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Introduction Obsessive-compulsive disorder (OCD) is a prevalent and disabling condition characterized by a wide variety of phenotypic expressions. Several studies have reinforced the hypothesis of OCD heterogeneity by proposing subtypes based on predominant symptomatology (Mataix-Cols et al., 2005), course (Tukel et al., 2007), and comorbidities (Mahasuar et al., 2011). Early-onset OCD could be considered a neurodevelopmental subtype of OCD, with evidence of distinct neurocircuits supporting disease progression (Park et al., 2022). Objectives The aim of the present study is to evaluate the sociodemographic and clinical differences between the early-onset and late-onset subtypes in a large patient cohort. Methods Two hundred and eighty patients diagnosed with OCD were consecutively recruited from the OCD Tertiary Clinic at Luigi Sacco University Hospital in Milan. Sociodemographic and clinical variables were analyzed for the entire sample and compared between the two subgroups (EO: early-onset, age

Introduction Antipsychotic (AP) are increasingly prescribed off-label and used as, but not limited to, anti-aggressive, anti-impulsive, and anti-suicidal medication. The use of second-generation AP (SGAs) has progressively increased compared to first-generation AP (FGAs). FGAs cause more extrapyramidal motor side effects and tardive dyskinesia than SGAs, whereas SGAs generally cause more weight gain and cardiometabolic adverse effects. Objectives Aim of this observational study was to describe the socio-demographic and clinical features of the patients receiving new AP treatment and the features of the pharmacological treatment itself in “real world” context. Furthermore, we aimed to compare socio-demographic and clinical characteristics of the subjects who were prescribed either FGAs or SGAs. Methods Data were collected on the latest new AP prescriptions issued across different settings (two psychiatric wards; five outpatients clinics; and one rehabilitation community) belonging to ASST Fatebenefratelli Sacco (located in Milan) in reverse chronological order from May 2023. Socio-demographic and clinical variables of the subjects who received new AP treatment were collected through medical records. We compared age, age at onset, age at first pharmacological treatment, duration of illness, duration of untreated illness, treatment duration, number of hospitalization and admissions to Day Hospital services, involuntary commitments and suicidal attempts in patients who received either FGAs or SGAs. Chi-square was used for qualitative variables and t-test for quantitative variables. Data were collected anonymously and analyzed using SPSS v.27. Results The sample included 155 new AP prescriptions, out of which 29.2% were formulated in the psychiatric wards, 66.9% in the outpatient clinics e 3.9% in the rehabilitative community. Mean age of the subjects was 41.1 ± 16.9 years, 53.2% were male. The most represented diagnoses were psychotic disorders (32.2%), personality disorders (24.8%), bipolar disorder (16.1%) and depressive disorder (12.8%). 90.7% of new AP prescriptions were SGAs. The most prescribed were aripiprazole (30.5%), quetiapine (21.2%) and olanzapine (15.2%); while the most prescribed FGAs were haloperidol (5.3%), zuclopenthixol (2%) and chlorpromazine (1.3%). 26.2% of the prescriptions were in monotherapy and 83.8% were for oral administration. The reasons for introduction were partial or absent response to previous treatments (52.3%), disease onset (23.5%), non-compliance (8.3%), adverse effects to previous treatments (6.8%) or other (9.1%). Patients treated with FGA had a longer duration of untreated illness (p

Introduction Sex hormone binding globulin (SHBG) levels are reported to be inversely associated with diabetes risk. It is unknown whether diabetes prevention interventions increase SHBG and whether resultant changes in SHBG affect diabetes risk. The purpose of this analysis was to determine whether intensive lifestyle intervention (ILS) or metformin changed circulating SHBG and if resultant changes influenced diabetes risk in the Diabetes Prevention Program (DPP).Research design and methods This is a secondary analysis from the DPP (1996–2001), a randomized trial of ILS or metformin versus placebo on diabetes risk over a mean follow-up of 3.2 years. The DPP was conducted across 27 academic study centers in the USA. Men, premenopausal and postmenopausal women without hormone use in the DPP were evaluated. The DPP included overweight/obese persons with elevated fasting glucose and impaired glucose tolerance. Main outcomes measures were changes in SHBG levels at 1 year and risk of diabetes over 3 years.Results ILS resulted in significantly higher increases (postmenopausal women: p

Asthma often remains uncontrolled, despite the fact that the pharmacological treatment has undergone large changes. We studied changes in the treatment of asthma over a 20-year period and identified factors associated with the regular use of inhaled corticosteroid (ICS) treatment. Changes in the use of medication were determined in 4617 randomly selected subjects, while changes in adults with persistent asthma were analysed in 369 participants. The study compares data from three surveys in 24 centres in 11 countries. The use of ICSs increased from 1.7% to 5.9% in the general population and the regular use of ICSs increased from 19% to 34% among persistent asthmatic subjects. The proportion of asthmatic subjects reporting asthma attacks in the last 12 months decreased, while the proportion that had seen a doctor in the last 12 months remained unchanged (42%). Subjects with asthma who had experienced attacks or had seen a doctor were more likely to use ICSs on a regular basis. Although ICS use has increased, only one-third of subjects with persistent asthma take ICSs on a regular basis. Less than half had seen a doctor during the last year. This indicates that underuse of ICSs and lack of regular healthcare contacts remains a problem in the management of asthma.

Introduction: Asthma, along with inhaled steroids, was initially considered a risk factor for worse clinical outcomes in COVID-19. This was related to the higher morbidity observed in asthma patients during previous viral outbreaks. This retrospective study aimed at evaluating the prevalence of asthma among patients admitted due to SARS-CoV-2 infection as well as the impact of inhaled therapies on their outcomes. Furthermore, a comparison between patients with asthma, COPD and the general population was made. Methods: All COVID-19 inpatients were recruited between February and July 2020 from four large hospitals in Northwest Italy. Data concerning medical history, the Charlson Comorbidity Index (CCI) and the hospital stay, including length, drugs and COVID-19 complications (respiratory failure, lung involvement, and the need for respiratory support) were collected, as well as the type of discharge. Results: patients with asthma required high-flow oxygen therapy (33.3 vs. 14.3%, p = 0.001) and invasive mechanical ventilation (17.9 vs. 9.5%, p = 0.048) more frequently when compared to the general population, but no other difference was observed. Moreover, asthma patients were generally younger than patients with COPD (59.2 vs. 76.8 years, p < 0.001), they showed both a lower mortality rate (15.4 vs. 39.4%, p < 0.001) and a lower CCI (3.4 vs. 6.2, p < 0.001). Patients with asthma in regular therapy with ICS at home had significantly shorter hospital stay compared to those with no treatments (25.2 vs. 11.3 days, p = 0.024). Discussion: Our study showed that asthma is not associated with worse outcomes of COVID-19, despite the higher need for respiratory support compared with the general population, while the use of ICS allowed for a shorter hospital stay. In addition, the comparison of asthma with COPD patients confirmed the greater frailty of the latter, according to their multiple comorbidities.

Introduction: Biologic drugs have dramatically improved severe eosinophilic asthma (SEA) outcomes. Our aim was to evaluate the long-term efficacy of biological therapy in SEA in a real-life setting and to identify the predictors for switching to another biological drug in patients with poor asthma control. The outcomes for efficacy were decreased annual exacerbations (AE) and improved asthma control test (ACT)., Methods: In 90 SEA patients being treated with a biological drug, clinical examination, ACT, blood eosinophils count and spirometry were assessed before (T0) and after 6 (T1), 12 (T2), 24 (T3) and 36 (T4) months from the start of biological therapy. Patients were considered responders (R) or non-responders (NR) to biologics depending on whether or not they had less than two AE and a 20% increase in the ACT after 12 months of treatment., Results: 75% of the patients were R, 25% NR. In R patients, biological therapy add-on was followed by significant improvement in AE and ACT throughout the whole follow-up period. The percentage of patients on oral corticosteroids (OCS) dropped from 40% to 12%. By contrast, the NR patients were shifted to another biological drug after 12 months of therapy, as they still had high AE and nearly unchanged ACT; 40% of them still needed OCS treatment. The predictors of switching to another biological drug were three or more AE, ACT below 17, nasal polyposis and former smoking ( p < 0.05). In NR, the shift to another biological drug was followed by a significant decrease in AE and an increase in the ACT., Discussion: This real-life study confirms the long-term efficacy of biologics in most SEA patients and indicates that even in non-responders to a first biological drug, it is worth trying a second one. It is hoped that the availability of additional biologics with different targets will help improve the personalization of SEA therapy.

Introduction: Lung cancer is the second most frequent malignancy worldwide, but its aetiology is still unclear. Inflammatory cytokines and Th cells, including Th17, are now emerging as being involved in NSCLC pathways, thus postulating a role of IL-17 in tumour angiogenesis by stimulating the vascular endothelial growth factor and the release of nitric oxide. Despite the fact that many biomarkers are used for chest malignancy diagnosis, data on FeNO levels and inflammatory cytokines in NSCLC are still few. Our study aimed to evaluate the relationship between pulmonary nitric oxide production and VEGF and Th17-related cytokines in the EBC of patients affected by early-stage NSCLC., Methods: FeNO measurement and lung function tests were performed in both patients affected by NCSLC and controls; EBC samples were also taken, and Th1 (IL-1, IL-6, IL-12, IFN-g, TNF-a), Th17 (IL-17, IL-23) and Th2 (IL-4, IL-5, IL-13) related cytokines were measured., Results: Th1 and Th17-related cytokines in EBC, except for IFN-gamma and TNF-alpha, were significantly higher in patients than in healthy controls, whereas no differences were seen for Th2-related cytokines. FeNO at the flow rate of 50 mL/s, JawNO and CalvNO levels were significantly higher in patients affected by NSCLC compared to controls. Significant correlations were found between FeNO 50 mL/s and IL-17, IL-1 and VEGF. JawNO levels positively correlated with IL-6, IL-17 and VEGF. No correlations were found between FeNO and Th2-related cytokines., Conclusion: This is the first report assessing a relationship between FeNO levels and Th17-related cytokines in the EBC of patients affected by early-stage NSCLC. IL-17, which could promote angiogenesis through the VEGF pathway, might be indirectly responsible for the increased lung production of NO in patients with NSCLC.

Background and Aims: Severe asthma is burdened by frequent exacerbations and use of oral corticosteroids (OCS) which worsen patients' health and increase healthcare spending. Aim of this study was to assess the clinical and economic effect of adding mepolizumab (MEP) for the treatment of these patients., Methods: Patients >18 years old, referred to 8 asthma clinics, starting MEP between May 2017 and December 2018, were enrolled and followed-up for 12 months. Information in the 12 months before mepolizumab were collected retrospectively. The evaluation parameters included: OCS use, number of exacerbations/hospitalizations, concomitant therapies, comorbidity, and annual number of working days lost due to the disease. The primary objective was to compare the annual total cost per patient pre- and post-MEP. Secondary outcomes included rates of exacerbations and number of OCS-dependent patients., Results: 106 patients were enrolled in the study: 46 male, median age 58 years. Mean annual cost pre- and post-MEP (cost of biologic excluded) was €3996 and €1,527, respectively. Total savings due to MEP resulted in €2469 (95%CI 1945-2993), 62% due to exacerbations reduction and 33% due to productivity increase. Such savings could fund about 22% of the total cost of MEP for one year. The introduction of MEP induced a clinical benefit by reducing both OCS-dependent patients (OR = 0.12, 95%CI 0.06-0.23) and exacerbation rate (RR = 0.19, 95%CI 0.15-0.24)., Conclusions: Patients with severe eosinophilic asthma experienced a clinical benefit in asthma control adding MEP to standard therapy. Biologic therapy can be, partially, funded by the savings produced by patients' improvement., (© 2021 The Authors.)

According to the data derived from several national and international registries, including SANI (Severe Asthma Network Italy), and considering the strong impact that frequent or regular use of oral corticosteroid has on quality of life (QoL) of severe asthmatics, as well as on the costs for managing corticosteroid-related diseases, oral corticosteroid sparing up to withdrawal should be considered a primary outcome in the management of severe asthma. New biologics have clearly demonstrated that this effect is possible, with concomitant reduction in the rate of exacerbations and in symptom control. Then, there is no reason for using so frequently oral corticosteroid before having explored all alternatives currently available for a large part of severe asthmatics., Competing Interests: GW Canonica received in the last three years research grants as well as lecture or advisory board fees from: A. Menarini, Alk-Abello, Allergy Therapeutics, AstraZeneca, Boehringer-Ingelheim, Chiesi Farmaceutici, Genentech, Guidotti-Malesci, Glaxo Smith Kline, Hal Allergy, Mylan, Merck, Mundipharma, Novartis, Regeneron, Sanofi-Aventis, Sanofi-Genzyme, StallergenesGreer, UCB pharma, Uriach Pharma, Valeas, ViborPharma. F Blasi received grants and/or personal fees from: AstraZeneca, Bayer, Chiesi, Guidotti, Glaxo Smith Kline, Grifols, Insmed, Menarini, Mundifarma, Novartis, Pfizer, Zambon. PL Paggiaro received grants and/or personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, Guidotti, Mundipharma, Novartis, Sanofi. S Aliberti received grants and/or personal fees from Actavis UK Ltd, Aradigm Corporation, AstraZeneca, Basilea, Bayer Healthcare, Chiesi, Grifols, Horizon, INSMED, Novartis, Raptor, Zambon. L Cosmi received personal fees from Glaxo Smith Kline and Novartis. S Centanni received grants and/or personal fees from AstraZeneca, Boheringer Ingelheim, Chiesi, Glaxo Smith Kline, Guidotti, Menarini, Novartis, Valeas. ME Conte received personal fees from Glaxo Smith Kline. S D’Alò received fees for clinical trials from Glaxo Smith Kline. S Del Giacco received grants and/or personal fees from AstraZeneca, Chiesi, Glaxo Smith Kline, Menarini. Novartis. F Puggioni received personal fees from Allergy therapeutics, Almirall, AstraZeneca, Chiesi, Glaxo Smith Kline, Guidotti, Menarini, Mundipharma, Novartis, Sanofi, Valeas. FLM Ricciardolo received grants, personal fees and/or other supports from AstraZeneca, Boehringer Ingelheim, Chiesi, Glaxo Smith Kline, Guidotti, Lusofarmaco, Menarini, Neopharmed, Novartis, Sanofi, Teva. L Richeldi received personal fees from Bayer, Boehringer Ingelheim, Celgene, FibroGen, Promedior, RespiVant, Roche, Sanofi-Aventis. P Santus received grants and/or personal fees from ALK Abellò, AstraZeneca, Berlin Chemie, Boheringer Ingheleim, Menarini International, Novartis, Sanofi, Valeas, Zambon. E Heffler received personal fees from AstraZeneca, Boheringer Ingheleim, Circassia, Glaxo Smith Kline, Nestlè Purina, Novartis, Sanofi, Teva, Valeas. GE Senna, G Passalacqua, A Spanevello, D Bagnasco, M Bonavia, M Bonini, L Brussino, C Bucca, MF Caiaffa, C Calabresi, G Camiciottoli, M Caminati, GE Carpagnano, C Caruso, AG Corsico, MT Costantino, N Crimi, M D'Amato, A Farsi, E Favero, MP Foschino Barbato, G Guarneri, G Guida, M Latorre, S Lo Cicero, C Lombardi, L Macchia, F Mazza, F Menzella, M Milanese, M Montagni, P Montuschi, E Nucera, R Parente, V Patella, G Pelaia, L Pini, L Ricciardi, E Ridolo, G Rolla, N Scichilone, G Spadaro, A Vianello, V Viviano, MR Yacoub, MC Zappa have nothing to disclose., (© 2020 The Authors.)

Background: Systemic sclerosis (SSc) is a connective tissue disorder which key feature is a fibrotic process. The role of Endothelin-1 (ET-1) and T-helper (Th)-1 cells in lung and skin fibrosis is well known, although Th17- and Treg-cells were found to be involved. However, no studies analyzed cytokines expression in gastric-juice of SSc patients. Our study aimed to evaluate proinflammatory and profibrotic cytokines in gastric-juice of SSc patients and to investigate their correlations with esophageal dysmotility., Methods: Patients performed upper-gastrointestinal-endoscopy with gastric-juice collection, esophageal manometry and thoracic CT-scan. GM-CSF, ET-1, Th-1 (IFN-γ, IL-1β, TNF-α, IL-2, IL-6, IL-9), Th-17 (IL-17, IL-21, IL-22, IL-23) and T-reg (IL-10, TGF-β) related cytokines were measured in 29 SSc-patients and 20 healthy-controls., Results: Patients showed significant lower levels of IL-6, IL-17, IL-22 and ET-1 ( p < 0.005) compared with controls. Patients with atrophic gastritis presented significant lower levels of IL-2, IL-9, IL-6, TGF-β, GM-CSF, IL-17 and ET-1 ( p < 0.005) compared to patients without gastritis. Increased values of IL-2, IL-9, IL-1β, IL-17, ET-1 and GM-CSF ( p < 0.005) were observed in patients with esophageal impairment. This is the first report of cytokines measurement in gastric juice of patients with SSc. The high IL-17 concentrations in gastric-juice of scleroderma patients with esophageal dysmotility support the signature of Th-17 cells in scleroderma esophageal fibrosis.

Background: Adherence to therapy is crucial for COPD patients, since non-adherence leads to worse quality of life, increased health-care expenditure and poor clinical outcome. The aim of this study was to identify the main determinants of suboptimal adherence to therapy in a cohort of COPD patients., Methods: General information (age, BMI, smoking, comorbidities, education, life style), lung function, exacerbations, symptoms and COPD treatment were collected. Adherence to therapy was assessed by self-reported 4-item Morisky Medication Adherence Scale (MMAS-4), and was related to anthropometric, socio/economic and health status data, obtained by questionnaires (COPD Assessment Test, CAT; Treatment Satisfaction Questionnaire, HRQoL; Katz Index of Independence of Daily Living Activities, Lawton Instrumental Activities of Daily Living Scale)., Results: 136 COPD patients were studied (age 72±8 yrs; 73.5% men; BMI 28.5±7.4 kg/m 2 ; FEV 1 53.5±19.0 % predicted). Nearly half of the patients (46.3%) had suboptimal adherence to therapy (score >0) and, as compared to those with optimal adherence, had higher prevalence of women and coronary artery disease, heavier smoking history and worse CCQ overall score. The results of multivariate analysis showed that the determinants of suboptimal adherence were female sex (OR 4.339, 95%CI 1.509-12.474, p =0.006), amount of pack/years smoked (OR 1.947, 95%CI 1.141-3.323, p =0.015), higher CCQ overall score (OR 3.318, 95%CI 1.050-9.892, p =0.049) and higher education (OR 2.758, 95%CI 1.083-7.022, p =0.033). Adherence was better in patients assuming triple inhaler therapy., Conclusions: Suboptimal adherence is frequent among COPD patients, particularly in women, heavy smokers and subjects with high educational level. Interventions to improve adherence should be especially addressed to patients with these characteristics., Competing Interests: Conflict of interest: All the authors declare no financial/personal interest or belief that could affect their objectivity., (©Copyright: the Author(s).)

Background : Pulmonary hypertension (PH) is a progressive disorder of the pulmonary circulation, associated with diverse medical conditions. Exercise limitation is the most prominent symptom in PH. Exercise capacity, commonly assessed through a six-minute walk test (6MWT), correlates with both functional status and survival in PH. Few studies have analysed the relation between respiratory function and exercise limitation. Therefore, we investigated the relationship between resting pulmonary function, exercise capacity, and exertional desaturation, assessed through the 6MWT, in unselected PH patients. Methods : Fifty consecutive patients with PH diagnosis, referred for pulmonary function testing (lung volume, spirometry, and diffusing capacity for carbon monoxide (DLCO)) and 6MWT, were recruited at Molinette University Hospital, Turin. Results : The majority of the patients (54%) had PH due to left heart disease. Airway obstruction (FEV 1 /VC-ratio < 0.7) was found in 46% of the patients and they performed significantly worse in the 6MWT than unobstructed patients (307 m vs. 377 m). Patients with PH due to left heart disease also performed significantly poorer 6MWT when airway obstruction was present (305 m vs. 389 m). Twenty-two patients (44%) presented exertional desaturation upon 6MWT. Lower DLCO divided by the alveolar volume (DLCO/VA), FEV 1 /VC-ratios and resting PaO 2 -values were significantly correlated with exertional desaturation after adjustments for age, sex, BMI, and smoking habits. DLCO/VA was the main determinant of exertional desaturation in a stepwise regression model. Conclusions : Spirometric parameters of airway obstruction were related to walk distance and exercise-induced desaturation in PH patients. This suggests a place for spirometry in clinical monitoring of PH patients., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

The earliest clinical manifestation of SSc is usually Raynaud's phenomenon, a small-arteries vasospasm driven by vascular tone dysregulation and microcirculatory abnormalities, resulting in digital ulcers (DU) in up to 50% of patients. Many cytokines as well as growth factors have been shown to play a role in promoting vascular smooth muscle cell proliferation and fibroblast activation, leading to ischemic damage as well as skin fibrosis. We aim to investigate a possible difference in venous and arterial blood levels of many cytokines (Th1- and Th17-related), GM-CSF, and endothelin-1 (ET1) in patients with and without DU. In the same patients, the correlations between capillary damage, evaluated by nailfold videocapillaroscopy (NVC), extension of skin fibrosis, calculated by modified Rodnan skin score (mRSS), and cytokines, ET-1, and GM-CSF levels were also measured. Patients with DU showed venous levels of IL-1 β ( p =0.024), IL-6 ( p =0.012), IL-22( p =0.006), and TGF- β ( p =0.046) significantly higher compared to arterial levels and arterial levels of GM-CSF and TNF-alpha significantly higher compared to venous levels ( p < 0.001). NVC abnormalities were correlated with arterial TNFa and venous IL22, IL23, and IL17 levels and negatively correlated with venous ET-1 levels, whereas mRSS showed a negative correlation with IL-21( ρ  = -0.427, p =0.050). The increased Th17-cytokine levels in venous compared to arterial blood of patients with DU suggest local cytokine production on ulcer site. The higher TNFa and GM-CSF levels in arterial blood of DU patients support the attempt to mitigate the hypoxic damage, and the correlation between Th17-cytokines, mRSS, NVC, and ET1 agrees with the potent profibrotic stimulus at the onset of the disease, which decreases as the SSc progresses., Competing Interests: Nicola S., Fornero M., Fusaro E., Peroni C., Priora M., Rolla G., Bucca C. and Brussino L. declare that they have no conflicts of interest., (Copyright © 2019 S. Nicola et al.)

Background: Asthma is one of the most common non-communicable respiratory diseases, affecting about 6% of the general population. Severe asthma, even if afflicts a minority of asthmatics, drives the majority of costs of the disease. The aim of this study is to create a pharmacoeconomic model to predict the costs of corticosteroid-related adverse events in severe asthmatics and applying it to the first published epidemiologic data from the Severe Asthma Network in Italy (SANI) registry., Methods: The analysis was conducted from the perspective of the Italian National Healthcare System (INHS). Model inputs, derived from literature, included: asthma epidemiology data, frequency of adverse events, percentage of severe asthma treated with OCS and adverse event cost (Diagnosis-Related Group (DRG) national tariffs). We estimated costs per different patient groups: non-asthma controls, mild/moderate and severe asthmatics. Final results report estimated direct cost per patient and total direct cost for overall target population, showing economic impact related to corticosteroid complication., Results: Based on epidemiological data input, in Italy, asthmatic subjects resulted about 3,999,600, of which 199,980 with severe asthma. The number of patients with severe asthma OCS-treated was estimated at 123,988. Compared to the non-asthma control cohort and to that with moderate asthma annual cost per severe asthmatic patient resulted respectively about €892 and €606 higher, showing a corticosteroids shadow cost ranging from 45% to 30%.Applying the cost per patient to the target population identified for Italy, the budget impact model estimated a total annual cost related to OCS-related adverse events of €242.7 million for severe asthmatics. In respect with non-asthmatic and moderate population, an incremental expenditure of about € 110.6 million and €75.2, respectively, were shown., Conclusions: Our study provides the first estimates of additional healthcare costs related to corticosteroid induced adverse events in severe asthma patient. Budget impact model results highlighted the relevant economic impact of OCS-related adverse events in severe asthma patients. The future extrapolation of additional data from SANI registry will support the development of a model to investigate the role of corticosteroids sparing drugs.

Background: Omalizumab may modulate airway remodeling in severe asthma. Using forced expiratory volume in 1 second (FEV 1 ) as a surrogate of airway remodeling, we aimed to investigate if an omalizumab add-on in severe allergic asthma may lead to a persistent reversal of airway obstruction and to evaluate the potential biomarkers of airway obstruction reversibility., Methods: Data were collected before (T0) and after omalizumab add-on for 1 year (T1, 32 patients), 2 years (T2, 26 patients) and 4 years (T4, 13 patients). All patients had baseline FEV 1 below 80 % predicted (60.5 ± 12.5 %). After omalizumab, 18 patients showed FEV 1 normalization (reversible airway obstruction; RAO+) already at T1 (88.7 ± 14.9 %, p < 0.0001) that persisted up to T4 (83.2 ± 7.9, p < 0.01), while 14 patients (RAO-) had FEV 1 persistently decreased, from T1 (65.2 ± 8.4%, p < 0.05) up to T4 (61.4 ± 6.2%, not significant). Both groups had significant improvement of symptoms and exacerbations after omalizumab at T1, which persisted up to T4. The comparison between pretreatment characteristics of the two groups showed that RAO+ patients, had higher values of circulating eosinophils, exhaled nitric oxide (F E NO), prevalence of rhinitis and nasal polyps, need of oral corticosteroids, shorter asthma duration, higher FEV 1 and response to albuterol test. The optimal cut-off points predicting FEV 1 normalization after omalizumab add-on were 30.5 ppb for F E NO and 305 cells/µl for eosinophils., Conclusions: This study suggests that omalizumab add-on contributes to the persistent reversal of airway obstruction in a consistent number of patients with severe allergic asthma, and this beneficial effect is predicted by elevated pretreatment F E NO and circulating eosinophils.

Background: The severe forms of asthma represent a major burden, because of severity of symptoms, costs and impact on everyday life. Recently, Mepolizumab (MEP) was approved and marketed for the treatment of hypereosinophilic severe asthma. This anti-IL-5 monoclonal antibody reduced exacerbation rates and oral corticosteroid (OCS) use in well selected patients. The aim of this study was to evaluate the characteristics of patients receiving MEP in a real-life setting. Thus, we describe a retrospective analysis of patients treated with MEP in six centres in North Western Italy, including those who participated in the main regulatory trials., Methods: The baseline data, before prescription, from six North Western Italy severe asthma clinics, between June 1st 2017 and December 31st 2017, were evaluated. The collected real-life data were then compared with those of SIRUS, MENSA, DREAM and MUSCA trials., Results: Sixty-five patients were included (45% female; mean age 56 years; age range 19-84). Main observed differences with regulatory trials could be observed in eosinophils blood count at baseline, where the mean of our real-life patients (653 cells/μL) was overall higher than the one of all trials (240 cells/μL, 296 cells/μL, 253 cells/μL; p  <  0.0001). The incidence of polyposis was also significantly higher in our sample (72% vs. 24%, 49%, 10%, 19%; p <  0.0001). The daily average dose of OCS was lower in our real-life patients (9 mg), if compared with SIRIUS (13.7 mg), MENSA (13.2) and MUSCA (13), and similar to the data published in DREAM (10.8)., Conclusions: The comparison of real-life patients' characteristics with regulatory trials, displayed several apparent discrepancies. The demographic and clinical aspects were similar in all groups, whereas other features (eosinophil count, pulmonary function FEV1%) differed. These data, for the first time, could represent a basis for a more accurate prescription of the drug., Competing Interests: All the procedures herein described were performed as per standard of care. The study was observational, with approved and commercialized drugs. No approval or registration was required according to the Italian laws.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Data on the prevalence of perennial versus seasonal allergic asthma in Italy are lacking; moreover, there is limited evidence on the effect of omalizumab on patient-reported outcomes in Italian patients with severe allergic asthma. PROXIMA, an observational, multicenter study, was designed to assess the prevalence of perennial versus seasonal allergic asthma (cross-sectional phase) and the effect of omalizumab on improving illness perception, quality of life (QoL) and asthma control of Italian patients with severe allergic asthma (longitudinal phase)., Methods: The study included a cross-sectional phase ( n  = 357) and a longitudinal phase ( n  = 123): during the longitudinal phase, patients received omalizumab (75-600 mg subcutaneously every month) and were followed-up for 12 months. The primary parameter of cross-sectional phase was prevalence of perennial allergic asthma and that of longitudinal phase was proportion of patients with asthma control (assessed using asthma control questionnaire [ACQ]). Secondary parameters assessed were patients' disease perception, level of asthma control, exacerbation rate during both cross-sectional and longitudinal phases, and patients' compliance to and persistence with omalizumab, and patients' QoL during the longitudinal phase., Results: Most patients (95.8%) had perennial allergies; 81% had polysensitization. Of 99 patients in the per-protocol set, 95 (95.96% [95% CI: 89.98-98.89%]) achieved asthma control (ACQ < 4) at both 6 and 12 months of omalizumab treatment; ACQ score decreased after 6 and 12 months ( P  < 0.0001). Omalizumab treatment resulted in a significant improvement in QoL and patients' illness perception and 87% decrease in exacerbation rate. The compliance rate with omalizumab was high (73.2%). No new safety signals were identified during treatment., Conclusion: This study demonstrated that in severe allergic asthma, omalizumab improves patient-reported outcomes such as patients' illness perception and QoL, while confirming improvement of asthma control and exacerbation rate reduction in Italian patients., Competing Interests: The study was conducted in accordance with the ethical principles laid down in the Declaration of Helsinki and the AIFA Guideline for classification and management of observational studies on drugs. All patients provided informed consent before participating in the study.Not applicable.Giorgio Walter Canonica reports having received research grants as well as lecture or advisory board fees from A. Menarini, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Genentech, Guidotti-Malesci, Glaxo Smith Kline, Mundipharma, Novartis, Sanofi-Aventis, Teva. Paola Rottoli reports receiving personal fees and other from Roche, personal fees from Boehringer Ingelheim, grants and personal fees from Novartis, personal fees from TEVA, other from Menarini, from null, outside the submitted work. Bruno Macciocchi reports receiving grants from Boehringer Ingelheim. Pierachille Santus reports receiving personal fees from Astra Zeneca, grants and personal fees from Boehringer ingelheim, grants from Almirall, grants and personal fees from Chiesi Farmaceutici, personal fees from Guidotti, personal fees from GSK, personal fees from Zambon Italia, outside the submitted work. Marta Bartezaghi and Laura Rigoni are the employees of Novartis.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Asthma is a chronic and heterogeneous disease, which is defined as severe disease whenever it requires treatment with a high dose of inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming ''uncontrolled" or if it remains ''uncontrolled" despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma, which is characterized by sputum eosinophilia, associated with mild to moderate increase in blood eosinophil count, frequently adult-onset, and associated with chronic rhinosinusitis with nasal polyps in half of the cases. Eosinophilic asthma is driven by T2 inflammation, characterized, among the others, by interleukin-5 production. IL-5 plays a key role in the differentiation, survival, migration, and activation of eosinophils, and it has become an appealing therapeutic target for eosinophilic asthma. In recent years two monoclonal antibodies (mepolizumab and reslizumab) directed against IL-5 and one monoclonal antibody directed against the alpha-subunit of the IL-5 receptor (benralizumab) have been developed. All these IL-5 target drugs have been shown to reduce the number of exacerbation in patients with severe asthma selected on the basis of peripheral blood eosinophil count. There are still a number of unresolved issues related to the anti-IL5 strategy in eosinophilic asthma, which are here reviewed. These issues include the effects of such therapy on airway obstruction and asthmatic symptoms, the level of baseline eosinophils that predicts a response to treatment, the relationship between blood and airway eosinophilia, and, perhaps most importantly, how to elucidate the pathogenetic role played by eosinophils in the individual patient with severe eosinophilic asthma.

Background: Intervention studies with vitamin D in asthma are inconclusive for several reasons, such as inadequate dosing or duration of supplementation or uncontrolled baseline vitamin D status. Our aim was to evaluate the benefit of long term vitamin D add-on in asthmatic patients with actual vitamin D deficiency, that is a serum 25-hydroxy vitamin D (25-OHD ) below 20 ng/mL., Methods: Serum 25-OHD, asthma exacerbations, spirometry and inhaled corticosteroids (CS) dose were evaluated in a cohort of 119 asthmatic patients. Patients with deficiency were evaluated again after one year vitamin supplementation., Results: 25-OHD was low in 111 patients and was negatively related to exacerbations ( p < 0.001), inhaled CS dose ( p = 0.008) and asthma severity ( p = 0.001). Deficiency was found in 90 patients, 55 of whom took the supplement regularly for one year, while 24 discontinued the study and 11 were not adherent. Patients with vitamin D deficiency after 12 months supplementation showed significant decrease of exacerbations (from 2.6 ± 1.2 to 1.6 ± 1.1, p < 0.001), circulating eosinophils (from 395 ± 330 to 272 ± 212 10⁶/L, p < 0.001), and need of oral CS courses (from 35 to 20, p = 0.007) and improvement of airway obstruction., Conclusions: Asthma exacerbations are favored by vitamin D deficiency and decrease after long-term vitamin D replacement. Patients who are vitamin D deficient benefit from vitamin D supplementation., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Inducible laryngeal obstruction (ILO) describes an inappropriate, transient, reversible narrowing of the larynx in response to external triggers. ILO is an important cause of a variety of respiratory symptoms and can mimic asthma. Current understanding of ILO has been hampered by imprecise nomenclature and variable approaches to assessment and management. A task force of the European Respiratory Society (ERS) and European Laryngological Society (ELS) was thus set up to address this, and to identify research priorities.A literature search identified relevant articles published until June 2016, using all identifiable terms for ILO, although including only articles using laryngoscopy. In total, 172 out of 252 articles met the inclusion criteria, summarised in sections on diagnostic approach, aetiology, comorbidities, epidemiology and treatment. The consensus taxonomy published by ERS, ELS and the American College of Chest Physicians (ACCP) in 2015 is used throughout this statement.We highlight the high prevalence of ILO and the clinical impact for those affected. Despite recent advances, most aspects of this condition unfortunately remain incompletely understood, precluding firm guidance. Specifically, validated diagnostic and treatment algorithms are yet to be established, and no randomised control studies were identified in this search; hence we also make recommendations for future research., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Breath tests cover the fraction of nitric oxide in expired gas ( F eNO ), volatile organic compounds (VOCs), variables in exhaled breath condensate (EBC) and other measurements. For EBC and for F eNO , official recommendations for standardised procedures are more than 10 years old and there is none for exhaled VOCs and particles. The aim of this document is to provide technical standards and recommendations for sample collection and analytic approaches and to highlight future research priorities in the field. For EBC and F eNO , new developments and advances in technology have been evaluated in the current document. This report is not intended to provide clinical guidance on disease diagnosis and management.Clinicians and researchers with expertise in exhaled biomarkers were invited to participate. Published studies regarding methodology of breath tests were selected, discussed and evaluated in a consensus-based manner by the Task Force members.Recommendations for standardisation of sampling, analysing and reporting of data and suggestions for research to cover gaps in the evidence have been created and summarised.Application of breath biomarker measurement in a standardised manner will provide comparable results, thereby facilitating the potential use of these biomarkers in clinical practice., Competing Interests: Conflict of interest: T. Tonia acts as a methodologist for the European Respiratory Society. Further disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative commenced during a World Health Organization workshop in 1999. The initial goals were (1) to propose a new allergic rhinitis classification, (2) to promote the concept of multi-morbidity in asthma and rhinitis and (3) to develop guidelines with all stakeholders that could be used globally for all countries and populations. ARIA-disseminated and implemented in over 70 countries globally-is now focusing on the implementation of emerging technologies for individualized and predictive medicine. MASK [MACVIA ( Contre les Maladies Chroniques pour un Vieillissement Actif )-ARIA Sentinel NetworK] uses mobile technology to develop care pathways for the management of rhinitis and asthma by a multi-disciplinary group and by patients themselves. An app (Android and iOS) is available in 20 countries and 15 languages. It uses a visual analogue scale to assess symptom control and work productivity as well as a clinical decision support system. It is associated with an inter-operable tablet for physicians and other health care professionals. The scaling up strategy uses the recommendations of the European Innovation Partnership on Active and Healthy Ageing. The aim of the novel ARIA approach is to provide an active and healthy life to rhinitis sufferers, whatever their age, sex or socio-economic status, in order to reduce health and social inequalities incurred by the disease.

Background . T2 inflammation of chronic rhinosinusitis with nasal polyps (CRSwNP) may be influenced by epithelial cytokines release (TSLP, IL-25, and IL-33). We investigated the release of TSLP, IL-25, and IL-33 by epithelial CRSwNP cells compared to epithelial sinus mucosa cells of patients with chronic rhinosinusitis without nasal polyps (CRSsNP). Methods . IL-25, IL-33, and TSLP were measured by ELISA in the supernatant of cell cultures derived by CRSwNP (9 patients, 6 atopic) and CRSsNP (7 patients, 2 atopic) in baseline condition and following stimulation with Dermatophagoides pteronyssinus (DP), Aspergillus fumigatus (AF), and poly(I:C). Results . CRSwNP epithelial cells released increased levels of IL-25 (from 0.12 ± 0.06 pg/ml to 0.27 ± 0.1 pg/ml, p < 0.01) and TSLP (from 0.77 ± 0.5 pg/ml to 2.53 ± 1.17 pg/ml, p < 0.001) following poly(I:C) stimulation, while CRSsNP epithelial cells released increased levels of IL-25 and IL-33 following AF and DP stimulation, respectively (IL-25: from 0.18 ± 0.07 pg/ml to 0.51 ± 0.1 pg/ml, p < 0.001; IL-33: from 2.57 ± 1.3 pg/ml to 5.7 ± 3.1 pg/ml, p < 0.001). Conclusions . CRSwNP epithelial cells release TSLP and IL-25 when stimulated by poly(I:C) but not by DP or AF, suggesting that viral infection may contribute to maintain and amplify the T2 immune response seen in CRSwNP., Competing Interests: The authors declare that they have no conflict of interests.

Individuals reporting episodes of breathing problems caused by re-occurring variable airflow obstructions in the larynx have been described in an increasing number of publications, with more than 40 different terms being used without consensus on definitions. This lack of an international consensus on nomenclature is a serious obstacle for the development of the area, as knowledge from different centres cannot be matched, pooled or readily utilised by others. Thus, an international Task Force has been created, led by the European Respiratory Society/European Laryngological Society/American College of Chest Physicians. This review describes the methods used to reach an international consensus on the subject and the resulting nomenclature, the 2013 international consensus conference nomenclature., (Copyright ©ERS 2015.)

The prevalence of asthma in the most advanced ages is similar to that of younger ages. However, the concept that older individuals may suffer from allergic asthma has been largely denied in the past, and a common belief attributes to asthma the definition of "rare" disease. Indeed, asthma in the elderly is often underdiagnosed or diagnosed as COPD, thus leading to undertreatment of improper treatment. This is also due to the heterogeneity of clinical and functional presentations of geriatric asthma, including the partial loss of reversibility and the lower occurrence of the allergic component in this age range. The older asthmatic patients are also characterized the coexistence of comorbid conditions that, in conjunction with age-associated structural and functional changes of the lung, may contribute to complicate the management of asthma. The current review addresses the main issues related to the management of allergic asthma in the geriatric age. In particular, the paper aims at revising current pharmacological and non pharmacological treatments for allergic asthmatics of advanced ages, primarily focusing on their safety and efficacy, although most behaviors are an arbitrary extrapolation of what has been tested in young ages. In fact, age has always represented an exclusion criterion for eligibility to clinical trials. Experimental studies and real life observations specifically testing the efficacy and safety of therapeutic approaches in allergic asthma in the elderly are urgently needed.

Background: Acute exacerbations of COPD (AECOPD) are common and strongly influence disease severity and relative healthcare costs. Vitamin D deficiency is frequent among COPD patients and its contributory role in disease exacerbations is widely debated. Our aim was to assess the relationship of serum vitamin D levels with COPD severity and AECOPD., Methods: Serum vitamin D (25-hydroxyvitamin D) levels were measured in 97 COPD patients and related to lung function, comorbidities, FEV1 decline, AECOPD and hospital admission during the previous year., Results: Most patients (96%) had vitamin D deficiency, which was severe in 35 (36%). No significant relationship was found between vitamin D and FEV1 or annual FEV1 decline. No difference between patients with and without severe vitamin D deficiency was found in age, gender, BMI, smoking history, lung function, and comorbidities, apart from osteoporosis (60.9% in severe deficiency vs 22.7%, p = 0.001). In multiple logistic regression models, severe deficiency was independently associated with AECOPD [adjusted odds ratios (aOR) of 30.5 (95% CI 5.55, 168), p < 0.001] and hospitalization [aOR 3.83 (95% CI 1.29, 11.4), p = 0.02]. The odds ratio of being a frequent exacerbator if having severe vitamin D deficiency was 18.1 (95% CI 4.98, 65.8) (p < 0.001), while that of hospitalization was 4.57 (95% CI 1.83, 11.4) (p = 0.001)., Conclusions: In COPD patients severe vitamin D deficiency was related to more frequent disease exacerbations and hospitalization during the year previous to the measurement of vitamin D. This association was independent of patients' characteristics and comorbidities.

We present a woman with heterozygous carnitine palmitoyl transferase 2 (CPT-2) deficiency who in the last 6 months suffered from episodic dyspnea and choking. Symptoms could not be attributed to her muscular energy defect, since heterozygous CPT-2 deficiency is usually asymptomatic or causes only mild muscle fatigability. Myopathy is usually triggered by concurrent factors, either genetic (additional muscle enzymes defects) or acquired (metabolic stress). The patient was referred to our respiratory clinic for suspect bronchial asthma. Spirometry showed mild decrease in inspiratory flows. Methacholine challenge was negative. Dyspnea was triggered by hyperventilation-induced hypocapnia, which produced marked decrease in airflow rates, particularly in inspiratory flows, consistent with laryngospasm. Nutritional assessment of the patient showed low serum level of calcium and vitamin D, attributable to avoidance of milk and dairy products for lactose intolerance and to insufficient sunlight exposure. After calcium and vitamin D supplementation episodic laryngospasm disappeared and hypocapnic hyperventilation test induced very mild change in airflow rates. Calcium and vitamin D deficiency may favour laryngeal spasm mimicking asthma, particularly in subjects with underlying myopathy.

Background: Cardiovascular disease (CVD) is a common comorbidity in patients with chronic airway obstruction, and is associated with systemic inflammation and airway obstruction. The aim of this study was to evaluate the predictors of CVD in two different conditions causing chronic airway obstruction, asthma and COPD., Methods: Lung function tests, clinical and echocardiographic data were assessed in 229 consecutive patients, 100 with asthma and 129 with COPD. CVD was classified into: pressure overload (PO) and volume overload (VO). Sub-analysis of patients with ischemic heart disease (IHD) and pulmonary hypertension (PH) was also performed., Results: CVD was found in 185 patients (81%: 51% COPD and 30% asthmatics) and consisted of PO in 42% and of VO in 38% patients. COPD patients, as compared to asthmatics, had older age, more severe airway obstruction, higher prevalence of males, of smokers, and of CVD (91% vs 68%), either PO (46% vs 38%) or VO (45% vs 30%). CVD was associated with older age and more severe airway obstruction both in asthma and COPD. In the overall patients the predictive factors of CVD were age, COPD, and male sex; those of PO were COPD, BMI, VC, FEV1 and MEF50 and those of VO were age, VC and MEF50. In asthma, the predictors of CVD were VC, FEV1, FEV1 /VC%, and PaO2, those of PO were VC, FEV1 and FEV1 /VC%, while for VO there was no predictor. In COPD the predictors of CVD were age, GOLD class and sex, those of VO age, VC and MEF50, and that of PO was BMI. Sub-analysis showed that IHD was predicted by COPD, age, BMI and FEV1, while PH (found only in 25 COPD patients), was predicted by VO (present in 80% of the patients) and FEV1. In subjects aged 65 years or more the prevalence of CVD, PO and VO was similar in asthmatic and COPD patients, but COPD patients had higher prevalence of males, smokers, IHD, PH, lower FEV1 and higher CRP., Conclusions: The results of this study indicate that cardiovascular diseases are frequent in patients with chronic obstructive disorders, particularly in COPD patients. The strongest predictors of CVD are age and airway obstruction. COPD patients have higher prevalence of ischemic heart disease and pulmonary hypertension. In the elderly the prevalence of PO and VO in asthma and COPD patients is similar.

Background: Hypoxia and snoring-related mechanical trauma contribute to airway inflammation in obstructive sleep apnoea (OSA). Increased exhaled nitric oxide (FENO), an airway inflammation marker, has been reported in OSA patients. We propose the measure of NO in the oral cavity (oNO) as marker of oropharyngeal inflammation in OSA., Methods: We compared oNO and FENO of 39 OSA patients with those of 26 mild asthmatics (ASTHMA), 15 patients with chronic rhinitis or rhinosinusitis (CRS) and 24 healthy subjects. A special device was used for oNO measurement. Apnoea/hypopnoea index (AHI), oxygen desaturation index, mean and nadir SaO2 were calculated from the polysomnography., Results: oNO was significantly increased in OSA (104.2 95%CI 80.2-135.5ppb) as compared to ASTHMA (71.9 95%CI 56.3-91.9ppb; p=0.015), CRS (54.4 95%CI 40.2-73.7ppb; p=0.009) and healthy subjects (63.6 95%CI 59-73ppb; p<0.001). oNO was directly related to AHI (r=0.466, p=0.003) and to minutes slept with SaO2 <90% (r=0.471, p=0.011) and it was inversely related to nadirSaO2 (r=-0.393, p=0.018). FENO was highest in asthmatics (40.3 95%CI 32.5-50.1ppb) and only slightly elevated in OSA (23.1 95%CI 19,8-28.3ppb) and CRS (22.8 95%CI 16.8-32.5ppb)., Conclusions: The finding that oral NO is increased in OSA and is related to upper airway obstructive episodes and to hypoxemia severity, strengthens the clinical and pathogenic role of oral inflammation in OSA.

Background: Rhinitis is a major risk factor for asthma, so that evaluation of the lower airways is recommended in patients with rhinitis. Exhaled nitric oxide (FE(NO)) is considered a marker of airway inflammation and it has been found to be useful for the screening of patients with suspected diagnosis of asthma. Our aim was to assess the validity and accuracy of FE(NO) to identify patients with asthma in 48 non-smoking patients with persistent rhinitis and asthma-like symptoms., Methods: Asthma was diagnosed on the basis of 12% improvement in FEV1 after salbutamol or a methocholine PD(20)FEV1<800 microg. Prior to lung function FE(NO) was measured with the single exhalation method at 50 ml/s., Results: The geometric mean (95% confidence interval) FE(NO) was significantly higher in the 18/48 asthmatics than in the non-asthmatic patients (60 ppb, CI 95%: 50-89, versus 30 ppb, CI 95%: 28-45, P=0.001). Receiver operating characteristic (ROC) curve for the diagnosis of asthma indicated that FE(NO) is an acceptable discriminator between patients with and without asthma (area under the ROC curve=0.78). None of the asthmatic patients had FE(NO) values<25 ppb and all the patients with FE(NO)>100 ppb (n=5) were asthmatics. The sensitivity and specificity of FE(NO) for detecting asthma, using 36 ppb as cut-off point, were 78% and 60% and the positive and negative predictive values were 54% and 82%, respectively., Conclusions: Measuring FE(NO) may be useful for the screening of rhinitic patients with asthma-like symptoms.

Background: Complete tooth loss (edentulism) produces anatomical changes that may impair upper airway size and function. The aim of this study was to evaluate whether edentulism favours the occurrence of obstructive sleep apnoea (OSA)., Methods: Polysomnography was performed in 48 edentulous subjects on two consecutive nights, one slept with and the other without dentures. Upper airway size was assessed by cephalometry and by recording forced mid-inspiratory airflow rate (FIF50). Exhaled nitric oxide (eNO) and oral NO (oNO), were measured as markers of airway and oropharyngeal inflammation., Results: The apnoea/hypopnoea index (AHI) without dentures was significantly higher than with dentures (17.4 +/- 3.6 versus 11.0 +/- 2.3. p = 0.002), and was inversely related to FIF50 (p = 0.017) and directly related to eNO (p = 0.042). Sleeping with dentures, 23 subjects (48%) had an AHI over 5, consistent with OSA, but sleeping without dentures the number of subjects with abnormal AHI rose to 34 (71%). At cephalometry, removing dentures produced a significant decrease in retropharyngeal space (from 1.522 +/- 0.33 cm to 1.27 +/- 0.42 cm, p = 0.006). Both morning eNO and oNO were higher after the night slept without dentures (eNO 46.1 +/- 8.2 ppb versus 33.7 +/- 6.3 ppb, p = 0.035, oNO 84.6 +/- 13.7 ppb versus 59.2 +/- 17.4 ppb, p = 0.001)., Conclusion: These findings suggest that complete tooth loss favours upper airway obstruction during sleep. This untoward effect seems to be due to decrease in retropharyngeal space and is associated with increased oral and exhaled NO concentration.

Angiotensin-converting enzyme (ACE) inhibitors may induce cough and rhinopharyngeal inflammation. Obstructive sleep apnea (OSA) is characterized by upper airway inflammation. We describe a patient who, during enalapril treatment, developed cough, upper airway symptoms, and diurnal sleepiness, with an increased number of obstructive apnea-hypopnea episodes (apnea-hypopnea index [AHI], 25) during sleep. Her symptoms and AHI improved 1 month after enalapril was discontinued and diuretic therapy (hydrochlorothiazide-spironolactone) was initiated. Similar findings were observed in 4 other patients with OSA who had ACE inhibitor-induced cough. The mean +/- SD AHI was 33.8+/-21.0 during enalapril treatment and 20.0+/-17.0 after withdrawal of this drug (P = .04). Exhaled nitric oxide, a marker of airway inflammation, was increased during enalapril treatment (15.0 +/- 4.3 parts per billion) and decreased after discontinuation of this drug (9.0 +/- 2.6; P = .03). No significant difference in the AHI and exhaled nitric oxide was observed in 4 patients with OSA who did not experience cough, before or after withdrawal of ACE inhibitor treatment. These findings suggest that ACE inhibitor treatment may contribute to OSA by inducing upper airway inflammation.

Purpose: Individuals with epilepsy commonly report daytime sleepiness, attributed to sleep disruption (frequent arousals, awakenings, and stage shifts) induced by ictal and interictal activity or antiepileptic drugs (AEDs) or both. To study the effect of levetiracetam (LEV) on sleep, at full doses but without the interference of epilepsy, we investigated the sleep architecture and daytime vigilance in healthy adults after 3 weeks of treatment., Methods: The study was of a double-blind crossover design with random allocation of multiple doses of two different treatments (randomly first LEV

Asthma represents a growing public health problem and the cost of asthma has been rising in many countries. The aim of this study was to estimate the direct and indirect cost of asthma among adult patients in Italy, and to assess the relationship between healthcare resource use and asthma severity according to the Global Initiative for Asthma (GINA) classification system. A multicentre cross-sectional study was conducted in 16 Italian hospital-based specialised asthma clinics. Data collection was based on self-administered questionnaires and took place during the period May 1-November 30, 1999, and 500 consecutive patients with asthma, aged 18-55 yrs, were enrolled during regularly scheduled visits. Direct costs (drugs, physician visits, emergency service use and hospitalisation), indirect costs (loss of paid workdays) and total costs were determined in euros (Euros) for 1999. Patients with more severe disease, as classified by the GINA guideline, exhibited more night-time and daytime symptoms and were more limited in performing normal daily activities. The mean total cost of asthma per patient per year was estimated to be Euros 1,260; drug costs accounted for 16%, physician costs 12%, emergency service and hospitalisation costs 20% and indirect costs 52% of the mean cost. Stratified by severity, the total annual cost per patient amounted to Euros 720, Euros 1,046, Euros 1,535 and Euros 3,328 for patients with intermittent, mild persistent, moderate persistent and severe persistent asthma, respectively. Asthma severity, as determined by the Global Initiative for Asthma classification, is significantly associated with symptoms, limitations in normal daily activities, asthma-related medical resource utilisation and both direct and indirect costs. Asthma control is not only a clinical but also an economic imperative.

Anxiety is associated with an increased risk of sudden death. QT dispersion is a marker of cardiac repolarization instability and is seen in conditions of high risk of sudden death. The purpose of this study was to evaluate autonomic nervous system control and QT dispersion in hypertensive subjects with anxiety symptoms. In a recent preliminary study, we observed that hypertensive individuals reporting high scores on a self-assessment anxiety scale had more marked left ventricular hypertrophy. In 105 hypertensive subjects divided into 3 groups according to severity of anxiety, we evaluated autonomic control by short-term power spectral analysis of RR and arterial pressure variability at rest (baseline) and during sympathetic stress (tilt test), left ventricular mass index, and heart rate-corrected QT (QTc) dispersion. At baseline, hypertensive subjects with higher anxiety symptom scores had significantly lower high-frequency RR values expressed in absolute terms (P<0.05) and in normalized units (P<0.05) than their counterparts without anxiety symptoms. Hypertensive subjects with anxiety also had a higher mean left ventricular mass index (P<0.001) and greater QTc dispersion (P<0.001). Both indexes and high frequency (P<0.05) correlated with severity of anxiety. These findings suggest that anxiety is associated with autonomic imbalance. This condition could favor an increase in left ventricular mass. Myocardial hypertrophy alone or combined with neuroautonomic imbalance may lead to QT dispersion.

In salt-sensitive hypertension, a high sodium intake causes plasma catecholamines to rise and pulmonary baroreceptor plasticity to fall. In salt-sensitive and salt-resistant hypertensive subjects during low and high sodium intakes, we studied autonomic nervous system activity by power spectral analysis of heart rate and arterial pressure variabilities and baroreceptor sensitivity. In all subjects, high sodium intake significantly enhanced the low-frequency power of heart rate and arterial pressures at rest and after sympathetic stress. It also increased heart rate and arterial pressure variabilities. During high sodium intake, salt-sensitive hypertensive subjects had significantly higher low-frequency powers of systolic arterial pressure (7.5 mm Hg2, P < .05) and of heart rate at rest (59.2 +/- 2.4 normalized units [NU], P < .001) than salt-resistant subjects (6.6 +/- 0.3 mm Hg2, 55.0 +/- 3.2 NU) and normotensive control subjects (5.1 +/- 0.5 mm Hg2, 41.6 +/- 2.9 NU). In salt-sensitive subjects, low sodium intake significantly reduced low-frequency normalized units (P < .001) and the ratio of low- to high-power frequency (P < .001). High-sodium intake significantly increased baroreflex sensitivity in control subjects (from 10.0 +/- 0.7 to 17.5 +/- 0.7 ms/mm Hg, P < .001) and salt-resistant subjects (from 6.9 +/- 0.7 to 13.9 +/- 0.9, P < .05) but not in salt-sensitive subjects (7.4 +/- 0.3 to 7.9 +/- 0.4). In conclusion, a high sodium intake markedly enhances cardiac sympathetic activity in salt-sensitive and salt-resistant hypertension. In contrast, although reduced sodium intake lowers arterial pressure and sympathetic activity, it does so only in salt-sensitive subjects. Hence, in salt-resistant subjects, neither arterial pressure nor sympathetic activity depends on salt intake. During a high sodium intake in normotensive subjects and salt-resistant hypertensive subjects, increased sympathetic activity is probably compensated by enhanced baroreflex sensitivity.

To examine the role of adhesion molecules in T cell recruitment and activation during allergen-induced late asthmatic response (LAR), we evaluated the expression of lymphocyte function-associated antigen-1 alpha (LFA-1 alpha) and intercellular adhesion molecule-1 (ICAM-1) on peripheral blood T lymphocyte subsets from atopic asthmatic patients and their changes following allergen inhalation challenge. 12 atopic asthmatic patients were studied. Six patients showed only a single early response after allergen challenge, and six developed a dual response. At baseline, dual responders (DR) had a significantly higher expression of ICAM-1 on CD4+ and CD8+ T lymphocytes as compared with both single early responders (P < 0.005 and P < 0.02, respectively) and controls (P < 0.001, both comparisons). Allergen challenge was followed by a decrease of CD8+ ICAM-1+ T lymphocytes in all DR (P < 0.05) and of CD4+ ICAM-1+ T lymphocytes in four out of six DR, at the time of the LAR. At the same time, a significant rise in serum levels of the soluble form of ICAM-1 was observed in DR. These results suggest that peripheral blood immunoregulatory T lymphocytes are in a higher state of activation in DR as compared with early responders. The upregulation of ICAM-1 on these cells may be important in enhancing airway inflammation in patients with LAR.

The aim of this study was to test the hypothesis that lung oedema causes an obstructive airway impairment, due to an increase in cholinergic bronchial tone in patients with chronic heart failure (CHF). Ten patients with CHF were tested by inhalation of ipratropium bromide and placebo, given in sequential randomized order, in double-blind fashion, after assessment of baseline lung function, both during acute cardiac decompensation and after 8-10 days of adequate treatment. The decrease in lung oedema was associated with a significant increase in vital capacity (VC) (from 70 +/- 4.4 to 83 +/- 5.4% pred), forced expiratory volume in one second (FEV1) (from 59 +/- 3.6 to 72 +/- 4.6% pred), FEV1/VC (from 61 +/- 2.8 to 64 +/- 2.3%) and residual volume (RV) (from 94 +/- 7.9 to 99 +/- 6.8% pred). Ipratropium bromide produced a far better bronchodilatation during acute decompensation when FEV1 increased from 59 +/- 3.6 to 70 +/- 3.7% pred, than after intensive treatment for heart failure, when FEV1 increased from 72 +/- 4.6 to 76 +/- 4.8% pred. The maximum absolute increase in FEV1 induced by ipratropium bromide was 286 +/- 32 ml at admission and only 111 +/- 15 ml after treatment. In conclusion, in chronic heart failure, airway obstruction is partially reversible after inhalation of an anti-muscarinic drug, when lung oedema is present, supporting the hypothesis that lung oedema increases cholinergic bronchial tone.

To better characterize airway hyperresponsiveness reported in cardiac patients questionnaire-recorded symptoms, bronchial responsiveness to methacholine (Mch) and to ultrasonically nebulized distilled water (UNDW), diurnal oscillations of peak expiratory flow (PEF) rate were evaluated in 32 patients with moderate mitral stenosis. Twenty patients were responsive to Mch (defined as provocative dose producing a 20% fall in forced expiratory volume in one second (PD20 FEV1) less than 3.2 mg) (geometric mean PD20 FEV1 851 +/- 154 micrograms SE). Only two patients showed a fall in FEV1 greater than 20% after UNDW challenge. Patients responsive to Mch challenge had lower FEV1 as percentage of vital capacity (FEV1/VC) (80 +/- 4.8 vs 83 +/- 3.8%, p less than 0.05), higher coefficient of variation of PEF (CV-PEF) (7.1 +/- 2.8 vs 5 +/- 2.4, p less than 0.05) and higher prevalence of wheeze (70 vs 25%, p less than 0.05) in comparison with patients non-responsive to Mch challenge. CV-PEF was significantly related to FEV1 (r = 0.347, p less than 0.05) and maximal expiratory flow at 50% expired volume (MEF50) (r = 0.405, p less than 0.05). The probability of responding to Mch bronchial challenge increased proportionally with the increase in CV-PEF and the decrease in FEV1, FEV1/VC and MEF50. Airway hyperresponsiveness of patients with mitral stenosis seems to be more similar to that reported in bronchitic than in asthmatic patients.