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Introduction: Chronic obstructive pulmonary disease (COPD) is a frequent cause of morbidity and mortality. Dysregulated and enhanced immune-inflammatory responses have been described in COPD. Recent data showed impaired immune responses and, in particular, of interferon (IFNs) signaling pathway in these patients., Aim: To evaluate in peripheral lung of COPD patients, the expression of some of the less investigated key components of the innate immune responses leading to IFN productions including: IFN-receptors (IFNAR1/IFNAR2), IRF-3 and MDA-5. Correlations with clinical traits and with the inflammatory cell profile have been assessed., Methods: Lung specimens were collected from 58 subjects undergoing thoracic surgery: 22 COPD patients, 21 smokers with normal lung function (SC) and 15 non-smoker controls (nSC). The expression of IFNAR1, IFNAR2, IRF-3 and MDA-5, of eosinophils and activated NK cells (NKp46+) were quantified in the peripheral lung by immunohistochemistry., Results: A significant increase of IRF-3 + alveolar macrophages were observed in COPD and SC compared with nSC subjects. However, in COPD patients, the lower the levels of IRF-3 + alveolar macrophages the lower the FEV1 and the higher the exacerbation rate. The presence of chronic bronchitis (CB) was also associated with low levels of IRF-3 + alveolar macrophages. NKp46 + cells, but not eosinophils, were increased in COPD patients compared to nSC patients (p < 0.0001)., Conclusions: Smoking is associated with higher levels of innate immune response as showed by higher levels of IRF-3 + alveolar macrophages and NKp46 + cells. In COPD, exacerbation rates, severe airflow obstruction and CB were associated with lower levels of IRF-3 expression, suggesting that innate immune responses characterize specific clinical traits of the disease., (© 2024. The Author(s).)

Thymic stromal lymphopoietin (TSLP), is a protein belonging to a class of epithelial cytokines commonly called alarmins, which also includes IL-25 and IL-33. Functionally, TSLP is a key player in the immune response to environmental insults, initiating a number of downstream inflammatory pathways. TSLP performs its role by binding to a high-affinity heteromeric complex composed of the thymic stromal lymphopoietin receptor (TSLPR) chain and IL-7Rα. In recent years, the important role of proinflammatory cytokines in the etiopathogenesis of various chronic diseases such as asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), chronic obstructive pulmonary diseases (COPDs), and chronic spontaneous urticaria has been studied. Although alarmins have been found to be mainly implicated in the mechanisms of type 2 inflammation, studies on monoclonal antibodies against TSLP demonstrate partial efficacy even in patients whose inflammation is not definable as T2 and the so-called low T2. Tezepelumab is a human anti-TSLP antibody that prevents TSLP-TSLPR interactions. Several clinical trials are evaluating the safety and efficacy of Tezepelumab in various inflammatory disorders. In this review, we will highlight major recent advances in understanding the functional role of TSLP, its involvement in Th2-related diseases, and its suitability as a target for biological therapies.

Purpose of Review: Global Initiative for Asthma (GINA) document provides a classification of asthma severity according with the current level of treatment required to achieve diseases control and underlines the limitations of this approach. In this review, we will provide an overview of recent investigations that have analyzed clinical and molecular features of moderate asthma., Recent Findings: Moderate asthma is heterogeneous in terms of response to inhaled treatment and pathogenetic mechanisms underlying the clinical features. Analysis of inflammatory pathways in patients who do not achieve disease remission allows identification of patient subgroups that may benefit from specific biological treatments., Summary: Scientific progress makes increasingly clear that there are biological mechanisms capable of identifying and justifying the degree of severity of asthma. The identification of these, combined with the development of new pharmacological treatments, will be the cornerstones of improving the management of asthma in its degrees of severity., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The efficacy mepolizumab in severe asthmatic patients is proven in the literature. Primarily to study the effect of mepolizumab on exacerbations, steroid dependence, and the continuation of efficacy in the long term. Secondarily to evaluate the effect of the drug on nasal polyps. Analyzing data from SANI (Severe Asthma Network Italy) clinics, we observed severe asthmatic patients treated with mepolizumab 100 mg/4 weeks, for a period of 3 years. 157 patients were observed. Exacerbations were reduced from the first year (-84.6%) and progressively to 90 and 95% in the second and third ones. Steroid-dependent patients decreased from 54% to 21% and subsequently to 11% in the second year and 6% in the third year. Patients with concomitant nasal polyps, assessed by SNOT-22, showed a 49% reduction in value from baseline to the third year. The study demonstrated the long-term efficacy of mepolizumab in a real-life setting.

Abdominal aortic aneurysm (AAA) is a progressive aortic dilatation, causing ∼80% mortality upon rupture. Currently, there is no approved drug therapy for AAA. Surgical repairs are invasive and risky and thus not recommended to patients with small AAAs which, however, account for ∼90% of the newly diagnosed cases. It is therefore a compelling unmet clinical need to discover effective non-invasive strategies to prevent or slow down AAA progression. We contend that the first AAA drug therapy will only arise through discoveries of both effective drug targets and innovative delivery methods. There is substantial evidence that degenerative smooth muscle cells (SMCs) orchestrate AAA pathogenesis and progression. In this study, we made an exciting finding that PERK, the endoplasmic reticulum (ER) stress Protein Kinase R-like ER Kinase, is a potent driver of SMC degeneration and hence a potential therapeutic target. Indeed, local knockdown of PERK in elastase-challenged aorta significantly attenuated AAA lesions in vivo. In parallel, we also conceived a biomimetic nanocluster (NC) design uniquely tailored to AAA-targeting drug delivery. This NC demonstrated excellent AAA homing via a platelet-derived biomembrane coating; and when loaded with a selective PERK inhibitor (PERKi, GSK2656157), the NC therapy conferred remarkable benefits in both preventing aneurysm development and halting the progression of pre-existing aneurysmal lesions in two distinct rodent models of AAA. In summary, our current study not only establishes a new intervention target for mitigating SMC degeneration and aneurysmal pathogenesis, but also provides a powerful tool to facilitate the development of effective drug therapy of AAA., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: The identification of type-2 inflammation in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) acquires a crucial role in the endotypization needed for selecting patients for biological drugs targeting type-2 inflammation: to date, the parameters used include systemic and histological biomarkers. The aim of this study was to investigate whether nasal cytology could identify type-2 inflammation in patients with CRSwNP., Methodology: Thirty-three consecutive patients with CRSwNP underwent nasal cytology sampling at the level of the lower nasal turbinate, and of the polypoid tissue, and surgical polyp tissue sample was collected. The cellularity of the 3 collected samples were compared., Results: Mean nasal polyp tissue, nasal polyps cytology and inferior turbinate cytology eosinophils counts were 43.7 ± 39.6 cells/HPF, 32.8 ± 44.7 cells/HPF and 27.6 ± 58.0 cells/HPF respectively with inferior turbinate cytology eosinophils significantly lower than nasal polyp tissue count (p = 0.007). Both mean nasal polyps cytology eosinophils and mean inferior turbinate cytology eosinophils were significantly higher in patients with type-2 CRSwNP (52.5 ± 67.0 cells/HPF vs 12.2 ± 17.3 cells/HPF, p = 0.012, and 32.0 ± 62.1 cells/HPF vs 2.9 ± 2.9 cells/HPF, p = 0.020 respectively)., Conclusions: Nasal cytology is suitable tool for assessing local biomarkers of type-2 inflammation in CRSwNP., (© 2022 The Author(s).)

Abdominal aortic aneurysm (AAA) is a prevalent vascular disease with high mortality rates upon rupture. Despite its prevalence in elderly populations, there remain limited treatment options; invasive surgical repair, while risky, is the only therapeutic intervention with proven clinical benefits. Dietary factors have long been suggested to be closely associated with AAA risks, and dietary therapies recently emerged as promising avenues to achieve non-invasive management of a wide spectrum of diseases. However, the role of dietary therapies in AAA remains elusive. In this article, we will summarize the recent clinical and pre-clinical efforts in understanding the therapeutic and mechanistic implications of various dietary patterns and therapeutic approaches in AAA., Competing Interests: Author BW is the corresponding author, the coordinator for this research topic, and has recused from the peer-review and editorial processes. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yin, Gregg, Riccio, Hoyt, Islam, Ahn, Le, Patel, Zhang, He, McKinney, Kent and Wang.)

Introduction: There is, so far, no universal definition of severe asthma. This definition usually relies on: number of exacerbations, inhaled therapy, need for oral corticosteroids, and respiratory function. The use of such parameters varies in the different definitions used. Thus, according to the parameters chosen, each patient may result in having severe asthma or not. The aim of this study was to evaluate how the choice of a specific definition of severe asthma can change the allocation of patients., Methods: Data collected from the Severe Asthma Network Italy (SANI) registry were analyzed. All the patients included were then reclassified according to the definitions of U-BIOPRED, NICE, WHO, ATS/ERS, GINA, ENFUMOSA, and TENOR., Results: 540 patients, were extracted from the SANI database. We observed that 462 (86%) met the ATS/ERS criteria as well as the GINA criteria, 259 (48%) the U-Biopred, 222 (41%) the NICE, 125 (23%) the WHO, 313 (58%) the Enfumosa, and 251 (46%) the TENOR criteria. The mean eosinophil value were similar in the ATS/ERS, U-Biopred, and Enfumosa (528, 532 and 516 cells/mcl), higher in WHO and Tenor (567 and 570 cells/mcl) and much higher in the NICE classification (624 cells/mcl). Lung function tests resulted similarly in all groups, with WHO (67%) and ATS/ERS-GINA (73%), respectively, showing the lower and upper mean FEV1 values., Conclusions: The present observations clearly evidence the heterogeneity in the distribution of patients when different definitions of severe asthma are used. However, the recent definition of severe asthma, provided by the GINA document, is similar to that indicated in 2014 by ATS/ERS, allowing mirror reclassification of the patients examined. This lack of homogeneity could complicate the access to biological therapies. The definition provided by the GINA document, which reflects what suggested by ATS/ERS, could partially overcome the problem., Competing Interests: None to declare., (© 2021 The Authors.)

Urinary tract infections are often polymicrobial and are mainly due to uropathogenic Escherichia coli (UPEC). We previously demonstrated a link among clinical fluoroquinolone susceptible E. coli reducing in vitro urothelial interleukin-8 (CXCL8) induced by E. coli K-12, polymicrobial cystitis, and pyuria absence. Here, we evaluated whether fifteen clinical fluoroquinolone susceptible UPEC were able to reduce CXCL8 induced by Enterococcus faecalis that had been isolated from the same mixed urines, other than CXCL8 induced by E. coli K-12. We also evaluated the connection between fluoroquinolone susceptibility and pathogenicity by evaluating the immune modulation of isogenic gyrA , a mutant UPEC resistant to ciprofloxacin. Using the 5637 bladder epithelial cell line, we observed that lower CXCL8 induced the most UPEC isolates than K-12 and the corresponding E. faecalis . During coinfections of UPEC/K-12 and UPEC/ E. faecalis , we observed lower CXCL8 than during infections caused by K-12 and E. faecalis alone. UPEC strains showed host-pathogen and pathogen-pathogen interaction, which in part explained their persistence in the human urinary tract and coinfections, respectively. Mutant UPEC showed lower modulating activity with respect to the wildtypes, confirming the connection between acquired fluoroquinolone resistance and the decrease of innate microbial properties.

Background: Coronavirus disease (COVID-19) infection represents a worldwide critical health burden from the sanitary perspective. This disease's symptoms range from a mild flu-like form to a severe life-threatening respiratory disease and respiratory failure. Several patients, however, remain paucisymptomatic. Among the symptoms that seem relevant are the changes in taste and smell, regardless of the disease's severity., Methods: Data from patients affected by COVID-19 infection, hospitalized from 15 to 29 April, 2020, were analyzed. Questionnaires about smell, taste, and nasal function were administered to all, and a proportion also received the Quick olfactory Sniffin' Sticks Test (q-Sticks) to objectivate the presence of anosmia or hyposmia. The results of instruments and Q-Sticks were then compared., Results: Thirty-seven patients (20 males, 54.1%), with a mean age 0f 69.19 years (SD = 17.96; median 76, IQR: 63-82) were evaluated. Among the patients, 8 (22%) were asymptomatic. Out of the remaining 29 patients, 28 (97%) had fever, 19 (66%) asthenia, 11 (38%) dry cough, 10 (34%) dyspnea, and 6 (21%) gastroenteric symptoms. The q-Sticks test was performed on 27 patients and showed that 6 with anosmia, and 16 patients had hyposmia, where only 5 (14%) patients complained of loss of smell by conducting the questionnaires., Conclusion: Although olfactory disturbances may be secondary to other factors, a sudden onset of anosmia or hyposmia should be assessed as a possible symptom of COVID-19 infection. The use of questionnaires or anamnestic collection is sometimes not enough, while adding to them a simple test such as the q-Sticks test can provide more accurate and reliable data. A simple, easy-to-perform, and reliable tool (q-Sticks) for olfactory disorders assessment can be administered to identify the real size of anosmia in patients with COVID-19 infection and detect the early stage of infection or paucisymptomatic patients, therefore becoming important to reduce the spreading of the pandemic., Competing Interests: None to disclose for all Authors., (© 2020 The Authors.)

Introduction: Severe asthma occurs in 5-10% of asthmatic patients, with nasal polyposis as one of the most frequent comorbidity. Benralizumab was recently marketed, thus we could analyse its effects in real-life in severe asthma, and compare the effects of the drug in patients with and without polyposis., Methods: Patients with severe asthma, receiving Benralizumab were enrolled in Italian asthma centres. The efficacy criteria for asthma (exacerbation rate, oral corticosteroid intake, hospitalizations, pulmonary function, exhaled nitric oxide) were evaluated at baseline and after 24 weeks of treatment. Patients were then sub-analysed according to the presence/absence of nasal polyposis., Results: Fifty-nine patients with severe uncontrolled asthma (21 males, age range 32-78) and treated with benralizumab for at least 24 weeks has been evaluated, showing significant improvements in asthma-related outcomes, except for pulmonary function and exhaled nitric oxide. This included a reduction in the sino-nasal outcome-22 score versus baseline of 13.7 points (p = .0037) in the 34 patients with nasal polyposis. Anosmia disappeared in 31% patients (p = .0034). When comparing the groups with and without nasal polyposis, a similar reduction of exacerbations was seen, with a greater reduction of the steroid dependence in patients with polyposis (-72% vs -53%; p < .0001), whereas lung function was significantly more improved (12% vs 34%, p = .0064) without polyposis patients., Conclusions: Benralizumab, after 6 months of treatment, confirmed its efficacy in severe asthma, and also in nasal polyposis, which is the most frequent comorbidity. The efficacy of Benralizumab in reducing steroid dependence was even higher in patients with polyposis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction : The development of biologic molecules led to a drastic change in the therapeutic approach to asthma. With the prospect of acting on different pathophysiological mechanisms of the disease, the idea of precision medicine was developed, in which a single molecule is able to modify a specific triggering mechanism. Thus, it seemed limiting to stop at the distinction of patients phenotypes and the concept of endotypes became more relevant in the therapeutic approach. Areas covered : This review deepened the topic of precision medicine through the transition from phenotyping to endotyping. We performed a review of the literature, preferring articles quoted in Medline and published in journals with an impact factor. Results showed that it is fundamental to take into consideration the role of biomarkers and the related therapies currently available for precision medicine. Expert opinion : The possible overlap of patients in different phenotypes requires a more precise classification, which considers endotypization. With the development of biological drugs able to modify and modulate some pathophysiological mechanisms of the disease, the theoretical concept of endotyping becomes practical, allowing the clinician to choose the specific mechanism to 'attack' in order to control the disease.

Background: Patients with severe allergic asthma (SAA) when treated with omalizumab may exhibit different extent of response. Identifying biomarkers that can predict the extent of treatment effectiveness in patients can be useful in personalizing omalizumab treatment., Methods: Patients from the longitudinal phase of the PROXIMA study were selected for this ancillary study. After 12 months of omalizumab treatment, patients were categorized according to their response to treatment as: "clinical responder" (Asthma Control Questionnaire [ACQ] total score <1 at Month 12 and/or with a reduction in number of exacerbation versus the previous year); "functional responder" (an increment of ≥0.1 L in forced expiratory volume in 1 s [FEV 1 ] at Month 12 versus baseline); and "super responder" (among clinical responders group, who also showed a functional response). Plasma galectin-3 (GAL-3) levels were quantified using a micro titer plate-based enzyme linked immunosorbent assay kit., Results: The Majority of patients (86.36%) in sub-study population were identified as clinical responders. Of the total patients identified as clinical responders, 64.86% were identified as super responders . A statistically significant difference in the baseline plasma GAL-3 levels between responders and non-responders was observed only in the functional responders group ( P  = 0.0446). Patients with plasma GAL-3 level of ≥11 ng/mL had a greater probability of being a super responder ( P  = 0.0118) or a functional responder ( P  = 0.0032)., Conclusion: Our findings support the use of plasma GAL-3 as a predictive marker to stratify responders and identify super responders and functional responders to omalizumab treatment in patients with severe allergic asthma using less invasive sample like plasma., Competing Interests: AMR, PLM, LDF, RR, DDS, GWC have no competing interests. FS and MB are employees of Novartis., (© 2019 The Authors.)

Airway remodeling is accepted to be a determining component within the natural history of asthma. It is a phenomenon characterized by changes in the airways structures that marches in parallel with and can be influenced by airway inflammation, floating at the interface between both natural and adaptive immunity and physical and mechanical cells behavior. In this review we aimed to highlight the comprehensive, yet not exhaustive, evidences of how immune cells induce, regulate and adapt to the recognized markers of airway remodeling. Mucous cell hyperplasia, epithelial dysfunction and mesenchymal transition, extracellular matrix protein synthesis and restructuration, fibroblast to myofibroblast transition, airway smooth muscle proliferation, bioactive and contractile properties, and vascular remodeling encompass complex physiopathological mechanisms that can be induced, suppressed or regulated by different cellular and molecular pathways. Growth factors, cytokines, chemokines and adhesion molecules expressed or derived either from the immune network of cells infiltrating the asthmatic airways and involving T helper lymphocytes, immune lymphoid cells, dendritic cells, eosinophils, neutrophils, mast cells or by the structural components such as epithelial cells, fibroblasts, myocytes, airway smooth muscle cells concur with protein cellular matrix component and metalloproteases in modifying the airway structure in a detrimental way. The consequences in lung function decline, fixed airway obstruction and clinical severity of the disease suggest the possibility of identify among the immune molecular pathway of remodeling some biological parameters or signal pathway to be either a good tracer for monitoring the disease evolution or a target for hypothetical phenotypes and endotypes. In the era of personalized medicine, a biomarker of remodeling might predict a response to small-molecule inhibitors or biologicals potentially targeting a fundamental aspect of asthma pathogenesis that impacts on the low responsiveness to airway inflammation directed treatments., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Severe asthma is a disease with a heavy socio-economic burden and a relevant impact on the life of patients. Mepolizumab (MEP) was recently introduced in practice. The previous data were favourable as efficacy and safety are concerned. Nowadays, we can report the clinical data after more than one year of use of MEP in the real-life setting., Objective: To evaluate the efficacy and safety of MEP in a real life framework, mainly concerning asthma exacerbations, steroid dependence, effects on respiratory function and adverse events., Methods: This retrospective analysis was performed on 138 patients, treated with MEP for at least 12 months, and referred to eleven severe asthma clinics in Italy. All patients met the criteria for severe uncontrolled asthma according to ATS/ERS guidelines and prescribing MEP conditions according to the Italian Drug Agency (AIFA)., Results: We could observe 138 patients (78 female, age 58 ± 10 years). The average age of onset of asthma was 34 ± 16 years. The blood eosinophil count decreased from 822 ± 491/μL at baseline to 117 ± 96/μL (p < .0001) after 12 months of therapy. Exacerbations decreased from 3.8/year to 0.7/year (-81%; p < .0001). Steroid-dependent patients before MEP (80%) with a daily dose of 10.1 ± 9.4 mg prednisone decrease at 28% after 12 months with a mean of 2.0 ± 4.2 mg/day (p < .0001). The occurrence of adverse events was overall low., Conclusions & Clinical Relevance: In this real-life setting, MEP confirmed its efficacy and safety profile, already shown in clinical trials. This was apparent concerning exacerbation rate, systemic steroids intake and safety., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Nasal cytology is an easy, cheap, non-invasive and point-of-care method to assess nasal inflammation and disease-specific cellular features. By means of nasal cytology, it is possible to distinguish between different inflammatory patterns that are typically associated with specific diseases (ie, allergic and non-allergic rhinitis). Its use is particularly relevant when other clinical information, such as signs, symptoms, time-course and allergic sensitizations, is not enough to recognize which of the different rhinitis phenotypes is involved; for example, it is only by means of nasal cytology that it is possible to distinguish, among the non-allergic rhinitis, those characterized by eosinophilic (NARES), mast cellular (NARMA), mixed eosinophilic-mast cellular (NARESMA) or neutrophilic (NARNE) inflammation. Despite its clinical usefulness, cheapness, non-invasiveness and easiness, nasal cytology is still underused and this is at least partially due to the fact that, as far as now, there is not a consensus or an official recommendation on its methodological issues. We here review the scientific literature about nasal cytology, giving recommendations on how to perform and interpret nasal cytology., (© 2018 John Wiley & Sons Ltd.)

Background: Bronchial asthma is a heterogeneous disease characterized by three cardinal features: chronic inflammation, variable airflow obstruction, and airway hyperresponsiveness. Asthma has traditionally been defined using nonspecific clinical and physiologic variables that encompass multiple phenotypes and are treated with nonspecific anti-inflammatory therapies. Based on the modulation of airway remodeling after 12 months of anti-immunoglobulin E (IgE) treatment, we identified two phenotypes (omalizumab responder, OR; and non-omalizumab responder, NOR) and performed morphometric analysis of bronchial biopsy specimens. We also found that these two phenotypes were correlated with the presence/absence of galectin-3 (Gal-3) at baseline (i.e., before treatment). The aims of the present study were to investigate the histological and molecular effects of long-term treatment (36 months) with anti-IgE and to analyze the behavior of OR and NOR patients., Methods: All patients were treated with the monoclonal antibody anti-IgE omalizumab for 36 months. The bronchial biopsy specimens were evaluated using morphometric, eosinophilic, and proteomic analysis (MudPIT). New data were compared with previous data, and unsupervised cluster analysis of protein profiles was performed., Results: After 36 months of treatment with omalizumab, reduction of reticular basement membrane (RBM) thickness was confirmed in OR patients (Gal-3-positive at baseline); similarly, the protein profiles (over 500 proteins identified) revealed that, in the OR group, levels of proteins specifically related to fibrosis and inflammation (e.g., smooth muscle and extracellular matrix proteins (including periostin), Gal-3, and keratins decreased by between 5- and 50-fold. Eosinophil levels were consistent with molecular data and decreased by about tenfold less in ORs and increased by twofold to tenfold more in NORs. This tendency was confirmed (p < 0.05) based on both fold change and DAVE algorithms, thus indicating a clear response to anti-IgE treatment in Gal-3-positive patients., Conclusions: Our results showed that omalizumab can be considered a disease-modifying treatment in OR. The proteomic signatures confirmed the presence of Gal-3 at baseline to be a biomarker of long-term reduction in bronchial RBM thickness, eosinophilic inflammation, and muscular and fibrotic components in omalizumab-treated patients with severe asthma. Our findings suggest a possible relationship between Gal-3 positivity and improved pulmonary function.

Precision medicine (PM) can be defined as a structural model aimed at customizing healthcare, with medical decisions/products tailored on an individual patient at a highly detailed level. In this sense, allergy diagnostics based on molecular allergen components allows to accurately define the patient's IgE repertoire. The availability of highly specialized singleplexed and multiplexed platforms support allergists with an advanced diagnostic armamentarium. The therapeutic intervention, driven by the standard diagnostic approach, but further supported by these innovative tools may result, for instance, in a more appropriate prescription of allergen immunotherapy (AIT). Also, the phenotyping of patients, which may have relevant effects on the treatment strategy, could be take advantage by the molecular allergy diagnosis.

Background: Chronic obstructive pulmonary disease (COPD) is a progressive lung disorder characterized by poorly reversible airway obstruction and its pathogenesis remains largely misunderstood. Local changes of regulatory T-cell populations in the lungs of COPD patients have been demonstrated although data concerning their pathologic role are contrasting. The aim of our study was to evaluate the relative percentage of regulatory T-cells in the peripheral blood of current and former smoker subjects, affected or not by COPD. Furthermore, the effect of different concentrations of budesonide and formoterol, on regulatory T-cells has been investigated., Methods: T regulatory lymphocytes were isolated and assessed as CD4(+)CD25(high)CD127(-) cells by flow cytometry and cultured for 48 hours in the absence or in the presence of budesonide and/or formoterol at different doses., Results: CD4(+)CD25(high)CD127(-) regulatory T-cells percentage was significantly reduced in COPD patients, both current and former smokers, with respect to volunteers. Furthermore, CD4(+)CD25(high)CD127(-) cells of COPD patients showed a not statistically significant response to drugs compared to healthy subjects., Discussion: Our results evidenced a different behaviour of CD4(+)CD25(high)CD127(-) Treg cells in COPD patients after in vitro treatments., Conclusions: Based on our data, we suggested a possible role of CD4 CD25(high)CD127 T-cells in COPD pathogenesis.

Although different phenotypes of severe asthma can be identified, all are characterized by common symptoms. Due to their heterogeneity, they exhibit differences in pathogenesis, etiology and clinical responses to therapeutic approaches. The identification of distinct molecular phenotypes to define severe asthmatic patients will allow us to better understand the pathophysiology of the disease and thus to more precisely target the treatment for each patient. To achieve this goal, a systematic search for new, reliable and stable biomarkers specific for each phenotype is essential. This review focuses on the current known molecular phenotypes of severe asthma and highlights the need for biomarkers that could (either alone or in combination) be predictive of the treatment outcome.

Severe asthma (SA) is a clinically and etiologically heterogeneous respiratory disease which affects among 5-10 % of asthmatic patients. Despite high-dose therapy, a large patients percentage is not fully controlled and has a poor quality of life. In this review, we describe the biomarkers actually known in scientific literature and used in clinical practice for SA assessment and management: neutrophils, eosinophils, periostin, fractional exhaled nitric oxide, exhaled breath condensate and galectins. Moreover, we give an overview on clinical and biological features characterizing severe asthma, paying special attention to the potential use of these ones as reliable markers. We finally underline the need to define different biomarkers panels to select patients affected by severe asthma for specific and personalized therapeutic approach.

Asthma and chronic obstructive pulmonary disease (COPD) are multifactorial respiratory diseases, characterized by reversible and irreversible airway obstruction, respectively. Even if the primary causes of these diseases remain unknown, inflammation is a central feature that leads to progressive and permanent pulmonary tissue damage (airway remodeling) up to the total loss of lung function. Therefore, the elucidation of the inflammation mechanisms and the characterization of the biological pathways, involved in asthma and COPD pathogenesis, are relevant in finding new possible diagnostic/prognostic biomarkers and for the validation of new drug targets. In this context, current advances in proteomic approaches, especially those based on MS, provide new tools to facilitate the discovery-driven studies of new biomarkers in respiratory diseases and improve the clinical reliability of the next generation of biomarkers for these diseases consisting of multiple phenotypes. This review will report an overview of the current proteomic methods applied to the discovery of candidate biomarkers for asthma and COPD, giving a special emphasis to emerging MS-based techniques., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Asthma is a chronic inflammatory disease. Reticular basement membrane (RBM) thickening is considered feature of airway remodelling (AR) particularly in severe asthma (SA). Omalizumab, mAb to IgE is effective in SA and can modulate AR. Herein we describe protein profiles of bronchial biopsies to detect biomarkers of anti-IgE effects on AR and to explain potential mechanisms/pathways. We defined the bronchial biopsy protein profiles, before and after treatment. Unsupervised clustering of baseline proteomes resulted in very good agreement with the morphometric analysis of AR. Protein profiles of omalizumab responders (ORs) were significantly different from those of non-omalizumab responders (NORs). The major differences between ORs and NORs lied to smooth muscle and extra cellular matrix proteins. Notably, an IgE-binding protein (galectin-3) was reliable, stable and predictive biomarker of AR modulation. Omalizumab down-regulated bronchial smooth muscle proteins in SA. These findings suggest that omalizumab may exert disease-modifying effects on remodelling components., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: An in vitro procedure based on a microarray containing many different allergen components has recently been introduced for use in allergy diagnosis. Recombinant and highly purified allergens belonging to different allergenic sources (inhalants, food, latex and hymenoptera) are present in the array. These components can either be genuine or cross-reactive, resistant or susceptible to heat and low pH, and innocuous or potentially dangerous. A large number of complex and heterogeneous relationships among these components has emerged, such that sometimes these interactions cannot be effectively managed by the allergist. In the 1960s, specialized languages and environments were developed to support the replacement of human experts with dedicated decision-making information systems. Currently, expert systems (ES) are advanced informatics tools that are widely used in medicine, engineering, finance and trading., Methods: We developed an ES, named Allergenius ®, to support the interpretation of allergy tests based on microarray technology (ImmunoCAP ISAC ®). The ES was implemented using Flex, a LPA Win-Prolog shell. Rules representing the knowledge base (KB) were derived from the literature and specialized databases. The input data included the patient's ID and disease(s), the results of either a skin prick test or specific IgE assays and ISAC results. The output was a medical report., Results: The ES was first validated using artificial and real life cases and passed all in silico validations. Then, the opinions of allergists with experience in molecular diagnostics were compared with the ES reports. The Allergenius reports included all of the allergists' opinions and considerations, as well as any additional information., Conclusions: Allergenius is a trustable ES dedicated to molecular tests for allergy. In the present version, it provides a powerful method to understand ISAC results and to obtain a comprehensive interpretation of the patient's IgE profiling.

The administration of a polyvalent mechanical bacterial lysate (PMBL) in elderly patients with COPD has been shown to reduce the number of exacerbation. This is largely related to the involvement of cells belonging to the innate and the adaptive immune system (including dendritic cells, granulocytes, T and B lymphocytes and NK cells) that actively cooperate inducing the production of specific opsonizing antibodies directed to the antigens of PMBL. We have evaluated the production of antibodies directed to respiratory and systemic pathogens in a group of elderly COPD patients, recruited in a clinical trial, ancillary to a larger multicenter double blind, placebo-controlled, parallel-designed clinical trial in which patients were randomized to daily receive either PMBL or placebo. The treated group not only experienced a reduced number of seroconversion, but also, better controlled the number of infectious episodes and COPD exacerbations. It was thus evident that the administration of PMBL resulted not only effective in inducing the secretion of specific antibodies, but also effective in reducing the infectious episodes trough the potentiation of the antibody-mediated arm of the immune response., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Lung ultrasonography (LUS) and computed tomography (CT) were compared for quantitative assessment of extravascular lung water (EVLW) in 10 isolated bovine lung lobes. LUS and CT were obtained at different inflation pressures before and after instillation with known amounts of hypotonic saline. A video-based quantitative LUS analysis was superior to both single-frame quantitative analysis and visual scoring in the assessment of EVLW. Video-based mean LUS intensity was strongly correlated with EVLW density (r(2)=0.87) but weakly correlated with mean CT attenuation (r(2)=0.49) and physical density (r(2)=0.49). Mean CT attenuation was weakly correlated with EVLW density (r(2)=0.62) but strongly correlated with physical density (r(2)=0.99). When the effect of physical density was removed by partial correlation analysis, EVLW density was significantly correlated with video-based LUS intensity (r(2)=0.75) but not mean CT attenuation (r(2)=0.007). In conclusion, these findings suggest that quantitative LUS by video gray-scale analysis can assess EVLW more reliably than LUS visual scoring or quantitative CT., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A role in pulmonary immunity has been ascribed to Natural Killer (NK) cells and several in vitro studies have shown a corticosteroid-induced inhibition of NK cells mediated cytotoxicity. Several clinical trials on chronic obstructive pulmonary disease (COPD) have suggested a relationship between COPD treatment and occurrence of respiratory infections. Aims of our study were to investigate if real life COPD treatment affects peripheral blood NK cells total count and their receptors expression and to assess if different doses of formoterol and budesonide, administered alone or in combination, are able to modulate the surface expression of activating (NKp30, NKp44, NKp46 and NKG2D) and inhibitory (KIR2DL2/L3, KIR3DL1 and NKG2A) receptors on peripheral blood NK cells of COPD patients. Moreover, we evaluated the potential effect of treatment with budesonide and/or formoterol on IFN-γ secretion in vitro. NK cells were isolated from peripheral blood of 7 healthy volunteers, 9 chronic bronchitis (CB) and 11 COPD patients. Total NK cells count and activating and inhibitory receptors expression were evaluated. NK cells were cultured for 20h in 96-well plates with IL-2 (100IU/ml)+IL-12 (2.5ng/ml), with or without budesonide (Bud; 1 and 0.01μM) and formoterol (For; 30 and 0.3nM) alone or in combination. Cells were analyzed by flow cytometry and IFN-γ was measured in cell supernatants by ELISA test. No difference between real life treated COPD, CB and healthy subjects was found concerning NK total count and NK cell receptors expression. When cells were stimulated over night with cytokines and treated with drugs, only NKG2D receptor was modulated. Its expression was significantly downregulated by budesonide alone and in combination with formoterol in COPD patients. IFN-γ production induced by stimulation with IL-2+IL-12 was decreased in a highly significant way (p<0.01) by all treatments in all groups. Even if in vitro experiments with budesonide, alone or in combination with formoterol, showed a modulation of NKG2D receptor expression and IFN-γ production, our ex vivo results show that real life LABA and ICS treatment does not influence peripheral NK cells count and their receptors phenotype., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

It has been demonstrated that Leukotriene modifiers reduce rhinitis symptoms, but montelukast preventive effect on inflammatory cells pattern in intranasal challenge studies has not been already assessed. This pilot study has been designed to explore the montelukast effects in preventing early/late inflammatory cells response to specific allergen challenge in persistent rhinitis. After a 4 week wash-out period, patients were randomised to receive montelukast/placebo for 4 weeks. Pre-post treatment nasal washing and scraping before and after specific nasal challenge were performed. No difference in baseline inflammatory cells count before and after treatment was shown between groups. Despite at a basal level a decrease of inflammatory cells in active group after treatment was observed, the statistical significance was not reached. The generalised mixed model showed that, after therapeutic interventions, the inflammatory cells increased 30' and 6 hour after challenge but, only in the active group the cells amounting was less for eosinophils (-34%), macrophages (-56%), lymphocytes (-45%) and neutrophils (-46%; p = 0.001). The longitudinal generalised linear model with just one time variable showed a decrease of all inflammatory cellular types although a significant relevance was reached only for macrophages (p = 0.038) and neutrophils (p = 0.001). The modulatory effect on neutrophils and macrophages could lead to montelukast still unexplored effects. Specific trials, sized according to the results of this pilot exploratory study, could add relevant evidences concerning the leukotrienes receptors antagonist treatment of specific rhinitis and asthma phenotypes.

Severe persistent asthma causes a substantial morbidity and mortality burden and is frequently not well controlled, despite intensive guideline-based therapy. The unique monoclonal antibody approved for patients with severe allergic asthma is omalizumab: a recombinant humanised murine against IgE antibodies. The aim of the present study is to investigate the effect of long-term anti-IgE on the thickening of the reticular basement membrane (RBM) and eosinophil infiltration in bronchial biopsies from patients with severe persistent allergic asthma. Biopsies were obtained from 11 patients with severe persistent allergic asthma before and after (12 months) treatment with omalizumab. RBM thickness and eosinophils were measured by using light microscope image analysis. A significant mean reduction in RBM thickness and eosinophil infiltration were measured after one-year omalizumab treatment. No correlation between eosinophil reduction and RBM thickness reduction was found. No correlation between each of the previous two parameters and clinical parameters was detected. In conclusion, our study showed that a substantial proportion of severe asthmatics reduced the original bronchial RBM thickness and eosinophil infiltration after one-year treatment with anti-IgE, thus emphasizing the possible role of omalizumab in affecting airway remodeling in severe persistent allergic asthma.

Background: Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) is involved in the activation pathways of T lymphocytes. It has been shown that the circulating form of CTLA-4 is elevated in patients with hymenoptera allergy and can be down regulated by immunotherapy., Objective: to assess the effects on CTLA-4 of venom immunotherapy, given with different induction protocols: conventional (6 weeks), rush (3 days) or ultra rush (1 day)., Methods: Sera from patients with hymenoptera allergy were collected at baseline and at the end of the induction phase. CTLA-4 and IL-10 were assayed in the same samples. A subset of patients were assayed also after 12 months of VIT maintenance., Results: Ninety-four patients were studied. Of them, 50 underwent the conventional induction, 20 the rush and 24 the ultra-rush. Soluble CTLA-4 was detectable in all patients at baseline, and significantly decreased at the end of the induction, irrespective of its duration. Of note, a significant decrease of sCTLA-4 could be seen already at 24 hours. In parallel, IL-10 significantly increased at the end of the induction. At 12 months, sCTLA-4 remained low, whereas IL-10 returned to the baseline values., Conclusions: Serum CTLA4 is an early marker of the immunological effects of venom immunotherapy, and its changes persist after one year of maintenance treatment.

Background: Statins are serum cholesterol-lowering agents used for the prevention and treatment of atherosclerotic vascular disease. There is, however, growing evidence that statins have immunomodulatory and anti-inflammatory activities and may prove invaluable in the treatment of immunological and inflammatory disorders., Objective: On these basis we evaluated the effect of statins on the proliferation of fibroblasts derived from human nasal polyps and turbinates and determined their ability to modulate airway remodelling., Methods: Fluvastatin (0.01-0.1-1 microM), Atorvastatin (0.1-1-10 microM) and Simvastatin (0.1-1-10 microM) were tested on cultured fibroblasts derived from human nasal polyps and turbinates stimulated or not with Fibroblast Growth Factor beta (10 ng/ml). All cultures were treated with 3H-Thymidine (1 microCi/ml) to test cell proliferation., Results: Our results show that proliferation of turbinate-derived fibroblasts is significantly inhibited by the three statins. Fluvastatin is already effective at the lowest dose (0.01 microM), whereas Atorvastatin and Simvastatin act at the plasmatic peak concentration (1 microM). No significant effect was found on fibroblasts derived from nasal polyps, except for Simvastatin which was effective after 144 hours of stimulation., Conclusions: These drugs show a remarkable antiprolhferative effect and their different outcome depending on the different kind of fibroblasts in vitro is prompting news in the studies about statin use for the treatment of chronic inflammatory diseases.

Background: Allergic rhinitis is a high-prevalence disease that affects quality of life (QOL), sleep quality and productivity of patients. According to the ARIA initiative, it is classified as intermittent and persistent, the latter being the most troublesome., Methods: The aim of this randomized, open-label, 6-month, pilot study was to determine whether levocetirizine 5 mg administered continuously once daily in the morning was better than levocetirizine 5 mg on-demand in symptomatic subjects with persistent allergic rhinitis. Total and individual symptom scores were recorded in a diary card throughout the study. QOL, quality of sleep, nasal cytology, rate of drug intake, and safety were also assessed at pre-defined time-points., Results: In all, adult patients (31 in each group) were enrolled, of whom 22 dropped out. Both treatment regimens considerably decreased the total and individual symptoms scores from baseline and achieved similar levels up to week 14. Continuous treatment was generally better than on-demand from week 15 onwards, reaching statistical significance from weeks 17 to 21 (from week 19 to 21 for nasal pruritus). Both regimens substantially improved QOL and sleep quality. Both treatments were well tolerated, although the on-demand group reported more adverse events., Conclusion: The present open label study in 62 patients indicates that levocetirizine 5 mg reliably controls persistent rhinitis over a period of 6 months, and shows a trend to be more effective in controlling the symptoms of rhinitis, improving QOL and decreasing nasal inflammation, when administered as long-term continuous therapy rather than as on-demand therapy.

Background: Bronchial asthma is characterized by lower airway inflammation and remodelling. Anti-inflammatory treatment with inhaled corticosteroids (ICS) provides the mainstay of asthma therapy together with bronchodilation induced by short- and long-acting inhaled beta(2)-agonists. Lower airway fibroblasts may play a critical role in airway inflammation and remodelling, suggesting that they might represent an important target for the major anti-asthmatic drugs. The aim of our study was to investigate the effects of beclomethasone dipropionate (BDP), salbutamol and formoterol either alone or in combination on in vitro cultures of human bronchial fibroblasts., Methods: Fibroblasts were cultured in the presence of pro-inflammatory and proliferative stimuli, BDP, salbutamol and formoterol. The effects of drugs on cell proliferation were ascertained by (3)H-thymidine incorporation. CD90 and CD44 expression were detected by flow cytometry and fibronectin secretion using the enzyme-linked immunosorbent assay technique., Results: This study showed that BDP alone has significant anti-proliferative effects on lung fibroblasts treated with basic fibroblast growth factor and the combination of BDP with formoterol or salbutamol strengthen these effects. Short-acting beta(2)-agonist (SABA) or long-acting beta(2)-agonist (LABA) by themselves did not show any significant effect on the different cultures. CD44 and CD90 expression and fibronectin production were modulated by pro-inflammatory and proliferative stimuli; the addition of the drugs brought them back near to the basal level., Conclusions: From this in vitro study, we can conclude that BDP, when combined with salbutamol or formoterol, exhibits enhanced anti-remodelling activity in bronchial fibroblasts, providing new insights on the additive effects of ICS and SABAs and LABAs for asthma therapy.

Asthma is a chronic airway disorder principally characterized by bronchial hyperreactivity and airflow obstruction. Increased epithelial and smooth muscle thickness, goblet cell hyperplasia, increased mucus secretion, abnormal deposition of extracellular matrix (ECM) components in the basement membrane (BM) layer and angiogenesis are all events which occur in asthma and are defined with the general term of remodeling. This is an important feature whose repetition and regeneration may bring to an abnormal or exaggerated response to airway insults. One of the characteristic aspects of asthma is an alteration in structural cell function. Airway smooth muscle cells (ASM), myofibroblasts and fibroblasts have the ability to secrete immunomodulatory cytokines and chemokines and to express cell surface receptors. These elements are all important for cell adhesion and leukocyte activation and may be integral components of the inflammatory response as well. In particular cells such as fibroblasts and myofibroblasts, important regulators in the development and maintenance of allergic airway inflammation, have been studied in depth by our group and several studies regarding their role in asthma therapy have been analyzed.

Rationale: The development of chronic obstructive pulmonary disease (COPD) in smokers and their susceptibility to infections is not fully understood. Recent evidences suggest that Clara cells play a part in host defense, immunomodulatory response and airways remodelling through the production of specific factors such as Clara cell 16 (CC-16). This protein has never been related to patients' lung function tests, blood gases parameters and diseases severity., Objectives: To evaluate a possible correlation between CC-16 expression in sputum, measured by a new methodological approach, and the degree of severity in patients with moderate and severe COPD. We also analyzed possible correlations between CC-16 and cytological sputum population, arterial blood gases and lung function., Main Findings: We analyzed 20 patients, mean age 72.95, classified on the basis of the global initiative for chronic obstructive lung disease guidelines (GOLD 2006). The samples were processed for cytological analysis and CC-16 levels were assessed by Western blot. We found lower levels of CC-16 in severe COPD compared to moderate ones (p<0.027). No statistically significant differences were found between CC-16 expression and sputum cellularity (except for macrophages), arterial blood gases, and spirometric parameters. Multiple linear regression analysis of CC-16 versus functional and cytological parameters showed no significance., Conclusions: We found a significantly different expression of CC-16 in COPD patients, according to their stage of severity, as defined by the GOLD 2006 guidelines. Considering CC-16 properties in innate immunity, a possible link between protein expression, innate immune system, and COPD infectious exacerbations may be hypothesized but further investigation are needed.

Background Levocetirizine (LCZ) has been shown to be effective in allergic rhinitis. We evaluated its clinical efficacy, antinflammatory actions and its effects on quality of life (QoL) with a specific instrument in the asthma-rhinitis comorbidity. Methods Fifty adult patients with persistent rhinitis with/without asthma were enrolled. After a 1-week run-in for baseline evaluation, they were randomized to LCZ or placebo for 8 weeks. Cromolyn and salbutamol were permitted on demand. Rhinoconjunctivitis and asthma symptoms were evaluated by diary cards. QoL was assessed by the specific Rhinasthma questionnaire and the generic SF-36 at different time-points. Nasal scrapings and lavages were also performed for inflammatory cell count and mediator assessment. Results Ten patients dropped out for unrelated reasons and the remaining completed the study with no side-effect. Symptoms began to decrease in the active group at the second week of treatment when the difference with the placebo group became significant (0.05) and so remained until the end of the trial. Starting from 2 weeks of therapy, there was a significant decrease vs. baseline in all the four components of the Rhinasthma questionnaire only in the active group. The intergroup comparison became significant (P<0.05) at 4 weeks. The SF-36 detected only sporadic differences between groups. Eosinophils and neutrophils in nasal scraping were significantly decreased in the LCZ group vs. baseline at all times. Nasal mediators were under the detection limits and no analysis could be performed. In the active group, only two patients used rescue medications compared with 13 patients in the placebo group. Conclusions LCZ is clinically effective and capable of improving the rhinitis-asthma-related QoL.

Background: In our previous in vitro model, allergen incubation of passively sensitized human airways reduced the response to salbutamol. However, whether cytokines play a role in this model is still unknown., Objective: To investigate interleukin 1beta and tumor necrosis factor a expression in allergen-challenged human airways., Methods: Nonasthmatic airways (n = 13) were passively sensitized by overnight atopic serum incubation and then challenged with allergen for 1 hour (n = 9). After repeated washouts, airways were immersed in physiologic salt solution for 6 hours and finally in formaldehyde for immunohistochemical studies. The effect of co-incubation in anti-interleukin 1beta and anti-tumor necrosis factor a specific neutralizing antibodies on salbutamol response was also studied (n = 4)., Results: No differences were found among control, sensitized, and challenged rings in the number of inflammatory cells. The percentage of basement membrane covered by epithelium was similar in the different conditions. There was a higher percentage of degranulating to total mast cells in allergen-challenged rings than in sensitized rings (P < .001). A significant correlation was observed between allergen-induced contraction and mast cell degranulation (r = 0.88; P < .001). The sensitization procedure was validated by paired allergen-induced contractions. No expression of the 2 cytokines was detectable up to 6 hours after allergen challenge, and specific neutralizing antibodies did not attenuate the impaired response to salbutamol in allergen-challenged rings., Conclusion: These data suggest that in our in vitro model of allergic inflammation, beta2 pathway dysfunction can occur without cytokine involvement, thus supporting previous results that suggest a role for leukotrienes.

CD40/CD40 ligand interaction is an important pathway for B and T cell cooperation and function; functional CD40 molecules have recently been found on nonhematopoietic cells. We detected CD40 in vivo on normal human respiratory epithelial cells and showed that its expression is increased on inflamed airway epithelium. Subsequently, we analyzed its expression and function on primary cultures of human airway epithelial cells. Our data show that CD40 is up-regulated by IFN-beta and IFN-gamma, its ligation increases the surface expression of CD54 and CD106 and it may stimulate the release of IL-6 and IL-8. The use of Janus kinase 3 (JAK3) and NF-kappaB inhibitors suggests that both basal and CD40-induced release of the two cytokines is JAK3-dependent. Using colocalization techniques, we revealed the existence of CD40/JAK3 and CD40/TNFR-associated factor 2 interplay. The extent of these interactions may be partial (2-40% of the cells) or massive (80-90% of the cells) in cultured cells. Stimulation via CD40 causes a significant increase in the number of cells expressing colocalization only in the cultures displaying low frequency of initial colocalization. Thus, airway epithelial cells, activated by CD40, may behave as effector cells of the inflammation process and should be considered priority targets for anti-inflammatory therapy. This work identifies CD40 and the correlated JAK3 signaling molecule as potential molecular targets to block the inflammatory functions of epithelial cells.

Background: Allergic rhinitis is characterized by an inflammatory response consequent to allergen exposure. Intranasal corticosteroids represent a first line treatment, but there is no adequate knowledge concerning the duration of symptomatic and antiinflammatory effects after their suspension. Thus, we aimed at investigating this issue., Methods: Twelve children with persistent allergic rhinitis were treated with FPANS for 30 days and were followed for 12 days after its suspension. Nasal symptoms, considered as TSS, and inflammatory cells, recovered by nasal scraping, were evaluated., Results: FPANS significantly reduced TSS (p<0.0001), neutrophils (p<0.001), and eosinophils (p<0.0001) after 4 days of treatment. Symptoms and cellular infiltrate quickly reappeared after suspension (respectively after 3 days for symptoms (p<0.05), after 4 days for neutrophils (p<0.05), and 6 days for eosinophils (p<0.001)., Conclusion: These findings suggest that nasal corticosteroid treatment is highly effective in nasal symptoms' relief and inflammation's control, but its suspension induces a rapid reappearance of them.

Intercellular adhesion molecules (ICAMs), in particular ICAM-1, appear to play a crucial role in the recruitment and migration of inflammatory cells to the site of an allergic reaction. Glucocorticoids and allergen-specific immunotherapy have been shown to exert effects on selected components of this system, both in vitro and in vivo, but further research is required to better understand the effects of these therapies. Nasal and conjunctival challenge models (including natural and experimental allergen exposure) represent useful and safe tools for studying the activity of antiallergy drugs in vivo. These tests allow the investigation of a wide variety of parameters including inflammatory infiltrate, ICAM-1 expression, and changes in the concentration of soluble inflammatory mediators. With these tools, anti-inflammatory activity related to the modulation of epithelial cell adhesion molecules has been demonstrated in vivo for several H(1)-receptor antagonists (azelastine, cetirizine, loratadine, levocabastine, oxatomide, and terfenadine). Fexofenadine is a nonsedating, long-acting antihistamine with highly selective H(1)-receptor antagonist activity and a particularly favorable safety profile. In addition, fexofenadine has proven anti-inflammatory activity and has been shown to inhibit a number of mediators at clinically relevant concentrations, including in vitro inhibition of ICAM-1 expression on conjunctival and nasal epithelial cells.

This study investigated the relationships between pathological changes in small airways (<6 mm perimeter) and lung function in 22 nonasthmatic subjects (20 smokers) undergoing lung resection for peripheral lesions. Preoperative pulmonary function tests revealed airway obstruction [ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) < 70%] in 12 subjects and normal lung function in 10. When all subjects were considered together, total airway wall thickness was significantly correlated with FEV1/FVC (r2 = 0.25), reactivity to methacholine (r2 = 0.26), and slope of linear regression of FVC against FEV1 values recorded during the methacholine challenge (r2 = 0.56). Loss of peribronchiolar alveolar attachments was significantly associated (r2 = 0.25) with a bronchoconstrictor effect of deep inhalation, as assessed from a maximal-to-partial expiratory flow ratio <1, but not with airway responses to methacholine. No significant correlation was found between airway smooth muscle thickness and lung function measurements. In conclusion, this study suggests that thickening of the airway wall is a major mechanism for airway closure, whereas loss of airway-to-lung interdependence may contribute to the bronchoconstrictor effect of deep inhalation in the transition from normal lung function to airway obstruction in nonasthmatic smokers.

A Th2 cytokine pattern has recently been reported both in allergic and nonallergic chronic rhinosinusitis in asthmatic children. The aim of the study was to evaluate the cytokine pattern in chronic rhinosinusitis in allergic and nonallergic asthmatic children before and after medical treatment. Thirty asthmatic children were evaluated, 18 males and 12 females (mean age 9.1 years). Sixteen were allergic and 14 were nonallergic. All children were asthmatic and suffered from chronic rhinosinusitis, whose diagnosis was confirmed by endoscopy. All of them were treated with amoxicilline-clavulanate (20 mg/kg b.i.d.) and fluticasone propionate aqueous nasal spray (100 microg daily) for 14 days; a short course of oral corticosteroid was also prescribed (deflazacort 1 mg/kg daily for 2 days, 0.5 mg/kg daily for 4 days and 0.25 mg/kg daily for 4 days). Rhinosinusal lavage and nasal cytology were performed in all subjects before and after medical treatment. IL4 and IFNgamma were measured by immunoassay and inflammatory cells were counted by conventional staining. Thirteen allergic children and 12 nonallergic children showed a negative endoscopy after the treatment. Allergic subjects showed a significant decrease of IL4 (p = 0.0002) and a significant increase of IFNgamma (p = 0.03) after the treatment. Nonallergic children showed a significant decrease of IL4 (p = 0.0007) and a nonsignificant increase of IFNgamma. A significant reduction of the inflammatory infiltrate was detected in all asthmatic children (p < 0.05). This study confirms a Th2 polarization in chronic rhinosinusitis both in allergic and nonallergic asthmatic children. Moreover, the medical treatment of chronic rhinosinusitis reversed the cytokine pattern from a Th2 towards a Th1 profile both in allergic and nonallergic children.