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Rationale Asthma phenotyping requires novel biomarker discovery. Objectives To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). Methods An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. Results In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. Conclusions The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA. © 2022 European Respiratory Society. All rights reserved.

Rationale: Asthma phenotyping requires novel biomarker discovery. Objectives: To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterized cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, chronic obstructive pulmonary disease (COPD) subjects and healthy controls (HC). Methods: An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HC in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a two-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. Results: In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HC. Ten proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, RANK, TGF-?1, and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, hsCRP, and BMI, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. Conclusions: The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2-independent biomarkers, and validated several proteins with established involvement in the pathophysiology of severe asthma.

Background: In all chronic airway diseases, the dynamics of airway function are influenced by underlying airway inflammation and bronchial hyperresponsiveness along with limitations in reversibility owing to airway and lung remodeling as well as mucous plugging. The relative contribution of each component translates into specific clinical patterns of symptoms, quality of life, exacerbation risk, and treatment success. Objective: We aimed to evaluate whether subgrouping of patients with obstructive airway diseases according to patterns of fluctuation in lung function allows identification of specific phenotypes with distinct clinical characteristics. Methods: We applied the novel method of fluctuation-based clustering (FBC) to twice-daily FEV1 measurements recorded over a 1-year period in a mixed group of 134 adults with mild-to-moderate asthma, severe asthma, or chronic obstructive pulmonary disease from the European BIOAIR cohort. Results: Independently of clinical diagnosis, FBC divided patients into 4 fluctuation-based clusters with progressively increasing alterations in lung function that corresponded to patterns of increasing clinical severity, risk of exacerbation, and lower quality of life. Clusters of patients with airway disease with significantly elevated levels of biomarkers relating to remodeling (osteonectin) and cellular senescence (plasminogen activator inhibitor-1), accompanied by a loss of airway reversibility, pulmonary hyperinflation, and loss of diffusion capacity, were identified. The 4 clusters generated were stable over time and revealed no differences in levels of markers of type 2 inflammation (blood eosinophils and periostin). Conclusion: FBC-based phenotyping provides another level of information that is complementary to clinical diagnosis and unrelated to eosinophilic inflammation, which could identify patients who may benefit from specific treatment strategies or closer monitoring. © 2021

Leptin, a 16-kd adipocyte-derived hormone originally described in metabolism regulation, plays a pleiotropic role in the immune system and inflammation (1). Leptin exerts its action through the leptin receptor (Ob-R), present in several tissues, human respiratory tract included. Leptin is a survival cytokine for human neutrophils and eosinophils (2, 3), other than for other cytotypes, included lung carcinoma cells (4). The following findings highlight the specific role of leptin both in the lung and in the nasal tract. We firstly find that ex-vivo leptin expression is increased and co-localized with lymphocytes T inflammatory cells, in bronchial mucosa of chronic obstructive pulmonary disease (COPD) patients and it is associated with COPD severity, airway inflammation and airflow obstruction (5). On the other side, previous our in vitro and ex-vivo results show that the leptin/leptin receptor pathway is decreased in the bronchial epithelium of subjects with mild, uncontrolled, untreated asthma, whereas RBM thickness and TGF-increased, when compared with healthy volunteers (6). In addition, in another our in vitro study, we assess that leptin increases adenocarcinoma cell line proliferation and the pathway with its receptor is increased by the flavonoid apigenin (4,5,7,-trihydroxyflavone) (7). Furthermore, our recent in vitro results report that the leptin/leptin receptor pathway is involved in human nasal epithelial homeostasis in allergic rhinitis and its expression is restored by Fluticasone Furoate in presence of the allergens (8). In conclusion: in the submucosa, leptin might act as a cytokine-like mediator capable of playing a role in airway inflammation in chronic obstructive pulmonary disease with a potential impact on the severity of the disease; in the epithelium, the leptin/leptin receptor pathway is involved both in airway and in nasal epithelial homeostasis, in asthma and in allergic rhinitis, promoting also, in a cancer context, epithelial cell proliferation. Its expression decreases in subjects with uncontrolled and severe asthma and in presence of allergen exposure and is inversely correlated with airway remodelling, and cancer cell apoptosis.

Rationale: Serum chitinases may be novel biomarkers of airway inflammation and remodeling, but less is known about factors regulating their levels. Objectives: To examine serum chitotriosidase activity and YKL-40 levels in patients with asthma and chronic obstructive pulmonary disease (COPD) and evaluate clinically relevant factors that may affect chitinase levels, including genetic variability, corticosteroid treatment, disease exacerbations, and allergen exposure. Methods: Serum chitotriosidase (CHIT1) activity and YKL-40 (CHI3L1) levels, as well as the CHIT1 rs3831317 and CHI3L1 rs4950928 genotypes, were examined in subsets of patients with mild to moderate asthma (n = 76), severe asthma (n = 93), and COPD (n = 64) taking part in the European multicenter BIOAIR (Longitudinal Assessment of Clinical Course and Biomarkers in Severe Chronic Airway Disease) study. Blood was obtained at baseline, before and after a 2-week oral steroid intervention, up to six times during a 1-year period, and during exacerbations. Baseline chitinase levels were also measured in 72 healthy control subjects. The effect of allergen inhalation on blood and sputum YKL-40 levels was measured in two separate groups of patients with mild atopic asthma; one group underwent repeated low-dose allergen challenge (n = 15), and the other underwent high-dose allergen challenge (n = 16). Measurements and Main Results: Serum chitotriosidase and YKL-40 were significantly elevated in patients with asthma and those with COPD compared with healthy control subjects. Genotype and age strongly affected both YKL-40 and chitotriosidase activity, but associations with disease remained following adjustment for these factors. Correlations were observed with lung function but not with other biomarkers, including exhaled nitric oxide, blood eosinophils, periostin, and IgE. Generally, acute exacerbations, allergen-induced airway obstruction, and corticosteroid treatment did not affect circulating chitinase levels. Conclusions: YKL-40 and chitotriosidase are increased in asthma and more so in COPD. The data in the present study support these substances as being relatively steroid-insensitive, non-T-helper cell type 2-type biomarkers distinctly related to chronic inflammatory disease processes. Copyright © 2016 by the American Thoracic Society.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most prevalent drugs inducing hypersensitivity reactions. The aim of this analysis was to estimate the prevalence of NSAID-induced respiratory symptoms in population across Europe and to assess its association with upper and lower respiratory tract disorders. Methods: The GA2LEN survey was conducted in 22 centers in 15 European countries. Each of 19 centers selected random samples of 5000 adults aged 15–74 from their general population, and in three centers (Athens, Munich, Oslo), a younger population was sampled. Questionnaires including questions about age, gender, presence of symptoms of asthma, allergic rhinitis, chronic rhinosinusitis, smoking status, and history of NSAID-induced hypersensitivity reactions were sent to participants by mail. Totally, 62 737 participants completed the questionnaires. Results: The mean prevalence of NSAID-induced dyspnea was 1.9% and was highest in the three Polish centers [Katowice (4.9%), Krakow (4.8%), and Lodz (4.4%)] and lowest in Skopje, (0.9%), Amsterdam (1.1%), and Umea (1.2%). In multivariate analysis, the prevalence of respiratory reactions to NSAIDs was higher in participants with chronic rhinosinusitis symptoms (Odds Ratio 2.12; 95%CI 1.78–2.74), asthma symptoms in last 12 months (2.7; 2.18–3.35), hospitalization due to asthma (1.53; 1.22–1.99), and adults vs children (1.53; 1.24–1.89), but was not associated with allergic rhinitis. Conclusion: Our study documented significant variation between European countries in the prevalence of NSAID-induced respiratory hypersensitivity reactions, and association with chronic airway diseases, but also with environmental factors. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Drug delivery by inhalation is important for treatment of various pulmonary conditions such as allergy, asthma and chronic obstructive pulmonary disease as it can administer high drug doses rapidly and directly to the site of disease while minimizing systemic exposure and toxicity associated with oral or intravenous dosing. Nevertheless, therapeutic efficacy of inhaled drugs is often limited by rapid clearance from the site of action due to absorption into systemic circulation or metabolic degradation in the lungs, thereby necessitating frequent dosing and increasing systemic liability. Drug-loaded microparticles have been explored as a mechanism to sustain local drug levels in the lungs by virtue of controlled release. However, many attempts to achieve sustained release from inhaled microparticles focused on microparticles with mucoadhesive properties, overlooking the fundamental importance of mucus clearance in the airway as an innate defense against inhaled particles [1]. In this work we describe the preparation and the characterization of a cationic solid lipid system subjected to alginate coating for sustained release of salmeterol xinafoate (SX) into the lungs. The presence of mucoadhesive polymers allows solid lipid microparticles (SLMs) to adhere better to the mucous layer on the respiratory epithelium as compared with conventional carriers. The obtained systems have been characterized in terms of size, zeta potential, mucoadhesive properties and loading capacity (LC). Afterwards, we evaluated the cytotoxicity in vitro of SX, free or entrapped into SLMs, and empty microparticles by MTS viability assays on 16-HBE (human bronchial epithelial cells) cell lines.

Long-term birth cohort studies are essential to understanding the life course and childhood predictors of allergy and the complex interplay between genes and the environment (including lifestyle and socioeconomic determinants). Over 100 cohorts focusing on asthma and allergy have been initiated in the world over the past 30 years. Since 2004, several research initiatives funded under the EU Framework Program for Research and Technological Development FP6-FP7 have attempted to identify, compare, and evaluate pooling data from existing European birth cohorts (GA2LEN: Global Allergy and European Network, FP6; ENRIECO: Environmental Health Risks in European Birth Cohorts, FP7; CHICOS: Developing a Child Cohort Research Strategy for Europe, FP7; MeDALL: Mechanisms of the Development of ALLergy, FP7). However, there is a general lack of knowledge about these initiatives and their potentials. The aim of this paper is to review current and past EU-funded projects in order to make a summary of their goals and achievements and to suggest future research needs of these European birth cohort networks. © 2012 S. Karger AG, Basel.