Borderline QuantiFERON results and the distinction between specific responses and test variability.

BACKGROUND: QuantiFERON (QFT) results near the cut-off are subject to debate. We aimed to investigate which borderline QFT results were due to Mycobacterium tuberculosis (Mtb)-specific responses or to test variability. METHODS: In a contact investigation, tuberculin skin test (TST), QFT and T-SPOT.TB (T-SPOT) were performed in 785 BCG-unvaccinated contacts. Contacts with a low-negative (<0.15), borderline (0.15-0.35), low-positive (0.35-0.70) or high-positive QFT (≥0.70 IU/mL) were compared with respect to exposure, TST and T-SPOT results. Development of active tuberculosis was assessed. RESULTS: Borderline QFT results occurred in threefold excess over test variability (p = 0.0027). In contacts with low-negative, borderline or positive QFT results, a positive TST occurred in 24.9%, 62.1% and 91.4% (p < 0.0001) and a positive T-SPOT result in 6.3%, 41.3% and 86.4%, respectively (p < 0.0001). Two-third (20/29) of contacts with a borderline and 14/16 (88%) with a low-positive QFT had a positive TST and/or T-SPOT, indicating probable Mtb-infection. During 12 years of follow-up, seven patients were diagnosed with active tuberculosis, two of whom after a low-positive QFT. CONCLUSIONS: In this study, most borderline and low-positive QFT results were Mtb-specific, showing the biological significance of a borderline QFT. The clinical relevance, however, will be most distinct in patients who are or will be immunocompromised.

Sarcoidosis and Purified Protein Derivative reactivity.

BACKGROUND: The possible association between (tuberculous and nontuberculous) mycobacterial infections and sarcoidosis is still a matter of dispute. Using diagnostic tests for specific T-cell responses, this association can be investigated in an innovative manner. OBJECTIVE: To measure the T-cell responsiveness to the purified protein derivative (PPD) antigen in blood and broncho-alveolar lavage (BAL) fluid in patients with sarcoidosis and patients with other causes of interstitial lung disease. It was hypothesized that if a mycobacterial infection of the lung is of importance for the development of sarcoidosis, T-cell responsiveness towards the PPD antigen would be increased in patients with sarcoidosis when compared to patients with other causes of interstitial lung disease. METHODS: A single-center study was conducted which included patients with and without sarcoidosis. Venous blood was collected and BAL was performed for, inter alia, Interferon Gamma Release Assay´s (IGRA) with different stimulating antigens, including PPD, ESAT-6, CFP-10 and, as a control, Epstein-Barr virus (EBV). RESULTS: A total of 118 patients were included. There is no difference between PPD reactivity in BAL fluid in patients with or without sarcoidosis. In patients without sarcoidosis, ELISpot PPD in blood shows more reactivity compared to patients with sarcoidosis, although this difference is not significant. ELISpot EBV and TB results are not significant different between both groups. CONCLUSION: These results provide no evidence for the involvement of different mycobacteria in the pathogenesis of sarcoidosis.

Tuberculosis during TNF-α inhibitor therapy, despite screening.

As part of a prospective study on the safety of TNF-α inhibitor therapy after screening for and treatment of latent tuberculosis infection (LTBI), we report two patients who developed active tuberculosis (TB) infection during TNF-α inhibitor therapy, despite negative screening for LTBI. The clinical history is suggestive of a primary infection acquired during travelling to TB-endemic countries. In this lesson of the month we would like to highlight the risk of travelling to TB-endemic areas in patients treated with TNF-α inhibitor therapy. Screening for latent tuberculosis infection is not enough to prevent tuberculosis in patients treated with TNF-α inhibitor therapy.

Added value of use of a purified protein derivative-based enzyme-linked immunosorbent spot assay for patients with Mycobacterium bovis BCG infection after intravesical BCG instillations.

In this case series, we describe four cases in which the use of gamma interferon release assays with purified protein derivative (PPD) as a stimulating antigen was able to demonstrate PPD-specific immune activation. This may help to improve the adequate diagnosis of (systemic) Mycobacterium bovis BCG infections after intravesical BCG instillations for bladder carcinoma.

Follow-up study of tuberculosis-exposed supermarket customers with negative tuberculin skin test results in association with positive gamma interferon release assay results.

We report a follow-up study of 29 subjects with negative tuberculin skin test (TST) results in association with positive gamma interferon release assay (IGRA) results, mainly due to responses to CFP-10 in the T-SPOT.TB assay, during a contact investigation. One year later, 12/29 subjects (41%) had converted to positive TST results in association with negative IGRA results.

Comparison of two interferon-gamma assays and tuberculin skin test for tracing tuberculosis contacts.

BACKGROUND: The tuberculin skin test (TST) has low specificity. QuantiFERON-TB Gold (QFT-G) and T-SPOT.TB are based on interferon (IFN)-gamma responses to Mycobacterium tuberculosis-specific antigens. A novel in-tube format of QFT-G (QFT-GIT) offers logistical advantages. OBJECTIVE: To compare TST, QFT-GIT, and T-SPOT.TB in bacillus Calmette-Guérin unvaccinated contacts and correlate results with measures of recent exposure. METHODS: When a supermarket employee with smear-positive tuberculosis had infected most close contacts, a contact investigation among more than 20,000 customers was performed. We recruited subjects randomly on the day of TST administration (n = 469) and subjects with TST of more than 0 mm on the day of TST reading (n = 316). QFT-GIT and T-SPOT.TB were performed. Demographic data and measures of exposure were collected. TST results were analyzed at a cutoff of 10 or 15 mm. Blood tests were interpreted following the manufacturers' criteria and by varying cutoff levels. RESULTS: Among 785 study participants, TST results were associated with age, whereas positive IFN-gamma responses were significantly associated with cumulative shopping time, most markedly for QFT-GIT. Among participants with a TST of 15 mm or greater, sensitivity of QFT-GIT and T-SPOT.TB was 42.2 and 51.3%, respectively. Interassay agreement was 89.6% (kappa = 0.59). By varying cutoff values, agreement between the IFN-gamma assays was optimal at 93.6% (kappa = 0.71) using a cutoff of 0.20 IU/ml for QFT-GIT and 13 spots for T-SPOT.TB. CONCLUSIONS: Blood test results were associated with exposure, whereas the TST was not. A possible lack of sensitivity of IFN-gamma assays in detecting individuals with TST of 15 mm or greater, despite negative bacillus Calmette-Guérin vaccination status, warrants further investigation into alternative cutoff values.