Publication year: 2012
Source:Respiratory Medicine, Volume 106, Issue 8

Richard Sterling, Jessica Lim, Lucy Frith, Neil G. Snowise, Loretta Jacques, Brett Haumann

Background Vilanterol (VI) is a novel once-daily long-acting beta2 agonist with inherent 24-h activity. The aim of this study was to evaluate the efficacy of three once-daily doses and one twice-daily dose of VI used concurrently with ICS in adult patients (≥18 years) with persistent asthma. Safety was also assessed. Methods Multicentre, randomised, double-blind, placebo-controlled, five-period crossover study consisting of 7-day treatment periods separated by 7-day wash-out periods. Seventy-five patients, maintained on ICS, received VI 6.25, 12.5 and 25 mcg once-daily (evening), VI 6.25 mcg twice-daily (morning/evening), and placebo. The primary endpoint was trough forced expiratory volume in 1 s (FEV1) (mean of 23 h and 24 h post evening dose) on Day 7; secondary endpoint was weighted mean 24-h serial FEV1 on Day 7. Results All VI groups demonstrated statistically significant increases in trough FEV1 versus placebo (p < 0.001). There was a statistically significant increase in weighted mean 24-h FEV1 for each VI group versus placebo (p < 0.001). The effects of once-daily VI on trough FEV1 and weighted mean 24-h FEV1 were dose dependent. The incidence of adverse events (AEs) was low in each VI treatment group and was not dose dependent (5–9%; placebo = 18%); no drug-related AEs or serious AEs were reported. Conclusion Once-daily treatment with VI was well tolerated and associated with improvements in lung function. The VI 6.25 mcg twice-daily dose showed the greatest change in trough FEV1, however, similar changes in weighted mean 24-h FEV1 with VI 12.5 mcg once-daily were observed. Although our study was not powered to demonstrate non-inferiority of once- versus twice-daily dosing of VI, the data suggest no advantage over a 24-h period of twice-daily over once-daily dosing for the same total daily dose. ClinicalTrials.gov: NCT00980200.

Publication year: 2012
Source:Respiratory Medicine, Volume 106, Issue 8

Sung-Il Woo, Ji-Hyuk Lee, Heon Kim, Jong-Won Kang, Yong-Han Sun, Youn-Soo Hahn

Background To facilitate the use of fractional exhaled nitric oxide (FENO) as a clinical test, FENO measurements need more clarification. Aim We sought to evaluate the yield of FENO measurement for the diagnosis of asthma and identify the determinants of FENO in children. Methods Two hundred forty five consecutive steroid-naïve patients aged 8–16 years with symptoms suggestive of asthma were included. Children were evaluated using FENO measurements, questionnaires, skin prick tests, spirometries, and methacholine challenge tests. Results Asthma was diagnosed in 167 children. The sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) of FENO measurements for the diagnosis of asthma at the best cutoff value of 22 ppb were 56.9%, 87.2%, 90.5%, and 48.6%, respectively. At a cutoff value of 42 ppb, specificity and PPV were all 100% but at the cost of very low sensitivity (23.4%) and NPV (37.9%). Both atopy and asthma were identified as independent risk factors associated with high FENO. The association of asthma with high FENO was found only in atopic children because FENO was low in non-atopic children regardless of asthma status. Although highest FENO was observed in atopic asthmatic patients, 28% of these patients had FENO values lower than 22 ppb. Conclusion Atopic asthmatic patients with low FENO values and non-atopic asthmatic patients were responsible for false-negative cases that might contribute to low sensitivity of FENO measurements in diagnosing asthma. High specificity of FENO measurements may help identify patients with atopic asthma among subjects with respiratory symptoms.

Publication year: 2012
Source:Respiratory Medicine, Volume 106, Issue 7

Manju Pillai, Amy L. Olson, Tristan J. Huie, Joshua J. Solomon, Evans R. Fernandez-Perez, Kevin K. Brown, Phillip Hanna, Teofilo Lee-Chiong, Jeffrey J. Swigris

Background In patients with fibrosing interstitial lung disease (fILD), gastroesophageal reflux (GER) is highly prevalent, perhaps because of the effects of lung fibrosis on altering intrathoracic pressure, diaphragm morphology and lower esophageal sphincter (LES) function. For unclear reasons, obstructive sleep apnea (OSA) is also highly prevalent among patients with fILD. We conducted this study to test our hypothesis that, in patients with fILD, OSA would exacerbate diaphragm/LES dysfunction and increase the propensity for—and severity of – GER. Methods We identified patients with fILD who underwent screening polysomnogram and pH or pH/impedence probe at our center during the same week. We examined the association between OSA and GER and used logistic regression to determine independent predictors of OSA or GER. Results In 54 included subjects, neither OSA (dichotomous) nor apnea hypopnea index (continuous) predicted the presence of GER. Regardless of body position (upright, recumbent), GER was no more frequent or severe among subjects with OSA vs. those without OSA. Subjects with idiopathic pulmonary fibrosis (IPF) had an odds of GER nearly seven-fold greater than subjects with other forms of fILD (odds ratio = 6.84, 95% confidence interval 1.36–34.43, p = 0.02). For the entire cohort and the subgroup with IPF, there was no correlation between pulmonary physiology and GER. Conclusions In fILD, OSA does not appear to promote GER. Research is needed to determine if compensatory mechanisms emanating from the crural diaphragm prevent GER in fILD patients with OSA and to sort out whether GER has a role in the pathogenesis of certain forms of fILD.

Background: Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory allergies.Objective: We sought to demonstrate the safety and efficacy of timothy grass (TG) and dust mite (DM) dual sublingual immunotherapy (SLIT) and to begin to investigate the immune mechanisms involved in successful immunotherapy with multiple allergens.Methods: The safety and efficacy of dual SLIT with TG and DM in children and adults with demonstrated allergies to TG and DM were investigated in a single-center, randomized, double-blind, controlled phase I study. Thirty subjects received either TG and DM dual SLIT (n = 20) or placebo (n = 10). Immune parameters were evaluated for differentiation of desensitized subjects from control subjects.Results: Subjects treated with dual SLIT had decreased rhinoconjunctivitis scores (P < .001) and medication use scores (P < .001) and reduced responses to TG and DM allergen based on results of skin prick tests or nasal disk challenges (P < .01 and P < .001, respectively) compared with placebo-treated control subjects. An increase in TG- and DM-specific IgG4 levels, reduced allergen-specific IgE levels, and subsequent basophil activation were observed in the active treatment group. Dual SLIT promoted allergen-specific suppressive CD4+CD25highCD127lowCD45RO+ forkhead box protein 3 (Foxp3)+ memory regulatory T cells with reduced DNA methylation of CpG sites within the Foxp3 locus.Conclusion: The results of this pilot study suggest that dual SLIT could be an effective means to treat subjects with sensitivities to a variety of allergens and that long-term tolerance might be induced by epigenetic modifications of Foxp3 in memory regulatory T cells.