Faculty Bibliography

OBJECTIVE:: To evaluate an interferon (IFN)-gamma release assay in diagnosing latent tuberculosis infection in pregnant adolescents and women at risk for exposure to Mycobacterium tuberculosis. METHODS:: This was a prospective study of women and adolescents receiving health care at Bellevue Hospital Outpatient Clinics in New York City. Each patient was assessed for M tuberculosis risk factors, had a tuberculin skin test placed, and an IFN-gamma release assay performed. The concordance between the tuberculin skin test and the IFN-gamma release assay was calculated and the results analyzed according to the likelihood of exposure to M tuberculosis. Mean mitogen IFN-gamma levels were used across groups to compare reliability between trimesters and assay performance in pregnant compared with nonpregnant females of childbearing age. RESULTS:: A total of 140 pregnant and 140 nonpregnant females were enrolled in the study. The IFN-gamma release assay was highly specific, and IFN-gamma release assay positivity was associated with a greater likelihood of exposure to M tuberculosis. The overall agreement between the tuberculin skin test and IFN-gamma release assay results was 88% for all pregnant patients, corresponding to a kappa of 0.452 (confidence interval 0.26-0.64). Interferon-gamma release from the mitogen did not appear to have any temporal association with pregnancy trimester in cross-sectional or longitudinal studies. The IFN-gamma release assay performed equally well in pregnant and nonpregnant females. CONCLUSION:: The IFN-gamma release assay performed equally well in each trimester of pregnancy with comparable results to nonpregnant females. Interferon-gamma release assays are much more specific, at least as sensitive, and may be a better predictor of disease progression than the tuberculin skin test. LEVEL OF EVIDENCE:: II.

There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis.

Early-life exposures to microbes, coupled with genetically determined susceptibility, have an impact on the natural history of childhood asthma. We hypothesized that childhood infection with Mycobacteria tuberculosis, a bacterium that has infected Homo sapiens for close to millennia, may be relevant to the risk of asthma development. The aim of this study was to evaluate any associations between tuberculosis infection with asthma and allergies using the cross-sectional and the U.S. nationally representative 1999-2000 National Health and Nutrition Examination Survey. Adjusted odds ratios (ORs) for having a history of asthma, allergic rhinitis, or atopic allergic symptoms were compared to evidence of tuberculosis infection as determined by the presence of tuberculin skin test results of 10 mm or greater. Children <20 years of age infected with tuberculosis were significantly less likely to have a history of asthma [OR 0.2; 95% confidence interval (CI): 0.0-0.9] or symptoms of asthma over the prior year (OR 0.1; 95% CI: 0.0-0.5) than children not infected with tuberculosis. This finding was not confounded by bacille Calmette-Guerin vaccination. Tuberculosis infection is associated with a substantially decreased risk of asthma in children. This finding is consistent with the hygiene hypothesis, which suggests that microbes that co-evolved with humans may influence developing immune systems in ways that have a protective effect against the development of asthma.

SETTING: Recent data suggest that interferon-gamma release assays may have reduced sensitivity in children. OBJECTIVE: To explore the cellular responses in children infected with tuberculosis (TB) to different mycobacterial antigens, including the peptides used in the QuantiFERON(R)-TB Gold In-Tube (QFT) assay. DESIGN: Cytokines were measured by multiplex analyte detection in supernatants after stimulation with peptides in QFT, purified protein derivative (PPD) and recombinant whole protein ESAT-6. Samples from 11 children with active TB, 46 healthy children with latent tuberculosis infection (LTBI), and 35 healthy non-infected children were analyzed. RESULTS: None of the cytokines examined in the QFT peptide stimulation assay distinguished between non-infected children and those aged <5 years with LTBI. Cytokines interleukin-2 and transforming growth factor-beta 1 (TGF-beta1) were shown to distinguish between stages of Mycobacterium tuberculosis infection after blood was stimulated with the QFT peptides. All children had significantly higher Th 1 and 2 cytokine production against PPD than against the other antigens tested. CONCLUSION: Measuring specific cytokine patterns after stimulation with the QFT peptides may not increase sensitivity in diagnosing LTBI in children, but there may be future diagnostic value in determining the stage of infection. PPD-stimulated blood produced a robust and diverse cytokine response in young children, making it an interesting antigen for in vitro diagnostic studies

SETTING: Recent reports indicate a role of chemokine inducible protein 10 (IP-10) in Mycobacterium tuberculosis infection substantiated by the detection of elevated levels in plasma and at infection foci in individuals infected with M. tuberculosis. OBJECTIVE: To evaluate IP-10 as a potential marker for the diagnosis of M. tuberculosis infection in children living in a region of low tuberculosis (TB) prevalence. DESIGN: IP-10 levels were obtained after whole blood stimulation with M. tuberculosis-specific antigens in 127 children. IP-10 results were evaluated upon gradations of exposure risk to M. tuberculosis and correlation with tuberculin skin test and an interferon-gamma release assay (IGRA). RESULTS: IP-10 reactivity correlated well to risk of exposure to M. tuberculosis in children. There was a strong correlation between IP-10 and IGRA results. IP-10 responses, unlike interferon-gamma (IFN-gamma), were not age-dependent and detected more positive results in children aged <5 years. In the children with active disease, the IGRA was more sensitive than IP-10 at detecting M. tuberculosis infection. CONCLUSION: Our findings suggest that IP-10 in combination with IFN-gamma may enhance the diagnostic performance of IGRAs in detecting M. tuberculosis infection, especially in young children

Tuberculids are chronic nodular skin eruptions believed to be a systemic reaction to Mycobacterium tuberculosis. We report on a 6-year-old boy with tender subcutaneous lesions on his legs. A tuberculin skin test resulted in 2.5 cm of induration and an interferon-gamma releasing assay was also markedly positive. A diagnosis of erythema induratum of Bazin was confirmed on skin biopsy. The patient was successfully treated with multi-drug antituberculosis therapy

BACKGROUND: The QuantiFERON-TB Gold test was the first blood test to be approved for the diagnosis of latent tuberculosis infection. Although it has been shown to be sensitive and specific in adults, limited data on its performance in children are available. METHODS: This was a prospective study of children receiving health care in New York, New York. Each child was assessed for risk factors for Mycobacterium tuberculosis infection, underwent tuberculin skin testing, and had a QuantiFERON-TB Gold In-Tube test performed. The concordance between tuberculin skin test and QuantiFERON-TB Gold In-Tube test results was calculated, and the results were analyzed according to the likelihood of exposure to M tuberculosis. RESULTS: Data for 207 children with valid tuberculin skin test and QuantiFERON-TB Gold In-Tube test results were analyzed. There was excellent correlation between negative tuberculin skin test results and negative QuantiFERON-TB Gold In-Tube test results; however, only 23% of children with positive tuberculin skin test results had positive QuantiFERON-TB Gold In-Tube test results. Positive QuantiFERON-TB Gold In-Tube test results were associated with increased likelihood of M tuberculosis exposure, and interferon gamma levels were higher in children with known recent exposure to M tuberculosis, compared with children with older exposure histories. Younger children produced lower interferon gamma levels in response to the mitogen (phytohemagglutinin) control used in the QuantiFERON-TB Gold In-Tube test, but indeterminant results were low for children of all ages. Performance characteristics were similar across all age groups. CONCLUSION: The QuantiFERON-TB Gold In-Tube test is a specific test for M tuberculosis exposure in children, with performance characteristics similar to those for adults residing in regions with low levels of endemic disease. Concerns about test sensitivity, especially for children <2 years of age, will require additional prospective long-term evaluation