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.

Background: follow-up studies on registries of severe/uncontrolled asthma (SUA) patients are scanty. Objective: to analyze baseline and follow-up characteristics of SUA patients and their longitudinal patterns. Methods: 180 adult patients (age >= 15 yrs) were investigated at baseline and 12-month follow-up through the Italian SUA registry (RItA). Latent transition analysis (LTA) was performed to detect cross-sectional SUA phenotypes and longitudinal patterns. Risk factors for longitudinal patterns were assessed through logistic regression. Results: a significant/borderline improvement of asthma control outcomes in the last 2-4 weeks emerged at follow-up with respect to baseline for: daily activities limitations (Delta -16%), frequent diurnal symptoms (Delta -25%), uncontrolled asthma symptoms according to ACT (Delta -26%). Last 12-month use of oral corticosteroids was less frequent at follow-up than at baseline (Delta -25%). Health status improvement was confirmed by lung function test results. Through LTA, two longitudinal patterns were detected considering last 12-month control outcomes: "persistence/worsening" (53.9%), "under control/improvement" (46.1%). A lower likelihood of having "persistence/ worsening" SUA was exhibited by patients under anti-IgE (OR 0.38, 95% CI 0.17-0.84) and inhaled corticosteroids-bronchodilator association treatment (OR 0.13, 95% CI 0.01-1.26, borderline value), while a higher likelihood was shown by older age at first asthma diagnosis (OR 1.04, 95% CI 1.01-1.07). Conclusion: the implementation of a SUA registry, the availability of patient-level data and the application of an innovative longitudinal analysis allowed to observe a general improvement in asthma control, one year after baseline, and a lower risk of SUA "persistence/worsening" in patients under anti-IgE and regular ICS-bronchodilator association use.

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 reallife. Methods: We retrospectively analyzed 134 severe asthmatics (61 males; mean age 58.3 +/- 11; mean FEV1%:72 +/- 21), treated with MEP for at least 6 months (mean duration:10.9 +/- 3.7 months). Results: FEV1% improved significantly after MEP. Mean FEF25-75 also increased from 37.4 +/- 25.4% to 47.2 +/- 27.2% (p < 0.0001). Mean baseline blood eosinophil level was 712 +/- 731/mu L (8.4 +/- 5.2%) decreasing to 151 +/- 384/mu L (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.

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: 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 beta(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.

Background: Both inflammatory and remodelling processes are associated with irreversible airway obstruction observed in severe asthma. Our aim was to characterize a group of severe asthmatic patients with or without persistent airway obstruction in relation to specific sputum inflammatory and remodelling biomarkers. Methods: Forty-five patients under regular high-dose inhaled corticosteroid/beta-2agonist treatment were studied, after a follow-up period of at least 2 years, with a minimum of 4 visits. Periostin, TGF-beta, RANTES, IL-8, GM-CSF, FGF-2, and cell counts were measured in induced sputum. Serum periostin was also measured. Results: Sputum induction was successfully performed in all but 5 patients. There were no significant differences in demographic and clinical data between patients with non-persistent obstruction (NO: FEV1/VC>88%pred.) and those with persistent obstruction (0: a not completely reversible obstruction with FEV1/VC<88%pred. at each visit before the study visit). Patients with persistent obstruction had significantly higher sputum periostin and TGF-beta concentrations than NO patients and a trend of higher serum periostin levels. GM-CSF and FGF-2 were significantly increased in NO compared to 0 patients. No differences between groups were found for RANTES, IL-8 and differential cell counts. Sputum periostin inversely correlated with functional parameters (prebronch. FEV1: rho = 0.36, p < 0.05; postbronch. FEV1: rho = 0.33, p = 0.05). Patients with high sputum periostin concentration (>103.3 pg/ml: median value) showed an absolute number of sputum eosinophils significantly higher than patients with low sputum periostin; this behavior was unobserved when serum periostin was considered. Conclusions: Only periostin and TGF-I3 identified a subgroup of severe asthmatic patients with persistent airway obstruction. Sputum periostin was also inversely associated with FEVi and proved to be a more sensitive biomarker than serum periostin to identify severe asthmatics with higher sputum eosinophilia.

Eosinophilic inflammation represents the pathophysiologic background of severe asthma in the majority of these patients. The best tool for assessing eosinophilic inflammation in severe asthma (blood or sputum eosinophils, Fractional exhaled Nitric Oxide [FeNO]) is still poorly defined, as well as whether these biomarkers are associated with different clinical severity features. 77 patients with severe asthma, after a long follow-up in order to optimize treatment, underwent blood/induced-sputum eosinophils and FeNO measurements. Patients were in a stable phase and under treatment with high dose ICS-LABA combination frequently associated with other controllers. In a multivariate/univariate analysis, risk factors for the greater number of exacerbations observed in the previous year were tested. Blood, sputum and exhaled air biomarkers were associated with at least one exacerbation. Instead, patients with exacerbations>3 in the previous year were associated with sputum eosinophils>50% but not with blood eosinophils or FeNO levels. In conclusion, blood eosinophils and FeNO levels may select severe asthmatics with>1 exacerbations in the previous year, while high sputum eosinophilia only seems to select patients with frequent exacerbations.

Nasal polyposis (NS) is one of the most impacting comorbidity on severe asthma (SA) control. A biological targeted therapy for SA might consider NP response. We evaluated in a large cohort of SA patients the main features related to NP severity aiming to achieve the best therapeutic choice. We enrolled 100 patients with SA. We recorded clinical and demographic data, particularly atopic features (skin prick test positivity, specific serum IgE, aspirin intolerance). Patients received a complete upper and lower airway evaluation, including nasal endoscopy, induced sputum and cytological analysis of nasal smear. NP was graded according to the HOX endoscopy score. Sino-Nasal Outcome Test (SNOT), ACT Score and the Short Form (SF)-36 were used. Sputum eosinophils were significantly related to NP, while atopic features were not. Sputum and blood eosinophils were related. ACT was related to blood eosinophilia and FEV1. Eosinophilia in nasal smear was significantly related to NP and HOX endoscopy score. SNOT was related to SF36 questionnaire. In conclusion, NP has a major impact on nasal and sputum eosinophilia, while it is not related to atopic features. These findings might help achieve the best biological treatment choice for SA patients.

BACKGROUND:Eosinophilic granulomatosis with polyangiitis (EGPA) is a necrotizing vasculitis that predominantly affects small- to medium-sized vessels. It is characterized by a wide spectrum of extrapulmonary symptoms, including sinonasal and paranasal sinus abnormalities. These are the most common features of this disease, constituting diagnostic criteria for EGPA. However, the actual clinical features, cellular mechanisms and impact on patients' quality of life (QoL) are still a matter of study.METHODS:Thirty-nine EGPA patients underwent multidimensional rhinological evaluations, including rhinofibroscopy, nasal cytology, and QoL questionnaires. This was coupled with respiratory and rheumatological assessments.RESULTS:Twenty-eight patients were diagnosed with chronic rhinosinusitis (CRS). Of these, 18 had nasal polyposis (NP). Chronic rhinitis was diagnosed in 10 patients. Of these, 3 had allergic rhinitis (AR) and seven had non-AR (NAR). Overall, only 1 patient (2.6%) was normal. Nasal cytology showed that hypereosinophilia was present in 17/28 patients with CRS, 4/7 patients with NAR and all patients with AR. SNOT-22 and SF-36 showed a severe impact of nasal symptoms on QoL. No differences in asthma control or rheumatological patterns for EGPA were observed among patients with or without NP.CONCLUSIONS:Even when the rheumatological assessment scored EGPA "under control" according to the Birmingham Vasculitis Activity Score and Vasculitis Damage Index, sinonasal diseases and related nasal inflammatory processes were not controlled. Therefore, there is a need for clinical monitoring and targeted treatment to control the inflammatory processes and improve the QoL of EGPA patients.

Nasal cytology is a precious tool to study nasal disorders, but in current literature, there is no consensus on the standardization of the processing procedure of the obtained samples. Therefore, we decided to test on specimens obtained by nasal scraping, a common way of nasal specimen sampling, two different processing techniques, smear and cytocentrifugation, and compare them in terms of inflammatory cell content, quality of slides, and validity on clinical assessment. We analyzed 105 patients with suspected sinonasal diseases, and in each patient, we performed nasal cytology with both techniques. Our analysis showed a good correlation between the two techniques for neutrophil and eosinophil percentages, both returned well-preserved cells, and showed higher neutrophil percentage in males and in smokers and higher eosinophil percentage in patients with polyposis, with a good concordance with clinical symptoms, as measured by a specific disease-related questionnaire (Sino-Nasal Outcome Test-22). Technically speaking, smeared slides were easier to prepare, with no need of dedicated equipment, but cell distribution was better in cytocentrifuged slides allowing shorter reading time. In conclusion, both techniques can be considered superimposable and worthy to be used.

According to ATS/ERS document on severe asthma (SA), the management of these patients requires the identification and proper treatment of comorbidities, which can influence the control of asthma.

Proceedings of the European Seminars in Respiratory Medicine course, Inhalation therapy in the next decade: Determinants of adherence to treatment in asthma and COPD, held in Taormina, Italy, on 3-4 March, 2017.

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.

Severe hypereosinophilic asthma (SEA) is the prodromal phase of EGPA, nevertheless there are no studies trying to recognize EGPA when the eosinophilic inflammation is still confined to upper and lower airway. Aims: To identify a panel of biological, clinical and functional markers to detect which severe asthmatic patient might be considered in a prodromal phase of EGPA. Methods: 30 patients with EGPA and 49 with SEA who do not fulfilled the diagnostic criteria of EGPA were enrolled. All patients underwent to a pulmonary and ENT visit. EGPA patients received rheumatologic assessment. Lung function and methacholine test were performed. Blood biomarkers were assessed: eosinophils, eosinophilic cationic protein, interleukins: IL5-IL4, IGE, IgG4, ANCA and sputum biomarkers: eosinophils, periostin, IL8, GMCSF. The ACT test, short form (SF)-36, SinoNasal Outcome Test and the Asthma Quality of Life Questionnaire were used. Results: No differences were observed between SEA and EGPA patients in lung function but SEA patients had a worst asthma control (p<0.001).Patients with SEA presented higher level of sputum eosinophils (p<0.002) while EGPA patients had had higher level of blood eosinophils in the past. The GMCSF was the only biomarker significantly increased in EGPA patients compared with SEA; in a post-hoc analysis, SEA patients with some features of diagnostic criteria of EGPA presented significantly higher level of sputum GMCSF (p<0.000). IgG4 was abnormally increased in one SEA patient positive for ANCA but without systemic manifestation. Conclusion: Sputum GMCSF might be a good biomarker of systemic eosinophilic disease; ANCA and IgG4, considered togheter, may support the suspicious of EGPA in SEA.

AIMTo find some simple clinical factors which can predict the quality of the sputum samples obtained in a large group of asthmatic subjects.METHODSWe compared the presence of sputum productive cough in the days preceding the test, easiness in expectoration during the test, and sputum macroscopic aspect (presence of visible plugs) with the quality of slides obtained from sputum processing. We also monitored changes in the quality in patients who repeated sputum collection several times, comparing those whose first sample was adequate with those whose first sample was inadequate. We analysed 547 sputum samples obtained from 238 asthmatic patients. Sputum was processed using the whole sample method.RESULTSPatients with productive cough in the days preceding the test and easy expectoration during the test produced a higher percentage of adequate samples than those without productive cough (86% vs 76 %, p=0.01) and with difficulty in expectoration (85% vs 63%, p=0.0001). "Good" macroscopic samples were associated with better quality of slides (91% vs 38%, p=0.0001). Patients with inadequate first sample (n=40) had a higher percentage of inadequate samples (55%) in the subsequent tests than patients (n=115) with adequate first sample (8%).CONCLUSIONSPatients with increased airway secretions in the days preceding the test, easy expectoration and "good" macroscopic aspect of the sputum are more likely to produce sputum sample adequate for inflammatory cell analysis. If the first sputum sample is adequate, subsequent samples are very likely to be adequate as well. If the first sputum sample is inadequate, the quality of subsequent samples cannot be predicted, since there are similar probabilities of having adequate or inadequate samples.

In a group of 157 bronchiectasis, a subgroup of 25 asthmatics was identified. A panel of asthma characteristcs included clinical history, risk factors for asthma, functional data (repeated posivitity to reversibility test and/or methacholine test). All subjects were evaluated into a protocol for bronchiectasis involving imaging analysys as BSI, a search of bacteria in the airway, spirometric evaluations, measurements of airway inflammation indices (induced sputum and FeNO). The 25 subjects with asthma were not different from the other group for age, sex, smoke habit, having mean age 58.8 (SD 16.9), 20 females, and 16 never smoking. Moreover, they were not different also for airway presence of bacteria, and for the main clinical symptoms, aas cough, dyspnoea, recurrent excerbations. The two groups did not show significant difference for BSI, and FEV1 baseline. In the subgroup of bronchiectasis with asthma, we found a higher number of subjects with a positive reversibility test than in bronchiectasis without asthma, 11 out of 25 with respect to 15 out of 112 (chi squared 15.2, p<0.0001). Subjects with asthma showed higher percentage of Eosinophils in the induced sputum, mean and range 14.4% (25.9) vs 2.6% (5.5), p<0.0001. On the other hand, Sputum Neutrophils were lower in asthmatics than in Bronchiectasis without asthma, 54.0% (31.3) vs 72.6% (25.1), p=0.005. Finally, NO measures were significantly higher in bronchiectasi with asthma, 35.7 ppb (41.7) vs 20.9 ppb (17.3), p=0.02. In conclusion, in bronchiectasis a subgroup with concomitant asthma may be identify, and subjects could be well treated.

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. (C) 2016 American Academy of Allergy, Asthma & Immunology