as a reliable alternative to the old tuberculin skin test (TST) for the immunodiagnosis of tuberculosis (TB) infection. The 2 commercially available tests, the enzyme-linked immunosorbent assay (ELISA), QuantiFERON-TB Gold Intube (QFT-IT), and the enzyme-linked immunospot assay (ELISPOT), T-SPOT.TB, are more accurate than TST for the diagnosis of TB, since they are highly specific and correlate better with the existence of risk factors for the infection. According to the available data, T-SPOT.TB obtains a higher number of positive results than QFT-IT, while its specificity seems to be lower. Although the sensitivity of the IFN-γ -based assays may be impaired to some extent by cellular immunosuppression and extreme ages of life, they perform better than TST in these situations. Data from longitudinal studies suggest that IFN-γ-based tests are better predictors of subsequent development of active TB than TST; however this prognostic value has not been consistently demonstrated. This review focuses on the clinical use of the IFN-γ -based tests in different risk TB groups, and notes the main limitations and areas for future development.     

Snapshot of Quantiferon TB gold testing in Northern Mexico

Most people infected with Mycobacterium tuberculosis have an asymptomatic condition named latent tuberculosis. These people do not have bacilli in the corporal secretions and are hard to diagnose by conventional laboratory tests. Diagnosis of latent tuberculosis infection (LTBI) in México is based on the tuberculin skin test (TST). This test has disadvantages, principally because the vaccine containing the Bacille Calmette-Guérin (BCG) is applied to 99% of this population and causes false positive TST outcomes. Recently, interferon-gamma release assays (IGRA) have been demonstrated to be a good test to detect latent tuberculosis with equal or better sensitivity to TST and without interference from BCG. However, in México the IGRA are an uncommon test due to the higher cost compared to TST. The main objective of this work was demonstrate the potential utility of the Quantiferon TB(?) gold in tube (QTB(?)-GIT) test to detect latent TB in a population from northern México. Samples from 106 subjects with close contact, or without contact, with actively infected TB patients were tested to detect LTBI. Our results show a significant difference between individuals in close contact with active TB patients (39.7%) compared to those without contact (3.2%), p < 0.01. The concordance between TST and QTB(?)-GIT was poor (κ = 0.31). Our preliminary results show that the QTB(?)-GIT has better capacity than TST to detect latent tuberculosis infection.     

Nuevas técnicas in vitro en el diagnóstico de la infección tuberculosa

The biological therapies based in the anti-tumor necrosis factor-α (TNF) are an effective alternative for the treatment of chronic inflammatory diseases. However, given that anti-TNF-α therapy has been associated with reactivation of latent tuberculosis infection, a previous evaluation of the patients is required in order to avoid their progression to active TB in case of being infected. Tuberculin skin testing (TST) is used to diagnose tuberculosis infection but it has low specificity in patients who have received the BCG vaccine and low sensitivity in patients with altered cell-mediated immunity. In vitro assays based on the detection of interferon-γ (IFN) released by T cells stimulated by specific Mycobacterium tuberculosis antigens have emerged as an option for the diagnosis of tuberculosis infection. The results to date show, that they are a viable alternative to TST thanks to their higher specificity and sensitivity. Although there are some preliminary results indicating that the IFN-γ tests could be used alone, at the moment it seems more prudent to use them in combination with the TST, considering infection when either of them is positive.     

Comparison of IGRA and TST in the diagnosis of latent tuberculosis among women of reproductive age in South India

BackgroundLatent tuberculosis infection (LTBI) is a mycobacterial infection defined on the basis of cellular immune response to mycobacterial antigens. The tuberculin skin test (TST) and the Interferon-Gamma Release Assay (IGRA) are the two tests currently used to establish the diagnosis of LTB. Literature suggests that a study regarding tuberculosis (TB) infection among women of reproductive age group is limited.MethodsFemale household contact, married, aged 18–49 years underwent written consent form and are screened for LTBI using the TST and IGRA. Participants are injected with TST [5 tuberculin unit (TU), purified protein derivative (PPD)] and IGRA [QuantiFERON®-TB Gold Plus kit (QFT-Plus)]. All the household contacts were followed-up for one year for incident TB cases. Statistical analysis was done using STATA version 14 (StataCorp., Texas, USA). Cohen's kappa test was used to determine the agreement between two tests.ResultsThe prevalence of LTBI was found to be 69% (either TST or IGRA positive). Positivity rate of IGRA was higher when compared to that of TST. Out of 139 participants, 68 (49%) tested positive for TST, 80 (57.6%) tested positive for IGRA and 52 (37.4%) tested positive for both. Discordant results were observed in about two fifth of the study population and there was poor agreement between the two tests.ConclusionLongitudinal studies are required to detect incident TB cases to evaluate the usefulness of these tests. The study was found that IGRA is more consistent to diagnosis of latent tuberculosis infection than the TST. Such studies can also be performed in varied settings among different populations which would help us to improve the diagnosis of LTBI and consequently help in TB control.     

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

BACKGROUND: QuantiFeron-TB (QIFN) is a whole-blood interferon-;gamma assay for the recognition of cell-mediated immune response to Mycobacterium tuberculosis infection. OBJECTIVES: To compare the QIFN assay with the tuberculin skin test (TST) in patients with newly diagnosed culture-proven tuberculosis (TB) and healthy volunteers with high or low risk of latent M tuberculosis infection and to identify factors associated with discordance between tests. METHOD: Two-hundred fifty-eight subjects underwent both assays. All participants completed a detailed questionnaire, and data from TB patients' medical records were collected. RESULTS: In the entire study population, agreement between tests was moderate and the correlation between the magnitude of QIFN response and the TST induration diameter was significant. In volunteers with no known risk of exposure to M tuberculosis, the specificity of the assays was comparable. However, in subjects with active TB or those vaccinated with bacille Calmette-Guérin, the QIFN assay detected more reactors than did the TST. In these individuals, agreement between assays was poor and no correlation or only a weak correlation was found between the diameter of TST induration and the magnitude of the interferon-gamma responses. CONCLUSIONS: The sensitivity of the QIFN assay is greater than that of the TST in patients with active TB before the initiation of anti-TB chemotherapy, but its specificity is influenced more by bacille Calmette-Guérin vaccination. The QIFN assay may provide an improvement over the current practice of the use of the TST to support diagnosis of active M tuberculosis infection in the clinic; however, QIFN cannot be considered an adequate replacement for the TST in the screening for latent infection.     

Advances in the diagnosis of tuberculosis infection

One-third of the world-wide population currently presents latent tuberculosis infection (LTI). In Spain, TB is situated as the third disease of mandatory notification. The standard technique for the diagnosis of ITL is the tuberculin test (PPD), although its most important drawback is its specificity since the proteins used are not specific for Mycobacterium tuberculosis. In recent years, research has been done and new diagnostic methods have been approved based on the in vitro quantification of the immune cell response, the so-called interferon gamma release assays (IGRA). Compared with PPD, the main difference is that IGRAs detect the release of interferon-gamma in response to specific tuberculous antigens. In the absence of a true reference test for the diagnosis of tuberculosis infection, it is difficult to establish the sensitivity and specificity of these new diagnostic techniques. IGRAs have been used in the detection of ITL in subjects with immune system alterations (HIV, EEI, IRC, rheumatologic diseases) with good results. They are also being extensively used in the study of contacts. In recent studies involving serial controls of said tests, they were observed to present conversions and reversions that occur after exposure to M. tuberculosis. Today and with the current knowledge, it seems that IGRAs can complement PPD, but not substitute them.     

Interferon-gamma release assays are a better tuberculosis screening test for hemodialysis patients: A study and review of the literature

Diagnosing latent tuberculosis (TB) infection (LTBI) in dialysis patients is complicated by poor response to tuberculin skin testing (TST), but the role of interferon-gamma release assays (IGRAs) in the dialysis population remains uncertain. Seventy-nine patients were recruited to compare conventional diagnosis (CD) with the results of two IGRA tests in a dialysis unit. Combining TST, chest x-ray and screening questionnaire results (ie, CD) identified 24 patients as possible LTBI. IGRA testing identified 22 (QuantiFERON Gold IT, Cellestis, USA) and 23 (T-spot.TB, Oxford Immunotec, United Kingdom) LTBI patients. IGRA and CD correlated moderately (κ=0.59). IGRA results correlated with history of TB, TB contact and birth in an endemic country. TST was not helpful in identifying LTBI patients in this population. The tendency for IGRAs to correlate with risk factors for TB, active TB infection and history of TB argues for their superiority over TST in dialysis patients. There was no superiority of one IGRA test over another.     

Suttons’s Law: Local Immunodiagnosis of Tuberculosis

Recently, important advances have been made in the immunodiagnosis of tuberculosis. New T cell interferon-γ release assays (TIGRA) are more specific and more sensitive than the tuberculin skin test (TST) for the diagnosis of Mycobacterium tuberculosis (MTB) infection. However, like the TST, TIGRA are unable to distinguish between active tuberculosis (TB), latent TB infection (LTBI) and treated TB if performed on blood mononuclear cells alone. In active TB, MTB-specific T cells are actively recruited to the site of infection and can rapidly be identified in extrasanguinous fluids, such as pleural effusions, ascites, cerebrospinal fluid, and in bronchoalveolar lavages. This review summarizes recent findings comparing systemic and local immune responses against MTB. Although bacteriological and histological methods have the highest specificity for TB in terms of diagnosing active TB and the number of TB patients in whom extrapulmonary TIGRAs have been evaluated is still limited, a comparison of local and systemic MTB-specific immune responses is a promising technique to rapidly distinguish active TB from latent MTB infection in routine clinical practice.     

Tuberculosis in children: New diagnostic blood tests

The interferon-gamma-release assays were developed to overcome the pitfalls and logistic difficulties of the tuberculin skin test (TST) for the diagnosis of latent tuberculosis infection (LTBI). These blood tests measure the in vitro production of interferon-gamma by sensitized lymphocytes in response to Mycobacterium tuberculosis-specific antigens. Two interferon-gamma-release assays are registered for use in Canada: the QuantiFERON-TB Gold In-Tube assay (Cellestis Inc, Australia) and the T.SPOT–TB test (Oxford Immunotec, United Kingdom). Evaluation of these tests has been hampered by the lack of a gold standard for LTBI, and limited paediatric data on their use. It appears that they are more specific than the TST, and may be useful for evaluating TST-positive patients at low risk of true LTBI. Moreover, they may add sensitivity if used in addition to the TST in immunocompromised patients, very young children and close contacts of infectious adults. A summary of these tests, their limitations and their application to clinical paediatric practice are described.     

Comparison of an interferon-gamma release assay with tuberculin skin testing in HIV-infected individuals

RATIONALE: Although interferon (IFN)-gamma release assays are approved for the diagnosis of latent tuberculosis infection (LTBI), limited data exist regarding their performance in HIV infection. OBJECTIVES: To compare tuberculin skin test (TST) results to the commercial IFN-gamma release assay QuantiFERON-TB Gold In-Tube (QFT) for the diagnosis of LTBI in HIV-infected adults. METHODS: A total of 294 HIV-infected subjects sampled from two San Francisco cohorts underwent TST, using 5 TU of purified protein derivative, and QFT, measuring IFN-gamma response to Mycobacterium tuberculosis-specific RD-1 antigens. MAIN RESULTS: Of 294 participants, 205 (70%) returned for an evaluable TST. Concordance between QFT and TST was 89.3% (kappa=0.37, p=0.007). However, in subjects with positive test results by either TST or QFT, only 28% (8/29) had positive test results by both modalities. TST-positive/QFT-negative discordant results were found in 5.1% of subjects and TST-negative/QFT-positive discordance in 5.6%. Indeterminate QFT results occurred in 5.1%, all due to a failure to respond to the phytohemagglutinin-positive control. Subjects with a CD4(+) count of less than 100 cells/mm(3) had a relative risk of an indeterminate result of 4.24 (95% confidence interval, 1.55-11.61; p=0.003) compared with those with a CD4(+) count of 100 or more. CONCLUSIONS: Overall concordance between QFT and TST in HIV infection was high, but agreement among subjects with positive tests by either modality was low.     

Diagnóstico y abordaje terapéutico de la infección tuberculosa latente

Detection and treatment of latent tuberculosis infection (LTBI) is an essential measure for tuberculosis (TB) control in low-incidence countries. However, such strategy is limited by the low predictive ability of the diagnostic tests for the development of active TB among infected people and the long-term and toxic treatment regimens. The in vitro interferon-gamma release assays are more specific and sensitive than the tuberculin skin test (TST), and enable a better selection of cases requiring treatment. Nonetheless, their capacity to predict development of TB is still poor. In addition, treatment regimens for LTBI are long, and compliance rates are low. This review discusses the use of the available diagnostic tests and the new approaches to the diagnosis of LTBI, as well as its management in different clinical scenarios.     

Interferon-γ Release Assays for Diagnosing Mycobacterium tuberculosis Infection in Renal Dialysis Patients

Background and objectives: End-stage renal disease (ESRD) patients are at high risk for tuberculosis (TB). IFN-γ release assays that assess immune responses to specific TB antigens offer potential advantages over tuberculin skin testing (TST) in screening such patients for Mycobacterium tuberculosis infection. This study sought to determine whether IFN-γ release assay results are more closely associated with recent TB exposure than TST results.Design, setting, participants, and measures: Prospective cohort investigation of patients at a hemodialysis center with a smear-positive case of TB. Patients without a history of TB underwent initial and repeat testing with TST, and with the IFN-γ assays QuantiFERON-TB Gold® (QFT-G) and ELISPOT test. Outcome measures included the prevalence of positive test results, identification of factors associated with positive results, and test result discordance.Results: A total of 100 (47% foreign born; median age, 55 yr; age range, 18 to 83 yr) of 124 eligible patients were enrolled. Twenty-six persons had positive TST results, 21 had positive QFT-G results, and 27 had positive ELISPOT results. Patients with TB case contact were likely to have a positive QFT-G result (P = 0.02) and ELISPOT results (P = 0.04), whereas TB case contact was not associated with positive TST results (P = 0.7). Positive TST results were associated with foreign birth (P = 0.04) and having had a TST in the previous year (P = 0.04).Conclusions: Positive IFN-γ assay results were more closely associated with recent TB exposure than were positive TST results. QFT-G and ELISPOT might offer a better method for detecting TB infection in ESRD patients.More than 300,000 persons in the United States with end-stage renal disease (ESRD) currently require renal replacement therapy (1). These patients are at increased risk for a variety of infections. The basis for their underlying immune dysfunction is not completely understood but thought to be mediated by uremia (2). Renal failure patients are at 8 to 25 times higher risk for tuberculosis (TB) than the general population (3–5). TB disease in these patients can be difficult to diagnose, as it is frequently extrapulmonary and insidious in onset (6). Recommendations for screening dialysis patients for latent Mycobacterium tuberculosis infection (LTBI) exist to decrease transmission of TB in this setting of highly susceptible patients (7).Despite such recommendations, screening dialysis patients for latent TB infection can be difficult. Their underlying immune suppression raises the likelihood of false-negative TB skin test (TST) results and makes interpretation of negative results unreliable. Dialysis patients have been shown to have significant rates of cutaneous anergy to antigens, such as Candida, mumps, or tetanus (8,9). Furthermore, as in immunocompetent populations, the TST can be falsely positive in persons with a history of previous nontuberculous mycobacterium infection or vaccination with bacillus Calmette-Guerin (BCG) (10).Newly developed blood tests might offer improved ways of screening ESRD patients for LTBI. The QuantiFERON-TB Gold® test (QFT-G) measures production of IFN-γ by sensitized lymphocytes after whole blood is stimulated with specific TB antigens. It became commercially available in the United States following approval by the Federal Drug Administration in May 2005. The enzyme-linked immuno-spot assay (ELISPOT) is a diagnostic platform that enumerates the number of reactive T lymphocytes releasing IFN-γ in the presence of TB antigens. Both of these technologies can be used to assess immune response to Culture Filtrate Protein 10 (CFP-10) and Early Secretory Antigen 6 (ESAT-6). These antigens are encoded on the RD-1 portion of the M. tuberculosis genome, and are not found in BCG strains or most nontuberculous mycobacterium. Accordingly, these tests are more specific for LTBI than the TST, which relies on purified protein derivative (11). To date, there has been limited evaluation of QFT-G and ELISPOT in screening immunosuppressed populations for TB, including those with ESRD.In October 2003, we were notified of a TB case in a dialysis center in southern California. We evaluated patients at the dialysis center and assessed the utility of using the IFN-γ assays during a TB-contact investigation. We compared the results of IFN-γ assays and TST and identified factors associated with positive test results and test result discordance.     

Diagnosing tuberculosis infection in the 21st century: new tools to tackle an old enemy

The century-old tuberculin skin test (TST) was until recently the only means of diagnosing latent tuberculosis infection (LTBI). Recent advances in mycobacterial genomics and human cellular immunology have resulted in two new blood tests that detect tuberculosis infection by measuring in vitro T-cell interferon (IFN)-gamma release in response to two unique antigens that are highly specific for Mycobacterium tuberculosis but absent from bacille Calmette-Guérin (BCG) vaccine and most nontuberculous mycobacteria. One assay, the enzyme-linked immunospot (ELISpot) [T-SPOT.TB; Oxford Immunotec; Oxford, UK] enumerates IFN-gamma-secreting T cells, while the other assay measures IFN-gamma concentration in supernatant by enzyme-linked immunosorbent assay (ELISA) [QuantiFERON-TB Gold; Cellestis; Carnegie, Australia]. A large and growing clinical evidence base indicates that both tests are more specific than the skin test because they are not confounded by prior BCG vaccination. In active tuberculosis, ELISA has similar sensitivity to the skin test, while ELISpot is significantly more sensitive. Current cross-sectional evidence suggests that for diagnosis of LTBI, sensitivity of ELISA is similar to TST, while ELISpot appears more sensitive. High specificity will enable clinicians to avoid unnecessary preventive treatment in BCG-vaccinated persons without infection who commonly have false-positive TST results. High sensitivity could enable accurate targeting of preventive treatment to patients with infection at the highest risk of progression to active tuberculosis who frequently have false-negative TST results due to impaired cellular immunity. However, longitudinal studies are needed to define the predictive value of positive blood test results for progression to tuberculosis.     

Recent advances in testing for latent TB

After more than a century of relying on skin testing for the diagnosis of latent TB infection, clinicians now have access to blood-based diagnostics in the form of interferon γ release assays (IGRAs). These tests are generally associated with higher sensitivity and specificity for diagnosis of latent TB infection. This article reviews the indications for testing and treatment of latent TB infection in the overall context of a TB control program and describes how IGRAs might be used in specific clinical settings and populations, including people having close contact with an active case of TB, the foreign born, and health-care workers.     

Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review

A major challenge in tuberculosis control is the diagnosis and treatment of latent tuberculosis infection. Until recently, there were no alternatives to the tuberculin skin test (TST) for diagnosing latent tuberculosis. However, an alternative has now emerged in the form of a new in-vitro test: the interferon-gamma assay. We did a systematic review to assess the performance of interferon-gamma assays in the immunodiagnosis of tuberculosis. By searching databases, contacting experts and test manufacturers, we identified 75 relevant studies. The results suggest that interferon-gamma assays that use Mycobacterium tuberculosis-specific region of difference 1 (RD1) antigens (such as early secretory antigenic target 6 and culture filtrate protein 10) may have advantages over the TST, in terms of higher specificity, better correlation with exposure to M tuberculosis, and less cross-reactivity due to BCG vaccination and non-tuberculous mycobacterial infection. However, interferon-gamma assays that use RD1 antigens in isolation may maximise specificity at the cost of sensitivity. Assays that use cocktails of RD1 antigens seem to overcome this problem, and such assays have the highest accuracy. RD1-based interferon-gamma assays can potentially identify those with latent tuberculosis who are at high risk for developing active disease, but this requires confirmation. There is inadequate evidence on the value of interferon-gamma assays in the management of immunocompromised individuals, children, patients with extrapulmonary or non-tuberculous mycobacterial disease, and populations in countries where tuberculosis is endemic. Current evidence suggests that interferon-gamma assays based on cocktails of RD1 antigens have the potential to become useful diagnostic tools. Whether this potential can be realised in practice remains to be confirmed in well designed, long-term studies.     

Results of a tuberculosis-specific IFN-gamma assay in children at high risk for tuberculosis infection.

The specificity of the tuberculin skin test (TST) for the diagnosis of latent tuberculosis infection (LTBI) is adversely affected by bacille Calmette-Guérin (BCG) vaccination and infection with non-tuberculous mycobacteria. Interferon-gamma release assays (IGRAs) using TB-specific antigens promise higher specificity. We compared a new IGRA and TST in 184 schoolchildren at high risk for LTBI. The IGRA and TST were positive in 33.2% and 43.5% of the children, respectively (P < 0.001). If studies confirm that this difference is due to higher specificity of this IGRA, it may have an important role to play in the diagnosis of LTBI and identification of children at true risk for TB.     

Detection of latent tuberculosis infection in peritoneal dialysis patients: new methods

OBJECTIVE: The risk for tuberculosis (TB) is increased in patients with chronic renal failure and dialysis. Tuberculin skin test (TST) is the classical diagnostic method for screening despite its low sensitivity. New methods based on interferon-gamma have been developed. The aim of this study was to evaluate if Quantiferon? TB-gold In Tube (QFT-GIT) could be useful in the diagnosis of TB infection in patients on peritoneal dialysis (PD). Patients and methods: Fifty-four patients on PD were included in the study. They were evaluated for latent tuberculosis with QFT-GIT, TST and an assessment by an expert pulmonologist using patient's medical history and x-rays. Agreement between test results was determined. Results:The prevalence of a positive TST was 29.6% for the first test and 31.5% for the second (booster effect). A positive chest x-ray increased the rate of detection of patients with latent TB infection up to 42.6% and the expert physician's evaluation to 44.4%. The correlation between QFT-GIT and TST was fair (k=0.36; P=.006), as it was between TST and expert physician's evaluation (k=0.257; P=.06). CONCLUSIONS: According to our experience QFT-GIT represents an important advantage in the diagnosis of latent TB infection in chronic renal failure patients on PD. It may complement but not replace TST.     

Interferon-gamma release assays in the detection of latent tuberculosis infection in patients with inflammatory arthritis scheduled for anti-tumour necrosis factor treatment

Biological agents, particularly anti-Tumour Necrosis Factor (TNF)-α agents, have emerged as an effective treatment in patients with chronic inflammatory diseases. An association between anti-TNF-α antibodies and reactivation of latent tuberculosis infection (LTBI) has been established. Appropriate screening for TB infection has become mandatory before starting a treatment based on TNF-α inhibition. The objective was to determine the usefulness of IFN-γ release assays in diagnosing LTBI in patients with inflammatory rheumatic diseases scheduled for anti-TNF-α treatment. The study included 53 individuals with inflammatory rheumatism. All patients had a TST, a chest radiograph, QuantiFERON Gold In-Tube (QFN-G-IT) and T-SPOT.TB. To investigate the influence of non-tuberculous mycobacteria (NTM) infections on non-BCG-vaccinated patients, with a positive TST result and both negative IFN-γ assays, we performed an ex vivo ELISPOT, stimulating the cells separately with NTM sensitins. TST was positive in 7 cases, T-SPOT.TB in 11 and QFN-G-IT in 9 cases. Agreement between TST and T-SPOT.TB and QFN-G-IT was 77.35% (κ = 0.33 and κ = 0.40, respectively), and between both in vitro tests, it was 83.01% (κ = 0.57). Of the three patients with positive TST and negative T-SPOT.TB and QFN-G-IT, one positive ELISPOT result was obtained after stimulation with NTM sensitins. Positive TST, T-SPOT.TB and QFN-G-IT results were not affected by the immunosuppressive therapies. IFN-γ release assays are useful methods for avoiding TST false-positive results, but in those patients with a high risk of developing active TB and in the absence of predictive value studies in this specific kind of population for knowing how safe is the use of IGRAs alone, the combined use of TST and IFN-γ tests should be recommended in order to increase the overall number of LTBI diagnoses.     

High incidence of anergy in inflammatory bowel disease patients limits the usefulness of PPD screening before infliximab therapy.

BACKGROUND & AIMS: Reports of tuberculosis (TB) in patients administered infliximab prompted the Food and Drug Administration to recommend that all patients being considered for this therapy be evaluated for the risk for latent TB infection by means of a tuberculin skin test (TST). The aim of this study is to evaluate the utility of a TST as an adequate screen for TB exposure in patients with inflammatory bowel disease (IBD). METHODS: Eighty-two consecutive patients with IBD (Crohn's disease, 70 patients; ulcerative colitis, 4 patients; indeterminate colitis, 8 patients) seen at Cedars-Sinai Medical Center IBD Center (Los Angeles, CA) being treated with or considered for infliximab therapy underwent a standard intradermal purified protein derivative (PPD) TST before or between infusions of infliximab. One or more control antigens (Candida, tetanus, and/or mumps) were concurrently placed on 69 of these patients. Skin tests were read for induration at 48-72 hours after placement, and results were recorded. RESULTS: None of 82 patients had a positive PPD TST result. Overall, 71% of patients (49 of 69 patients) with controls placed failed to react to any antigen. Eighty-three percent of patients (40 of 48 patients) who were administered corticosteroids and/or immunosuppressive medications, not including infliximab, for at least 1 month were anergic compared with 43% of patients (9 of 21 patients; P < 0.002) who were not administered those medications. CONCLUSIONS: Given the high prevalence of anergy, a negative TST result in patients with IBD administered infliximab is an unreliable indicator for TB exposure. Evaluation for TB risks should include not only a TST, but also a detailed history of travel, TB exposures, and such symptoms as chronic cough and weight loss, and a chest radiograph should be considered.