Clinical and Inflammatory Features of Exacerbation-Prone Asthma: A Cross-Sectional Study Using Multidimensional Assessment.

BACKGROUND: Reducing asthma exacerbations is a major target of current clinical guidelines, but identifying features of exacerbation-prone asthma (EPA) using multidimensional assessment (MDA) is lacking. OBJECTIVE: To systemically explore the clinical and inflammatory features of adults with EPA in a Chinese population. METHODS: We designed a cross-sectional study using the Severe Asthma Web-based Database from the Australasian Severe Asthma Network (ASAN). Eligible Chinese adults with asthma (n = 546) were assessed using MDA. We stratified patients based on exacerbation frequency: none, few (1 or 2), and exacerbation prone (≥3). Univariate and multivariable negative binomial regression analyses were performed to investigate features associated with the frequency of exacerbations. RESULTS: Of 546 participants, 61.9% had no exacerbations (n = 338), 29.6% had few exacerbations (n = 162), and 8.4% were exacerbation prone (n = 46) within the preceding year. EPA patients were characterized by elevated blood and sputum eosinophils but less atopy, with more controller therapies but worse asthma control and quality of life (all p < 0.05). In multivariable models, blood and sputum eosinophils (adjusted rate ratio = 2.23, 95% confidence interval = [1.26, 3.84] and 1.67 [1.27, 2.21], respectively), FEV1 (0.90 [0.84, 0.96]), bronchodilator responsiveness (1.16 [1.05, 1.27]), COPD (2.22 [1.41, 3.51]), bronchiectasis (2.87 [1.69, 4.89]), anxiety (2.56 [1.10, 5.95]), and depression (1.94 [1.20, 3.13]) were found. Further, upper respiratory tract infection (1.83 [1.32, 2.54]) and food allergy (1.67 [1.23, 2.25]) were at high risk of asthma symptom triggers. CONCLUSION: EPA is a clinically recognizable phenotype associated with several recognizable traits that could be addressed by targeted treatment.

24-Hour Serial Spirometric Assessment of Once-Daily Fluticasone Furoate/Umeclidinium/Vilanterol Versus Twice-Daily Budesonide/Formoterol in Patients with COPD: Analysis of the FULFIL Study.

INTRODUCTION: Few studies have utilized 24-h serial spirometry to compare the effects of inhaled chronic obstructive pulmonary disease (COPD) therapies on lung function. The FULFIL study previously reported significant lung function improvements with once-daily single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus twice-daily single-inhaler budesonide/formoterol (BUD/FOR) in patients with symptomatic COPD at risk of exacerbations. METHODS: This prespecified analysis evaluated 24-h serial spirometry data from a subgroup of 406 patients in FULFIL. BUD/FOR twice-daily dosing was maintained during 24-h spirometry. A post hoc analysis evaluated serial forced expiratory volume in 1 s (FEV1) at day 1 and week 24 by disease severity at screening (FEV1 < 50% predicted and no moderate or severe exacerbation in prior year, FEV1 < 50% predicted and ≥ 1 moderate or severe exacerbation in prior year, and FEV1 ≥ 50% and < 80% predicted and ≥ 2 moderate or ≥ 1 severe exacerbations in prior year). RESULTS: Odds of achieving a ≥ 100-mL increase from baseline in FEV1 within the first 6 h post dose on day 1 were significantly greater with FF/UMEC/VI than BUD/FOR [odds ratio 2.79 (95% confidence interval 1.56-4.98); p < 0.001]. FF/UMEC/VI led to greater improvements in weighted mean FEV1 over 0-6, 0-12, 0-24, and 12-24 h on day 1 and at week 24, with the greatest between-group differences at week 24 (range 196-210 mL; all p < 0.001). Significant between-treatment differences in FEV1 and forced vital capacity (FVC) in favor of FF/UMEC/VI versus BUD/FOR were seen at all time points at week 24 (FEV1 range 156-231 mL, all p < 0.001; FVC range 139-309 mL, all p ≤ 0.002). Serial FEV1 results were consistent irrespective of disease severity at screening. CONCLUSION: These findings further demonstrate sustained lung function benefits with once-daily FF/UMEC/VI single-inhaler triple therapy in patients with symptomatic COPD at risk of exacerbations across a range of disease severities.

Forced expiratory volumes in 3 s is a sensitive clinical measure for assessment of bronchodilator reversibility in elderly Chinese with severe lung function impairment.

Purpose: Sensitively assessing bronchial reversibility by spirometry is difficult in patients with serious airflow limitation and the elderly. Some patients cannot exhale for ≥6 s to achieve FVC testing criteria. The aim of this study was to assess if FEV3 could be a more sensitive and an acceptable surrogate for evaluating bronchial reversibility in such patients. Patients and methods: Subjects who had undergone pulmonary function examination in Beijing hospital from July 2003 to April 2015 were included in the study. Patients with FEV1<50% of the predicted value were classified as the severely lung function-impaired group. Correlation between the severity of lung function impairment and changes in FEV1, FEV3 and FVC in response to a bronchodilator was estimated. Results: A total of 7745 tests on elderly subjects with a median age of 71 years were reviewed. The severely lung function-impaired group of 1728 accounted for 22.3% of the total number of subjects. There were significantly more patients in the severely lung function-impaired group who exhibited positive response in FEV3 or FVC and negative response in FEV1 after bronchodilator test (FEV1 negative response but FVC positive response, χ2=626.97, P<0.001; FEV1 negative response but FEV3 positive response, χ2=372.83, P<0.001). With the progressive increase in lung function impairment, ΔFEV1 increased and then declined, while ΔFVC and ΔFEV3 increased progressively. Changes in FEV3 or FVC significantly exceeded the change in FEV1 in the severely lung function-impaired groups (P<0.001). Conclusion: In elderly subjects, especially those with severe lung function impairment, FEV3 combined with FVC is a more effective and sensitive primary clinical outcome measure to detect bronchial reversibility. In subjects who cannot complete ≥6 s forced expiration and whose FVC is unreliable, FEV3 combined with FEV1 might be clinically more valuable in detecting bronchial reversibility.

Real-life rapidity of benralizumab effects in patients with severe allergic eosinophilic asthma: Assessment of blood eosinophils, symptom control, lung function and oral corticosteroid intake after the first drug dose.

Benralizumab is a humanized monoclonal antibody which binds to the α subunit of the interleukin-5 (IL-5) receptor and to the FcγRIIIa receptor expressed by natural killer cells, thus suppressing the pro-eosinophil actions of IL-5 and triggering eosinophil apoptosis via the very effective mechanism of antibody-dependent cell-mediated cytotoxicity (ADCC). Because of its recent approval and introduction in clinical practice for the add-on biological therapy of severe eosinophilic asthma, real-life investigations are still lacking. In this regard, our present real-life study refers to 13 patients with severe allergic eosinophilic asthma, currently under treatment with benralizumab at the Respiratory Unit of "Magna Græcia" University Hospital located in Catanzaro, Italy. Already 4 weeks after the first subcutaneous injection of benralizumab at the dosage of 30 mg, blood eosinophil count rapidly dropped down from 814.7 ±â€¯292.3 cells/µL to 51.3 ±â€¯97.5 cells/µL (p < 0.0001). This relevant hematologic change was associated with quick and significant increases in asthma control test (ACT) score (from 15.31 ±â€¯2.78 to 21.15 ±â€¯3.58; p < 0.0001), pre-bronchodilator forced expiratory volume in 1 s (FEV1) (from 1441 ±â€¯757.9 mL to 1887 ±â€¯837.3 mL; p < 0.001), and morning peak expiratory flow (PEF) (from 4.21 ±â€¯2.20 to 5.33 ±â€¯1.99 L/sec; p < 0.01). Furthermore, the marked improvement in global health status experienced by our patients allowed them to progressively lower and then completely interrupt, within 4 weeks, their daily intake of oral corticosteroids (OCS), which thereby fell from 15.58 ±â€¯8.30 to 0 mg (p < 0.0001) of prednisone. Therefore, such preliminary results suggest that in patients with severe allergic eosinophilic asthma benralizumab can exert, within a real-life context, a very rapid and effective therapeutic action, already detectable 4 weeks after the first drug administration.

GOLD assessment of COPD severity in the Clinical Practice Research Datalink (CPRD).

PURPOSE: To evaluate availability of spirometry and symptom data in the Clinical Practice Research Datalink (United Kingdom) to assess COPD severity using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2016 definition and comparing it with an algorithm used in other studies. METHODS: This was a descriptive, noninterventional, secondary database cohort study of patients with COPD aged 40 years or older, who initiated treatment with specific COPD medications. Patients were classified according to COPD severity (1) in GOLD 2016 "ABCD" categories based on symptoms (Medical Research Council dyspnea grade, COPD Assessment Test, breathlessness), percent predicted FEV1, and exacerbation history and (2) as mild, moderate, severe, or very severe based on treatment and exacerbation history. RESULTS: The study included 63 900 patients with COPD aged 40 years or older that were new users of 1 or more COPD medication of interest. Percent predicted FEV1 was available for 80.9% of patients; symptoms for 75.6% of patients. Classification into GOLD 2016 ABCD categories was possible for 75.6% of the patients. The GOLD 2016 ABCD definition classified more patients under the high-risk categories (22.1%, A; 18.8%, B; 21.3%, C; 37.9%, D) than did the adapted algorithm (7.9%, mild; 48.6%, moderate; 42.1%, severe; 1.4%, very severe). CONCLUSION: Using our adaptation of the GOLD 2016 COPD severity classification, the information in the Clinical Practice Research Datalink allowed us to ascertain COPD severity in approximately 75% of patients with COPD. Algorithms that include medication use tend to misclassify patients with the extreme COPD severity categories.

The utility of drug reaction assessment trials for inhaled therapies in patients with chronic lung diseases.

BACKGROUND: Current guidelines recommend a Drug Reaction Assessment (DRA) before beginning inhaled therapies to assess for bronchoconstriction and tolerability. There is limited evidence to support this recommendation. METHODS: In this study we aimed to establish the predictors of successful DRAs in different patient groups using a cohort of all DRAs performed in adults between 2011 and 2016 at the Royal Brompton Hospital. Spirometry, age, gender, height, and underlying lung disease were recorded. A multivariable logistic regression model was constructed to ascertain variables associated with successful DRAs. RESULTS: There were 1492 DRA trials using hypertonic saline (32%), antimicrobials (63%), or rhDNase (5%). The majority of patients (94%, n = 1408) passed the DRA. Mean FEV1% predicted was 58.03 (SD 23.36). Female sex, type of inhaled product, and FEV1% predicted were established as significant predictors for DRA success. An FEV1% predicted > 55% was associated with greater probability of DRA success (Odds Ratio [OR]: 2.96 (1.80,4.86) p < 0.0001). Those receiving dry powder, inhaled antibiotics were more likely to pass the DRA compared to nebulised antibiotics (OR: 3.99 (1.38,11.51) p = 0.01)). CONCLUSION: This study classifies distinct patient groups with varying baseline risks which can be used to predict tolerability when adding an inhaled product to their management plan. Some "low risk" patients may in future be able to self-assess their tolerability for inhaled therapies at home to avoid unneeded hospital monitoring.

Cost-Effectiveness of Fixed-Dose Combinations Therapies for Chronic Obstructive Pulmonary Disease Treatment.

BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD), a progressive lung disorder associated with decline of respiratory function, affects 10.2% of Spanish adults (40-80 years of age). This study aimed to assess the cost-effectiveness of two fixed-dose combinations of long-acting muscarinic antagonist and long-acting ß2-agonist therapies for COPD, with Spanish National Health System perspective. METHODS: A Markov model with five health states based on severity levels defined by GOLD 2010 criteria was used to simulate in monthly cycles the evolution along a 5-year period of a cohort of moderate-to-severe COPD patients, treated with aclidinium-formoterol (ACL/FF) 400/12 µg or tiotropium-olodaterol (TIO/OLO) 5/5 µg fixed-dose combinations. Clinical data on lung-function improvement were obtained from a network meta-analysis and applied to mean baseline forced-expiratory-volume in 1 s (FEV1) for the first 24-weeks period. Natural history for lung-function decline (41 ml/year) was applied until the end of simulation. Risk of exacerbation and pneumonia occurrence were considered. Pharmaceutical costs were calculated with dosages according to indication and public ex-factory prices. The health state-specific disease management and event costs, and utilities were derived from the literature. Total costs (€ 2016) and benefits [life-year-gained (LYG) and quality-adjusted-life-year (QALY)] were discounted (3.0% yearly). Sensitivity analyses were performed. RESULTS: Both therapies provided the same outcomes (4.073 LYG and 2.928 QALY) at 5-year period. ACL/FF 400/12 µg provided marginally lower costs (€ - 332) compared to TIO/OLO 5/5 µg. CONCLUSION: ACL/FF 400/12 µg was a cost-saving therapy in patients with moderate-to-severe COPD in Spain, and provided equivalent effects compared to TIO/OLO 5/5 µg.

Longterm clinical outcomes of omalizumab therapy in severe allergic asthma: Study of efficacy and safety.

Omalizumab has been shown to be an effective add-on therapy for patients with uncontrolled severe persistent allergic asthma. There has been a steady accumulation of evidence on the long-term effectiveness of omalizumab; however, data on real-life outcomes beyond one year of treatment is limited. In this study, we report on long-term outcomes of omalizumab treatment. We collected data from our severe asthma registry on hospitalisations, exacerbations, corticosteroid sparing, asthma control, lung function, biomarkers and side effects, to determine if the benefit was sustained and treatment was safe on the long term. Forty-five patients [mean age 44.9 years (range 19-69), females 37/45 (82%), mean duration of omalizumab treatment = 60.7 ± 30.9 months (range 23-121) were included in the analysis. We observed a reduction in the annual acute asthma related hospital admissions for the total population from 207 at baseline to 40 on treatment (80.7% reduction), whilst the per patient annual hospitalisations were reduced from a mean of 4.8 to 0.89 post-omalizumab treatment (p < 0.00001). There was a 76.7% reduction in daily mean maintenance OCS dose (prednisolone equivalent) from 25.8 mg (n = 43) to 6.0 mg (p < 0.0001), associated with clinically significant improvement in asthma control questionnaire (ACQ) from mean score of 4.1 (range 3.7-4.7) to 2.27 (range 0.5-4.1) p < 0.0001. The mean % predicted FEV1 has improved from 59.2% at baseline to 75.7% on treatment (p = 0.001). There was a statistically non-significant reduction in median peripheral blood eosinophils (PBE) from 300 cells/µl (range 40-1050) at baseline to 175 cells/µl (range 0-1500) post-treatment (p = 0.068), and statistically significant reduction of median fraction exhaled nitric oxide (FeNO) level from 37 parts per billion (range 12-178) to 24 ppb (range 7-50) (p = 0.0067). The work/school missed days were reduced in 17/19 patients who were at employment or school. The overall safety profile of the treatment seemed acceptable and was consistent with published experience. In conclusion, results from this real-life study demonstrate that improved outcomes in patients with severe allergic asthma are sustained with longer-term omalizumab therapy.

Novel approach to continuous adventitious respiratory sound analysis for the assessment of bronchodilator response.

BACKGROUND: A thorough analysis of continuous adventitious sounds (CAS) can provide distinct and complementary information about bronchodilator response (BDR), beyond that provided by spirometry. Nevertheless, previous approaches to CAS analysis were limited by certain methodology issues. The aim of this study is to propose a new integrated approach to CAS analysis that contributes to improving the assessment of BDR in clinical practice for asthma patients. METHODS: Respiratory sounds and flow were recorded in 25 subjects, including 7 asthma patients with positive BDR (BDR+), assessed by spirometry, 13 asthma patients with negative BDR (BDR-), and 5 controls. A total of 5149 acoustic components were characterized using the Hilbert spectrum, and used to train and validate a support vector machine classifier, which distinguished acoustic components corresponding to CAS from those corresponding to other sounds. Once the method was validated, BDR was assessed in all participants by CAS analysis, and compared to BDR assessed by spirometry. RESULTS: BDR+ patients had a homogenous high change in the number of CAS after bronchodilation, which agreed with the positive BDR by spirometry, indicating high reversibility of airway obstruction. Nevertheless, we also found an appreciable change in the number of CAS in many BDR- patients, revealing alterations in airway obstruction that were not detected by spirometry. We propose a categorization for the change in the number of CAS, which allowed us to stratify BDR- patients into three consistent groups. From the 13 BDR- patients, 6 had a high response, similar to BDR+ patients, 4 had a noteworthy medium response, and 1 had a low response. CONCLUSIONS: In this study, a new non-invasive and integrated approach to CAS analysis is proposed as a high-sensitive tool for assessing BDR in terms of acoustic parameters which, together with spirometry parameters, contribute to improving the stratification of BDR levels in patients with obstructive pulmonary diseases.

Self-assessment of Allergic Rhinitis and Asthma (SACRA) Questionnaire-based Allergic Rhinitis Treatment Improves Asthma Control in Asthmatic Patients with Allergic Rhinitis.

Objective This study was conducted to investigate whether the add-on treatment of allergic rhinitis (AR) based on the Self-assessment of Allergic Rhinitis and Asthma (SACRA) questionnaire for assessing AR control improves both AR and asthma control in asthmatic patients with AR. Methods This multi-center prospective study was performed in Nagano prefecture, Japan. Two hundred five asthmatic patients and 23 respiratory physicians participated in the study. We administered add-on AR treatments based on the results of the SACRA questionnaire. After the first SACRA questionnaire, 67 asthmatic patients agreed to receive an add-on AR treatment. Three months after the AR treatment, a secondary SACRA questionnaire, asthma control test (ACT), and pulmonary function tests were performed. Results After the add-on AR treatment, the visual analogue scales (VASs) for AR and asthma, as assessed by the SACRA questionnaire and ACT score, were significantly improved in the patients of the AR+ group. With regard to the pulmonary function tests, the percent predicted vital capacity, and percent predicted forced expiratory volume in one second were also significantly improved. Regardless of whether the patients had previously undergone leukotriene receptor antagonists (LTRA) treatment, the VASs for AR and asthma and the ACT score were significantly improved in the AR+ group. However, the vital capacity (VC), forced vital capacity (FVC) and forced expiratory volume (FEV1) were only significantly improved in the AR+ group that had previously undergone LTRA treatment. Conclusion SACRA questionnaire-based add-on AR treatment would be convenient for the detection of AR by respiratory physicians and would offer improved asthma control. This questionnaire can also be used to assess the therapeutic effects.

Adenosine monophosphate is not superior to histamine for bronchial provocation test for assessment of asthma control and symptoms.

BACKGROUND: Adenosine monophosphate (AMP) may reflect airway inflammation and hyperresponsiveness, but relationship between AMP and histamine (His, a conventional stimulus) bronchial provocation test (BPT) in asthma is not fully elucidated. OBJECTIVES: To compare both BPTs and determine their utility in reflecting changes of asthmatic symptoms. METHODS: BPTs were performed in a cross-over fashion, at 2-4 day intervals. Cumulative doses eliciting 20% FEV1 fall (PD20 FEV1 ), diagnostic performance and adverse events (AEs) were compared. Patients with PD20 FEV1 lower than geometric mean were defined as responders, otherwise poor responders. Patients with uncontrolled and partly controlled asthma, who maintained their original inhaled corticosteroids therapy, underwent reassessment of airway responsiveness and asthmatic symptoms 3 and 6 months after. RESULTS: Nineteen uncontrolled, 22 partly controlled and 19 controlled asthmatic patients and 24 healthy subjects were recruited. Lower PD20 FEV1 geometric means were associated with poorer asthma control in His-BPT (0.424 µmol vs 1.684 µmol vs 3.757 µmol), but not AMP-BPT (11.810 µmol vs 7.781 µmol vs 10.220 µmol). Both BPTs yielded similar overall diagnostic performance in asthma (area under curve: 0.842 in AMP-BPT vs 0.850 in His-BPT). AEs, including wheezing and tachypnea, were similar and mild. Ten patients with uncontrolled and 10 partly controlled asthma were followed-up. At months 3 and 6, we documented an increase in PD20 FEV1 -AMP and PD20 FEV1 -His, which did not correlate with reduction asthmatic symptom scores. This overall applied in responders and poor responders of AMP-BPT and His-BPT. CONCLUSION: Despite higher screening capacity of well-controlled asthma, AMP-BPT confers similar diagnostic performance and safety with His-BPT. AMP-BPT might not preferentially reflect changes asthmatic symptoms.

Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study.

BACKGROUND: The 24-week safety and efficacy of lumacaftor/ivacaftor combination therapy was shown in two randomised controlled trials (RCTs)-TRAFFIC and TRANSPORT-in patients with cystic fibrosis who were aged 12 years or older and homozygous for the F508del-CFTR mutation. We aimed to assess the long-term safety and efficacy of extended lumacaftor/ivacaftor therapy in this group of patients in PROGRESS, the long-term extension of TRAFFIC and TRANSPORT. METHODS: PROGRESS was a phase 3, parallel-group, multicentre, 96-week study of patients who completed TRAFFIC or TRANSPORT in 191 sites in 15 countries. Patients were eligible if they were at least 12 years old with cystic fibrosis and homozygous for the F508del-CFTR mutation. Exclusion criteria included any comorbidity or laboratory abnormality that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering the study drug to the participant, history of drug intolerance, and history of poor compliance with the study drug. Patients who previously received active treatment in TRANSPORT or TRAFFIC remained on the same dose in PROGRESS. Patients who had received placebo in TRANSPORT or TRAFFIC were randomly assigned (1:1) to receive lumacaftor (400 mg every 12 h)/ivacaftor (250 mg every 12 h) or lumacaftor (600 mg once daily)/ivacaftor (250 mg every 12 h). The primary outcome was to assess the long-term safety of combined therapy. The estimated annual rate of decline in percent predicted FEV1 (ppFEV1) in treated patients was compared with that of a matched registry cohort. Efficacy analyses were based on modified intention-to-treat, such that data were included for all patients who were randomly assigned and received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01931839. FINDINGS: Between Oct 24, 2013, and April 7, 2016, 1030 patients from the TRANSPORT and TRAFFIC studies enrolled in PROGRESS, and 1029 received at least one dose of study drug. 340 patients continued treatment with lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h; 176 patients who had received placebo in the TRANSPORT or TRAFFIC studies initiated treatment with lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h, the commercially available dose, for which data are presented. The most common adverse events were infective pulmonary exacerbations, cough, increased sputum, and haemoptysis. Modest blood pressure increases seen in TRAFFIC and TRANSPORT were also observed in PROGRESS. For patients continuing treatment, the mean change from baseline in ppFEV1 was 0·5 (95% CI -0·4 to 1·5) at extension week 72 and 0·5 (-0·7 to 1·6) at extension week 96; change in BMI was 0·69 (0·56 to 0·81) at extension week 72 and 0·96 (0·81 to 1·11) at extension week 96. The annualised pulmonary exacerbation rate in patients continuing treatment through extension week 96 (0·65, 0·56 to 0·75) remained lower than the placebo rate in TRAFFIC and TRANSPORT. The annualised rate of ppFEV1 decline was reduced in lumacaftor/ivacaftor-treated patients compared with matched controls (-1·33, -1·80 to -0·85 vs -2·29, -2·56 to -2·03). The efficacy and safety profile of the lumacaftor 600 mg once daily/ivacaftor 250 mg every 12 h groups was generally similar to that of the lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h groups. INTERPRETATION: The long-term safety profile of lumacaftor/ivacaftor combination therapy was consistent with previous RCTs. Benefits continued to be observed with longer-term treatment, and lumacaftor/ivacaftor was associated with a 42% slower rate of ppFEV1 decline than in matched registry controls. FUNDING: Vertex Pharmaceuticals Incorporated.

Continuous alternating inhaled antibiotic therapy in CF: A single center retrospective analysis.

INTRODUCTION: The efficacy of inhaled antibiotics to treat chronic Pseudomonas aeruginosa pulmonary infection in patients with cystic fibrosis (CF) has been well established. Few data are available on the value of continuous alternating inhaled antibiotic therapy (CAIT), a strategy increasingly used in the management of CF. OBJECTIVE: To investigate the effect of CAIT on clinical outcome in adult CF patients treated at the University Hospital Leuven. METHODS: Patients with a documented CF diagnosis who received inhaled antibiotics between March 2010 and January 2015 were retrospectively evaluated. In patients receiving CAIT patient characteristics, recorded spirometry data and number of IV antibiotic days were collected retrospectively at fixed time intervals, from 6months before to one year after the start of the 2nd inhaled antibiotic. For patients on inhaled antibiotic monotherapy (IAMT), the same data were obtained at similar intervals during the study period. RESULTS: A total of 49 of 89 patients using chronic inhaled antibiotic therapy received CAIT. Patients receiving CAIT had a lower baseline FEV1 and were more likely to be homozygous for F508del compared to patients receiving IAMT. FEV1 deteriorated on average by a factor of 0.904 per year (95% CI: 0.851-0.960) prior to the start of CAIT. The initiation of CAIT was associated with an average improvement in FEV1 by a factor of 1.148 per year (95% CI: 1.068-1.236, p=0.0002). The analysis of specific types of antibiotics revealed evidence of positive effects of adding COLI to TOBI and COLI to AZLI. We found no effect of the initiation of CAIT on the number of IV antibiotic days (p=0.80). CONCLUSION: CF patients with more advanced lung disease are more likely to receive CAIT. In this patient group, CAIT was associated with a significant improvement in FEV1. Further data are warranted to identify the value of CAIT.

Continuous alternating inhaled antibiotics for chronic pseudomonal infection in cystic fibrosis.

BACKGROUND: Inhaled antibiotics are standard of care for treating chronic pseudomonal respiratory infections in cystic fibrosis patients, initially approved for intermittent administration. However, use of continuous inhaled antibiotic regimens of differing combinations is growing. METHODS: This double-blind trial compared continuous alternating therapy (CAT) to an intermittent treatment regimen. Subjects were treated with 3cycles of 28-days inhaled aztreonam (AZLI) or placebo 3-times daily alternating with 28-days open-label tobramycin inhalation solution (TIS). RESULTS: 90 subjects were randomized over 18months. Study enrollment was limited, in part because of evolving practices by clinicians of adopting a CAT regimen in clinical practice; consequently the study was underpowered. AZLI/TIS treatment reduced exacerbation rates by 25.7% (p=0.25; primary endpoint) and rates of respiratory hospitalizations by 35.8% compared with placebo/TIS (p=0.14). AZLI/TIS CAT therapy was well tolerated. CONCLUSIONS: This trial illustrates challenges with studying treatment regimens in a constantly evolving CF care environment. Nonetheless, the results of this trial indicate that AZLI/TIS CAT is well tolerated and may provide additional clinical benefit in CF patients compared with intermittent use of TIS alone. Clinicaltrials.gov: NCT01641822.

Forecasting US ivacaftor outcomes and cost in cystic fibrosis patients with the G551D mutation.

Ivacaftor, a breakthrough treatment for cystic fibrosis (CF) patients with the G551D genetic mutation, lacks long-term clinical and cost projections. This study forecasted outcomes and cost by comparing ivacaftor plus usual care versus usual care alone.A lifetime Markov model was conducted from a US payer perspective. The model consisted of five health states: 1) forced expiratory volume in 1 s (FEV1) % pred ≥70%, 2) 40%≤ FEV1 % pred <70%, 3) FEV1 % pred <40%, 4) lung transplantation and 5) death. All inputs were extracted from published literature. Budget impact was also estimated. We estimated ivacaftor's improvement in outcomes compared with a non-CF referent population.Ivacaftor was associated with 18.25 (95% credible interval (CrI) 13.71-22.20) additional life-years and 15.03 (95% CrI 11.13-18.73) additional quality-adjusted life-years (QALYs). Ivacaftor was associated with improvements in survival and QALYs equivalent to 68% and 56%, respectively, for the survival and QALY gaps between CF usual care and their non-CF peers. The incremental lifetime cost was $3 374 584. The budget impact was $0.087 per member per month.Ivacaftor increased life-years and QALYs in CF patients with the G551D mutation, and moved morbidity and mortality closer to that of their non-CF peers. Ivacaftor costs much more than usual care, but comes at a relatively limited budget impact.

Cost-effectiveness of combination therapy umeclidinium/vilanterol versus tiotropium in symptomatic COPD Spanish patients.

PURPOSE: Umeclidinium/vilanterol (UMEC/VI) is a novel fixed dose combination of a long-acting muscarinic receptor antagonist (LAMA) and a long-acting beta 2 receptor antagonist (LABA) agent. This analysis evaluated the incremental cost-effectiveness ratio (ICER) of UMEC/VI compared with tiotropium (TIO), from the Spanish National Health System (NHS) perspective. METHODS: A previously published linked equations cohort model based on the epidemiological longitudinal study ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points) was used. Patients included were COPD patients with a post-bronchodilator forced expiratory volume in 1 second (FEV1) ≤70% and the presence of respiratory symptoms measured with the modified Medical Research Council dyspnea scale (modified Medical Research Council ≥2). Treatment effect, expressed as change in FEV1 from baseline, was estimated from a 24-week head-to-head phase III clinical trial comparing once-daily UMEC/VI with once-daily TIO and was assumed to last 52 weeks following treatment initiation (maximum duration of UMEC/VI clinical trials). Spanish utility values were derived from a published local observational study. Unitary health care costs (€2015) were obtained from local sources. A 3-year time horizon was selected, and 3% discount was applied to effects and costs. Results were expressed as cost/quality-adjusted life years (QALYs). Univariate and probabilistic sensitivity analysis (PSA) was performed. RESULTS: UMEC/VI produced additional 0.03 QALY and €590 vs TIO, leading to an ICER of €21,475/QALY. According to PSA, the probability of UMEC/VI being cost-effective was 80.3% at a willingness-to-pay of €30,000/QALY. CONCLUSION: UMEC/VI could be considered as a cost-effective treatment alternative compared with TIO in symptomatic COPD patients from the Spanish NHS perspective.

Assessment of Parasympathetic Activity in Athletes: Comparing Two Different Methods.

INTRODUCTION: A variety of methods are used to assess parasympathetic activity in athletes targeting different organs; however, the reliability of or interchangeability between measurement procedures is not clear. OBJECTIVE: The purpose of this study is to identify the repeatability of two parasympathetic activity measurement procedures, the HR variability during a 4-s exercise test (4sET), and the contractile properties of the pupil (pupillometry), and to assess their agreement. The secondary objective of this study is to assess their relationship with the bronchodilating effect of inhaled ipratropium bromide (iIB), blocking parasympathetic signals to the lungs. METHODS: Forty athletic subjects were enrolled in a cross-sectional study. After 15-min resting in semidarkness, subjects underwent pupillometry (PLR-200™, NeurOptics Inc., CA), followed by 4sET on a cycle ergometer. HR variability was assessed by Polar Electro® HR monitor (RS-800CX/G3; Oy, Kempele, Finland). Both protocols were repeated after 5 min. Statistical analysis was performed according to Bland and Altman and by using Pearson's correlation coefficient and intraclass correlation. Lung function measurements by flow volume curves were performed before and 45 min after iIB. RESULTS: The means of differences were 1.21% (limits of agreement, -3.59 to 6.02) for pupil constriction and 0.05 mm (-0.28 to 0.39) for pupil amplitude. The mean of differences for 4sET was 0.005 (-0.31 to 0.32). A very weak intraclass correlation (r = -0.01, P = 0.58) showed no agreement between the methods. No correlation was observed between pupillometry variables or 4sET with the change in lung function after iIB. CONCLUSION: Pupillometry showed better repeatability compared with the 4sET. There is poor agreement between parasympathetic activity levels measured in three different target organs of athletic subjects; the heart, the pupil, and the lung. Thus, methods assessing parasympathetic activity in different target organs cannot be used interchangeably.

Mannitol versus hypertonic saline: Safety and efficacy of mannitol and hypertonic saline in sputum induction and bronchial hyperreactivity assessment.

Eosinophilic asthma phenotype predicts good response to corticosteroids and associates to asthmatic exacerbations. Sputum induction by hypertonic saline (HS) inhalation is technically demanding. Bronchial hyperresponsiveness (BHR) to osmotic agents indirectly mirrors active airway inflammation. We compared the safety and ability of HS and mannitol to induce sputum and measure BHR. We evaluated the stability of inflammatory phenotypes. We studied 35 non-smoking asthmatics randomized to undergo HS and mannitol challenges on 2 days 1 week apart. Sputum was sampled for cell analysis and phenotyped as eosinophilic (≥3% eosinophils) and non-eosinophilic (<3%) asthma. Nineteen subjects had BHR to mannitol and nine of them also had BHR to HS. Drops in forced expiratory volume in 1 s were higher from HS challenge than from mannitol challenge. Adequate sputum samples were obtained from 80% subjects (68% mannitol and 71% HS). Eosinophils and macrophages from both challenges correlated. Neutrophils were higher in sputum from HS. Ninety percent samples were equally phenotyped with HS and mannitol. Fractional exhaled nitric oxide, sputum eosinophils and BHR correlated in both challenges. HS and mannitol showed similar capacity to produce valuable sputum samples. BHR to both osmotic stimuli partially resembled airway eosinophilic inflammation but mannitol was more sensitive than HS to assess BHR. Eosinophilic phenotype remained stable in most patients with both stimuli.

Assessment of montelukast, doxofylline, and tiotropium with budesonide for the treatment of asthma: which is the best among the second-line treatment? A randomized trial.

PURPOSE: Data comparing various second-line treatments for asthma with subjective and objective assessment are lacking. This study aimed to compare the efficacy and safety of montelukast, doxofylline, and tiotropium with a low-dose budesonide in patients with mild to moderate persistent asthma. METHODS: Patients, all of whom were concurrently using inhaled budesonide (400 µg), were treated for 6 months with formoterol (12 µg), montelukast (10 mg), doxofylline (400 mg), or tiotropium (18 µg). Outcomes included forced expiratory volume in 1 second (FEV1), Saint George Respiratory Questionnaire (SGRQ) scores, asthma symptom scores (daytime and nighttime), and assessment of tolerability and rescue medication use. FINDINGS: A total of 297 patients completed the study. In all 4 groups, significant improvements were observed in all the outcome measures, with formoterol treatment having greater and earlier improvements than the other 3 second-line controller medications with budesonide. Among the second-line treatments, monteradlukast improved the FEV1 from day 45 (P < 0.01), SGRQ scores from day 30 (P < 0.0001), daytime scores from day 30 (P < 0.05), nighttime scores from day 30 (P < 0.0001), and rescue medication use from day 15 (P < .0001) at a faster rate than doxofylline or tiotropium with budesonide. No patients discontinued the treatment because of adverse reactions. IMPLICATIONS: Among the tested second-line treatment regimens, the budesonide/montelukast combination was found to be superior to either the budesonide/doxofylline or budesonide/tiotropium combination in all the outcome measures without adversely affecting the tolerability of the patients. Further clinical studies with blinding techniques are likely to be useful.