Absence of interferon-gamma release assay conversion following tuberculin skin testing.

BACKGROUND: The tuberculin skin test (TST) has been the established screening method for tuberculosis (TB) for over a century. Interferon-gamma release assays (IGRAs) using Mycobacterium tuberculosis-specific antigens are increasingly used as diagnostic tests for TB. Tuberculin comprises multiple antigens, including the antigens used in the QuantiFERON-TB Gold In-Tube (QFT-GIT) assay. Exposure to these antigens by means of a TST may prime an immune response that leads to a false-positive result in a subsequent IGRA, limiting the validity of IGRAs in patients in whom these tests are performed sequentially. The current data on the influence of prior TST on IGRAs show inconsistent results. METHODS: Sixteen non-bacille Calmette-Guérin immunised medical students with no history of TB exposure and minimal risk of exposure to TB during the study period were tested simultaneously with a TST and QFT-GIT. The QFT-GIT assay was repeated 6 and 10 weeks later. RESULTS: At baseline, all TST and QFT-GIT results were negative and remained negative 6 and 10 weeks after the TST. CONCLUSION: These data show that negative QFT-GIT results are reproducible and suggest that a TST does not result in conversion of subsequent QFT-GIT assays in the absence of concomitant TB exposure. Therefore, a positive QFT-GIT should not be attributed to boosting induced by a previous TST.

Tuberculous dactylitis--an easily missed diagnosis.

The prevalence of tuberculosis (TB) continues to rise worldwide. Current migration patterns and increased travel to high-prevalence TB countries will result in more frequent presentations of less common forms of TB. Tuberculous dactylitis, a form of tuberculous osteomyelitis, is well recognised in countries with a high prevalence of TB. We provide a systematic review of all published cases of tuberculous dactylitis in children and adolescents and describe a case to illustrate the typical features of the disease. Our review revealed 37 cases of tuberculous dactylitis in children and adolescents, all reported in the last 17 years. Children less than 10 years of age are most frequently affected and the hand is the most commonly affected site. Concurrent pulmonary TB is present in a fifth of cases and systemic symptoms are usually absent. Positive TST and IGRA support the presumptive diagnosis, but cannot be used as rule-out tests. The definitive diagnosis relies on the detection M. tuberculosis by PCR or culture. Treatment should comprise of a standard three to four drug anti-tuberculous regimen. The optimal treatment duration remains unknown. Surgery has a limited role in the treatment in general but may play a supportive role, and curettage of the cavity has been recommended for avascular lesions.

Performance of a whole blood interferon gamma assay for detecting latent infection with Mycobacterium tuberculosis in children.

BACKGROUND: The diagnosis of latent Mycobacterium tuberculosis (MTB) infection with a tuberculin skin test (TST) in children is complicated by the potential influence of prior exposure to Bacille Calmette Geurin (BCG) vaccination or environmental mycobacteria. A whole blood assay has recently been developed to quantitatively measure interferon gamma (IFN-gamma) production by lymphocytes specific to the MTB antigens ESAT-6 and CFP-10, but its use and assessment in children has been limited. A study was undertaken to compare the performance of the whole blood IFN-gamma assay with the TST in diagnosing latent tuberculosis (TB) infection or TB disease in children in routine clinical practice. METHODS: One hundred and six children with a high risk of latent TB infection or TB disease were enrolled in the study. High risk was defined as contact with TB disease, clinical suspicion of TB disease, or recent arrival from an area of high TB prevalence. The whole blood IFN-gamma assay was undertaken in 101 children. RESULTS: Seventeen (17%) of the 101 assays yielded inconclusive results due to failure of positive or negative control assays. There was poor correlation between the whole blood IFN-gamma assay and the TST (kappa statistic 0.3) with 26 (70%) of the 37 children defined as latent TB infection by TST having a negative whole blood IFN-gamma assay. There were no instances of a positive whole blood IFN-gamma assay with a negative TST. Mitogen (positive) control IFN-gamma responses were significantly correlated with age (Spearman's coefficient = 0.53, p<0.001) and, in children with latent TB infection identified by TST, those with a positive IFN-gamma assay were older (median 12.9 v 6.92 years, respectively, p = 0.007). The whole blood IFN-gamma assay was positive in all nine children with TB disease. CONCLUSION: There was poor agreement between the whole blood IFN-gamma assay and TST for the diagnosis of latent TB. The whole blood IFN-gamma assay may have lower sensitivity than the TST in diagnosing TB infection in children. A significant proportion of whole blood IFN-gamma assays fail when used as a screening assay in routine practice.

Urokinase-type plasminogen activator in colorectal cancer: relationship with clinicopathological features and patient outcome.

Urokinase-type plasminogen activator (u-PA) is a serine protease that has been implicated in cancer invasion and metastasis. We quantitated u-PA levels in normal colorectal mucosa, adenomatous polyps, and colorectal cancers and correlated these levels with clinicopathological features and patient survival. Detergent extracts were prepared from 133 colorectal cancers, 133 corresponding colorectal mucosal samples, and 15 synchronous adenomatous polyps. u-PA levels were determined using an ELISA, and a cancer:normal u-PA ratio was calculated for each case. u-PA levels were higher in cancers than in normal tissues, whereas adenomas had intermediate levels (P < 0.0001). u-PA levels were unrelated to clinical or pathological features. Survival was decreased in patients with a high cancer:normal u-PA ratio (P = 0.007). Multivariate survival analysis of patients undergoing curative surgery confirmed that the u-PA cancer:normal ratio was related to outcome (relative risk, 2.67; P = 0.02) and was independent of tumor stage (relative risk, 2.26; P = 0.03). Our study suggests that a high ratio of cancer to normal mucosal u-PA indicates an increased risk of colorectal cancer progression. Measurement of u-PA may provide useful prognostic information in patients undergoing curative surgery for colorectal cancer. The aggressive behavior of colorectal cancers with a high u-PA ratio suggests that the protease might be a suitable target for the development of therapeutic agents to prevent invasion and metastasis.