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Tiotropium Respimat(R) in asthma: a double-blind, randomised, dose-ranging study in adult patients with moderate asthma.

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Tiotropium, a once-daily long-acting anticholinergic bronchodilator, when administered via Respimat(R) (tiotropium Respimat(R)) significantly reduces the risk of severe exacerbations and improves lung function in patients with severe persistent asthma that is not fully controlled despite using inhaled corticosteroids (ICS) and long-acting beta2-agonists. To further explore the dose-response curve in asthma, we investigated the efficacy and safety of three different doses of tiotropium Respimat(R) as add-on to ICS in symptomatic patients with moderate persistent asthma.

METHODS: In this randomised, double-blind, placebo-controlled, four-way crossover study, patients were randomised to tiotropium Respimat(R) 5 mug, 2.5 mug or 1.25 mug or placebo Respimat(R), once daily in the evening. Each treatment was administered for 4 weeks, without washout between treatment periods. Eligibility criteria included >=60% and <=90% of predicted normal forced expiratory volume in 1 second (FEV1) and seven-question Asthma Control Questionnaire mean score of >=1.5. Patients were required to continue maintenance treatment with stable medium-dose ICS for at least 4 weeks prior to and during the treatment period. Long-acting beta2-agonists were not permitted during the treatment phase. The primary efficacy end point was peak FEV1 measured within 3 hours after dosing (peak FEV1(0-3h)) at the end of each 4-week period, analysed as a response (change from study baseline).

RESULTS: In total, 149 patients were randomised and 141 completed the study. Statistically significant improvements in peak FEV1(0-3h) response were observed with each tiotropium Respimat(R) dose versus placebo (all P < 0.0001). The largest difference from placebo was with tiotropium Respimat(R) 5 mug (188 mL). Trough FEV1 and FEV1 area under the curve (AUC)(0-3h) responses were greater with each tiotropium Respimat(R) dose than with placebo (all P < 0.0001), and both were greatest with 5 mug. Peak forced vital capacity (FVC)(0-3h), trough FVC and FVC AUC(0-3h) responses, versus placebo, were greatest with tiotropium Respimat(R) 5 mug (P < 0.0001, P = 0.0012 and P < 0.0001, respectively). Incidence of adverse events was comparable between placebo and all tiotropium Respimat(R) groups.

CONCLUSIONS: Once-daily tiotropium Respimat(R) add-on to medium-dose ICS improves lung function in symptomatic patients with moderate asthma. Overall, improvements were largest with tiotropium Respimat(R) 5 mug.Trial registration: ClinicalTrials.gov identifier NCT01233284.

A longitudinal study of lung function from 1 month to 18 years of age.

Our hypothesis was that factors associated with wheeze will be associated with changes in lung function trajectory between 1 month and 18 years of age.

METHODS: Measurements of lung function were made in individuals aged 1, 6 and 12 months (V'maxFRC), and also at ages 6, 12 and 18 years (FEF25-75). Changes in lung function over time relative to sex, a history of asthma, maternal asthma and other factors were explored using random coefficient models.

RESULTS: Lung function (maximal flow at functional residual capacity in infants and FEF25-75 in children) was determined in 241 individuals at 1 month, 192 at 6 months, 164 at 12 months, 106 at 6 years, 183 at 12 years and 141 at 18 years. In the multivariable model, maternal asthma (mean reduction in lung function 9.8%), flow limitation (mean reduction 17.4%), infant atopy (mean reduction 12.6%) and maternal smoking (mean reduction in lung function 8.1%) were acting independently. When interactions with time were sought, the reduction in lung function associated with maternal asthma and infant atopy were consistent over time, but % lung function increased in boys by a mean of 1%/year compared with girls, in flow-limited individuals by 3.0%/year and by 0.9%/year for those exposed to maternal smoking during pregnancy compared to other cohort members.

CONCLUSIONS: Decrements in lung function in 18-year-olds associated with maternal asthma and early onset atopy may be determined by 1 month of age. Low initial lung function in some individuals can 'recover' in some settings.

Management based on exhaled nitric oxide levels adjusted for atopy reduces asthma exacerbations in children: A dual centre randomized controlled trial.

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NOWhile several randomized control trials (RCTs) have evaluated the use of fractional exhaled nitric oxide (FeNO) to improve asthma outcomes, none used FeNO cut-offs adjusted for atopy, a determinant of FeNO levels. In a dual center RCT, we assessed whether a treatment strategy based on FeNO levels, adjusted for atopy, reduces asthma exacerbations compared with the symptoms-based management (controls).

Children with asthma from hospital clinics of two hospitals were randomly allocated to receive an a-priori determined treatment hierarchy based on symptoms or FeNO levels. There was a 2-week run-in period and they were then reviewed 10 times over 12-months.

The primary outcome was the number of children with exacerbations over 12-months. Sixty-three children were randomized (FeNO = 31, controls = 32); 55 (86%) completed the study. Although we did achieve our planned sample size, significantly fewer children in the FeNO group (6 of 27) had an asthma exacerbation compared to controls (15 of 28), P = 0.021; number to treat for benefit = 4 (95% CI 3-24). There was no difference between groups for any secondary outcomes (quality of life, symptoms, FEV1 ). The final daily inhaled corticosteroids (ICS) dose was significantly (P = 0.037) higher in the FeNO group (median 400 µg, IQR 250-600) compared to the controls (200, IQR100-400).

Taking atopy into account when using FeNO to tailor asthma medications is likely beneficial in reducing the number of children with severe exacerbations at the expense of increased ICS use. However, the strategy is unlikely beneficial for improving asthma control. A larger study is required to confirm or refute our findings. Pediatr Pulmonol. © 2014 Wiley Periodicals, Inc.

Classification of childhood asthma phenotypes and long-term clinical responses to inhaled anti-inflammatory medications.

Although recent studies have identified the presence of phenotypic clusters in asthmatic patients, the clinical significance and temporal stability of these clusters have not been explored.

OBJECTIVE: Our aim was to examine the clinical relevance and temporal stability of phenotypic clusters in children with asthma.

METHODS: We applied spectral clustering to clinical data from 1041 children with asthma participating in the Childhood Asthma Management Program. Posttreatment randomization follow-up data collected over 48 months were used to determine the effect of these clusters on pulmonary function and treatment response to inhaled anti-inflammatory medication.

RESULTS: We found 5 reproducible patient clusters that could be differentiated on the basis of 3 groups of features: atopic burden, degree of airway obstruction, and history of exacerbation. Cluster grouping predicted long-term asthma control, as measured by the need for oral prednisone (P < .0001) or additional controller medications (P = .001), as well as longitudinal differences in pulmonary function (P < .0001). We also found that the 2 clusters with the highest rates of exacerbation had different responses to inhaled corticosteroids when compared with the other clusters. One cluster demonstrated a positive response to both budesonide (P = .02) and nedocromil (P = .01) compared with placebo, whereas the other cluster demonstrated minimal responses to both budesonide (P = .12) and nedocromil (P = .56) compared with placebo.

CONCLUSION: Phenotypic clustering can be used to identify longitudinally consistent and clinically relevant patient subgroups, with implications for targeted therapeutic strategies and clinical trials design.

Changes in respiratory activity induced by mastication during oral breathing in humans

We examined the effect of oral breathing on respiratory movements, including the number of respirations and the movement of the thoracic wall at rest and while chewing gum. Forty normal nose breathers were selected by detecting expiratory airflow from the mouth using a CO2 sensor. Chest measurements were recorded using a Piezo respiratory belt transducer, and electromyographic (EMG) activity of the masseter and trapezius muscles were recorded at rest and while chewing gum during nasal or oral breathing. Oral breathing was introduced by completely occluding the nostrils with a nose clip. During oral breathing, the respiration rate was significantly lower while chewing gum than while at rest (P < 0.05). While chewing gum, the respiration rate was significantly lower during oral breathing ...

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