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Introduction Inhaled corticosteroid/formoterol fumarate (ICS/FF) as needed is recommended by the Global Initiative for Asthma (GINA) as sole therapy in adults with mild asthma, with low-dose maintenance ICS plus short-acting β2-agonist (SABA) as an alternative. SABA alone is no longer recommended. Given these changes in recommendations, the observational PRIME study aimed to describe real-world treatment patterns in mild asthma in Europe. Methods Adults with asthma receiving low-dose maintenance ICS, or as needed ICS/FF or SABA were followed for 6 months. Data collected included Asthma Control Test (ACT), Asthma Control Questionnaire 5-item (ACQ-5), forced expiratory volume in 1 s (FEV1) and asthma exacerbations. Results The study was conducted in 883 patients in Germany, Italy, Poland and Spain; 833 (94.3%) completed follow-up. At enrolment, 32.2% received maintenance ICS, 56.3% ICS/FF as needed and 11.6% SABA as needed; 57.4%, 61.2% and 54.9%, respectively, had well-controlled asthma (ACQ-5/ACT definition). After 6 months, changes in mean FEV1 were small in the maintenance ICS and ICS/FF as needed groups, whereas there was a decline in FEV1 in the SABA as needed group. ACQ-5 total score improved from baseline in all three groups; 0.4%, 0.4% and 2.0% patients, respectively, had a severe exacerbation during the study. Conclusions More patients received ICS/FF as needed than SABA as needed, suggesting that physicians are aware of the latest treatment recommendations. This real-world study provides additional support to the use of ICS/FF as needed as preferred treatment for patients with mild asthma, whereas SABA as needed was associated with a fall in lung function and more severe exacerbations.

Abstract Patient‐reported outcome measures (PROMs) are used to assess a patient's health status at a particular point in time. They are essential in the development of person‐centred care. This paper reviews studies performed on PROMs for assessing AR and asthma control, in particular VAS scales that are included in the app MASK‐air® (Mobile Airways Sentinel networK) for asthma and rhinitis. VASs were initially developed on paper and pencil and tested for their criterion validity, cut‐offs and responsiveness. Then, a multicentric, multinational, double‐blind, placebo‐controlled, randomised control trial (DB‐PC‐RCT) using an electronic VAS form was carried out. Finally, with the development of MASK‐air® in 2015, previously validated VAS questions were adapted to the digital format and further methodologic evaluations were performed. VAS for asthma, rhinitis, conjunctivitis, work and EQ‐5D are included in the app. Additionally, two control‐medication scores for allergic symptoms of asthma (e‐DASTHMA) were validated for their criterion validity, cut‐offs and responsiveness.

Background: Second-generation oral H1-antihistamines, including bilastine, represent the emerging treatments of allergic rhinitis (including rhinoconjunctivitis) and chronic urticaria in both adults and children. This study analyses available evidence supporting the use of bilastine amongst second-generation antihistamines for the symptomatic treatment of allergic rhinitis and urticaria in adults and children. Methods: Consensus amongst experts from 17 countries on the ideal treatment of rhinitis and urticaria, and the specific role of bilastine was measured by means of a modified Delphi process. A total of 12 statements were voted on by the experts using a five-point Likert scale (1 = strongly disagree; 2 = disagree; 3 = undecided; 4 = agree; 5 = strongly agree). The definition of consensus was set at a minimum of 80% concordance for 4+5 scores (agree or strongly agree). Results: All proposed statements reached consensus, with a concordance of ≥98% for five statements and ≥96% for seven. Conclusions: The wide consensus obtained for the proposed statements suggests a prominent role for bilastine in the management of allergic rhinitis and urticaria.

IntroductionChronic obstructive lung diseases, such as asthma and COPD, appear to have a more extensive impact on overall functioning than previously believed. The latest data from clinical trials suggests a potential link between cognitive deterioration and chronic obstructive inflammatory lung disease. This raises the question of whether these diseases affect cognitive functions and whether any relevant biomarker may be identified.MethodsThis prospective observational study included 78 patients divided equally into asthma, COPD, and control groups (n=26, 27 and 25 respectively). The participants underwent identical examinations at the beginning of the study and after at least 12 months. The test battery comprised 16 questionnaires (11 self-rated, 5 observer-rated, assessing cognition and mental state), spirometry, and blood samples taken for PKA and CREB mRNA evaluation.ResultsA 2.3-fold increase in CREB mRNA was observed between examinations (p=0.014) for all participants; no distinctions were observed between the asthma, COPD, and control groups. Pooled, adjusted data revealed a borderline interaction between diagnosis and CREB expression in predicting MMSE (p=0.055) in COPD, CREB expression is also associated with MMSE (β=0.273, p=0.034) like with the other conducted tests (β=0.327, p=0.024) from COPD patients. No correlations were generally found for PKA, although one significant negative correlation was found between the first and second time points in the COPD group (β=-0.4157, p=0.049),.DiscussionChronic obstructive lung diseases, such as asthma and COPD, may have some linkage to impairment of cognitive functions. However, the noted rise in CREB mRNA expression might suggest a potential avenue for assessing possible changes in cognition, especially in COPD; such findings may reveal additional transcription factors linked to cognitive decline.

Abstract Rationale It is unclear how each individual asthma symptom is associated with asthma diagnosis or control. Objectives To assess the performance of individual asthma symptoms in the identification of patients with asthma and their association with asthma control. Methods In this cross‐sectional study, we assessed real‐world data using the MASK‐air® app. We compared the frequency of occurrence of five asthma symptoms (dyspnea, wheezing, chest tightness, fatigue and night symptoms, as assessed by the Control of Allergic Rhinitis and Asthma Test [CARAT] questionnaire) in patients with probable, possible or no current asthma. We calculated the sensitivity, specificity and predictive values of each symptom, and assessed the association between each symptom and asthma control (measured using the e‐DASTHMA score). Results were validated in a sample of patients with a physician‐established diagnosis of asthma. Measurement and Main Results We included 951 patients (2153 CARAT assessments), with 468 having probable asthma, 166 possible asthma and 317 no evidence of asthma. Wheezing displayed the highest specificity (90.5%) and positive predictive value (90.8%). In patients with probable asthma, dyspnea and chest tightness were more strongly associated with asthma control than other symptoms. Dyspnea was the symptom with the highest sensitivity (76.1%) and the one consistently associated with the control of asthma as assessed by e‐DASTHMA. Consistent results were observed when assessing patients with a physician‐made diagnosis of asthma. Conclusions Wheezing and chest tightness were the asthma symptoms with the highest specificity for asthma diagnosis, while dyspnea displayed the highest sensitivity and strongest association with asthma control.

BackgroundTo date, studies investigating the association between pre-biologic biomarker levels and post-biologic outcomes have been limited to single biomarkers and assessment of biologic efficacy from structured clinical trials.AimTo elucidate the associations of pre-biologic individual biomarker levels or their combinations with pre-to-post biologic changes in asthma outcomes in real-life.MethodsThis was a registry-based, cohort study using data from 23 countries, which shared data with the International Severe Asthma Registry (May 2017-February 2023). The investigated biomarkers (highest pre-biologic levels) were immunoglobulin E (IgE), blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO). Pre- to approximately 12-month post-biologic change for each of three asthma outcome domains (i.e. exacerbation rate, symptom control and lung function), and the association of this change with pre-biologic biomarkers was investigated for individual and combined biomarkers.ResultsOverall, 3751 patients initiated biologics and were included in the analysis. No association was found between pre-biologic BEC and pre-to-post biologic change in exacerbation rate for any biologic class. However, higher pre-biologic BEC and FeNO were both associated with greater post-biologic improvement in FEV1 for both anti-IgE and anti-IL5/5R, with a trend for anti-IL4Rα. Mean FEV1 improved by 27-178 mL post-anti-IgE as pre-biologic BEC increased (250 to 1000 cells/µL), and by 43-216 mL and 129-250 mL post-anti-IL5/5R and -anti-IL4Rα, respectively along the same BEC gradient. Corresponding improvements along a FeNO gradient (25-100 ppb) were 41-274 mL, 69-207 mL and 148-224 mL for anti-IgE, anti-IL5/5R, and anti-IL4Rα, respectively. Higher baseline BEC was also associated with lower probability of uncontrolled asthma (OR 0.392; p=0.001) post-biologic for anti-IL5/5R. Pre-biologic IgE was a poor predictor of subsequent pre-to-post-biologic change for all outcomes assessed for all biologics. The combination of BEC + FeNO marginally improved the prediction of post-biologic FEV1 increase (adjusted R2: 0.751), compared to BEC (adjusted R2: 0.747) or FeNO alone (adjusted R2: 0.743) (p=0.005 and

Chronic inflammatory diseases of the lung are some of the leading causes of mortality and significant morbidity worldwide. Despite the tremendous burden these conditions put on global healthcare, treatment options for most of these diseases remain scarce. Inhaled corticosteroids and beta-adrenergic agonists, while effective for symptom control and widely available, are linked to severe and progressive side effects, affecting long-term patient compliance. Biologic drugs, in particular peptide inhibitors and monoclonal antibodies show promise as therapeutics for chronic pulmonary diseases. Peptide inhibitor-based treatments have already been proposed for a range of diseases, including infectious disease, cancers and even Alzheimer disease, while monoclonal antibodies have already been implemented as therapeutics for a range of conditions. Several biologic agents are currently being developed for the treatment of asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and pulmonary sarcoidosis. This article is a review of the biologics already employed in the treatment of chronic inflammatory pulmonary diseases and recent progress in the development of the most promising of those treatments, with particular focus on randomised clinical trial outcomes.

Background The use of anti-interleukin-5 (IL5) for severe asthma is based on criteria from randomised controlled trials (RCTs), but in real-life patients might not fulfil the eligibility criteria but may benefit from biologics. We aimed to characterise patients starting anti-IL5(R) in Europe and evaluate the discrepancies between initiation of anti-IL5(R) in real life and in RCTs. Materials and methods We performed a cross-sectional analysis with data from the severe asthma patients at the start of anti-IL5(R) in the Severe Heterogeneous Asthma Research collaboration Patient-centred (SHARP Central) registry. We compared the baseline characteristics of the patients starting anti-IL5(R) from 11 European countries within SHARP with the baseline characteristics of the severe asthma patients from 10 RCTs (four for mepolizumab, three for benralizumab and three for reslizumab). Patients were evaluated following eligibility criteria from the RCTs of anti-IL5 therapies. Results Patients starting anti-IL5(R) in Europe (n=1231) differed in terms of smoking history, clinical characteristics and medication use. The characteristics of severe asthma patients in the SHARP registry differed from the characteristics of patients in RCTs. Only 327 (26.56%) patients fulfilled eligibility criteria of all the RCTs; 24 patients were eligible for mepolizumab, 100 for benralizumab and 52 reslizumab. The main characteristics of ineligibility were: ≥10 pack-years, respiratory diseases other than asthma, Asthma Control Questionnaire score ≤1.5 and low-dose inhaled corticosteroids. Conclusion A large proportion of patients in the SHARP registry would not have been eligible for anti-IL5(R) treatment in RCTs, demonstrating the importance of real-life cohorts in describing the efficacy of biologics in a broader population of patients with severe asthma.

Summary: Background: Validated questionnaires are used to assess asthma control over the past 1–4 weeks from reporting. However, they do not adequately capture asthma control in patients with fluctuating symptoms. Using the Mobile Airways Sentinel Network for airway diseases (MASK-air) app, we developed and validated an electronic daily asthma control score (e-DASTHMA). Methods: We used MASK-air data (freely available to users in 27 countries) to develop and assess different daily control scores for asthma. Data-driven control scores were developed based on asthma symptoms reported by a visual analogue scale (VAS) and self-reported asthma medication use. We included the daily monitoring data from all MASK-air users aged 16–90 years (or older than 13 years to 90 years in countries with a lower age of digital consent) who had used the app in at least 3 different calendar months and had reported at least 1 day of asthma medication use. For each score, we assessed construct validity, test–retest reliability, responsiveness, and accuracy. We used VASs on dyspnoea and work disturbance, EQ-5D-VAS, Control of Allergic Rhinitis and Asthma Test (CARAT), CARAT asthma, and Work Productivity and Activity Impairment: Allergy Specific (WPAI:AS) questionnaires as comparators. We performed an internal validation using MASK-air data from Jan 1 to Oct 12, 2022, and an external validation using a cohort of patients with physician-diagnosed asthma (the INSPIRERS cohort) who had had their diagnosis and control (Global Initiative for Asthma [GINA] classification) of asthma ascertained by a physician. Findings: We studied 135 635 days of MASK-air data from 1662 users from May 21, 2015, to Dec 31, 2021. The scores were strongly correlated with VAS dyspnoea (Spearman correlation coefficient range 0·68–0·82) and moderately correlated with work comparators and quality-of-life-related comparators (for WPAI:AS work, we observed Spearman correlation coefficients of 0·59–0·68). They also displayed high test–retest reliability (intraclass correlation coefficients range 0·79–0·95) and moderate-to-high responsiveness (correlation coefficient range 0·69–0·79; effect size measures range 0·57–0·99 in the comparison with VAS dyspnoea). The best-performing score displayed a strong correlation with the effect of asthma on work and school activities in the INSPIRERS cohort (Spearman correlation coefficients 0·70; 95% CI 0·61–0·78) and good accuracy for the identification of patients with uncontrolled or partly controlled asthma according to GINA (area under the receiver operating curve 0·73; 95% CI 0·68–0·78). Interpretation: e-DASTHMA is a good tool for the daily assessment of asthma control. This tool can be used as an endpoint in clinical trials as well as in clinical practice to assess fluctuations in asthma control and guide treatment optimisation. Funding: None.

Abstract MASK‐air®, a validated mHealth app (Medical Device regulation Class IIa) has enabled large observational implementation studies in over 58,000 people with allergic rhinitis and/or asthma. It can help to address unmet patient needs in rhinitis and asthma care. MASK‐air® is a Good Practice of DG Santé on digitally‐enabled, patient‐centred care. It is also a candidate Good Practice of OECD (Organisation for Economic Co‐operation and Development). MASK‐air® data has enabled novel phenotype discovery and characterisation, as well as novel insights into the management of allergic rhinitis. MASK‐air® data show that most rhinitis patients (i) are not adherent and do not follow guidelines, (ii) use as‐needed treatment, (iii) do not take medication when they are well, (iv) increase their treatment based on symptoms and (v) do not use the recommended treatment. The data also show that control (symptoms, work productivity, educational performance) is not always improved by medications. A combined symptom‐medication score (ARIA‐EAACI‐CSMS) has been validated for clinical practice and trials. The implications of the novel MASK‐air® results should lead to change management in rhinitis and asthma.

Patients with moderate-to-severe asthma may now be treated using a variety of monoclonal antibodies that target key inflammatory cytokines involved in disease pathogenesis. Existing clinical data on anti-IgE, anti-IL-5 and other immunological pathways indicate these therapies to offer reduced exacerbation rates, improved lung function, greater asthma control and better quality of life. However, as several patients still do not achieve satisfactory clinical response with the antibodies available, many more biologics, aiming different immunological pathways, are under evaluation. This review summarizes recent data on existing and potential monoclonal antibodies in asthma. Recent advances have resulted in the registration of a new antibody targeting TSLP (tezepelumab), with others being under development. Some of the researched monoclonal antibodies (e.g. anti-IL-13 tralokinumab and lebrikizumab or anti-IL-17A secukinumab) have shown optimistic results in preliminary research; however, these have been discontinued in asthma clinical research. In addition, as available monoclonal antibody treatments have shown little benefit among patients with T2-low asthma, research continues in this area, with several antibodies in development. This article summarizes the available pre-clinical and clinical data on new and emerging drugs for treating severe asthma, discusses discontinued treatments and outlines future directions in this area.

Abstract Digital health is an umbrella term which encompasses eHealth and benefits from areas such as advanced computer sciences. eHealth includes mHealth apps, which offer the potential to redesign aspects of healthcare delivery. The capacity of apps to collect large amounts of longitudinal, real‐time, real‐world data enables the progression of biomedical knowledge. Apps for rhinitis and rhinosinusitis were searched for in the Google Play and Apple App stores, via an automatic market research tool recently developed using JavaScript. Over 1500 apps for allergic rhinitis and rhinosinusitis were identified, some dealing with multimorbidity. However, only six apps for rhinitis (AirRater, AllergyMonitor, AllerSearch, Husteblume, MASK‐air and Pollen App) and one for rhinosinusitis (Galenus Health) have so far published results in the scientific literature. These apps were reviewed for their validation, discovery of novel allergy phenotypes, optimisation of identifying the pollen season, novel approaches in diagnosis and management (pharmacotherapy and allergen immunotherapy) as well as adherence to treatment. Published evidence demonstrates the potential of mobile health apps to advance in the characterisation, diagnosis and management of rhinitis and rhinosinusitis patients.

Introduction Treatment with biologics for severe asthma is informed by international and national guidelines and defined by national regulating bodies, but how these drugs are used in real-life is unknown. Materials and methods The European Respiratory Society (ERS) SHARP Clinical Research Collaboration conducted a three-step survey collecting information on asthma biologics use in Europe. Five geographically distant countries defined the survey questions, focusing on seven end-points: biologics availability and financial issues, prescription and administration modalities, inclusion criteria, continuation criteria, switching biologics, combining biologics and evaluation of corticosteroid toxicity. The survey was then sent to SHARP National Leads of 28 European countries. Finally, selected questions were submitted to a broad group of 263 asthma experts identified by national societies. Results Availability of biologics varied between countries, with 17 out of 28 countries having all five existing biologics. Authorised prescribers (pulmonologists and other specialists) also differed. In-hospital administration was the preferred deliverance modality. While exacerbation rate was used as an inclusion criterion in all countries, forced expiratory volume in 1 s was used in 46%. Blood eosinophils were an inclusion criterion in all countries for interleukin-5 (IL-5)-targeted and IL-4/IL-13-targeted biologics, with varying thresholds. There were no formally established criteria for continuing biologics. Reduction in exacerbations represented the most important benchmark, followed by improvement in asthma control and quality of life. Only 73% (191 out of 263) of surveyed clinicians assessed their patients for corticosteroid-induced toxicity. Conclusion Our study reveals important heterogeneity in the use of asthma biologics across Europe. To what extent this impacts on clinical outcomes relevant to patients and healthcare services needs further investigation.

Abstract Background Allergic rhinitis (AR) management requires a coordinated effort from healthcare providers and patients. Pharmacists are key members of these integrated care pathways resolving medication‐related problems, optimizing regimens, improving adherence and recommending therapies while establishing liaisons between patients and physicians. Methods Allergic Rhinitis and its Impact on Asthma (ARIA) first published a reference document on the pharmacist's role in allergic rhinitis management in 2004. Several guidelines were developed over the past 20 years improving the care of allergic rhinitis patients through an evidence‐based, integrated care approach. Results This ARIA/EAACI/FIP Position Paper is based on the latest ARIA in the Pharmacy guidelines and provides: (a) a structured approach to pharmacists identifying people with AR and/or allergic conjunctivitis as well as those at risk of poor disease control; (b) an evidence‐based clinical decision support tool for optimising the management of allergic rhinitis in the community pharmacy; and (c) a framework of referral to the physician. Conclusion This document is not intended to be a mandatory standard of care but is provided as a basis for pharmacists and their staff to develop relevant local standards of care for their patients, within their local practice environment. Pharmacy care varies between countries, and the guide should be adapted to the local situation.

Abstract The single‐inhaler extrafine formulation triple combination beclometasone dipropionate (BDP), formoterol fumarate (FF) plus glycopyrronium bromide (GB) is available for asthma management in adults. Its use in adolescents has not yet been evaluated. This study investigated the pharmacokinetic profile of BDP/FF/GB in adults and adolescents, with the aim of ruling out higher plasma exposure in adolescents compared to adults. In this open‐label, non‐randomized study, patients with asthma aged 12–17 (adolescents) and 18–64 years (adults) self‐administered a single dose of BDP/FF/GB 400/24/50 μg via pressurized metered‐dose inhaler (pMDI). The primary objective was to rule out higher systemic exposure to beclometasone 17‐monopropionate (B17MP; active metabolite of BDP), formoterol, and GB in terms of the area under the plasma concentration‐time curve from 0 to the last quantifiable concentration (AUC0–t) in adolescents versus adults. A total of 40 adolescents and 40 adults entered the study (mean age of 14.8 and 43.6 years, respectively). The primary objective (AUC0–t) was met, with the upper 90% confidence interval of the geometric mean ratio between adolescents and adults

Abstract Background Asthma is a heterogeneous chronic inflammatory disease of the bronchi, the course of which is significantly influenced by extrinsic factors (specific and non‐specific). Methods The aim of this study was to evaluate the effect of these factors represented by nasal allergen challenge (specific factors) and methacholine challenge test (non‐specific) on changes in mRNA expression of genes encoding the TGF‐β (TGF‐β1 and TGF‐β3)‒Smad (mitogen‐activated protein kinase 1/3 [MPK1/3], Smad1/3/6/7) signaling pathway in asthmatic patients. Results Seventy‐five subjects were included in the study, of whom 27 were applied an intranasal allergen provocation and 48 a methacholine provocation. There were 9 men and 18 women in the intranasal provocation group, and 17 men and 31 women in the methacholine test group. We found that both examined the types of challenges contributed to changes in the relative expression of genes of the TGF‐β (TGF‐β1 and TGF‐β3)‒Smad (MPK1/3, Smad1/3/6/7) signaling pathway in asthmatic patients. A decrease was noted for MAPK1, MAPK3, Smad3, Smad6, and Smad7 genes and an increase of up to 2.5 times for TGF‐β1 gene. Conclusions Our experiment allows us to conclude that the change in the mRNA expression of the TGF‐β1–MPK1/3 and Smad3/6/7 genes occurs after an intranasal allergen and bronchial methacholine challenge.

Abstract Background Lebrikizumab is a monoclonal antibody that modulates activity of interleukin‐13. The Phase 3 ACOUSTICS study assessed lebrikizumab efficacy and safety in adolescents with uncontrolled asthma despite standard‐of‐care treatment. Methods Adolescents (aged 12–17 years) with uncontrolled asthma, prebronchodilator forced expiratory volume in 1 s 40%–90% predicted, and stable background therapy were randomised 1:1:1 to receive lebrikizumab 125 or 37.5 mg or placebo subcutaneously once every 4 weeks. Primary efficacy endpoint was asthma exacerbation rate over 52 weeks. Results Between August 2013 and July 2016, 579 patients were screened and 346 were randomised; 224 (65%) completed the study with 52 weeks of treatment. Lebrikizumab 125 mg (n = 116) reduced the exacerbation rate at 52 weeks versus placebo (n = 117; adjusted rate ratio [RR] 0.49 [95% CI 0.28–0.83]; 51% rate reduction). Lebrikizumab 37.5 mg (n = 113) was less effective at reducing exacerbations (RR 0.60 [95% CI 0.35–1.03]; 40% rate reduction). In patients with blood eosinophil counts ≥300 cells/μl, both lebrikizumab doses reduced exacerbations (125 mg: RR 0.44 [95% CI 0.21–0.89]; 37.5 mg: 0.42 [95% CI 0.19–0.93]). Treatment‐emergent adverse events, serious adverse events, and adverse events leading to study discontinuation occurred in 155 (68%), 7 (3%), and 5 (2%) of 229 patients who received lebrikizumab (both 125 and 37.5 mg doses) and in 72 (62%), 4 (3%), and 1 (1%) of 117 who received placebo, respectively. No deaths occurred. Conclusion Lebrikizumab 125 mg reduced asthma exacerbation rates in adolescents with uncontrolled asthma. However, the study was prematurely terminated (sponsor's decision) potentially limiting interpretation of results. Clinical trial registration NCT01875003 (www.ClinicalTrials.gov).

IntroductionTGF-β and its receptors play a crucial role in asthma pathogenesis and bronchial remodeling in the course of the disease. TGF-β1, TGF-β2, and TGF-β3 isoforms are responsible for chronic inflammation, bronchial hyperreactivity, myofibroblast activation, fibrosis, bronchial remodeling, and change the expression of approximately 1000 genes in asthma. TGF-β SNPs are associated with the elevated plasma level of TGF-β1, an increased level of total IgE, and an increased risk of remodeling of bronchi.MethodsThe analysis of selected TGF-β1, TGF-β2, TGF-β3-related single-nucleotide polymorphisms (SNP) was conducted on 652 DNA samples with an application of the MassARRAY® using the mass spectrometry (MALDI-TOF MS). Dataset was randomly split into training (80%) and validation sets (20%). For both asthma diagnosis and severity prediction, the C5.0 modelling with hyperparameter optimization was conducted on: clinical and SNP data (Clinical+TGF), only clinical (OnlyClinical) and minimum redundancy feature selection set (MRMR). Area under ROC (AUCROC) curves were compared using DeLong’s test.ResultsMinor allele carriers (MACs) in SNP rs2009112 [OR=1.85 (95%CI:1.11-3.1), p=0.016], rs2796821 [OR=1.72 (95%CI:1.1-2.69), p=0.017] and rs2796822 [OR=1.71 (95%CI:1.07-2.71), p=0.022] demonstrated an increased odds of severe asthma. Clinical+TGF model presented better diagnostic potential than OnlyClinical model in both training (p=0.0009) and validation (AUCROC=0.87 vs. 0.80,p=0.0052). At the same time, the MRMR model was not worse than the Clinical+TGF model (p=0.3607 on the training set, p=0.1590 on the validation set), while it was better in comparison with the Only Clinical model (p=0.0010 on the training set, p=0.0235 on validation set, AUCROC=0.85 vs. 0.87). On validation set Clinical+TGF model allowed for asthma diagnosis prediction with 88.4% sensitivity and 73.8% specificity.DiscussionDerived predictive models suggest the analysis of selected SNPs in TGF-β genes in combination with clinical factors could predict asthma diagnosis with high sensitivity and specificity, however, the benefit of SNP analysis in severity prediction was not shown.

Abstract Background Evidence regarding the effectiveness of allergen immunotherapy (AIT) on allergic rhinitis has been provided mostly by randomised controlled trials, with little data from real‐life studies. Objective To compare the reported control of allergic rhinitis symptoms in three groups of users of the MASK‐air® app: those receiving sublingual AIT (SLIT), those receiving subcutaneous AIT (SCIT), and those receiving no AIT. Methods We assessed the MASK‐air® data of European users with self‐reported grass pollen allergy, comparing the data reported by patients receiving SLIT, SCIT and no AIT. Outcome variables included the daily impact of allergy symptoms globally and on work (measured by visual analogue scales—VASs), and a combined symptom‐medication score (CSMS). We applied Bayesian mixed‐effects models, with clustering by patient, country and pollen season. Results We analysed a total of 42,756 days from 1,093 grass allergy patients, including 18,479 days of users under AIT. Compared to no AIT, SCIT was associated with similar VAS levels and CSMS. Compared to no AIT, SLIT‐tablet was associated with lower values of VAS global allergy symptoms (average difference = 7.5 units out of 100; 95% credible interval [95%CrI] = −12.1;−2.8), lower VAS Work (average difference = 5.0; 95%CrI = −8.5;−1.5), and a lower CSMS (average difference = 3.7; 95%CrI = −9.3;2.2). When compared to SCIT, SLIT‐tablet was associated with lower VAS global allergy symptoms (average difference = 10.2; 95%CrI = −17.2;−2.8), lower VAS Work (average difference = 7.8; 95%CrI = −15.1;0.2), and a lower CSMS (average difference = 9.3; 95%CrI = −18.5;0.2). Conclusion In patients with grass pollen allergy, SLIT‐tablet, when compared to no AIT and to SCIT, is associated with lower reported symptom severity. Future longitudinal studies following internationally‐harmonised standards for performing and reporting real‐world data in AIT are needed to better understand its ‘real‐world’ effectiveness.

Abstract Vaccination is a highly effective preventive measure against COVID‐19. However, complementary treatments are needed to better control the disease. Fermented vegetables and spices, agonists of the antioxidant transcription factor nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) and TRPA1/V1 channels (Transient Receptor Potential Ankyrin 1 and Vanillin 1), may help in the control of COVID‐19. Some preliminary clinical trials suggest that curcumin (spice) can prevent some of the COVID‐19 symptoms. Before any conclusion can be drawn and these treatments recommended for COVID‐19, the data warrant confirmation. In particular, the benefits of the foods need to be assessed in more patients, through research studies and large trials employing a double‐blind, placebo‐controlled design.

Abstract Background Treatment adherence greatly influences the clinical outcomes in various fields of medicine, including management of asthma and COPD. With the recent implementation of a nationwide e-Health solutions in Poland, new and unique opportunities for studying primary non-adherence in asthma and COPD emerged. The aim was to study primary non-adherence to inhaled medications available in Poland indicated in asthma and/or COPD and analyse the impact of patients’ demographics and inhalers’ characteristics (dry powder inhalers (DPIs) vs metered dose inhalers (MDIs) and presence of a dosage counter) on primary non-adherence. Methods A retrospective analysis of all e-prescriptions issued in Poland in 2018 (n = 119,880) from the national e-prescription pilot framework. Results Primary non-adherence for inhalable medications reached 15.3%. It significantly differed among age groups—the lowest (10.8%) was in 75 + years-old patients, highest (18%) in 65–74 years-old patients. No gender differences in primary non-adherence were found. The highest non-adherence was observed for ICS + LABA combinations (18.86%). A significant difference was found between MDI and DPI inhalers and between inhalers with/without a dosage counter. Conclusions Out of e-prescriptions for inhaled medications issued in 2018 in Poland, 15.3% were not redeemed. The degree of primary non-adherence was influenced by age, but not gender. Significant differences between MDIs and DPIs and between inhalers with/without a dosage counter were observed.

Abstract New recommendations from the Global Initiative for Asthma (GINA) were released in a pocket guide form on April 12, 2019. These recommendations provide very important changes to the management of asthma, especially regarding the treatment of intermittent and mild asthma. Due to safety concerns, GINA experts no longer recommend treatment with a short-acting β2 agonist alone. Henceforth, all adults and adolescents (but not yet children) with mild asthma should receive either symptom-driven or daily low-dose ICS. The main goal of this new approach is to reduce the risk of serious asthma exacerbations and asthma-related deaths in the population of patients with mild asthma. Herein, the authors present the epidemiological and clinical data regarding the risks of excessive SABA use and the benefits of regular treatment with inhaled corticosteroids. The authors deliver a critical review on the evolution of the changes in the GINA experts’ standpoint and provide evidence-based background for the new approach to asthma treatment. Moreover, the authors identify gaps and unmet needs still present in the current asthma management recommendations and discuss them thoroughly.

Abstract Reported COVID-19 deaths in Germany are relatively low as compared to many European countries. Among the several explanations proposed, an early and large testing of the population was put forward. Most current debates on COVID-19 focus on the differences among countries, but little attention has been given to regional differences and diet. The low-death rate European countries (e.g. Austria, Baltic States, Czech Republic, Finland, Norway, Poland, Slovakia) have used different quarantine and/or confinement times and methods and none have performed as many early tests as Germany. Among other factors that may be significant are the dietary habits. It seems that some foods largely used in these countries may reduce angiotensin-converting enzyme activity or are anti-oxidants. Among the many possible areas of research, it might be important to understand diet and angiotensin-converting enzyme-2 (ACE2) levels in populations with different COVID-19 death rates since dietary interventions may be of great benefit.

Abstract Background MASK‐air® is an app that supports allergic rhinitis patients in disease control. Users register daily allergy symptoms and their impact on activities using visual analog scales (VASs). We aimed to assess the concurrent validity, reliability, and responsiveness of these daily VASs. Methods Daily monitoring VAS data were assessed in MASK‐air® users with allergic rhinitis. Concurrent validity was assessed by correlating daily VAS values with those of the EuroQol‐5 Dimensions (EQ‐5D) VAS, the Control of Allergic Rhinitis and Asthma Test (CARAT) score, and the Work Productivity and Activity Impairment Allergic Specific (WPAI‐AS) Questionnaire (work and activity impairment scores). Intra‐rater reliability was assessed in users providing multiple daily VASs within the same day. Test–retest reliability was tested in clinically stable users, as defined by the EQ‐5D VAS, CARAT, or “VAS Work” (i.e., VAS assessing the impact of allergy on work). Responsiveness was determined in users with two consecutive measurements of EQ‐5D‐VAS or “VAS Work” indicating clinical change. Results A total of 17,780 MASK‐air® users, with 317,176 VAS days, were assessed. Concurrent validity was moderate–high (Spearman correlation coefficient range: 0.437–0.716). Intra‐rater reliability intraclass correlation coefficients (ICCs) ranged between 0.870 (VAS assessing global allergy symptoms) and 0.937 (VAS assessing allergy symptoms on sleep). Test–retest reliability ICCs ranged between 0.604 and 0.878—“VAS Work” and “VAS asthma” presented the highest ICCs. Moderate/large responsiveness effect sizes were observed—the sleep VAS was associated with lower responsiveness, while the global allergy symptoms VAS demonstrated higher responsiveness. Conclusion In MASK‐air®, daily monitoring VASs have high intra‐rater reliability and moderate–high validity, reliability, and responsiveness, pointing to a reliable measure of symptom loads.

An amendment to this paper has been published and can be accessed via the original article.

Abstract Background The Nature Step to Respiratory Health was the overarching theme of the 12th General Meeting of the Global Alliance against Chronic Respiratory Diseases (GARD) in Helsinki, August 2018. New approaches are needed to improve respiratory health and reduce premature mortality of chronic diseases by 30% till 2030 (UN Sustainable Development Goals, SDGs). Planetary health is defined as the health of human civilization and the state of the natural systems on which it depends. Planetary health and human health are interconnected, and both need to be considered by individuals and governments while addressing several SDGs. Results The concept of the Nature Step has evolved from innovative research indicating, how changed lifestyle in urban surroundings reduces contact with biodiverse environments, impoverishes microbiota, affects immune regulation and increases risk of NCDs. The Nature Step calls for strengthening connections to nature. Physical activity in natural environments should be promoted, use of fresh vegetables, fruits and water increased, and consumption of sugary drinks, tobacco and alcohol restricted. Nature relatedness should be part of everyday life and especially emphasized in the care of children and the elderly. Taking “nature” to modern cities in a controlled way is possible but a challenge for urban planning, nature conservation, housing, traffic arrangements, energy production, and importantly for supplying and distributing food. Actions against the well-known respiratory risk factors, air pollution and smoking, should be taken simultaneously. Conclusions In Finland and elsewhere in Europe, successful programmes have been implemented to reduce the burden of respiratory disorders and other NCDs. Unhealthy behaviour can be changed by well-coordinated actions involving all stakeholders. The growing public health concern caused by NCDs in urban surroundings cannot be solved by health care alone; a multidisciplinary approach is mandatory.

Abstract Background In all societies, the burden and cost of allergic and chronic respiratory diseases are increasing rapidly. Most economies are struggling to deliver modern health care effectively. There is a need to support the transformation of the health care system into integrated care with organizational health literacy. Main body As an example for chronic disease care, MASK (Mobile Airways Sentinel NetworK), a new project of the ARIA (Allergic Rhinitis and its Impact on Asthma) initiative, and POLLAR (Impact of Air POLLution on Asthma and Rhinitis, EIT Health), in collaboration with professional and patient organizations in the field of allergy and airway diseases, are proposing real-life ICPs centred around the patient with rhinitis, and using mHealth to monitor environmental exposure. Three aspects of care pathways are being developed: (i) Patient participation, health literacy and self-care through technology-assisted “patient activation”, (ii) Implementation of care pathways by pharmacists and (iii) Next-generation guidelines assessing the recommendations of GRADE guidelines in rhinitis and asthma using real-world evidence (RWE) obtained through mobile technology. The EU and global political agendas are of great importance in supporting the digital transformation of health and care, and MASK has been recognized by DG Santé as a Good Practice in the field of digitally-enabled, integrated, person-centred care. Conclusion In 20 years, ARIA has considerably evolved from the first multimorbidity guideline in respiratory diseases to the digital transformation of health and care with a strong political involvement.

Exendin-4 (Ex-4), better known in its synthetic form and used clinically as exenatide, currently applied in the treatment of diabetes, induces a beneficial impact on nerve cells, and shows promising effects in obstructive lung diseases. At an advanced age, the development of the neurodegenerative process of brain tissue is masked by numerous concomitant diseases. The initial latent phase of neurodegenerative disease results in occurrence of manifestations at an advanced stage. To protect the brain and to simultaneously ensure proper treatment of common coexisting conditions in late life, such as diabetes, chronic obstructive pulmonary disease, or asthma, a pleiotropic medication should be chosen. Molecular mechanisms of Ex-4 exert neuroprotective effects or lead to secondary neurogenesis. Additionally, Ex-4 plays an important role in anti-inflammatory actions which are necessary both in the case of asthma and Parkinson’s disease. Specific receptors in the lungs also reduce the secretion of surfactants, which decreases the risk of exacerbation in chronic obstructive lung disease. In a great number of patients suffering from diabetes, asthma, or chronic lung disease, there is a great potential for both treatment of the main condition and protection against brain neurodegeneration.

COVID-19 is described in a clinical case involving a patient who proposed the hypothesis that Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-interacting nutrients may help to prevent severe COVID-19 symptoms. Capsules of broccoli seeds containing glucoraphanin were being taken before the onset of SARS-CoV-2 infection and were continued daily for over a month after the first COVID-19 symptoms. They were found to reduce many of the symptoms rapidly and for a duration of 6–12 h by repeated dosing. When the patient was stable but still suffering from cough and nasal obstruction when not taking the broccoli capsules, a double-blind induced cough challenge confirmed the speed of onset of the capsules (less than 10 min). A second clinical case with lower broccoli doses carried out during the cytokine storm confirmed the clinical benefits already observed. A third clinical case showed similar effects at the onset of symptoms. In the first clinical trial, we used a dose of under 600 μmol per day of glucoraphanin. However, such a high dose may induce pharmacologic effects that require careful examination before the performance of any study. It is likely that the fast onset of action is mediated through the TRPA1 channel. These experimental clinical cases represent a proof-of-concept confirming the hypothesis that Nrf2-interacting nutrients are effective in COVID-19. However, this cannot be used in practice before the availability of further safety data, and confirmation is necessary through proper trials on efficacy and safety.

Asthma is a chronic and heterogenic respiratory tract disorder with a high global prevalence. The underlying chronic inflammatory process and airway remodeling (AR) contribute to the symptomatology of the disease. The most severely ill asthma patients may now be treated using a variety of monoclonal antibodies aiming key inflammatory cytokines involved in asthma pathogenesis. Although clinical data shows much beneficial effects of biological therapies in terms of reduction of exacerbation rates, improvement of lung functions, asthma control and patients' quality of life, little is known on the effects of these monoclonal antibodies on AR—a key clinical trait of long-term asthma management. In this review, the authors summarize the data on the proven effects of monoclonal antibodies in asthma on AR. To date, in terms of reversing AR, the mostly studied was omalizumab. However, some studies also addressed this clinical issue in context of other severe asthma biological therapies (mepolizumab, benralizumab, tralokinumab). Still, data on effects of particular biological therapies on AR in severe asthma are incomplete and require further studies. According to the American Thoracic Society research recommendations, future research shall focus on AR in asthma and improve drugs targeting AR, including the available and future monoclonal antibodies.

BackgroundIn allergic conditions such as allergic rhinitis and urticaria, orally administered H1-antihistamines belong to first-line therapy and therefore, are widely prescribed. Due to the frequent, and often chronic, course of allergic diseases, adherence is of great importance. In 2018 a novel, nationwide e-prescription system was piloted in Poland, which allowed to analyze primary non-adherence to orally administered H1 antihistamines.ObjectivesTo assess the primary non-adherence to orally administered H1-antihistamines in Poland, defined as not redeeming the drug issued on a particular e-prescription within its validity period.MethodsThe study was based on all e-prescriptions issued in Poland in 2018, issued for 119.880 drugs. The analysis included nine major orally administered H1 antihistamines available in Poland.ResultsOut of 2280 analyzed e-prescriptions on orally administered antihistamines, 1803 (79.1%) of them were redeemed. Therefore, the level of primary non-adherence reached 21%. Among women it reached 19.9%, but it was not significantly lower than among men (23.4%, p=0.064). The highest non-adherence (31.3%) was observed in the age group 19-39, whilst the highest adherence rate (84.6%) was observed in those 75 years or older. The most frequently prescribed second-generation antihistamine was bilastine—596 e-prescriptions with 23.7% primary non-adherence.ConclusionsMore than 1 out of 5 e-prescriptions on orally administered H1-antihistamines were not redeemed in Poland in 2018. Age, but not gender, significantly influenced the degree of primary non-adherence to these drugs. To authors knowledge, this is the first real-life study on primary non-adherence to H1-antihistamines in Poland and one of the very few on this subject worldwide.

Asthma is a chronic and heterogenic disease of the respiratory system, one of the most common lung diseases worldwide. The underlying pathologies, which are chronic inflammatory process and airway remodeling (AR), are mediated by numerous cells and cytokines. Particularly interesting in this field is the platelet-derived growth factor (PDGF), one of the members of the human growth factor family. In this article, the authors analyze the available data on the role of PDGF in asthma in experimental models and in human research. PDGF is expressed in airway by various cells contributing to asthma pathogenesis—mast cells, eosinophils, and airway epithelial cells. Research confirms the thesis that this factor is also secreted by these cells in the course of asthma. The main effects of PDGF on bronchi are the proliferation of airway smooth muscle (ASM) cells, migration of ASM cells into the epithelium and enhanced collagen synthesis by lung fibroblasts. The importance of AR in asthma is well recognized and new therapies should also aim to manage it, possibly targeting PDGFRs. Further studies on new and already existing drugs, mediating the PDGF signaling and related to asthma are necessary. Several promising drugs from the tyrosine kinase inhibitors group, including nilotinib, imatinib masitinib, and sunitinib, are currently being clinically tested and other molecules are likely to emerge in this field.

Abstract Background Interleukin(IL)-33 is an epithelial alarmin important for eosinophil maturation, activation and survival. The aim of this study was to examine the association between IL-33, its receptor expression and airway eosinophilic inflammation in non-atopic COPD. Methods IL-33 concentrations were measured in exhaled breath condensate (EBC) collected from healthy non-smokers, asthmatics and non-atopic COPD subjects using ELISA. Serum and sputum samples were collected from healthy non-smokers, healthy smokers and non-atopic COPD patients. Based on sputum eosinophil count, COPD subjects were divided into subgroups with airway eosinophilic inflammation (sputum eosinophils > 3%) or without (sputum eosinophils ≤3%). IL-33 and soluble form of IL-33 receptor (sST2) protein concentrations were measured in serum and sputum supernatants using ELISA. ST2 mRNA expression was measured in peripheral mononuclear cells and sputum cells by qPCR. Hemopoietic progenitor cells (HPC) expressing ST2 and intracellular IL-5 were enumerated in blood and induced sputum by means of flow cytometry. Results IL-33 levels in EBC were increased in COPD patients to a similar extent as in asthma and correlated with blood eosinophil count. Furthermore, serum and sputum IL-33 levels were higher in COPD subjects with sputum eosinophilia than in those with a sputum eosinophil count ≤3% (p

Background: A key player in the fibrotic process is the transforming growth factor β (TGF‐β) which enhances extracellular matrix production by increasing the transcription of matrix proteins. The cytokine TGF‐β first binds to the TGFβRII receptor (dimer), resulting in the recruitment of the TGFβRI receptor (dimer). The complex thus formed leads to the phosphorylation of the kinase domain of TGFβRI, which in turn results in activation of the Smad pathway. This is therefore a targeted pathway for research into the application of peptide inhibitors in blocking the TGF‐β‐Smad signaling pathway. The aim of this study was to design a peptide inhibitor (homologous to the cytokine TGF‐β) which, after binding to the TGFβRI/TGFβRII receptor, would block the cytokine binding and thus prevent the formation of an activating complex. Methods: Preliminary work on the design and synthesis of inhibitors for TGFβRI/TGFβRII has allowed us to identify and describe five key regions of the TGF‐β—TGFβRI/TGFβRII interface. The following five peptide inhibitors were synthesized for Region 1: 1.1 ALDAAYCFR, 1.2 LDAAYCFRN, 1.3 DAAYCFRNV, 1.4 AAYCFRNVQ, 1.5 AYCFRNVQD. The expression of the SEAP reporter gene, Smad2, Smad3, Smad4, and JNK1 gene was measured using quantitative real‐time polymerase chain reaction. Results: For Region 1 peptide inhibitors tested for TGFβRI/TGFβRII, reduced SEAP (reporter gene) expression was observed in cells of the MFB‐F11 line, which suggests inhibited the formation of cytokine‐receptor complexes. Conclusions: For IP1_2, 1_3 and 1_5 Region 1 peptides tested for TGFβRI/TGFβRII, reduced cytokine‐receptor signal by adding newly designed inhibitors. The study revealed an impact of these peptide inhibitors on the reduction of mRNA expression of Smad2, Smad3, Smad4 and JNK1 genes. [ABSTRACT FROM AUTHOR]

Interleukin 33 (IL-33) is an alarmin cytokine from the IL-1 family. IL-33 is localized in the nucleus and acts there as a gene regulator. Following injury, stress or cell death, it is released from the nucleus, and exerts its pro-inflammatory biological functions via the transmembrane form of the ST2 receptor, which is present mainly as attached to immune cells. In recent years, IL-33 became a focus of many studies due to its possible role in inflammatory disorders. Among respiratory disorders, the contribution of IL-33 to the development of asthma, in particular, has been most identified. Increased level of IL-33 in lung epithelial cells and blood serum has been observed in asthma patients. The IL-33/ST2 interaction activated the Th2 mediated immune response and further production of many pro-inflammatory cytokines. Single nucleotide polymorphisms in the IL-33 gene cause a predisposition to the development of asthma. Similarly, in chronic pulmonary obstructive disease (COPD), both increased expression of IL-33 and the ST2 receptor has been observed. Interestingly, cigarette smoke, a key inducer of COPD, not only activates IL-33 production by epithelial and endothelial cells, but also induces the expression of IL-33 in peripheral blood mononuclear cells. Knowledge regarding its contribution in other respiratory disorders, such as obstructive sleep apnea, remains greatly limited. Recently it was shown that IL-33 is one of the inflammatory mediators by which levels in blood serum are increased in OSA patients, compared to healthy control patients. This mini review summarizes current knowledge on IL-33 involvement in chosen chronic respiratory disorders and proposes this interleukin as a possible link in the pathogenesis of these diseases.

Atopic dermatitis (AD) is a chronic and recurrent inflammatory dermatosis. We recently described an association of the C allele of the single nucleotide polymorphism (SNP) rs26618 in the ERAP1 gene and a synergism of ERAP1 and ERAP2 effects on AD risk. Here, we examined whether polymorphisms of other antigen-presenting machinery genes encoding immunoproteasome components LMP2 and LMP7 and peptide transporter components TAP1 and TAP2 may also affect susceptibility to AD or its outcome. We found that the LMP7 rs2071543*T allele decreased disease risk by about 1.5-fold (odds ratio 0.66, 95% confidence interval 0.44–0.99). On the other hand, the LMP2 rs1351383*C allele reduced the mean age at diagnosis from 23 to 15 years (p < 0.001). Similarly, the TAP1 rs1135216*C allele decreased the mean age at diagnosis from almost 20 to 14 years (p = 0.033). The results are discussed in light of other reports on the role of these polymorphisms in human disease.

To date, there has been no reliable test to identify unfavorable course of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), especially in aspirin intolerant patients. The research aimed to analyze the expression of transcript variants of PTGS1 and PTGS2 genes in the pathobiology of the disease. The study was performed on 409 adult patients: 206 CRSwNP patients including 44 (21.36%) aspirin intolerant patients and 203 healthy volunteers in the control group. Transcript variants of the PTGS1 and PTGS2 genes named as follows: COX1.1 for NM_000962, COX1.2 for NM_080591, COX1.3 for NM_001271165.1, COX1.4 for NM_001271368.1, COX1.5 for NM_001271166.1, COX2.1 for NM_000963.3, COX2.2 for AY_151286 and COX2.3 for BQ_722004 were confirmed using direct sequencing and quantified using targeted qPCR. The coexistence of all examined transcript variants in the study and the control group and significant differences between both were found. In aspirin sensitive patients, the levels of COX1.2, COX1.3, COX1.4 and COX1.5 isoforms were higher compared to aspirin-tolerant patients. The severity of symptoms was bigger in patients with higher expressions of variants: COX1.1 (R with dCt = −0.134; p = 0.0490), COX1.3 (R = −0.1429; p = 0.0400) and COX1.5 (Rs = −0.1499; p = 0.032). The expression of COX1.1 (Rs = −0.098; p = 0.049) and COX1.5 (Rs = −0.141; p = 0.043) isoforms increased with polyposis advancement in endoscopy. With the CT extent of sinuses opacification, COX1.1 isoform also significantly increased (Rs = −0.163; p = 0.020). The isoforms COX1.3, COX1.4, COX1.5 and COX2.1 may promote milder CRSwNP course. On the contrary, the variants COX1.1, COX1.2 and COX2.2 may be involved in a more aggressive disease.