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.     

Use of an interferon-gamma release assay to diagnose latent tuberculosis infection in foreign-born patients

BACKGROUND: The tuberculin skin test (TST) has a low specificity in the setting of bacille Calmette-Guérin (BCG) vaccination. Interferon-gamma release assays (IGRAs) appear to be more specific but have not been validated in this population under routine clinical conditions. We sought to validate the routine clinical use of the T-SPOT.TB test (Oxford Immunotec; Oxford, UK), an IGRA, in a predominantly foreign-born population with a high rate of BCG vaccination. METHODS: We compared the TST and the T-SPOT.TB test in 96 subjects at a New York City Department of Health tuberculosis clinic. We aimed to determine which test better predicted being a close contact of a case of active tuberculosis, a surrogate for latent tuberculosis infection. RESULTS: A positive T-SPOT.TB test result was strongly associated with being a close contact of a case of active tuberculosis after adjustment for potential confounders (adjusted odds ratio, 2.9; 95% confidence interval, 1.1 to 7.3; p = 0.03). A positive TST result was associated with being a contact only in subjects without BCG vaccination (p = 0.02). The T-SPOT.TB test was more specific for being a close contact than the TST (p < 0.001). Specificity in BCG-vaccinated subjects was 3% for the TST compared with 70% for the T-SPOT.TB test (p < 0.001). CONCLUSIONS: The T-SPOT.TB test is superior in routine clinical use to the TST for identifying high-risk individuals among foreign-born populations with high rates of BCG vaccination.     

The effect of neonatal bacille Calmette-Guérin vaccination on purified protein derivative skin test results in Canadian aboriginal children

BACKGROUND: The effect that neonatal bacille Calmette-Guérin (BCG) vaccination has on tuberculin skin test (TST) results is not well evaluated in preschool children. METHODS: This was a retrospective cohort study of TST results in aboriginal children in Saskatchewan reserve communities. Records from the centralized provincial tuberculosis program were searched for aboriginal children aged 0 to 4 years during the time period 1991 to 1999. Only the first TST result reported as part of infant and preschool screening programs was considered. Children with active tuberculosis and those evaluated as part of a contact-tracing program were excluded. The BCG-vaccinated and unvaccinated groups were compared using wheal size cut points of 5 mm, 10 mm, and 15 mm. RESULTS: Data from 1,086 children with neonatal BCG vaccination and 1,867 unvaccinated children were analyzed. The rate of TST reactions was higher in vaccinated children at all ages, using a cut point of 5 mm. The rate of TST reactions was no different in vaccinated children >or= 1 year old when using a cut point of 15 mm. When using a cut point of 10 mm, the rate of TST reactions was higher at age 1 year but not different at age 4 years in the vaccinated children. CONCLUSION: The rate of TST reactions in preschool aboriginal children living on a reserve who have received neonatal BCG vaccination is affected by the cut point and age. The BCG vaccination status and age should therefore be considered when interpreting TST reactivity in the clinical assessment of aboriginal children participating in a tuberculosis control program.     

A systematic review of the diagnosis of occupational asthma

Background:This study systematically reviews literature regarding the diagnosis of occupational asthma (OA) and compares specific inhalation challenge (SIC) testing with alternative tests.Methods:Electronic databases and trials registries were searched; additional references were identified from bibliographic searches of included studies, hand searches of conferences, and author contacts. Various study designs (clinical trials, cohorts, cross-sectional, or case series) were included involving workers with suspected OA. All diagnostic tests were compared to a “reference standard,” and two researchers independently extracted 2 × 2 data. Pooled sensitivities and specificities (95% confidence intervals [CIs]) were derived.Results:Seventy-seven studies were included. For high molecular weight (HMW) agents, the nonspecific bronchial provocation (NSBP) test, skin-prick test (SPT), and serum-specific IgE had sensitivities > 73% when compared to SIC. Specificity was highest for specific IgE vs SIC (79.0%; 95% CI, 50.5 to 93.3%). The highest sensitivity among low molecular weight asthmagens occurred between combined NSBP and SPT vs SIC (100%; 95% CI, 74.1 to 100%). When compared to SIC, specific IgE and SPT had similar specificities (88.9%; 95% CI, 84.7 to 92.1%; and 86.2%; 95% CI, 77.4 to 91.9%, respectively). For HMW agents, high specificity was demonstrated for positive NSBP tests and SPTs alone (82.5%; 95% CI, 54.0 to 95.0%) or when combined with specific IgE (74.3%; 95% CI, 45.0 to 91.0%) vs SIC. Sensitivity was somewhat lower (60.6% and 65.2%, respectively).Conclusions:In appropriate clinical situations when SIC is not available, the combination of a NSBP test with a specific SPT or specific IgE may be an appropriate alternative to SIC in diagnosing OA. While positive results of single NSBP test, specific SPT, or serum-specific IgE testing would increase the likelihood of OA, a negative result could not exclude OA.     

Diagnostic classification of persistent rhinitis and its relationship to exhaled nitric oxide and asthma: a clinical study of a consecutive series of patients

BACKGROUND: Rhinitis and asthma represent the manifestation of one syndrome. Our hypothesis is that in patients with symptoms of persistent rhinitis, lower airway inflammation, lower respiratory symptoms, and lung function abnormalities compatible with asthma are more frequently associated with the diagnosis of allergic rhinitis (AR) and chronic rhinosinusitis (CRS) than with nonallergic rhinitis (NAR). METHODS: One hundred eight of 590 consecutive patients referred in 1 year for rhinitis were enrolled on the basis of nasal symptoms lasting > 4 weeks. Asthma was diagnosed on the basis of symptoms and a positive bronchodilation testing result and/or methacholine hyperresponsiveness. Exhaled nitric oxide (Feno) was measured with the single exhalation method at 50 mL/s. RESULTS: AR was diagnosed in 39%, NAR in 21%, and CRS in 40%. The prevalence of asthma was significantly higher in AR patients (33%) and CRS patients (42%) than in NAR patients (8.7%) [p = 0.036 and p = 0.005, respectively]. Feno was significantly higher in patients with AR and CRS compared to patients with NAR (44.3 parts per billion [ppb]; 95% confidence interval [CI], 34 to 54 ppb; and 53 ppb; 95% CI, 42 to 64 ppb; vs 22 ppb; 95% CI, 18 to 27 ppb; p = 0.002 and p = 0.001, respectively). Patients with asthma had Feno values significantly higher than patients without asthma (64 ppb; 95% CI, 51 to 77 ppb; vs 33.3 ppb; 95% CI, 28 to 39 ppb; p < 0.001). CONCLUSIONS: The diagnostic classification of persistent rhinitis helps to predict lower airway inflammation (increased Feno) and prevalence of asthma: AR and CRS are associated with higher mean Feno values and higher prevalence of asthma than NAR.     

The β2-adrenoreceptor gene promoter polymorphisms may modulate β2-agonist- and glucocorticoid-induced IgE synthesis

Backgroundβ2-adrenoreceptor (β2-AR) agonists and glucocorticoids (GCS) were shown to induce IgE synthesis in human PBMCs. Serum total IgE levels are associated with single nucleotide polymorphisms (SNPs) of the β2-AR gene. We aimed to assess the association of the effect of fenoterol (β2-AR agonist) on IL-4-driven and budesonide-induced IgE synthesis with genetic variants of β2-AR.MethodsThe study included 25 individuals: 13 with allergic asthma and/or allergic rhinitis and 12 healthy volunteers. PBMCs were cultured with IL-4, fenoterol and/or budesonide, and IgE concentrations in supernatants were assessed. Five SNPs in positions: −47, −20, 46, 79 and 252 of β2-AR were determined by direct DNA sequencing.ResultsIn −47 T/T and −20 T/T patients, incubation with fenoterol resulted in decreased IgE production, whereas in −47 C/T and −47 C/C as well as in −20 C/T and −20 C/C individuals, it was enhanced. In contrast to fenoterol, budesonide-induced IgE synthesis was significantly increased in −47 T/T and −20 T/T patients as compared to −47 C/T, −47 C/C, −20 C/T and −47 C/C individuals. Polymorphisms in positions 46, 79 and 252 were not associated with fenoterol- or budesonide-modulated IgE synthesis. No differences in the distribution of IgE synthesis was seen between atopic and non-atopic individuals carrying the same alleles.ConclusionsThe differential effect of β2-agonists and GCS on IgE synthesis may be associated with genetic variants of promoter region of the β2-AR gene.     

Uteroglobin-related protein 1 and clara cell protein in induced sputum of patients with asthma and rhinitis

Rationale: Uteroglobin-related protein 1 (UGRP1) and Clara cell protein (CC16), members of the secretoglobin family, increasingly appear to play a role in airway inflammatory response. OBJECTIVE: To explore levels of UGRP1 and CC16 in induced sputum of patients with asthma and rhinitis. METHODS: Induced-sputum samples of patients with asthma or rhinitis (n = 32 each; atopic asthma, n = 24; atopic rhinitis, n = 20) and from 19 nonsmoking nonatopic control subjects were analyzed for cytology and levels of UGRP1, CC16, and albumin. Measurements and main results: Sputum UGRP1 increased in both asthma and rhinitis, most strikingly so in asthma, in which changes were most significant in atopic individuals. By contrast, sputum CC16 did not change significantly in either condition, although it was positively correlated with UGRP1 in patients and control subjects. Changes in sputum UGRP1 in atopic asthma were not linked to permeability changes reflected by increased albumin levels but correlated positively with sputum macrophages and negatively with eosinophils. The observed differences in UGRP1 and CC16 may be linked to different cell populations being responsible for their secretion; UGRP1 is mainly secreted in larger conducting airways, whereas CC16 is mainly secreted by the nasal and peripheral airways epithelium. CONCLUSIONS: The increase in UGRP1 but not of CC16 in asthma and rhinitis suggests that UGRP1 may play a role in these inflammatory diseases.     

Cost-effectiveness of interferon-gamma release assay screening for latent tuberculosis infection treatment in Germany

OBJECTIVES: To assess the cost-effectiveness of the new QuantiFERON-TB Gold In-Tube (QFT-G) [Cellestis; Carnegie, VIC, Australia] assay for screening and treating of persons who have had close contact with tuberculosis (TB) patients and are suspected of having latent tuberculosis infection (LTBI) [hereafter called close-contacts] in Germany. METHODS: The health and economic outcomes of isoniazid treatment of 20-year-old close-contacts were compared in a Markov model over a period of 20 years, using two different cutoff values for the tuberculin skin test (TST), the QFT-G assay alone, or the QFT-G assay as a confirmatory test for the TST results. RESULTS: QFT-G assay-based treatment led to cost savings of $542.9 and 3.8 life-days gained per LTBI case. TST-based treatment at a 10-mm induration size cutoff gained $177.4 and 2.0 life-days gained per test-positive contact. When the cutoff induration size for the TST was reduced to 5 mm, the incremental cost-effectiveness ratio fell below the willingness-to-pay threshold ($30,170 per life-years gained) but resulted in unnecessary treatment of 77% of contacts owing to false-positive TST results. Combination with the 5-mm induration size TST cutoff value compared to the results of the QFT-G assay alone reduced the total costs per 1,000 contacts by 1.8% to $222,869. The number treated to prevent 1 TB case was 22 for the two QFT-G assay-based procedures, 40 for the TST at a cutoff induration size of 10 mm, and 96 for the TST at a cutoff induration size of 5 mm. When the sensitivity rates of the TST and the QFT-G assay were compounded, the QFT-G assay strategy alone was slightly less costly (0.6%) than the two-step approach. CONCLUSIONS: Using the QFT-G assay, but especially combining the QFT-G assay following the TST screening of close-contacts at a cutoff induration size of 5 mm before LTBI treatment is highly cost-effective in reducing the disease burden of TB.     

Differences in airway cytokine profile in severe asthma compared to moderate asthma

BACKGROUND: Some studies of severe asthma suggest that persistence or alteration in the pattern of inflammation may be associated with the severity of the disease. Whether there are differences in the expression of the principal cytokines and chemokines relevant to eosinophilic and neutrophilic inflammation in the airway tissues of severe compared to moderate asthmatics has not been determined. The aim of this study was to compare the patterns of expression of representative T-helper (Th) type 1 (interferon [IFN]-gamma) and Th-2 cytokines (interleukin [IL]-4, IL-5) and the neutrophil- and eosinophil-associated chemokines (IL-8 and eotaxin) in the airway tissues of patients with severe and moderate asthma. METHODS: Subjects with severe asthma (n = 24) and a comparison moderate asthma group (n = 26) were assessed using spirometry, induced sputum, exhaled nitric oxide, and bronchial biopsy. The expression of proteins of interest in the epithelium and subepithelium of the airway wall was examined by immunocytochemistry. RESULTS: Subjects with severe asthma were more symptomatic, had a lower FEV(1), and had more sputum neutrophilia (p = 0.007) and eosinophilia (p = 0.001). Exhaled nitric oxide was similar between groups. IL-8 and IFN-gamma expression were increased and IL-4 expression was decreased in severe asthma compared to moderate disease (p < 0.001 for each comparison). Eotaxin and IL-5 expression did not differ between the groups. CONCLUSION: Patients with severe asthma have increases in neutrophils and eosinophils in the sputum, and differ in airway cytokine/chemokine expression from moderate asthmatics. Excess neutrophilia may be explained by increased expression of IL-8, but differences in eosinophilia do not appear to be associated with IL-5 and eotaxin expression.     

Portable exhaled nitric oxide as a screening tool for asthma in young adults during pollen season

BACKGROUND: The fraction of exhaled NO (FeNO) is valuable for the follow-up of asthmatic patients. However, its usefulness as a screening tool for asthma is not established. METHODS: We screened a population of 961 university students with a modified European Community Respiratory Health Survey questionnaire that has been previously used for the screening of respiratory symptoms related to asthma. All subjects with a positive answer to at least one question (n = 149) were submitted to FeNO measurement with a portable nitric oxide analyzer. Subsequently, they were submitted to spirometry and evaluated by a physician blinded to FeNO measurements. Seventy students with no respiratory symptoms served as control subjects. RESULTS: Asthma was diagnosed in 63 subjects, and allergic rhinitis was diagnosed in 57 subjects. Asthmatics presented higher FeNO values than control subjects (median, 20 parts per billion [ppb]; interquartile range, 14 to 31 ppb; vs median, 11 ppb; interquartile range, 7 to 13 ppb, respectively; p < 0.0001), whereas they did not differ from patients with allergic rhinitis (median, 17 ppb; interquartile range, 12 to 23 ppb; p = 0.28). FeNO values > 19 ppb presented 85.2% specificity and 52.4% sensitivity for the diagnosis of asthma (area under the curve [AUC], 0.723). The diagnostic performance of FeNO was better in nonsmokers (AUC, 0.805), yet FeNO values > 25 ppb were characterized by specificity > 90% for the diagnosis of asthma both in smokers and in nonsmokers. However, FeNO was not a good marker for the differentiation between asthma and allergic rhinitis. CONCLUSIONS: FeNO measurement with a portable analyzer is useful for the screening for asthma in young adults. Significant confounding factors are allergic rhinitis and current smoking.     

Paternal asthma, mold exposure, and increased airway responsiveness among children with asthma in Costa Rica

BACKGROUND: Little is known about the determinants of airway hyperresponsiveness (AHR) among children with asthma in Hispanic America. METHODS: We examined the relations among selected familial and environmental factors, markers of allergy, spirometric measures of lung function, and AHR in a cross-sectional study of 403 Costa Rican children with asthma between the ages of 6 and 14 years. Study participants completed a protocol that included questionnaires, spirometry, measurements of serum total and allergen-specific IgE, peripheral blood eosinophil count, and body mass index, and the assessment of airway responsiveness to methacholine (ie, a methacholine challenge test [MCT]). AHR to MCT was defined as the provocative dose of methacholine causing a 20% fall in FEV(1). Linear regression was used for the univariate and multivariate analyses. RESULTS: Of the 403 asthmatic children who underwent an MCT, 350 (86.8%) had AHR to methacholine. In a multivariate analysis, paternal asthma (p = 0.004), parental report of mold/mildew in the child's home (p = 0.04), FEV(1)/FVC ratio (p < 0.0001), and a positive IgE response to Der p 1 (p = 0.008) were significantly associated with AHR among Costa Rican children with asthma. CONCLUSION: Our results suggest that paternal asthma and environmental exposure to mold/mildew are strong determinants of AHR in Costa Rican children with asthma. FEV(1)/FVC ratio may be a useful measure of AHR (a marker of asthma severity) among Costa Ricans and other Hispanic Americans for whom reference values for FEV(1) are not currently available.     

Fraction of exhaled nitric oxide at 50 mL/s: reference values for adult lifelong never-smokers

BACKGROUND: The measurement of fractional exhaled nitric oxide (FENO) is used as a marker of airway inflammation. The aim of this study was to establish reference values of FENO for adults. METHODS: FENO at a flow rate of 50 mL/s was analyzed in 3,376 adults using a chemiluminescence analyzer according to American Thoracic Society/European Respiratory Society guidelines. Blood samples were analyzed, and atopy was defined as the presence of specific IgE. All subjects responded to a respiratory questionnaire. Those who had never smoked (n = 1,803) were selected for this study. After the exclusion of subjects with physician-diagnosed asthma, asthma symptoms, ever wheezing, dry cough, or use of inhaled steroids, 1,131 healthy never-smokers remained, including 845 nonatopic and 286 atopic subjects. RESULTS: Based on multiple regression modeling, we propose the following reference equation for healthy never-smoking adults: Ln(FENO) = 0.057 + 0.013 x height (in centimeters) + 0.0088 x age (in years). The residual SD was 0.51, and the explanatory value was 9%. In a model, based on nonatopic subjects alone, the reference equation obtained was slightly different, as follows: Ln(FENO) = -0.0026 + 0.013 x height (in centimeters) + 0.010 x age (in years). The residual SD for this equation was 0.48, and the explanatory value was 11%. CONCLUSIONS: Normal values of FENO for adults may be predicted on the basis of age and height. However, as the reference equations only account for about 9 to 11% of the variation, the most important information that could be extracted from the study is that the upper limits of FENO range from 24.0 to 54.0 parts per billion, depending on age and height.     

The effect of montelukast on bronchial hyperreactivity in preschool children

INTRODUCTION: The effect of montelukast therapy on bronchial hyperreactivity (BHR) as measured by the methacholine challenge test in preschool children has not yet been reported. OBJECTIVE: To determine the effect of montelukast (4 mg/d) on BHR as evaluated by a provocative concentration of a substance causing a 20% fall in FEV(1) (PC(20)) values in preschool asthmatic children. PATIENTS: A total of 26 preschool children (8 girls) aged 3.3 to 6.0 years (mean [+/- SD] age, 4.7 +/- 0.8 years) with mild asthma. DESIGN: Double-blind randomized, placebo controlled, crossover study. Each child received 4 weeks of treatment with 4 mg of either montelukast or placebo separated by a 2-week washout period. Primary outcomes were PC(20) values and the stage number (triple dose) at which FEV(1) values dropped by 20%(.) Post-montelukast therapy PC(20) was compared to those for the post-placebo period. RESULTS: Following 4 weeks of montelukast treatment, the mean PC(20) was 4.79 +/- 4.69 mg/mL, while after 4 weeks of placebo the mean PC(20) was 2.07 +/- 2.37 mg/mL (p = 0.001). The montelukast/placebo ratio for PC(20) was 2.56 with a 95% confidence interval (CI) of 1.71 to 3.99. The median difference in stage was one triple dose with a 95% CI of 0.5 to 1.5. CONCLUSIONS: Four weeks of treatment with montelukast resulted in a decreased BHR compared with placebo.     

Targeting airway inflammation in asthma: current and future therapies

Asthma is a chronic inflammatory disease of the airway that requires long-term antiinflammatory therapy. Inhaled corticosteroids (ICSs) are recommended for first-line treatment of persistent disease, but not all patients achieve asthma control even when these agents are used in high doses and in combination with other medications, including a long-acting beta(2)-agonist or a leukotriene modifier. Such patients may require additional therapy. As information about asthma pathophysiology and inflammatory phenotypes continues to increase, and additional antiinflammatory options become available, it may be possible to target antiinflammatory therapy to various aspects of the disease and consequently to improve the treatment of patients with inadequate responses to standard ICS-based therapy. Several novel antiinflammatory therapies are in different stages of clinical development. The most clinically advanced of these is omalizumab, a recombinant humanized monoclonal antibody that specifically targets IgE and is indicated for patients with moderate-to-severe asthma caused by allergies. Omalizumab has demonstrated efficacy in patients with moderate-to-severe asthma and documented evidence of allergen sensitivity. Other key therapy options in clinical development either target proinflammatory cytokines (eg, interleukin-4 and tumor necrosis factor-alpha) or inflammatory cells (eg, T-helper type 2 cells and eosinophils). This review provides an overview of the current and future approaches targeting airway inflammation in patients with asthma.     

Pulmonary impairment after tuberculosis

BACKGROUND: Pulmonary impairment subsequent to a cure of pulmonary tuberculosis has been described only in selected populations. METHODS: We compared pulmonary function in a case-control study of 107 prospectively identified patients with pulmonary tuberculosis who had completed at least 20 weeks of therapy and 210 patients with latent tuberculosis infection (LTBI). RESULTS: Both groups had similar risk factors for pulmonary impairment. Impairment was present in 59% of tuberculosis subjects and 20% of LTBI control subjects. FVC, FEV1, FEV1/FVC ratio, and the midexpiratory phase of forced expiratory flow were significantly lower in the treated pulmonary tuberculosis patients than in the comparison group. Ten patients with a history of pulmonary tuberculosis (9.4%) had less than half of their expected vital capacity vs one patient (0.53%) in the LTBI group. Another 42 patients (39%) with tuberculosis had between 20% and 50% of the expected vital capacity vs 36 patients with LTBI (17%). After adjusting for risk, survivors of tuberculosis were 5.4 times more likely to have abnormal pulmonary function test results than were LTBI patients (p > 0.001; 95% confidence interval, 2.98 to 9.68). Birth in the United States (odds ratio [OR], 2.64; p = 0.003) and age (OR, 1.03; p = 0.005) increased the odds of impairment. Pulmonary impairment was more common in cigarette smokers; however, after adjusting for demographic and other risk factors, the difference did not reach statistical significance (p = 0.074). CONCLUSIONS: These findings indicate that pulmonary impairment after tuberculosis is associated with disability worldwide and support more aggressive case prevention strategies and posttreatment evaluation. For many persons with tuberculosis, a microbiological cure is the beginning not the end of their illness.     

Bronchial hyperresponsiveness, airway inflammation, and airflow limitation in endurance athletes

BACKGROUND: Whereas a high prevalence of bronchial abnormalities has been reported in endurance athletes, its underlying mechanisms and consequences during exercise are still unclear. STUDY OBJECTIVES: The purpose of this study was to assess the following: (1) bronchial responsiveness to methacholine and to exercise; (2) airway inflammation; and (3) airflow limitation during intense exercise in endurance athletes with respiratory symptoms. DESIGN: Cross-sectional observational study. SETTING: Lung function and exercise laboratory at a university hospital. PATIENTS AND MEASUREMENTS: Thirty-nine endurance athletes and 13 sedentary control subjects were explored for the following: (1) self-reported respiratory symptoms; (2) bronchial hyperresponsiveness (BHR) to methacholine and exercise; (3) airflow limitation during intense exercise; and (4) bronchial inflammation using induced sputum and nitric oxide (NO) exhalation. RESULTS: Fifteen athletes (38%) showed BHR to methacholine and/or exercise in association with bronchial eosinophilia (mean [+/- SD] eosinophil count, 4.1 +/- 8.5% vs 0.3 +/- 0.9% vs 0%, respectively), higher NO concentrations (19 +/- 10 vs 14 +/- 4 vs 13 +/- 4 parts per billion, respectively), a higher prevalence of atopy, and more exercise-induced symptoms compared with non-hyperresponsive athletes and control subjects (p < 0.05). Furthermore, airflow limitation during intense exercise was observed in eight athletes, among whom five had BHR. Athletes with airflow limitation reported more symptoms and had FEV1, FEV1/FVC ratio, and forced expiratory flow at midexpiratory phase values of 14%, 9%, and 29%, respectively, lower compared with those of nonlimited athletes (p < 0.05). CONCLUSION: BHR in endurance athletes was associated with the criteria of eosinophilic airway inflammation and atopy, whereas airflow limitation during exercise was primarily a consequence of decreased resting spirometric values. Both BHR and bronchial obstruction at rest with subsequent expiratory flow limitation during exercise may promote respiratory symptoms during exercise in athletes.     

The effect of previous tuberculin skin test on the follow-up examination of whole-blood interferon-gamma assay in the screening for latent tuberculosis infection

BACKGROUND: A two-step procedure using a tuberculin skin test (TST) followed by an interferon (IFN)-gamma assay in cases in which the TST result is positive has been advocated to screen for latent tuberculosis infection. However, TST could also boost the in vitro immune response. In this study, we evaluated the effect of TST on the results of the IFN-gamma assay. METHODS: Our study included 84 health-care workers who had been working in the department of pulmonary medicine for > 1 year. First, a whole-blood IFN-gamma assay was performed, and then the TST was applied. Two to 4 weeks later, a follow-up IFN-gamma assay was performed. A commercially available IFN-gamma assay (QuantiFERON-TB GOLD; Cellestis Ltd; Carnegie, VIC, Australia) was used. RESULTS: Valid TST results were available in 82 individuals because 2 participants refused to undergo the TST after the IFN-gamma assay. The TST result was positive in 36 of 82 participants (42.7%), and the IFN-gamma assay was positive in 16 of 82 participants (19.5%). The overall agreement between the two tests was 67.5% (kappa = 0.31; 95% confidence interval, 0.22 to 0.40). The IFN-gamma levels increased significantly from 0.05 to 0.19 (p = 0.011), and 3 of 18 participants (16.7%) had conversion of their IFN-gamma assay results in the TST-positive group. However, in the TST-negative group, the IFN-gamma levels did not change after the TST. CONCLUSION: The agreement between the results of the TST and the IFN-gamma assay was low, and IFN-gamma level could be influenced by the TST, in the TST-positive population, when a follow-up IFN-gamma assay is performed 2 to 4 weeks later.     

Clinical utility of the QuantiFERON TB-2G test for elderly patients with active tuberculosis

OBJECTIVE: To evaluate the response to the QuantiFERON-TB-2 Gold (QFT-2G) test (Cellestis Ltd; Carnegie, VIC, Australia) in elderly patients with active tuberculosis (TB) to determine whether the QFT-2G test might be a feasible method for diagnosing TB infection in this group of patients. METHODS: The subjects were 30 elderly patients with active TB and 100 younger patients with active TB. The QFT-2G test results were analyzed in relation to combined and separate responses to early secretory antigenic target 6-kD (ESAT-6) protein and culture filtrate protein 10 (CFP-10) antigens. RESULTS: Of the 30 elderly patients with active TB, 27% had a positive tuberculin skin test (TST) result and 77% had a positive QFT-2G test result. Of the 100 younger patients with active TB, 70% had a positive TST result and 87% had a positive QFT-2G test result. Although there was no significant difference between the two patient groups in the positive rate for the QFT-2G test results (p = 0.185), there was a significant difference in the rates of positive TST results between the elderly and younger patients (p = 0.012). The positive test result rate for both ESAT-6 and CFP-10 antigens in the elderly patients (17%) was significantly lower than that in younger patients (37%; p = 0.038). There was an indeterminate result for the QFT-2G test in five elderly patients, and this might have been related to the presence of lymphocytopenia due to underlying disease. A negative result on the QFT-2G test was detected in two elderly patients, and this might have been related to the severity of the active TB. CONCLUSION: We confirmed that the QFT-2G test might be a more useful method of diagnosing TB infection than the TST for elderly patients if peripheral lymphocyte counts have been preserved.     

Portable exhaled nitric oxide measurement: Comparison with the "gold standard" technique

Background:The measurement of fractional exhaled nitric oxide (FENO) can assist in the diagnosis of asthma and may also act as a useful surrogate inflammatory marker on which to base treatment decisions in asthma management algorithms. Until recently, this technique was confined to research facilities and secondary care institutions. A portable nitric oxide analyzer (MINO; Aerocrine AB; Smidesvägen, Sweden) has been developed, but few data exist comparing this device with established, larger laboratory-based analyzers (NIOX; Aerocrine AB).Methods:A total of 101 asthmatic patients (64 treated with regular inhaled corticosteroids) and 50 healthy volunteers had simultaneous FENO measurements undertaken using NIOX and MINO devices.Results:In both asthmatic patients and healthy volunteers, there was a good correlation between the measurements obtained using each device (r= 0.94 and 0.96, respectively). Altman-Bland plots confirmed this agreement. Receiver operating characteristic curves discriminating asthmatic patients from healthy volunteers obtained using the NIOX and MINO showed a sensitivity of 83.2% and a specificity of 72% using cutoff values of 13 and 12.5 parts per billion, respectively.Conclusion:FENO values obtained using a portable analyzer correlate well with those obtained using an established laboratory analyzer and can be used to discriminate asthmatic from nonasthmatic patients. This may facilitate the measurement of asthmatic airway inflammation in primary care.     

Metaanalysis of the efficacy of sublingual immunotherapy in the treatment of allergic asthma in pediatric patients, 3 to 18 years of age

BACKGROUND: Recent studies have documented the efficacy and safety of sublingual immunotherapy (SLIT) in patients with rhinitis, but the value of this treatment in those with asthma is still debated. We evaluated the efficacy of SLIT in the treatment of allergic asthma in children by a metaanalysis of randomized, double-blind, and placebo-controlled (DBPC) clinical trials. METHODS: Electronic databases were searched up to May 31, 2006, for randomized DBPC trials assessing SLIT in pediatric cases of asthma. Effects on primary outcomes (ie, symptom scores and concomitant use of rescue medication) were calculated with standardized mean differences (SMDs) using the random-effects model. We performed the metaanalysis using a statistical software package (RevMan, 4.2.8; The Cochrane Collaboration; Oxford, UK), and we followed the recommendations of the Cochrane Collaboration and the Quality of Reporting of Metaanalyses guidelines. RESULTS: Seventy-three articles were identified and reviewed. Nine studies, all published after 1990, fulfilled the selection criteria. A total of 441 patients had a final assessment and were included in the analysis. Two hundred thirty-two patients received SLIT, and 209 patients received placebo. The results of the present analysis demonstrated a relevant heterogeneity due to widely differing scoring systems. Overall, there was a significant reduction in both symptoms (SMD - 1.14; 95% confidence interval [CI], - 2.10 to - 0.18; p = 0.02) and medication use (SMD, - 1.63; 95% CI, - 2.83 to - 0.44; p = 0.007) following SLIT. CONCLUSION: SLIT with standardized extracts reduces both symptom scores and rescue medication use in children with allergic asthma compared with placebo.