A UK community-based survey on the prevalence of rhinosinusitis.

OBJECTIVES: There is limited information about the prevalence of rhinosinusitis in the UK community. This study aimed to identify its prevalence and investigate any association with demographic variables. The secondary aims were to determine the degree of impairment, impact on quality of life and any costs incurred by patients. DESIGN: We used a modified version (MSNOT-20) of a quality-of-life instrument, the sinonasal outcome test-20 (SNOT-20), in a small and successful pilot project. It was then used in a community-based survey and a second phase 6 months later to test repeatability. Nasal examination and comparison of its quality-of-life section with other health-related quality-of-life tools occurred in the second phase. SETTING AND PARTICIPANTS: The questionnaire was administered by post to 2000 Farnborough (UK) residents, selected through stratified randomisation. The relation of an abnormal MSNOT-20 score with hay fever, asthma, smoking, food allergy, work productivity and social limitation was also analysed. MAIN OUTCOME AND RESULTS: The response rate was 79.8%; over thirty per cent of the community suffer from upper respiratory tract symptoms with impact on multiple domains of quality of life including emotional, financial costs and loss of days at work. The MSNOT-20 provided a more sensitive assessment of health-related quality of life than the Short Form 36 questionnaire. CONCLUSION: Rhinosinusitis is prevalent in the Farnborough community and associated with significant morbidity and impairment on quality of life. The MSNOT-20 is a useful disease-specific quality-of-life tool in rhinosinusitis.

Airway and peripheral urokinase plasminogen activator receptor is elevated in asthma, and identifies a severe, nonatopic subset of patients.

RATIONALE: Genetic polymorphisms in the asthma susceptibility gene, urokinase plasminogen activator receptor (uPAR/PLAUR) have been associated with lung function decline and uPAR blood levels in asthma subjects. Preliminary studies have identified uPAR elevation in asthma; however, a definitive study regarding which clinical features of asthma uPAR may be driving is currently lacking. OBJECTIVES: We aimed to comprehensively determine the uPAR expression profile in asthma and control subjects utilizing bronchial biopsies and serum, and to relate uPAR expression to asthma clinical features. METHODS: uPAR levels were determined in control (n = 9) and asthmatic (n = 27) bronchial biopsies using immunohistochemistry, with a semi-quantitative score defining intensity in multiple cell types. Soluble-cleaved (sc) uPAR levels were determined in serum through ELISA in UK (cases n = 129; controls n = 39) and Dutch (cases n = 514; controls n = 96) cohorts. MEASUREMENTS AND MAIN RESULTS: In bronchial tissue, uPAR was elevated in inflammatory cells in the lamina propria (P = 0.0019), bronchial epithelial (P = 0.0002) and airway smooth muscle cells (P = 0.0352) of patients with asthma, with uPAR levels correlated between the cell types. No correlation with disease severity or asthma clinical features was identified. scuPAR serum levels were elevated in patients with asthma (1.5-fold; P = 0.0008), and we identified an association between high uPAR serum levels and severe, nonatopic disease. CONCLUSIONS: This study provides novel data that elevated airway and blood uPAR is a feature of asthma and that blood uPAR is particularly related to severe, nonatopic asthma. The findings warrant further investigation and may provide a therapeutic opportunity for this refractory population.

CD48 on blood leukocytes and in serum of asthma patients varies with severity.

BACKGROUND: CD48 is a membrane receptor (mCD48) on eosinophils and mast cells and exists in a soluble form (sCD48). CD48 has a pivotal role in murine asthma and in the proinflammatory interactions of mast cells with eosinophils via its ligand CD244. Thus, CD48 might be important in human asthma. METHODS: Therefore, two separate cohorts (IL and UK) comprising mild, moderate, and severe asthma and healthy volunteers were evaluated for blood leukocyte mCD48 expression and sCD48 in serum. Asthmatic bronchial biopsies were immunostained for CD48. sCD48 effect on CD244-dependent eosinophil activation was evaluated. RESULTS: Eosinophil mCD48 expression was significantly elevated in moderate while downregulated in severe asthma. mCD48 expression on B, T, and NK cells and monocytes in severe asthma was significantly increased. sCD48 levels were significantly higher in mild while reduced in severe asthma. sCD48 optimal cutoff values for differentiating asthma from health were identified as >1482 pg/ml (IL) and >1619 pg/ml (UK). In asthmatic bronchial biopsies, mCD48 was expressed predominantly by eosinophils. sCD48 inhibited anti-CD244-induced eosinophil activation. CONCLUSIONS: mCD48 and sCD48 are differentially expressed in the peripheral blood of asthma patients of varying severity. sCD48 inhibits CD244-mediated eosinophil activation. These findings suggest that CD48 may play an important role in human asthma.

Respiratory hypersensitivity reactions to NSAIDs in Europe: the global allergy and asthma network (GA2 LEN) survey.

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 GA2 LEN 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.

Stability of phenotypes defined by physiological variables and biomarkers in adults with asthma.

BACKGROUND: Although asthma is characterized by variable airways obstruction, most studies of asthma phenotypes are cross-sectional. The stability of phenotypes defined either by biomarkers or by physiological variables was assessed by repeated measures over 1 year in the Pan-European BIOAIR cohort of adult asthmatics. METHODS: A total of 169 patients, 93 with severe asthma (SA) and 76 with mild-to-moderate asthma (MA), were examined at six or more visits during 1 year. Asthma phenotype clusters were defined by physiological variables (lung function, reversibility and age of onset of the disease) or by biomarkers (eosinophils and neutrophils in induced sputum). RESULTS: After 1 year of follow-up, the allocation to clusters was changed in 23.6% of all asthma patients when defined by physiological phenotypes and, remarkably, in 42.3% of the patients when stratified according to sputum cellularity (P = 0.034). In the SA cohort, 30% and 48.6% of the patients changed allocation according to physiological and biomarker clustering, respectively. Variability of phenotypes was not influenced by change in oral or inhaled corticosteroid dose, nor by the number of exacerbations. Lower stability of single and repeated measure was found for all evaluated biomarkers (eosinophils, neutrophils and FeNO) in contrast to good stability of physiological variables (FEV1 ), quality of life and asthma control. CONCLUSION: Phenotypes determined by biomarkers are less stable than those defined by physiological variables, especially in severe asthmatics. The data also imply that definition of asthma phenotypes is improved by repeated measures to account for fluctuations in lung function, biomarkers and asthma control.

The relation of airway obstruction to asthma, chronic rhinosinusitis and age: results from a population survey of adults.

RATIONALE: There is conflicting evidence on whether patients with asthma experience an accelerated decline in lung function with age. We examined the association between postbronchodilator lung function, asthma, chronic rhinosinusitis (CRS), and atopy with age using a large European sample. METHODS: In 17 centers in 11 European countries, case-control studies were nested within representative cross-sectional surveys of adults aged less than 75 years. Representative samples of participants with asthma, CRS or both and controls were assessed for postbronchodilator ventilatory function, smoking history, atopy, and treatment. Multiple regression was used to assess the interactive effects of age and diagnostic group on decline in postbronchodilator ventilatory function. RESULTS: A total of 3337 participants provided adequate data (778 with asthma, 399 with CRS, 244 with both asthma and CRS and 1916 controls who had neither asthma nor CRS). Participants with asthma had lower FEV1 /FVC (-4.09% (95% CI: -5.02, -3.15, P < 0.001) and a steeper slope of FEV1 /FVC against age (-0.14%/annum [95%CI: -0.19, -0.08]) equivalent to smoking 1-2 packs of cigarettes per day. Those with atopy had a slope equivalent to controls. CONCLUSIONS: People with asthma have a steeper decline in postbronchodilator lung function with age, but neither CRS nor atopy alone were associated with such decline.

Geographical variation in the prevalence of sensitization to common aeroallergens in adults: the GA(2) LEN survey.

BACKGROUND: Geographical variation in the prevalence of sensitization to aeroallergens may reflect differences in exposure to risk factors such as having older siblings, being raised on a farm or other unidentified exposures. OBJECTIVE: We wanted to measure geographical variation in skin prick test positivity and assess whether it was explained by differences in family size and/or farm exposure. We also compared prevalence in younger and older subjects. METHODS: Within the Global Allergy and Asthma European Network (GA(2) LEN) survey, we measured the prevalence of skin prick positivity to a panel of allergens, and geometric mean serum total immunoglobulin E (IgE), in 3451 participants aged 18-75 years in 13 areas of Europe. Estimated prevalence was standardized to account for study design. We compared prevalence estimates in younger and older subjects and further adjusted for age, gender, smoking history, farm exposure, number of older siblings and body mass index (BMI). RESULTS: Skin prick test positivity to any one of the measured allergens varied within Europe from 31.4% to 52.9%. Prevalence of sensitization to single allergens also varied. Variation in serum total IgE was less marked. Younger participants had higher skin prick sensitivity prevalence, but not total IgE, than older participants. Geographical variation remained even after adjustment for confounders. CONCLUSION: Geographical variation in the prevalence of skin prick test positivity in Europe is unlikely to be explained by geographical variation in gender, age, smoking history, farm exposure, family size and BMI. Higher prevalence in younger, compared to older, adults may reflect cohort-associated increases in sensitization or the influence of ageing on immune or tissue responses.

Staphylococcus aureus enterotoxin-specific IgE is associated with asthma in the general population: a GA(2)LEN study.

BACKGROUND: Specific IgE to Staphylococcus aureus enterotoxins (SE-IgE) has been associated with asthma. In the general population, we aimed to determine the prevalence of and risk factors for serum SE-IgE and to examine the association with asthma. METHODS: A postal questionnaire was sent to a random sample of adults in 19 centers across Europe. A random sample of respondents was invited for clinical examination upon which they answered a questionnaire, underwent skin prick tests (SPTs) for common aeroallergens, and provided blood for measurement of total IgE and SE-IgE. Risks were analyzed within centers using weighted logistic regression, and overall estimates calculated using fixed-effects meta-analysis. RESULTS: 2908 subjects were included in this analysis. Prevalence of positive SE-IgE was 29.3%; no significant geographic variation was observed. In contrast to positive skin prick tests, SE-IgE was more common in smokers (<15 pack-year: OR 1.11, P = 0.079, ≥15 pack-year: OR 1.70, P < 0.001), and prevalence did not decrease in older age-groups or in those with many siblings. Total IgE concentrations were higher in those with positive SE-IgE than in those with positive SPT. SE-IgE was associated with asthma (OR 2.10, 95% confidence interval [1.60-2.76], P = 0.001) in a concentration-dependent manner. This effect was independent of SPT result and homogeneous across all centers. CONCLUSIONS: We report for the first time that SE-IgE is common in the general population throughout Europe and that its risk factors differ from those of IgE against aeroallergens. This is the first study to show that SE-IgE is significantly and independently associated with asthma in the general population.

Genome-wide association study to identify genetic determinants of severe asthma.

BACKGROUND: The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. OBJECTIVE: To identify common genetic variants affecting susceptibility to severe asthma. METHODS: A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. RESULTS: An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10((-8)) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10((-8)) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. CONCLUSIONS: The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

Analysis of allergen immunotherapy studies shows increased clinical efficacy in highly symptomatic patients.

BACKGROUND: The assessment of allergen immunotherapy (AIT) efficacy in the treatment for seasonal allergic rhinoconjunctivitis (SAR) symptoms is challenging. Allergen immunotherapy differs from symptomatic therapy in that while symptomatic therapy treats patients after symptoms appear and aims to reduce symptoms, AIT is administered before symptoms are present and aims to prevent them. Thus, clinical studies of AIT can neither establish baseline symptom levels nor limit the enrolment of patients to those with the most severe symptoms. Allergen immunotherapy treatment effects are therefore diluted by patients with low symptoms for a particular pollen season. The objective of this analysis was to assess the effect possible to achieve with AIT in the groups of patients presenting the most severe allergic symptoms. METHODS: Study centres were grouped into tertiles categorized according to symptom severity scores observed in the placebo patients in each centre (low, middle and high tertiles). The difference observed in the average score in each tertile in active vs placebo-treated patients was assessed. This allowed an estimation of the efficacy that could be achieved in patients from sites where symptoms were high during the pollen season. RESULTS: An increased treatment effect was observed in the most severe patients and was independent of the study analysed and symptom score used. CONCLUSIONS: The use of a tertile approach to analyse efficacy in AIT in SAR clinical studies can give a more accurate assessment of potential clinical benefit.

Asthma in adults and its association with chronic rhinosinusitis: the GA2LEN survey in Europe.

BACKGROUND: The prevalence of asthma and its association with chronic rhinosinusitis (CRS) have not been widely studied in population-based epidemiological surveys. METHODS: The Global Allergy and Asthma Network of Excellence (GA(2) LEN) conducted a postal questionnaire in representative samples of adults living in Europe to assess the presence of asthma and CRS defined by the European Position Paper on Rhinosinusitis and Nasal Polyps. The prevalence of self-reported current asthma by age group was determined. The association of asthma with CRS in each participating centre was assessed using logistic regression analyses, controlling for age, sex and smoking, and the effect estimates were combined using standard methods of meta-analysis. RESULTS: Over 52,000 adults aged 18-75 years and living in 19 centres in 12 countries took part. In most centres, and overall, the reported prevalence of asthma was lower in older adults (adjusted OR for 65-74 years compared with 15-24 years: 0.72; 95% CI: 0.63-0.81). In all centres, there was a strong association of asthma with CRS (adjusted OR: 3.47; 95% CI: 3.20-3.76) at all ages. The association with asthma was stronger in those reporting both CRS and allergic rhinitis (adjusted OR: 11.85; 95% CI: 10.57-13.17). CRS in the absence of nasal allergies was positively associated with late-onset asthma. CONCLUSION: Geographical variation in the prevalence of self-reported asthma was observed across Europe, but overall, self-reported asthma was more common in young adults, women and smokers. In all age groups, men and women, and irrespective of smoking behaviour, asthma was also associated with CRS.

Preliminary study of the cellular characteristics of primary bronchial fibroblasts in patients with asthma: expression of alpha-smooth muscle actin, fibronectin containing extra type III domain A, and smoothelin.

BACKGROUND: The relationship between fibroblasts, myofibroblasts, and smooth muscle cells within the airway wall remains poorly understood. OBJECTIVE: The cellular characteristics of primary bronchial fibroblasts from patients with asthma were investigated by evaluating the expression of 3 proteins: alpha-smooth muscle actin (SMA), fibronectin containing extra type III domain A (EDAcFN), and smoothelin. METHODS: Expression of SMA, EDAcFN, and smoothelin was evaluated in primary fibroblasts from 3 patients with asthma of varying symptom severity, embryonic fibroblasts, and a healthy control. In addition, primary bronchial fibroblasts from patients with asthma were assessed for SMA at various incubation times (4 hours to 76 hours) and with different extracellular matrices (ECMs). Immunofluorescence was assessed by manually counting cells that stained positively as fine filamentous structures under a fluorescence microscope. RESULTS: Expression of filamentous SMA tended to increase with the length of incubation. The positive to total cell ratio for filamentous cells did not differ significantly between the various kinds of ECMs onto which cells were plated (P > .05). Primary bronchial fibroblasts from asthma patients produced more prominent expression of EDAcFN than control fibroblasts. Smoothelin was not expressed in any fibroblasts. CONCLUSIONS: More than 50% of primary bronchial fibroblasts were defined as myofibroblasts. Primary bronchial fibroblasts in patients with asthma had more potential for tissue fibrosis than control fibroblasts. No mature smooth muscle cells were observed in primary bronchial fibroblasts in patients with asthma.

Staphylococci and staphylococcal superantigens in asthma and rhinitis: a systematic review and meta-analysis.

BACKGROUND: There is a need for new treatment options of allergic respiratory diseases based on a better knowledge of their pathogenesis. An association between bacterial products and allergic airway diseases has been suggested by the results of human and animal studies that describe a link between Staphylococcus aureus enterotoxins and atopic diseases. The aim of the systematic review is to assess the evidence for a role of Staphylococcus aureus enterotoxins, as an environmental risk factor, for the development and/or the severity of asthma and allergic rhinitis. METHODS: We performed a systematic review of controlled clinical studies in adults and/or children affected by asthma/early wheeze and/or allergic rhinitis. To be eligible, studies had to use reproducible methods to provide evidence of exposure to S. aureus, clinical outcome and disease severity. RESULTS: Ten studies, published between 2000 and 2007, fulfilled all eligibility criteria. Patients with asthma or allergic rhinitis showed an increased prevalence of positivity for measures of exposure to S. aureus in nine studies: differences were statistically significant (P < 0.05) in seven studies. In a meta-analysis of study results, patients with asthma were more likely than controls to have serum-specific IgE to Staphylococcus aureus enterotoxins (OR = 3.3, 95% CI: 1.6-7.1, P = 0.002); similarly, patients with allergic rhinitis were more likely than controls to test positive for local or systemic exposure to Staphylococcus aureus and/or or its enterotoxins (OR = 2.4, 95% CI: 1.3-4.7, P = 0.008). CONCLUSIONS: A potential role of S. aureus superantigens in allergic respiratory diseases is supported by results of this meta-analysis of clinical studies.

New topics in bradykinin research.

Bradykinin has been implicated to contribute to allergic inflammation and the pathogenesis of allergic conditions. It binds to endothelial B(1) and B(2) receptors and exerts potent pharmacological and physiological effects, notably, decreased blood pressure, increased vascular permeability and the promotion of classical symptoms of inflammation such as vasodilation, hyperthermia, oedema and pain. Towards potential clinical benefit, bradykinin has also been shown to exert potent antithrombogenic, antiproliferative and antifibrogenic effects. The development of pharmacologically active substances, such as bradykinin receptor blockers, opens up new therapeutic options that require further research into bradykinin. This review presents current understanding surrounding the role of bradykinin in nonallergic angioedema and other conditions seen by allergists and emergency physicians, and its potential role as a therapeutic target.

Reliability of EP3OS symptom criteria and nasal endoscopy in the assessment of chronic rhinosinusitis--a GA² LEN study.

BACKGROUND: The European Position Paper on Rhinosinusitis and Nasal Polyps (EP3OS) incorporates symptomatic, endoscopic, and radiologic criteria in the clinical diagnosis of chronic rhinosinusitis (CRS), while in epidemiological studies, the definition is based on symptoms only. We aimed to assess the reliability and validity of a symptom-based definition of CRS using data from the GA(2) LEN European survey. METHODS: On two separate occasions, 1700 subjects from 11 centers provided information on symptoms of CRS, allergic rhinitis, and asthma. CRS was defined by the epidemiological EP3OS symptom criteria. The difference in prevalence of CRS between two study points, the standardized absolute repeatability, and the chance-corrected repeatability (kappa) were determined. In two centers, 342 participants underwent nasal endoscopy. The association of symptom-based CRS with endoscopy and self-reported doctor-diagnosed CRS was assessed. RESULTS: There was a decrease in prevalence of CRS between the two study phases, and this was consistent across all centers (-3.0%, 95% CI: -5.0 to -1.0%, I(2) = 0). There was fair to moderate agreement between the two occasions (kappa = 39.6). Symptom-based CRS was significantly associated with positive endoscopy in nonallergic subjects, and with self-reported doctor-diagnosed CRS in all subjects, irrespective of the presence of allergic rhinitis. CONCLUSION: Our findings suggest that a symptom-based definition of CRS, according to the epidemiological part of the EP3OS criteria, has a moderate reliability over time, is stable between study centers, is not influenced by the presence of allergic rhinitis, and is suitable for the assessment of geographic variation in prevalence of CRS.

How to design and evaluate randomized controlled trials in immunotherapy for allergic rhinitis: an ARIA-GA(2) LEN statement.

Specific immunotherapy (SIT) is one of the treatments for allergic rhinitis. However, for allergists, nonspecialists, regulators, payers, and patients, there remain gaps in understanding the evaluation of randomized controlled trials (RCTs). Although treating the same diseases, RCTs in SIT and pharmacotherapy should be considered separately for several reasons, as developed in this study. These include the severity and persistence of allergic rhinitis in the patients enrolled in the study, the problem of the placebo, allergen exposure (in particular pollen and mite), the analysis and reporting of the study, the level of symptoms of placebo-treated patients, the clinical relevance of the efficacy of SIT, the need for a validated combined symptom-medication score, the differences between children and adults and pharmacoeconomic analyses. This statement reviews issues raised by the interpretation of RCTs in sublingual immunotherapy. It is not possible to directly extrapolate the rules or parameters used in medication RCTs to SIT. It also provides some suggestions for the research that will be needed. Interestingly, some of the research questions can be approached with the available data obtained from large RCTs.

Osimertinib plus platinum-pemetrexed in newly diagnosed epidermal growth factor receptor mutation-positive advanced/metastatic non-small-cell lung cancer: safety run-in results from the FLAURA2 study.

BACKGROUND: The phase III FLAURA2 (NCT04035486) study will evaluate efficacy and safety of first-line osimertinib with platinum-pemetrexed chemotherapy versus osimertinib monotherapy in epidermal growth factor receptor mutation-positive (EGFRm) advanced/metastatic non-small-cell lung cancer (NSCLC). The safety run-in, reported here, assessed the safety and tolerability of osimertinib with chemotherapy prior to the randomized phase III evaluation. PATIENTS AND METHODS: Patients (≥18 years; Japan: ≥20 years) with EGFRm locally advanced/metastatic NSCLC received oral osimertinib 80 mg once daily (QD), with either intravenous (IV) cisplatin 75 mg/m2 or IV carboplatin target area under the curve 5, plus pemetrexed 500 mg/m2 every 3 weeks (Q3W) for four cycles. Maintenance was osimertinib 80 mg QD with pemetrexed 500 mg/m2 Q3W until progression/discontinuation. The primary objective was to evaluate safety and tolerability of the osimertinib-chemotherapy combination. RESULTS: Thirty patients (15 per group) received treatment [Asian, 73%; female, 63%; median age (range) 61 (45-84) years]. Adverse events (AEs) were reported by 27 patients (90%): osimertinib-carboplatin-pemetrexed, 100%; osimertinib-cisplatin-pemetrexed, 80%. Most common AEs were constipation (60%) with osimertinib-carboplatin-pemetrexed and nausea (60%) with osimertinib-cisplatin-pemetrexed. In both groups, 20% of patients reported serious AEs. No specific pattern of AEs leading to dose modifications/discontinuations was observed; one patient discontinued all study treatments including osimertinib due to pneumonitis (study-specific discontinuation criterion). Hematologic toxicities were as expected and manageable. CONCLUSIONS: Osimertinib-chemotherapy combination had a manageable safety and tolerability profile in EGFRm advanced/metastatic NSCLC, supporting further assessment in the FLAURA2 randomized phase.

Interleukin 4 is localized to and released by human mast cells.

Recent attention has focused on the T helper type 2 (Th2) lymphocyte as a source of interleukin 4 (IL-4) in allergic disease. However, Th2 cells themselves require a pulse of IL-4 to initiate this synthesis. Here we provide immunohistochemical evidence of IL-4 localization to human mast cells of the skin and respiratory tract, and demonstrate that immunoglobulin E-dependent stimulation of purified human lung mast cells leads to the rapid release of IL-4 into the extracellular environment. We propose that mast cell activation in an allergic response provides a rapid and local pulse of IL-4 into the local environment essential for the triggering of T lymphocytes into sustained IL-4 production and to initiate inflammatory cell accumulation and activation.

The allergen specificity of the late asthmatic reaction.

BACKGROUND: Allergen inhalation challenge in asthma may induce both early (EAR) and late (LAR) asthmatic reactions. The EAR is IgE and mast cell dependent. The mechanism of the LAR is less well defined and we have hypothesized may be allergen dependent. The aim of this study was to investigate the allergen specificity of the LAR to allergen inhalation in asthma. METHODS: In a randomized, double-blind, crossover design six asthmatic volunteers with dual sensitization to house dust mite (HDM) allergen and grass pollen (GP) allergen underwent inhalation allergen challenge with these separate allergens on two occasions separated by 14 days. Lung function changes were followed for 8-h postchallenge. Bronchial reactivity (histamine PC(20)) and airway inflammation, assessed by induced sputum differential cell count, were measured 24-h pre and postallergen challenge. The allergen inhalation challenges were matched to achieve the same magnitude of EAR. RESULTS: Despite comparable group mean EAR percent falls in FEV(1) (25.8% following GP and 28.0% following HDM (P = 0.917), the LAR was statistically greater on the HDM challenge day (13.0%vs 22.8% [P = 0.046]) and was associated with a significant airway eosinophil recruitment (mean (SD) of 5.4 (4.8)% to 22.1 (18.2)% (P = 0.028) that was not evident on the GP allergen challenge day. CONCLUSIONS: These findings identify the allergen specificity of the LAR and indicate that factors independent of IgE contribute to the LAR. Such findings have relevance both to the understanding of the allergen-induced airway responses in asthma and the need for homogeneity in inhaled-allergen challenge studies in asthma.

Osteopontin is expressed and functional in human eosinophils.

BACKGROUND: Eosinophils are critically involved in allergic inflammation and tissue remodeling. Osteopontin (OPN) is a glycoprotein molecule which exhibits pro-fibrogenic and pro-angiogenic properties and has recently also been implicated in allergic diseases. In this study, we investigated the expression and function of OPN in human eosinophils. METHODS: Osteopontin mRNA (RT-PCR) and protein (immunofluorescence) expression in peripheral blood eosinophils from atopic human subjects were evaluated. Soluble OPN release was determined in resting and activated eosinophils. The contribution of OPN to eosinophil-induced angiogenesis was determined using the chick embryo chorio- allantoic membrane (CAM) assay and OPN-induced eosinophil chemotaxis was determined (ChemoTx System microplate wells). Finally, OPN expression in bronchoalveolar lavage (BAL) fluids from mild asthmatic and normal control subjects was determined. RESULTS: Osteopontin is expressed in human eosinophils and is increased following GM-CSF and IL-5 activation. Eosinophil-derived OPN contributes to eosinophil-induced angiogenesis. Recombinant OPN promotes eosinophil chemotaxis in vitro and this effect is mediated by alpha(4)beta(1) integrin binding. Soluble OPN is increased in the bronchoalveolar lavage fluid from mild asthmatic subjects and correlates with eosinophil counts. CONCLUSIONS: We therefore conclude that OPN is likely to contribute to the process of angiogenesis observed in the airways in asthma.