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Introduction: Although some factors associated with asthma symptom deterioration and risk of exacerbation have been identified, these are not yet fully characterised. We conducted a clinical modelling and simulation study to understand baseline factors affecting symptom control, reliever use and exacerbation risk in patients with moderate-severe asthma during follow-up on regularly dosed inhaled corticosteroid (ICS) monotherapy, or ICS/long-acting beta 2 -agonist (LABA) combination therapy., Methods: Individual patient data from randomised clinical trials (undertaken between 2001 and 2019) were used to model the time course of symptoms (n = 7593), patterns of reliever medication use (n = 3768) and time-to-first exacerbation (n = 6763), considering patient-specific and extrinsic factors, including treatment. Model validation used standard graphical and statistical criteria. Change in symptom control scores (Asthma Control Questionnaire 5 [ACQ-5]), reduction in reliever use and annualised exacerbation rate were then simulated in patient cohorts with different baseline characteristics and treatment settings., Results: Being a smoker, having higher baseline ACQ-5 and body mass index affected symptom control scores, reliever use and exacerbation risk (p < 0.01). In addition, low forced expiratory volume in 1 s percent predicted, female sex, season and previous exacerbations were found to contribute to a further increase in exacerbation risk (p < 0.01), whereas long asthma history was associated with more frequent reliever use (p < 0.01). These effects were independent from the underlying maintenance therapy. In different scenarios, fluticasone furoate (FF)/vilanterol was associated with greater reductions in reliever use and exacerbation rates compared with FF or fluticasone propionate (FP) alone or budesonide/formoterol, independently from other factors (p < 0.01)., Conclusions: This study provided further insight into the effects of individual baseline characteristics on treatment response and highlighted significant differences in the performance of ICS/LABA combination therapy on symptom control, reliever use and exacerbation risk. These factors should be incorporated into clinical practice as the basis for tailored management of patients with moderate-severe asthma., (© 2024. The Author(s).)

Background: Severe eosinophilic asthma (SEA) may be the prodromal phase of eosinophilic granulomatosis with polyangiitis (EGPA). Nevertheless, few studies have tried to recognize EGPA in the early stages of the disease., Objective: To identify a panel of clinical and biological markers to detect which severe asthmatic patient might be considered in a prodromal phase of EGPA and crafting a strategy for diagnostic decision-making., Methods: A total of 30 patients with EGPA and 49 with SEA were enrolled. A complete pulmonary, ear, nose, and throat, and rheumatologic assessment were made. Blood (eosinophil count, eosinophilic cationic protein, IL-5, IL-4, total-IgE, IgG 4 , and antineutrophil cytoplasmic antibody), sputum (eosinophils count, periostin, IL-8, and granulocyte-monocyte colony-stimulating factor [GM-CSF]), and nasal smear (eosinophilia) biomarkers were assessed. Asthma Control Test, Short Form-36, SinoNasalOutcome Test-22, and Asthma Quality of Life Questionnaire were also used., Results: Patients with SEA had poorer asthma control (P < .001) and a higher level of sputum eosinophils (P < .002), whereas patients with EGPA reported higher levels of blood eosinophils in the past. Sputum GM-CSF was the only biomarker significantly increased in patients with EGPA compared with those with SEA (P < .0001). Among patients with SEA, those with some suggestive but not diagnostic criteria of EGPA, particularly tissue eosinophilic infiltrates, presented higher levels of sputum GM-CSF (P < .0005), blood, and sputum eosinophils (P < .0006 and P < .011) than the other patients., Conclusion: Sputum GM-CSF and eosinophils might be useful biomarkers to support early diagnosis and treatment choices in patients with SEA, suspected of having EGPA., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: Patients' perceptions of asthma symptoms, and attitudes regarding diagnosis and management, can affect their ability to reach good asthma control. The aim of the study was to explore patients' perceptions of asthma management, with focus on treatment with oral corticosteroids (OCS)., Methods: A DOXAPHARMA survey was conducted. A questionnaire with 46 multiple choice questions was completed by 50 patients with severe uncontrolled asthma, and 258 with mild-moderate controlled or partly controlled asthma. Participants were representative of Italian asthmatic patients-with medium age, long asthma duration, delayed diagnosis, poor asthma control, and frequent exacerbations., Results: Many asthmatics reported inadequate pharmacologic treatment. The majority but not all patients regularly used ICS/LABA. Oral treatment was common, mainly with OCS, particularly in severe asthmatics. One-fourth of patients did not regularly use inhaled therapy, and adherence was poor, resulting in frequent OCS use to treat exacerbations, which were common in mild-moderate cases. Patients were fairly satisfied with asthma therapies, but many had concerns about long-term corticosteroid use. Patients complained about poor management of comorbidities associated with asthma and OCS use, but were generally satisfied with their patient/doctor relationships. Many patients failed to achieve optimal health-related quality of life (HRQoL), mainly those with severe asthma who used OCS treatment and emphasized how OCS therapy impacted QoL., Conclusions: The survey results confirmed many problems related to mild-moderate and severe asthma management in Italy and highlighted the overuse of OCS rather than more effective and safe treatments, which had strong negative effects on HRQoL.

In the field of severe asthma, the concept of disease control has recently been integrated by the one of clinical remission. With this new concept, we move on to analyze the efficacy of therapy on multiple parameters simultaneously, starting with the mandatory discontinuation of the systemic glucocorticoids, to which is added the effect on exacerbations, respiratory function, and symptoms control. The Italian severe asthma registry SANI (Severe Asthma Network Italy) drafted criteria for the definition of disease remission, allowing patients to be classified into two groups, partial and complete remission. The greater dynamism of the definition, provided by SANI, allows us to hypothesize its practical use, concerning therapy management of severe asthma patients, starting from the level of remission, with the aim to facilitate the clinical decision on replacement, continuation or modulation of patients' therapy.

Severe asthma affects about 10% of the population with asthma and is characterized by low lung function and a high count of blood leukocytes, mainly eosinophils. Various definitions are used in clinical practice and in the literature to identify asthma remission: clinical remission, inflammatory remission, and complete remission. This work highlights a consensus for asthma remission using a Delphi method. In the context of the Severe Asthma Network Italy, which accounts for 57 severe asthma centers and more than 2,200 patients, a board of six experts drafted a list of candidate statements in a questionnaire, which has been revised to minimize redundancies and ensure clear and consistent wording for the first round (R1) of the analysis. Thirty-two statements were included in the R1 questionnaire and then submitted to a panel of 80 experts, which used a 5-point Likert scale to measure agreement regarding each statement. Then, an interim analysis of R1 data was performed, and items were discussed and considered to produce a consistent questionnaire for round 2 (R2) of the analysis. Then, the board set the R2 questionnaire, which included only important topics. Panelists were asked to vote on the statements in the R2 questionnaire afterward. During R2, the criteria of complete clinical remission (the absence of the need for oral corticosteroids, symptoms, exacerbations or attacks, and pulmonary function stability) and those of partial clinical remission (the absence of the need for oral corticosteroids, and two of three criteria: the absence of symptoms, exacerbations or attacks, and pulmonary stability) were confirmed. This Severe Asthma Network Italy Delphi analysis defined a valuable and independent tool that is easy to use, to test the efficacy of different treatments in patients with severe asthma enrolled into the SANI registry., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The article traces the concept of asthma control within GINA guidelines over the past 25 years. In the first 15 years after 1995, the main objective of asthma management was to obtain the control of all clinical and functional characteristics of asthma. A landmark study (GOAL) showed for the first time that a good control of asthma is a reasonable outcome that can be achieved in a large proportion of asthmatics with a regular appropriate treatment. In the following years, more emphasis was placed on the role of exacerbations as critical manifestations of poor asthma control, whose frequency is associated with excessive FEV1 decline and increased risk of death. Accordingly, the 2014 GINA report makes a clear distinction between the control of the day-by-day symptoms and the reduction in the risk of severe exacerbations, stating that both conditions should be obtained. The 2019 update included a significant change in the management of mild asthma, prioritizing the prevention of exacerbations to that of mild symptoms. This view was repeated in the 2021 update, where the prevention of exacerbations, together with an acceptable symptom control with a minimal use of rescue medication, appeared to be the real main goal of asthma management. While a discrepancy between current symptoms and exacerbations may be present in mild asthma, a significant relationship between these two features is observed in moderate-severe asthma: a persistent poor symptom control is a major risk factor for exacerbations, whereas achieving symptom control through regular treatment is associated with a reduction in exacerbation rate. Thus, the opinion that frequent symptoms are not important in the absence of acute exacerbations should be discouraged, whereas education of patients to a good symptom perception and to improve adherence to regular treatment should be implemented. Furthermore, the persistence of risk factors, such as increased airway inflammation, even in a patient with minor daily symptoms, should be considered for optimizing treatment.

Background: Transient increases in blood eosinophil counts have been observed in dupilumab clinical trials., Objective: To assess eosinophil counts and eosinophilia-related treatment-emergent adverse events (TEAEs) across 11 dupilumab clinical trials, comparing adult and adolescent patients with asthma and adult patients with chronic rhinosinusitis with nasal polyps (CRSwNP), atopic dermatitis, and eosinophilic esophagitis., Methods: Eosinophil counts, rates of eosinophilia-related TEAEs or treatment-emergent eosinophilia (>1,500 cells/μL), discontinuations, clinical symptoms, and efficacy in patients with asthma or CRSwNP with treatment-emergent eosinophilia are presented., Results: Transient increases in mean eosinophil counts were observed in dupilumab-treated patients with asthma (mean range across studies at baseline: 349-370 cells/μL; week 4: 515-578 cells/μL), CRSwNP (baseline: 440-448 cells/μL; week 16: 595 cells/μL), and atopic dermatitis (baseline: 434-600 cells/μL; week 4: 410-710 cells/μL), followed by a decline starting by week 24 to baseline or lower. No increases were seen in patients with eosinophilic esophagitis (baseline: 310 cells/μL; week 4: 230 cells/μL). In dupilumab-treated patients across all studies, rates of eosinophilia TEAEs were 0% to 13.6%. Clinical symptoms associated with increased eosinophils were rare (seven of 4,666 dupilumab-treated patients, including six cases of eosinophilic granulomatosis with polyangiitis) and occurred only in patients with asthma or CRSwNP. Eosinophilia was not associated with reduced dupilumab efficacy., Conclusions: Transient increases in eosinophil counts with dupilumab treatment did not affect efficacy and were rarely of clinical consequence. It remains important for physicians to base judgment on individual patient history and baseline eosinophil counts and to be alert to hypereosinophilic symptoms., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The prevalence of asthma in Italy is estimated to be around 4%; it affects approximately 2,000,000 citizens, and up to 80-90% of patients have mild-to-moderate asthma. Despite the clinical relevance of mild-to-moderate asthma, longitudinal observational data are very limited, including data on disease progression (worsening vs. improvement), the response to treatment, and prognosis. Studies are needed to develop long-term, observational, real-life research in large cohorts. The primary outcomes of this study will be based on prospective observation and the epidemiological evolution of mild and moderate asthma. Secondary outcomes will include patient-reported outcomes, treatments over time, disease-related functional and inflammatory patterns, and environmental and life-style influences., Methods: This study, called the Mild/Moderate Asthma Network of Italy (MANI), is a research initiative launched by the Italian Respiratory Society and the Italian Society of Allergology, Asthma and Clinical Immunology. MANI is a cluster-based, real world, cross-sectional, prospective, observational cohort study that includes 20,000 patients with mild-to-moderate asthma. (ClinicalTrials.gov Identifier: NCT04796844)., Results and Conclusion: Despite advances in asthma care, several research gaps remain to be addressed through clinical research. This study will add important new knowledge about long-term disease history, the transferability of clinical research results to daily practice, the efficacy of currently recommended strategies, and their impact on the burden and evolution of the disease., Abbreviations: MANI:Mild/Moderate Asthma Network of ItalySANI:Severe Asthma Network ItalyGINA:Global Initiative for AsthmaSABA:short acting β2-agonistsICS:inhaled corticosteroidsCRF:Case Report Form.

Background: Several severe asthma comorbidities have been identified: an emerging one is bronchiectasis. We evaluated the frequency of bronchiectasis on severe asthma in a real-life setting, through the 'Severe Asthma Network Italy' (SANI) registry., Methods: SANI registry encompasses demographic, clinical, functional and inflammatory data of Italian severe asthmatics. Data obtained by the enrolled patients were analyzed, focusing the attention on those patients with concomitant clinically relevant bronchiectasis., Results: About 15.5% patients have bronchiectasis. Bronchiectasis diagnosis was associated with a higher prevalence of chronic rhinosinusitis with nasal polyps (54.6% vs. 38%, p = 0.001) and higher serum IgE levels (673.4 vs. 412.1 kUI/L, p = 0.013). Patients with bronchiectasis had worse asthma control (ACT: 16.7 vs 18.2, p = 0.013), worse quality of life (AQLQ: 4.08 vs. 4.60, p = 0.02) and lower lung function (FEV 1 % predicted 67.3 vs. 75.0, p = 0.002). A higher rate of severe asthma exacerbations in the previous 12 months (85.2% vs. 61.5%, p < 0.001) was found in patients with bronchiectasis., Conclusion: severe asthma associated with bronchiectasis represents a particularly severe asthma variant, possibly driven by an eosinophilic endotype. We, therefore, suggest that bronchiectasis should necessarily be assessed in severe asthmatic patients.

Objective: This study analysed whether the persistence of both reversible airway obstruction (RAO) and elevated BE counts was associated to reduced asthma control and accelerated lung function decline in treated severe asthmatics., Methods: About 202 severe asthmatics were studied after 12-120 months of step-5 treatment associated to anti-IgE therapy. Following treatments, reversibility tests, after inhaling 400 mcg of Salbutamol, were performed. FEV 1  > 12% or ≤12% changes differentiated RAO+ from RAO- subjects. Blood eosinophil (BE) counts after treatment were considered., Results: Pre-/post-treatment bronchodilator FEV 1 % and ACT were lower (61% [50-71], 74.4% [62.5-83.7] and 20[18-22]), whereas BE were higher (380 cells/µl [170-590]) in RAO+ compared to RAO- subjects (77% [64-88], p = 0.0001, 81.8% [66.1-94.3], p = 0.0001, 21[18-23], p = 0.045 and 230 cells/µl [80-360], p = 0.003). A negative relationship between SABA-induced FEV 1 % changes and pre-bronchodilator FEV 1 % (β = -0.551%; p = 0.0001) and ACT (β = -0.059; p = 0.038) was found. Conversely, post-treatment BE levels were positively related (β = 145.565 cells/µl; p = 0.003) to FEV 1  > 12% increases. A rising trend of pre-/post-bronchodilator FEV 1 % in time was observed in RAO- subjects with BE < 300 cells/µl. Conversely, we highlighted significant declining tendencies of pre/post-bronchodilator FEV 1 % in RAO+ patients with BE > 300 cells/µl reaching lower values after more than 36 months of step-5 treatment (59.6% [39.9-72.1] vs 74[66.5-89.2] of RAO+ individuals with BE < 300 cells/µl [p = 0.026] and 81.6% [66.1-91.8] of RAO-subjects with BE > 300 cells/µl [p = 0.009])., Conclusion: Persistent SABA-induced FEV 1  > 12%, especially when associated to BE > 300 cells/ml, may be a marker of accelerated lung function decline in severe asthmatics despite maximal step-5 treatment. The highest bronchodilation associated to the lowest BE levels should be the main goal of asthma treatment to prevent such decline., (© 2021 John Wiley & Sons Ltd.)

The risks of overusing short-acting β 2 -agonists (SABA), including an increase in asthma-related deaths, are many and well known. The Global Initiative on Asthma (GINA) 2019 and 2020 updates recommend as-needed inhaled corticosteroid (ICS)/formoterol as the preferred rescue medication in mild asthma as monotherapy and also in moderate to severe asthma when the maintenance and reliever therapy (MART) strategy is used. Using SABA for symptom relief, however, was the standard of treatment for many years, and consequently this practice persists, particularly in patients not taking ICS regularly. Here, we examine the rationale for this shift from a long-standing recommendation for as-needed SABA treatment to the use of as-needed ICS/formoterol and consider clinical evidence on strategies for asthma treatment and patient management.

Background: The clinical and laboratory features of patients enrolled in the Severe Asthma Network in Italy (SANI) registry, a web-based observatory collecting demographic, clinical, functional and inflammatory data of patients with severe asthma were evaluated, with a special emphasis to chronic rhinosinusitis with nasal polyposis (CRSwNP)., Methods: For each eligible patients the following information has been collected: demographic data, clinical features, asthma control in the previous month according to the GINA (Global INitiative for Asthma) Guidelines and standardized questionnaires, concomitant regular and on demand treatments and inflammatory markers., Results: 695 patients with severe asthma enrolled in 66 SANI centers were analyzed. The prevalence of chronic rhinosinusitis with nasal polyposis was 40.6%. Atopic dermatitis and bronchiectasis was significantly more frequent in patients with CRSwNP than in subjects without nasal polyposis; similarly, FeNO values are significantly higher in subject with CRSwNP than in patients without nasal polyposis. Finally, patients with CRSwNP had a significantly higher number of asthma exacerbations per year, more days on oral corticosteroids and were more likely to be OCS long term users., Conclusion: OCS sparing is needed in patients with severe asthma, mainly in subjects with CRSwNP, adopting adequate strategies such as a better adherence to the treatment with inhaled therapy according to the GINA recommendations, the use of biologic agents and a multidisciplinary approach of the patient., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Mepolizumab (MEP) has been recently introduced to treat severe eosinophilic asthma. Trials have demonstrated a significant effectiveness in this asthma phenotype. We evaluated MEP efficacy on lung function, symptoms, asthma exacerbations, biologic markers, steroid dependence and controller treatment level in real-life., Methods: We retrospectively analyzed 134 severe asthmatics (61 males; mean age 58.3 ± 11; mean FEV 1 %:72 ± 21), treated with MEP for at least 6 months (mean duration:10.9 ± 3.7 months)., Results: FEV 1 % improved significantly after MEP. Mean FEF 25-75 also increased from 37.4 ± 25.4% to 47.2 ± 27.2% (p < 0.0001). Mean baseline blood eosinophil level was 712 ± 731/μL (8.4 ± 5.2%) decreasing to 151 ± 384/μL (1.6 ± 1.6%) (p < 0.0001), FENO levels decreased likewise. MEP treatment also led to a significant ACT improvement (mean pre:14.2 ± 4.4; mean post:20.5 ± 28) and exacerbations significantly fell from 3.8 ± 1.9 to 0.8 ± 1.1 (p < 0.0001). 74% of patients were steroid-dependent before MEP. 45.4% and 46.4% of them showed a suspension and dose reduction respectively (p < 0.0001). A significant number reduced also ICS doses. Only 67% of subjects used SABA as needed before MEP, falling to 20% after MEP. About 40% of patients highlighted a maintenance therapy step-down. Subjects showing an omalizumab treatment failure before MEP had a similar positive response when compared with omalizumab untreated patients., Conclusion: In real-life, MEP improved significantly all outcomes even small airway obstruction, suggesting its possible role also in distal lung region treatment. Furthermore, it demonstrated its high effectiveness in OC/ICS-sparing, in reducing SABA as needed and in stepping-down maintenance therapy. MEP is a valid alternative for patients with previous omalizumab treatment failure., Competing Interests: Declaration of competing interest On behalf of all authors, the corresponding author states that there is no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Aims: Severe asthma may require the prescription of one of the biologic drugs currently available, using surrogate markers of airway inflammation (serum IgE levels and allergic sensitization for anti-IgE, or blood eosinophils for anti-IL5/IL5R). Our objective: to assess upper and lower airway inflammation in severe asthmatics divided according to the eligibility criteria for one of the target biologic treatments., Methods: We selected 91 severe asthmatics, uncontrolled despite high-dose ICS-LABA, and followed for >6 months with optimization of asthma treatment. Patients underwent clinical, functional and biological assessment, including induced sputum and nasal cytology. They were then clustered according to the eligibility criteria for omalizumab or mepolizumab/benralizumab., Results: Four clusters were selected: A (eligible for omalizumab, n  = 23), AB (both omalizumab and mepolizumab, n  = 26), B (mepolizumab, n  = 22) and C (non-eligible for both omalizumab and mepolizumab, n  = 20). There was no difference among clusters for asthma control (Asthma Control Test and Asthma Control Questionnaire 7), pre-bronchodilator forced expiratory volume in 1 s, serum IgE and fractional exhaled nitric oxide levels. Sputum eosinophils were numerically higher in clusters AB and B, in agreement with the higher levels of blood eosinophils. Allergic rhinitis was more frequent in clusters A and AB, while chronic rhinosinusitis with nasal polyps prevalence increased progressively from A to C. Eosinophils in nasal cytology were higher in clusters AB, B and C., Conclusion: Eosinophilic upper and lower airway inflammation is present in the large majority of severe asthmatics, independently from the prescription criteria for the currently available biologics, and might suggest the use of anti-IL5/IL5R or anti IL4/13 also in patients without blood eosinophilia. The reviews of this paper are available via the supplemental material section .

Background: To date, no studies have assessed the efficacy of single-inhaler triple therapy in asthma. Here we report on two studies that compared the single-inhaler extrafine combination of beclometasone dipropionate (BDP; inhaled corticosteroid), formoterol fumarate (FF; long-acting β 2 agonist), and glycopyrronium (G; long-acting muscarinic antagonist) with the combination of BDP with FF., Methods: Two parallel-group, double-blind, randomised, active-controlled, phase 3 trials (Triple in Asthma With Uncontrolled Patients on Medium Strength of ICS + LABA [TRIMARAN] and Triple in Asthma High Strength Versus ICS/LABA HS and Tiotropium [TRIGGER]) recruited patients from 171 sites across 16 countries (TRIMARAN), and from 221 sites across 17 countries (TRIGGER). The sites were a mixture of secondary and tertiary care centres and specialised investigation units. Eligible patients were adults (aged 18-75 years) with uncontrolled asthma, a history of one or more exacerbations in the previous year, and previously treated with inhaled corticosteroid (TRIMARAN: medium dose; TRIGGER: high dose) plus a long-acting β 2 agonist. Enrolled patients were initially treated with BDP/FF (TRIMARAN: 100 μg BDP and 6 μg FF; TRIGGER: 200 μg BDP and 6 μg FF) for 2 weeks, then randomly assigned to treatment using an interactive response technology system with a balanced block randomisation scheme stratified by country. Patients, investigators, site staff, and sponsor staff were masked to BDP/FF/G and BDP/FF assignment. In TRIMARAN, patients were randomly assigned (1:1) to 52 weeks of BDP/FF/G (100 μg BDP, 6 μg FF, and 10 μg G) or BDP/FF (100 μg BDP and 6 μg FF), two inhalations twice daily. In TRIGGER, patients were randomly assigned (2:2:1) to 52 weeks of BDP/FF/G (200 μg BDP, 6 μg FF, and 10 μg G) or BDP/FF (200 BDP and 6 μg FF), both two inhalations twice daily, or open-label BDP/FF (200 μg BDP and 6 μg FF) two inhalations twice daily plus tiotropium 2·5 μg two inhalations once daily. Coprimary endpoints for both trials (BDP/FF/G vs BDP/FF) were pre-dose forced expiratory volume in 1 s (FEV 1 ) at week 26 and rate of moderate and severe exacerbations over 52 weeks. Safety was assessed in all patients who received at least one dose of study treatment. These trials were registered with ClinicalTrials.gov, NCT02676076 (TRIMARAN), NCT02676089 (TRIGGER)., Findings: Between Feb 17, 2016, and May 17, 2018, 1155 patients in TRIMARAN were given BDP/FF/G (n=579) or BDP/FF (n=576). Between April 6, 2016, and May 28, 2018, 1437 patients in TRIGGER were given BDP/FF/G (n=573), BDP/FF (n=576), or BDP/FF plus tiotropium (n=288). Compared with the BDP/FF group, week 26 predose FEV 1 improved in the BDP/FF/G group by 57 mL (95% CI 15-99; p=0·0080) in TRIMARAN and by 73 mL (26-120; p=0·0025) in TRIGGER, with reductions in the rate of moderate and severe exacerbations of 15% (rate ratio 0·85, 95% CI 0·73-0·99; p=0·033) in TRIMARAN and 12% (0·88, 0·75-1·03; p=0·11) in TRIGGER. Four patients had treatment-related serious adverse events, one in TRIMARAN in the BDP/FF/G group and three in TRIGGER-one in the BDP/FF/G and two in the BDP/FF group. Three patients in the BDP/FF/G group in TRIMARAN and two patients in TRIGGER-one in the BDP/FF/G group and one in the BDP/FF group-had adverse events leading to death. None of the deaths were considered as related to treatment., Interpretation: In uncontrolled asthma, addition of a long-acting muscarinic antagonist to inhaled corticosteroid plus long-acting β 2 -agonist therapy improves lung function and reduces exacerbations., Funding: Chiesi Farmaceutici., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Severe Asthma Network in Italy (SANI) is a registry of patients recruited by accredited centers on severe asthma., Objective: To analyze epidemiological, clinical, inflammatory, functional, and treatment characteristics of severe asthmatics from the SANI registry., Methods: All consecutive patients with severe asthma were included into the registry, without exclusion criteria to have real-life data on demographics, asthma control, treatments (including biologics), inflammatory biomarkers, and comorbidities., Results: A total of 437 patients (mean age: 54.1 years, 57.2% females, 70.7% atopics, 94.5% in Global Initiative for Asthma severity step V) were enrolled into the study. The mean annual exacerbation rate was 3.75. The mean blood eosinophil level was 536.7 cells/mcL, and the average serum total IgE was 470.3 kU/L. Approximately 64% of patients were on regular oral corticosteroid treatment, 57% with omalizumab and 11.2% with mepolizumab. Most common comorbidities were rhinitis, nasal polyposis, and bronchiectasis. Patients with nasal polyposis had higher age of disease onset, higher blood eosinophil count, and lower frequency of atopy and atopic eczema. Bronchiectasis was associated with more frequent severe exacerbations, higher blood eosinophils, and total IgE. Stratifying patients, those with late-onset asthma were less frequently atopic (with less frequent allergic rhinitis and food allergy), and more frequently with nasal polyposis and higher serum total IgE levels., Conclusions: This study revealed a high frequency of relevant comorbidities and that a substantial proportion of patients have late-onset asthma; all these features define specific different disease phenotypes. Severe asthma complexity and comorbidities require multidisciplinary approaches, led by specifically trained pulmonologists and allergists., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Although general practitioners (GPs) are frequently the first healthcare professionals whom asthma patients refer to for their symptoms, few studies have explored the extent of adherence to guidelines for asthma management based on data provided directly by GPs. Aims of the present study were to assess drug prescriptions for asthma by GPs and to evaluate prescriptive adherence to GINA guidelines (GL) and its relationship with disease control in real life., Methods: 995 asthmatic patients (45% males, mean age 43.3 ± 17.7 yrs) were enrolled by 107 Italian GPs distributed throughout the country. Data on diagnosis, disease severity, prescribed anti-asthmatic drugs and control were collected through questionnaires filled out by GPs taking into consideration the 2009 GINA Guidelines. Data on drug use and chronic sinusitis, nasal polyposis, chronic bronchitis, emphysema were reported by patients through a self-administered questionnaire., Results: The large majority of patients were classified by GPs as having intermittent (48.4%) or mild persistent asthma (25.3%); 61% had co-morbid allergic rhinitis (AR). The prevalent therapeutic regimen used by patients was a combination of inhaled corticosteroids (ICS) plus long-acting β 2 -agonists (LABA) (54.1%), even in the intermittent/mild persistent group. ICS as mono-therapy or in combination with other drugs but LABA, was the second most frequently adopted treatment (14.4%). In general, the GPs adherence to GL treatment indications was 28.8%, with a significant association with a good asthma control (OR 1.85, 95% CI 1.18-2.92). On the other hand, comorbidity (OR 0.52, 95% CI 0.32-0.84), moderate (0.44, 0.28-0.69) and severe (0.06, 0.02-0.20) persistent asthma showed significant negative effects on asthma control., Conclusions: Our results show that over-treatment of intermittent/mild persistent asthma is frequent in the GPs setting while therapeutic regimens are more appropriately applied for moderate/severe asthma. In general, we found low adherence to GINA GL treatment recommendations even if its relevance in asthma control was confirmed., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Bronchiectasis is a clinical and radiological diagnosis associated with cough, sputum production and recurrent respiratory infections. The clinical presentation inevitably overlaps with other respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD). In addition, 4-72% of patients with severe COPD are found to have radiological bronchiectasis on computed tomography, with similar frequencies (20-30%) now being reported in cohorts with severe or uncontrolled asthma. Co-diagnosis of bronchiectasis with another airway disease is associated with increased lung inflammation, frequent exacerbations, worse lung function and higher mortality. In addition, many patients with all three disorders have chronic rhinosinusitis and upper airway disease, resulting in a complex "mixed airway" phenotype.The management of asthma, bronchiectasis, COPD and upper airway diseases has traditionally been outlined in separate guidelines for each individual disorder. Recognition that the majority of patients have one or more overlapping pathologies requires that we re-evaluate how we treat airway disease. The concept of treatable traits promotes a holistic, pathophysiology-based approach to treatment rather than a syndromic approach and may be more appropriate for patients with overlapping features.Here, we review the current clinical definition, diagnosis, management and future directions for the overlap between bronchiectasis and other airway diseases., Competing Interests: Conflict of interest: E. Polverino reports personal fees from Bayer, Grifols, Insmed and Zambon, outside the submitted work. Conflict of interest: K. Dimakou has nothing to disclose. Conflict of interest: J. Hurst has nothing to disclose. Conflict of interest: M.A. Martinez-Garcia reports personal fees from Bayer, Grifols, Zambon, Teva, AstraZeneca, GSK and Novartis, outside the submitted work. Conflict of interest: M. Miravitlles has nothing to disclose. Conflict of interest: P. Paggiaro reports grants and personal fees from AstraZeneca, grants and personal fees from Chiesi, personal fees and non-financial support from GSK, personal fees from Guidotti, personal fees and non-financial support from Menarini, personal fees from Mundipharma, personal fees and non-financial support from Novartis, and grants and personal fees from Sanofi, outside the submitted work. Conflict of interest: M. Shteinberg reports having received research grants from Novartis and Trudell pharma; travel grants from Actelion, Boehringer Ingelheim, GSK and Rafa; speaker's fees from Boehringer Ingelheim, GSK, AstraZeneca, Teva and Novartis; and is a member of the EMBARC collaboration. Conflict of interest: S. Aliberti reports grants and personal fees from Bayer Healthcare, grants and personal fees from Aradigm Corporation, grants and personal fees from Grifols, personal fees from AstraZeneca, personal fees from Basilea, personal fees from Zambon, personal fees from Novartis, personal fees from Raptor, grants and personal fees from Chiesi, personal fees from Actavis UK Ltd, personal fees from Horizon, and grants and personal fees from INSMED, outside the submitted work. Conflict of interest: J.D. Chalmers reports grants and personal fees from Bayer, grants and personal fees from Grifols, grants and personal fees from Insmed, personal fees from Zambon, grants and personal fees from Boehringer Ingelheim, grants and personal fees from GSK, grants from AstraZeneca, and grants and personal fees from Pfizer, outside the submitted work., (Copyright ©ERS 2018.)

Objective: To assess the impact of occupational exposure to irritants or sensitizers on the occurrence, recrudescence and worsening of asthma and to identify unrecognized cases of work related asthma (WRA) including Work-Exacerbated Asthma (WEA) and Occupational Asthma (OA), in a general asthma clinic population sample., Setting, Design and Participants: The study was a population-based cross sectional survey. 1289 asthmatic subjects (from 15 to 46 yrs old) living in a vast district of Tuscany (Italy) were identified from the Medical Reimbursement Register of the National Health System. 893 subjects agreed to take part in the study. Subjects who were currently working or had worked in past were classified in different categories of occupational risk exposure (No, Low or High) according to the italian standard classification for industries and job titles, associated with the judgment of occupational hygiene experts., Results: 41% of subjects worked in industries and in job titles at risk for exposure to airway irritants and/or sensitizers, 48.6% reported an occupational exposure to gases, dust and fumes, more males than females. Prevalence of WEA and OA was higher in subjects who worked at higher risk exposure; these subjects reported a higher prevalence of markers of asthma severity (asthma control, level of treatment, FEV1) than subjects without WRA. Risk of WEA was significantly associated to female gender, older age, and self-reported exposure, while risk of OA was associated to job title with higher exposure risk to occupational asthmogens., Conclusions: Our study shows a high prevalence of WRA (especially WEA) associated with employment in industries and job titles at risk for airways sensitizers and/or irritants; data also support a role for occupational exposure in determining a poor asthma control and a higher level of asthma severity., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Asthma is a complex chronic inflammatory disease of multifactorial etiology. International guidelines increasingly recognize that a standard "one size fits all" approach is no longer an effective approach to achieve optimal treatment outcomes, and a number of disease phenotypes have been proposed for asthma, which has the potential to guide treatment decisions. Among the many asthma phenotypes, allergic asthma represents the widest and most easily recognized asthma phenotype, present in up to two-thirds of adults with asthma. Immunoglobulin E (IgE) production is the primary and key cause of allergic asthma leading to persistent symptoms, exacerbations and a poor quality of life. Therefore, limiting IgE activity upstream could stop the entire allergic inflammation cascade in IgE-mediated allergic asthma. The anti-IgE treatment omalizumab has an accepted place in the management of severe asthma (Global Initiative for Asthma [GINA] step 5) and represents the first (and, currently, only) targeted therapy with a specific target in severe allergic asthma. This review summarizes current knowledge of the mechanisms and pathogenesis of severe asthma, examines the actual role of IgE in asthma and the biological rationale for targeting IgE in allergic asthma and reviews the data for the efficacy and safety of omalizumab in the treatment of severe asthma. Current knowledge of the role of IgE in asthma, extensive clinical trial data and a decade of use in clinical practice has established omalizumab as a safe and effective targeted therapy for the treatment of patients with severe persistent IgE-mediated allergic asthma., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Asthma considerably impairs patients' quality of life and increases healthcare costs. Severity, morbidity, and degree of disease control are the major drivers of its clinical and economic impact. National scientific societies are required to monitor the application of international guidelines and to adopt strategies to improve disease control and better allocate resources., Aim: to provide a detailed picture of the characteristics of asthma patients and modalities of asthma management by specialists in Italy and to develop recommendations for the daily management of asthma in a specialist setting., Method: A quantitative research program was implemented. Data were collected using an ad hoc questionnaire developed by a group of specialists selected by the Italian Pneumology Society/Italian Respiratory Society., Results: The records of 557 patients were analyzed. In the next few years, specialists are expected to focus their activity patients with more severe disease and will be responsible for selection of patients for personalized biological therapy; however, only 20% of patients attending Italian specialist surgery can be considered severe. In 84.4% of cases, the visit was a follow-up visit requested in 82.2% of cases by the specialist him/herself. The Asthma Control Test is used only in 65% of patients. When available, a significant association has been observed between the test score and asthma control as judged by the physician, although concordance was only moderate (κ = 0.68). Asthma was considered uncontrolled by the specialist managing the case in 29.1% of patients; nevertheless, treatment was not stepped up in uncontrolled or partly controlled patients (modified in only 37.2% of patients)., Conclusions: The results of this survey support re-evaluation of asthma management by Italian specialists. More resources should be made available for the initial visit and for more severely ill patients. In addition, more extensive use should be made of validated tools, and available drugs should be used more appropriately., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: It is unknown whether Omalizumab effectiveness changes over the course of time. Our retrospective real-life study tried to analyze whether Omalizumab response may be influenced by treatment duration., Methods: 340 severe asthmatics treated with Omalizumab for different periods of time were recruited. They were subdivided into 4 groups according to the Omalizumab treatment length: <12, between 12 and 24, between 24 and 60 and >60 months. Omalizumab treatment results (FEV 1 , exacerbations, ACT, SABA use, asthma control levels, medications used e and ICS doses) were compared., Results: ACT, exacerbations, GINA control levels, ICS doses and SABA use were similar in all groups with different Omalizumab treatment durations. Using a linear regression model, corrected for all confounding variables, a higher significant positive increase in FEV 1 % in subjects treated for 12-24 (β = 9.49; p = 0.034) or 24-60 months (β = 8.56; p = 0.043) was found when compared with subjects treated for a shorter period. Treatment duration was positively associated with a step down of the other associated therapies (OR: 1.013; p = 0.019). This association was more relevant (OR: 4.167; p = 0.005) when we considered Omalizumab treatment duration >60 months compared to the shorter therapy. In particular, the percentage of subjects that were taking Montelukast, LABAs and oral corticosteroids was lower in the group treated with Omalizumab for a longer period of time., Conclusion: In real-life, the positive Omalizumab response remained stable for over 60 months. Long term Omalizumab treatment may lead to a discontinuation of some associated medications and to a slowing down of FEV 1 decline., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: A high strength of beclomethasone/formoterol fumarate (BDP/FF) in a pressurised metered dose inhaler (pMDI), which contains extrafine BDP (200 μg/actuation) and FF (6 μg/actuation) has been developed to treat those asthmatics who are not adequately controlled on previous treatments., Methods: A 12-week, randomized, double-blind, parallel group study was performed to compare the efficacy and safety of pMDI BDP/FF 200/6 (two actuations bid) with BDP 100 μg (four actuation bid) in a population of 376 randomized adult asthmatics not adequately controlled with high dose of inhaled corticosteroids (ICS) or medium dose of ICS plus long acting β 2 agonists (LABA)., Results: The primary endpoint [change from baseline over the entire treatment period in average pre-dose morning peak expiratory flow (PEF)] demonstrated the superiority of BDP/FF over BDP monotherapy, with an adjusted mean difference of 19 L/min, which is above the minimal important clinical difference reported for this parameter. Overall, BDP/FF and BDP showed a similar improvement of symptom-based parameters and of the use of rescue medication after 3-month treatment. The safety profile of the two drugs was comparable, although BDP monotherapy, but not BDP/FF, slightly reduced the levels of serum cortisol., Conclusions: The study proved that pMDI BDP/FF 200/6 μg was superior to BDP alone in improving lung function with comparable safety profiles. Therefore it may be considered as an effective treatment for adults with asthma not adequately controlled with high dose of ICS monotherapy or medium dose of ICS/LABA combinations., Trial Registration: ClinicalTrials.gov: NCT01577082 , date 06/04/2012.

Background: In phase 2 trials, lebrikizumab, an anti-interleukin-13 monoclonal antibody, reduced exacerbation rates and improved FEV 1 in patients with uncontrolled asthma, particularly in those with high concentrations of type 2 biomarkers (eg, periostin or blood eosinophils). We undertook replicate phase 3 studies to assess the efficacy and safety of lebrikizumab in patients with uncontrolled asthma despite inhaled corticosteroids and at least one second controller medication., Methods: Adult patients with uncontrolled asthma, pre-bronchodilator FEV 1 40-80% predicted, and stable background therapy were randomly assigned (1:1:1) with an interactive voice-web-based response system to receive lebrikizumab 37·5 mg or 125 mg, or placebo subcutaneously, once every 4 weeks. Randomisation was stratified by screening serum periostin concentration, history of asthma exacerbations within the last 12 months, baseline asthma medications, and country. The primary efficacy endpoint was the rate of asthma exacerbations over 52 weeks in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells per μL), analysed with a Poisson regression model corrected for overdispersion with Pearson χ 2 that included terms for treatment group, number of asthma exacerbations within the 12 months before study entry, baseline asthma medications, geographic region, screening periostin concentration, and blood eosinophil counts as covariates. Both trials are registered at ClinicalTrials.gov, LAVOLTA I, number NCT01867125, and LAVOLTA II, number NCT01868061., Findings: 1081 patients were treated in LAVOLTA I and 1067 patients in LAVOLTA II. Over 52 weeks, lebrikizumab reduced exacerbation rates in biomarker-high patients in the 37·5 mg dose group (rate ratio [RR] 0·49 [95% CI 0·34-0·69], p<0·0001) and in the 125 mg dose group (RR 0·70 [0·51-0·95], p=0·0232) versus placebo in LAVOLTA I. Exacerbation rates were also reduced in biomarker-high patients in both dose groups versus placebo in LAVOLTA II (37·5 mg: RR 0·74 [95% CI 0·54-1·01], p=0·0609; 125 mg: RR 0·74 [0·54-1·02], p=0·0626). Pooling both studies, the proportion of patients who experienced treatment-emergent adverse events (79% [1125 of 1432 patients] for both lebrikizumab doses vs 80% [576 of 716 patients] for placebo), serious adverse events (8% [115 patients] for both lebrikizumab doses vs 9% [65 patients] for placebo), and adverse events leading to study drug discontinuation (3% [49 patients] for both lebrikizumab doses vs 4% [31 patients] for placebo) were similar between lebrikizumab and placebo. The following serious adverse events were reported in the placebo-controlled period: one event of aplastic anaemia and five serious adverse events related to raised concentrations of eosinophils in patients treated with lebrikizumab and one event of eosinophilic pneumonia in the placebo group., Interpretation: Lebrikizumab did not consistently show significant reduction in asthma exacerbations in biomarker-high patients. However, it blocked interleukin-13 as evidenced by the effect on interleukin-13-related pharmacodynamic biomarkers, and clinically relevant changes could not be ruled out., Funding: F Hoffmann-La Roche., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Many patients with asthma remain symptomatic despite treatment with inhaled corticosteroids (ICS) with or without long-acting β2-agonists (LABAs). Tiotropium add-on to ICS plus a LABA has been shown to improve lung function and reduce exacerbation risk in patients with symptomatic asthma., Objective: To determine whether the efficacy of tiotropium add-on therapy is dependent on patients' baseline characteristics., Methods: Two randomized, double-blind, parallel-group, twin trials (NCT00772538 and NCT00776984) of once-daily tiotropium Respimat(®) 5 μg add-on to ICS plus a LABA were performed in parallel in patients with severe symptomatic asthma. Exploratory subgroup analyses of peak forced expiratory volume in 1 s (FEV1), trough FEV1, time to first severe exacerbation, time to first episode of asthma worsening, and seven-question Asthma Control Questionnaire responder rate were performed to determine whether results were influenced by baseline characteristics., Results: 912 patients were randomized: 456 received tiotropium and 456 received placebo. Tiotropium improved lung function, reduced the risk of asthma exacerbations and asthma worsening, and improved asthma symptom control, compared with placebo, independent of baseline characteristics including gender, age, body mass index, disease duration, age at asthma onset, and FEV1 % predicted at screening and reversibility., Conclusion: Once-daily tiotropium 5 μg compared with placebo improved lung function, reduced the risk of asthma exacerbations and asthma worsening, and improved asthma symptom control, independent of a broad range of baseline characteristics, as add-on to ICS plus LABAs in patients with severe symptomatic asthma., Trial Registry: ClinicalTrials.gov; numbers NCT00772538 and NCT00776984 URL: www.clinicaltrials.gov., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic necrotizing vasculitis that occurs in patients with asthma, nasal disease, blood and tissue eosinophilia, and extrapulmonary manifestations., Objective: The aim of our study was to assess the clinical, functional, and inflammatory status of upper and lower airways in 37 patients with EGPA, examined 6.4 ± 4.7 years after diagnosis, when they were in partial or complete remission from systemic involvement while on treatment with low-dose oral corticosteroids as maintenance therapy., Methods: All patients performed spirometry and were assessed for bronchial hyperreactivity, sputum eosinophilia, and fractional exhaled nitric oxide; asthma control was evaluated according to the Global Initiative for Asthma (GINA) guidelines and the Asthma Control Test. Markers of systemic disease were compared with the data available at diagnosis. Nasal involvement was evaluated by using the Sino-Nasal Outcome Test, nasal endoscopy, and nasal cytology. The impact on the quality of life was evaluated by using generic (36-item short form health survey) and organ-specific questionnaires., Results: At the time of the study visit, almost all patients were receiving low-dose oral corticosteroids and immunomodulating drugs, but only 50% were being treated with inhaled corticosteroids. Although low systemic disease activity was documented in the large majority of patients, poorly controlled asthma and rhinosinusitis with eosinophilic airway inflammation were demonstrated in almost all patients. A significant correlation was found between sputum and blood eosinophilia and between fractional exhaled nitric oxide and asthma control. The 36-item short form health survey questionnaire results significantly correlated with the Sino-Nasal Outcome Test but not with the Asthma Control Test., Conclusions: Systemic treatment controls systemic involvement in EGPA, but not asthma and nasal diseases, which negatively affects patients' quality of life., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Tiotropium, a once-daily long-acting anticholinergic bronchodilator, has demonstrated efficacy in patients with asthma who were symptomatic despite treatment with medium- to high-dose inhaled corticosteroids (ICS)., Objective: The objective of this study was to evaluate the efficacy and safety of once-daily tiotropium Respimat (5 μg or 2.5 μg), compared with placebo Respimat, as add-on therapy to low- to medium-dose ICS for adults with symptomatic asthma., Methods: A phase III, double-blind, placebo-controlled trial was conducted (NCT01316380). Adults with symptomatic asthma receiving low- to medium-dose ICS (200-400 μg budesonide or equivalent dose) and a pre-bronchodilator forced expiratory volume in 1 second (FEV1) ≥60% and ≤90% of predicted normal were randomized to 12 weeks of treatment with once-daily tiotropium Respimat 5 μg or 2.5 μg, or placebo Respimat, as add-on therapy to ICS. The primary endpoint was peak FEV1(0-3h) response., Results: In total, 464 patients were randomized (61% female; mean age 43 years; mean baseline FEV1 78% of predicted normal). After 12 weeks, both tiotropium Respimat doses were superior to placebo (adjusted mean difference from placebo: 5 μg, 128 mL; 2.5 μg, 159 mL; both P < .001). Both doses of tiotropium Respimat were also superior to placebo with regard to the secondary endpoints of adjusted mean trough FEV1 and FEV1 area under the curve(0-3h) responses, and the other endpoints of morning and evening peak expiratory flow. Adverse events were comparable across the treatment groups., Conclusions: Once-daily tiotropium Respimat add-on therapy to low- to medium-dose ICS in adults with symptomatic asthma is an efficacious bronchodilator, and its safety and tolerability are comparable with those of placebo Respimat., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Over the past 20 years, the Global Initiative for Asthma (GINA) has regularly published and annually updated a global strategy for asthma management and prevention that has formed the basis for many national guidelines. However, uptake of existing guidelines is poor. A major revision of the GINA report was published in 2014, and updated in 2015, reflecting an evolving understanding of heterogeneous airways disease, a broader evidence base, increasing interest in targeted treatment, and evidence about effective implementation approaches. During development of the report, the clinical utility of recommendations and strategies for their practical implementation were considered in parallel with the scientific evidence.This article provides a summary of key changes in the GINA report, and their rationale. The changes include a revised asthma definition; tools for assessing symptom control and risk factors for adverse outcomes; expanded indications for inhaled corticosteroid therapy; a framework for targeted treatment based on phenotype, modifiable risk factors, patient preference, and practical issues; optimisation of medication effectiveness by addressing inhaler technique and adherence; revised recommendations about written asthma action plans; diagnosis and initial treatment of the asthma-chronic obstructive pulmonary disease overlap syndrome; diagnosis in wheezing pre-school children; and updated strategies for adaptation and implementation of GINA recommendations., (Copyright ©ERS 2015.)

Few data are available on the proportion of asthmatics achieving a good asthma control (according GINA guidelines) and on the level of airway inflammation during omalizumab treatment. The aim of this cross-sectional national observational study was to assess the level of control (according to GINA guidelines) achieved in a group of asthmatics on omalizumab treatment, and to characterize the factors that influence the lack of control. We studied 306 asthmatics under omalizumab treatment for a median of 32 months (range 4-120). The level of control according to GINA was good in 25.2%, partial in 47.1% and poor in 24.5% of patients (data were missing for the remaining 3.2%). Comparison between poorly controlled and partially or well controlled asthmatics showed a statistically significant higher prevalence of some comorbidities in the first group, namely obesity, gastro-oesophageal reflux disease (GORD), aspirin intolerance and mental disorders (all p < 0.001). Similarly, asthmatics with at least one exacerbation in the last year showed a significantly higher prevalence of obesity, chronic rhinosinusitis, nasal polyps, GORD, and aspirin intolerance (all p < 0.05) than patients without exacerbations. When we selected patients without relevant comorbidities (upper airways disease, GORD, obesity, aspirin intolerance) and not currently smoking (N = 73), the percentage of well or partially controlled asthmatics was significantly higher than in patients with comorbidities (84.9% vs 71.1%, p = 0.02); the rate of asthmatics without exacerbations in the last year was also higher (73.6% vs 51.1%, p = 0.001). During omalizumab treatment, a high percentage of asthmatics obtain a good or partial control of asthma. Comorbidities are associated with the lack of asthma control and persistence of exacerbations., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Treatment guidelines for patients with moderate persistent asthma recommend regular therapy with a combination of an inhaled corticosteroid and a longacting β2 agonist plus as-needed rapid-acting bronchodilators. We investigated whether symptom-driven budesonide and formoterol combination therapy administered as needed would be as effective as regular treatment with this combination plus as-needed symptom-driven terbutaline for patients with moderate asthma., Methods: In this non-inferiority randomised clinical trial, we recruited adult patients (18-65 years of age) with stable moderate persistent asthma, according to 2006 Global Initiative for Asthma guidelines. Patients were recruited from outpatient clinics of secondary and tertiary referral hospitals and university centres. After a 6-week run-in period of inhaled regular budesonide and formoterol plus as-needed terbutaline, the patients were randomly assigned in a 1:1 ratio to receive placebo twice daily plus as-needed treatment with inhaled 160 μg budesonide and 4·5 μg formoterol (as-needed budesonide and formoterol therapy) or twice-daily 160 μg budesonide and 4·5 μg formoterol combination plus symptom-driven 500 μg terbutaline (regular budesonide/formoterol therapy) for 1 year. Randomisation was done according to a list prepared with the use of a random number generator and a balanced-block design stratified by centre. Patients and investigators were masked to treatment assignment. The primary outcome was time to first treatment failure measured after 1 year of treatment using Kaplan-Meier estimates, and the power of the study was calculated based on the rate of treatment failure. Analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00849095., Findings: Between April 20, 2009, and March 31, 2012, we screened 1010 patients with moderate asthma and randomly assigned 866 eligible patients to the two treatment groups (424 to as-needed budesonide and formoterol therapy and 442 to regular budenoside and formoterol therapy). Compared with regular budesonide and formoterol therapy, as-needed budesonide and formoterol treatment was associated with a lower probability of patients having no treatment failure at 1 year (Kaplan-Meier estimates 53·6% for as-needed treatment vs 64·0% for regular treatment; difference 10·3% [95% CI 3·2-17·4], at a predefined non-inferiority limit of 9%). Patients in the as-needed budesonide and formoterol group had shorter time to first treatment failure than those in the regular therapy group (11·86 weeks vs 28·00 weeks for the first quartile [ie, the time until the first 25% of patients experienced treatment failure]). The difference in treatment failures was largely attributable to nocturnal awakenings (82 patients in the as-needed treatment group vs 44 in the regular treatment group). Both treatment regimens were well tolerated., Interpretation: In patients with moderate stable asthma, as-needed budesonide and formoterol therapy is less effective than is the guideline-recommended regular budesonide and formoterol treatment, even though the differences are small., Funding: Italian Medicines Agency., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In difficult-to-treat asthmatics, uncontrolled despite a high level of therapy and followed for 3 years with a mean number of sputum samples/patient = 10, sputum eosinophilia (≥3%) was observed in 87% of all sputum samples. Persistent sputum eosinophilia is a characteristic of severe uncontrolled asthma.

Background: GINA guideline recommends stepping down treatment of asthma patients where control is achieved. The aim of this analysis was to estimate the costs and health outcomes associated with step down of controlled patients on high dose fluticasone/salmeterol (FP/S 1000/100 μg daily) to either medium dose FP/S (500/100 μg) dry powder or extrafine beclometasone/formoterol (BDP/F 400/24 μg) pMDI in three European countries., Methods: A patient-level simulation Markov model was constructed to enable the simulation of three comparative arms (FP/S 1000/100, FP/S 500/100, BDP/F 400/24). Transition probabilities and healthcare resources consumption were derived from a multinational clinical trial comparing BDP/F 400/24 μg vs. FP/S 500/100 μg as step down therapy in asthma. Direct costs and health state utilities were sourced from public source and published literature. The analysis was conducted from a health system perspective, based on six months horizon. Probabilistic sensitivity analyses were conducted., Results: The ICER (Incremental Cost-Effectiveness Ratio) associated with high dose dry powder FP/S 1000/100 μg vs. extrafine BDP/F 400/24 μg was above 70,000 GBP and 200,000 €/QALY (Quality Adjusted Life Years). An ICER of 29,000 GBP/QALY and above 30,000 €/QALY was associated with medium dose dry powder FP/S 500/100 μg vs. BDP/F 400/24 μg., Conclusions: It was found that maintaining controlled patients on high dose FP/S is not cost-effective. Extrafine BDP/F 400/24 μg daily can be considered to be a cost-effective option in the countries analyzed to maintain control of asthmatic patients stepped down from high dose FP/S 1000/100 μg daily dry powder or suspension formulations., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Context: It is well known that ozone exposure decreases lung function and increases airway neutrophilia, but large variability has been observed among asthmatic patients., Objective: To find possible predictors of functional and inflammatory airway response to ozone in asthmatic patients., Materials and Methods: We studied 120 patients with mild-to-moderate asthma, randomly exposed to either air or ozone (0.3 ppm for 2 h) in a challenge chamber. Symptoms and pulmonary function test (PFT) were measured before and immediately after exposure. Six hours after exposure, induced sputum was collected. Patients were evaluated according to their functional (FEV₁ responders) or neutrophilic (neutrophil responders) response to ozone. We considered, as possible predictors of response: age, baseline FEV₁, previous treatment with inhaled corticosteroids (ICS), baseline sputum neutrophils, baseline sputum eosinophils, methacholine responsiveness, atopy and smoking habit., Results: FEV₁ responders had lower baseline FEV₁, and a lower percentage of these had received ICS treatment. Neutrophil responders were younger, with lower baseline sputum inflammation and greater methacholine responsiveness. These results were confirmed by multivariate logistic analysis., Discussion and Conclusion: Patients not previously treated with ICS and patients with lower FEV₁ are more prone to functional response to ozone. Lower baseline airway inflammation and greater bronchial hyperresponsiveness may predict neutrophilic airway response to ozone in asthmatic patients. Thus, determinants of functional and inflammatory responses to ozone are different.

Background and Objective: Symptomatic, steroid-naïve asthmatic patients may have low sputum eosinophil numbers. The aim of the study was to determine whether low sputum eosinophil numbers persisted over time, during treatment with salmeterol monotherapy., Methods: Forty steroid-naïve, symptomatic asthmatic patients, with sputum eosinophils <3%, were randomized to receive open-label salmeterol (50 µg twice a day, n = 30) or fluticasone (125 µg twice a day, n = 10) and were then assessed at 1, 3 and 6 months. All patients underwent spirometry, a methacholine challenge test and sputum induction at each visit. Symptom scores and peak expiratory flow were recorded throughout the study. Patients were permitted to withdraw from the study at any time, if they experienced exacerbations or deterioration of symptoms., Results: The average sputum eosinophil percentage remained normal (≤1.9%) in both groups over the study period. The eosinophil percentages were ≤1.9% in 65 of the 80 samples obtained from salmeterol-treated patients throughout the study period. Eight patients had an asthma exacerbation or deterioration, during which one developed sputum eosinophilia. Twelve patients, 11 of whom were randomized to salmeterol and one to fluticasone, developed transient sputum eosinophilia at least once during the study. This was not associated with asthma exacerbation (except for one patient). Sputum neutrophil percentage did not change in either group., Conclusions: Low sputum eosinophil numbers persisted over 6 months in a majority of patients with non-eosinophilic asthma who received salmeterol monotherapy. However, transient sputum eosinophilia occurred in 40% indicating that non-eosinophilic asthma may not be a stable phenotype., (© 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.)

Objective: Asthma is a disease with elevated prevalence within the general population. Although general practitioners (GPs) are among the first health-care professionals to whom patients refer for their symptoms, there are few evaluations of this disease based on data provided by the GPs. The aim of this observational study is to assess the impact of asthma and comorbid allergic rhinitis on individual/social burden, quality of life, and disease control in asthmatic patients of Italian GPs., Methods: Throughout Italy, 107 GPs enrolled 995 patients diagnosed with asthma and using anti-asthmatic drug prescriptions, or with asthma-like symptoms during the previous 12 months. Data were collected through questionnaires filled out by GPs and patients., Results: Of the 995 asthmatic patients, 60.6% had concomitant allergic rhinitis (R+A), 39.4% had asthma alone. The latter, compared to those with R+A, showed significantly lower prevalence of intermittent asthma (37.5% vs. 55.6%) and higher prevalence of mild, moderate, and severe persistent asthma (28.4% vs. 23.2%, 28.7% vs. 18.8%, and 5.4% vs 2.4%, respectively). Individual/social burden due to asthma was frequent and increased with disease severity: 87.5% of severe persistent asthma patients reported at least one medical consultation in the last 12 months, 37.5% emergency department visits, 26.7% hospitalization, and 62.5% limitations in daily activities. Control and quality of life were inversely associated with disease severity and were worse in patients with R+A than in those with asthma alone., Conclusions: This study showed the negative impact of high severity levels and comorbid allergic rhinitis on quality of life of asthmatic patients and on individual/social burden due to asthma in an Italian GPs setting.

Background: Short-acting beta2-agonists like salbutamol and terbutaline are used as rescue medications for acute bronchoconstriction and relief of symptoms due to their rapid onset of action. The aim of this study was to assess whether inhaled beclomethasone dipropionate (BDP)/formoterol fumarate (FF) combination in extrafine formulation is non-inferior to salbutamol in the speed of reverting methacholine-induced bronchoconstriction and symptoms., Methods: Fifty-six asthmatic patients were examined in a multicentre, randomised, double blind, double dummy, active treatment and placebo controlled three period cross-over study. On three different days, a single dose of BDP/FF 100/6 μg in pressurised metered-dose inhaler (pMDI) extrafine formulation or salbutamol 200 μg pMDI or placebo was inhaled after FEV(1) had dropped by 30-45% with methacholine challenge., Results: The median time to recovery of FEV(1) to 85% of baseline was similar for BDP/FF and salbutamol (3.66 and 2.15 min, respectively), but significantly longer for placebo (21.1 min). The planned analysis on adjusted mean time to recovery showed that the difference from methacholine-induced bronchoconstriction between BDP/FF and salbutamol was 3.82 min (95% confidence interval: -0.85 to 8.5), therefore greater than 3 min supposed in the study design. The difference between BDP/FF and salbutamol was not clinically significant. The two active treatments were also comparable in terms of the relief of symptoms (as assessed by the Borg dyspnoea scale)., Conclusions: BDP/FF combination has a fast onset of action, similar to that of salbutamol, and may represent a good alternative as rescue medication in asthmatic patients., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Some patients with asthma have frequent exacerbations and persistent airflow obstruction despite treatment with inhaled glucocorticoids and long-acting beta-agonists (LABAs)., Methods: In two replicate, randomized, controlled trials involving 912 patients with asthma who were receiving inhaled glucocorticoids and LABAs, we compared the effect on lung function and exacerbations of adding tiotropium (a total dose of 5 μg) or placebo, both delivered by a soft-mist inhaler once daily for 48 weeks. All the patients were symptomatic, had a post-bronchodilator forced expiratory volume in 1 second (FEV(1)) of 80% or less of the predicted value, and had a history of at least one severe exacerbation in the previous year., Results: The patients had a mean baseline FEV(1) of 62% of the predicted value; the mean age was 53 years. At 24 weeks, the mean (±SE) change in the peak FEV(1) from baseline was greater with tiotropium than with placebo in the two trials: a difference of 86±34 ml in trial 1 (P=0.01) and 154±32 ml in trial 2 (P<0.001). The predose (trough) FEV(1) also improved in trials 1 and 2 with tiotropium, as compared with placebo: a difference of 88±31 ml (P=0.01) and 111±30 ml (P<0.001), respectively. The addition of tiotropium increased the time to the first severe exacerbation (282 days vs. 226 days), with an overall reduction of 21% in the risk of a severe exacerbation (hazard ratio, 0.79; P=0.03). No deaths occurred; adverse events were similar in the two groups., Conclusions: In patients with poorly controlled asthma despite the use of inhaled glucocorticoids and LABAs, the addition of tiotropium significantly increased the time to the first severe exacerbation and provided modest sustained bronchodilation. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov numbers, NCT00772538 and NCT00776984.).

Background: Asthma guidelines suggest that therapy can be reduced once asthma is controlled. Despite these recommendations, asthmatic patients are seldom stepped down in clinical practice, and questions remain about when and how to reduce asthma therapy. The purpose of the present study was to evaluate lung function and asthma control in patients who were stepped down from the highest recommended dose of inhaled corticosteroid/long acting β2 agonist combination therapy., Methods: This was a prospective, randomised, controlled, two-arm parallel group study. Asthmatic patients who were fully controlled with a high daily dose (1000/100 μg) of fluticasone/salmeterol were randomly assigned to 6 months of open-label treatment with either 500/100 μg fluticasone/salmeterol Diskus daily or 400/24 μg extrafine beclomethasone/formoterol pMDI daily. The primary outcome was the change in morning peak expiratory flow (PEF) values between baseline and the end of treatment. The secondary outcomes included asthma control and exacerbation frequency., Results: Four hundred twenty-two patients were included in the analysis. The PEF values remained above 95% of the predicted values throughout the study. The end-study morning PEF rates showed equivalence between the groups (difference between means, 2.49 L/min; 95% CI, -13.43 to 18.42). No changes from baseline were detected in PEF and forced expiratory volume in 1 second measured at the clinics, in the symptom scores or in the use of rescue medication. Asthma control was maintained in 95.2% of the patients at 6 months. No significant differences between the groups were detected in any other parameter, including exacerbation frequency and adverse events., Conclusions: Stepping down patients whose asthma is controlled with the highest recommended dose of fluticasone/salmeterol to either 500/100 μg fluticasone/salmeterol daily or 400/24 μg extra-fine beclomethasone/formoterol daily provides comparable maintenance of lung function and asthma control., Trial Registration: clinicaltrials.gov NCT00497237.

Although bronchial hyperresponsiveness to cholinergic agents is a main feature of asthma, the role of anticholinergic drugs in chronic asthma management has been largely underestimated. Several single-dose studies comparing acute bronchodilation induced by ipratropium bromide with salbutamol have shown that salbutamol was more effective than ipratropium in asthma treatment. Recently, tiotropium has been studied in asthma, when added to low-dose inhaled corticosteroids in unselected moderate asthmatics or in patients with uncontrolled asthma, or patients with chronic obstructive pulmonary disease and history of asthma. Later, studies on patients with Arg/Arg β(2)-receptor polymorphism demonstrated a similar efficacy of tiotropium in comparison with salmeterol when both were added to low-dose inhaled corticosteroids. Further long-term studies are currently in progress, for the evaluation of the efficacy of tiotropium on clinical asthma control, and on the rate and severity of asthma exacerbations, as well as the potential modification of inflammatory mechanisms and varying efficacy in specific asthma phenotypes (such as smoking asthmatics).

Background: Asthma Control Test (ACT) is a simple tool for assessing the level of asthma control in clinical practice, and it has been validated in comparison with a general clinical assessment of asthma control, including forced expiratory volume in the first second (FEV(1))., Objective: To evaluate the relationship between ACT score and clinical and functional findings of asthma control and biomarkers of airway inflammation., Methods: A total of 68 asthmatic patients observed in our asthma clinic (33 regularly treated with inhaled corticosteroids (ICS) and 35 ICS-naïve) filled ACT questionnaire and underwent the following measurements: (a) FEV(1) before and after salbutamol; (b) exhaled nitric oxide; (c) bronchial hyperresponsiveness to methacholine; (d) sputum eosinophil count; and (e) daytime and nighttime symptoms, rescue salbutamol, and twice-daily peak expiratory flow (PEF) recording on a 4-week diary card., Results: ACT score significantly correlated with symptom score, rescue medication use, and PEF variability, but not with FEV(1), FEV(1) reversibility, and markers of airway inflammation, which could not distinguish controlled from uncontrolled patients according to ACT, regardless of ICS treatment., Conclusion: ACT score is a valid tool to simply assess the current level of asthma control in terms of symptoms, rescue medication use, and PEF variability. Pulmonary function and biomarkers of airway inflammation are not related to the clinical asthma control as assessed by ACT and may represent additional measurements potentially useful in asthma management.

Asthma and chronic obstructive pulmonary disease (COPD) represent the leading chronic respiratory diseases of interest in the word, owing to their high prevalence and burden on the health system. Care of these patients, undergoing frequent exacerbations, is a heavy burden on healthcare systems. In the last few years, large improvements in the management of asthma and COPD have been made, owing to new drugs and management strategies, and to the improvement of the nonpharmacologic treatment of COPD. There are still many unmet needs in the treatment of these diseases. In asthma, strategies to improve control should be implemented. There is a need to use more biomarkers to tailor treatment, in the assessment and choice of appropriate therapy, especially in severe patients. In COPD, there is growing evidence of individual differences in lung function decline rate and associated differences in appropriate management strategies. Early effective and prolonged bronchodilation can slow disease progression and reduce the frequency of exacerbations. New perspectives include the use of biologic drugs (anticytokine monoclonal antibodies) in selected categories of severe asthmatics, potential new inhibitors of chemokines and cytokines involved in the pathobiology of asthma and COPD, and a further improvement of current drugs and better implementation of management strategies, particularly in COPD patients.