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We present a new aerosol microphysics and gas aerosol partitioning submodel (Global Modal-aerosol eXtension, GMXe) implemented within the ECHAM/MESSy Atmospheric Chemistry model (EMAC, version 1.8). The submodel is computationally efficient and is suitable for medium to long term simulations with global and regional models. The aerosol size distribution is treated using 7 log-normal modes and has the same microphysical core as the M7 submodel (Vignati et al., 2004). The main developments in this work are: (i) the extension of the aerosol emission routines and the M7 microphysics, so that an increased (and variable) number of aerosol species can be treated (new species include sodium and chloride, and potentially magnesium, calcium, and potassium), (ii) the coupling of the aerosol microphysics to a choice of treatments of gas/aerosol partitioning to allow the treatment of semi-volatile aerosol, and, (iii) the implementation and evaluation of the developed submodel within the EMAC model of atmospheric chemistry. Simulated concentrations of black carbon, particulate organic matter, dust, sea spray, sulfate and ammonium aerosol are shown to be in good agreement with observations (for all species at least 40% of modeled values are within a factor of 2 of the observations). The distribution of nitrate aerosol is compared to observations in both clean and polluted regions. Concentrations in polluted continental regions are simulated quite well, but there is a general tendency to overestimate nitrate, particularly in coastal regions (geometric mean of modelled values/geometric mean of observed data [approximate]2). In all regions considered more than 40% of nitrate concentrations are within a factor of two of the observations. Marine nitrate concentrations are well captured with 96% of modeled values within a factor of 2 of the observations.

Rhinoviruses are among the most common viruses to infect man, causing a range of serious respiratory diseases including exacerbations of asthma and COPD. Type I IFN and IL-15 are thought to be required for antiviral immunity; however, their function during rhinovirus infection in vivo is undefined. In RV-infected human volunteers, IL-15 protein expression in fluid from the nasal mucosa and in bronchial biopsies was increased. In mice, RV induced type I IFN-dependent expressions of IL-15 and IL-15Rα, which in turn were required for NK- and CD8+ T-cell responses. Treatment with IL-15–IL-15Rα complexes (IL-15c) boosted RV-induced expression of IL-15, IL-15Rα, IFN-γ, CXCL9, and CXCL10 followed by recruitment of activated, IFN-γ-expressing NK, CD8+, and CD4+ T cells. Treating infected IFNAR1−/− mice with IL-15c similarly increased IL-15, IL-15Rα, IFN-γ, and CXCL9 (but not CXCL10) expression also followed by NK-, CD8+-, and CD4+-T-cell recruitment and activation. We have demonstrated that type I IFN-induced IFN-γ and cellular immunity to RV was mediated by IL-15 and IL-15Rα. Importantly, we also show that IL-15 could be induced via a type I IFN-independent mechanism by IL-15 complex treatment, which in turn was sufficient to drive IFN-γ expression and lymphocyte responses.

Most asthma exacerbations are triggered by virus infections, the majority being caused by human rhinoviruses (RV). In mouse models, γδT cells have been previously demonstrated to influence allergen-driven airways hyper-reactivity (AHR) and can have antiviral activity, implicating them as prime candidates in the pathogenesis of asthma exacerbations. To explore this, we have used human and mouse models of experimental RV-induced asthma exacerbations to examine γδT-cell responses and determine their role in the immune response and associated airways disease. In humans, airway γδT-cell numbers were increased in asthmatic vs. healthy control subjects during experimental infection. Airway and blood γδT-cell numbers were associated with increased airways obstruction and AHR. Airway γδT-cell number was also positively correlated with bronchoalveolar lavage (BAL) virus load and BAL eosinophils and lymphocytes during RV infection. Consistent with our observations of RV-induced asthma exacerbations in humans, infection of mice with allergic airways inflammation increased lung γδT-cell number and activation. Inhibiting γδT-cell responses using anti-γδTCR (anti-γδT-cell receptor) antibody treatment in the mouse asthma exacerbation model increased AHR and airway T helper type 2 cell recruitment and eosinophilia, providing evidence that γδT cells are negative regulators of airways inflammation and disease in RV-induced asthma exacerbations.

IntroductionAlveolar gas transfer measurements are known to be raised in many patients with asthma, potentially due to ventilation-perfusion mismatch. In contrast, in the other major airways disease, COPD, alveolar gas transfer is often reduced due to emphysema. Mucus plugging in airways disease can also negatively affect gas transfer. Differences in response to biologics have been noted between patients with asthma and COPD, although they are often clinically difficult to differentiate.ObjectiveTo assess whether alveolar gas transfer, KCO, as measured at baseline, affects response to biologics in patients in the UK Severe Asthma Registry.MethodsPatients within the UK Severe Asthma Registry with recorded KCO at baseline and data on biologic response were identified. Mean KCO was compared between those patients achieving and those not achieving a positive composite response to biologics, a ≥ 50% reduction in oral steroid requiring exacerbations and/or in maintenance oral steroids. Characteristics and outcomes were also compared between patient subgroups stratified by KCO (<70%, 70–120%, >120%).ResultsBaseline KCO was reported in 3586 patients in UKSAR. 216 patients had a KCO <70%, 2919 a KCO 70–120%, and 451 a KCO >120%. Comparing subgroups, with increasing KCO there were significantly increased proportions of patients who had never smoked (KCO <70%, 31.0% never smoked; KCO 70–120%, 60.0%; KCO >120%, 67.4%; p<0.001) and who were male (KCO <70%, 34.3% male; KCO 70–120%, 36.4%; KCO >120%, 52.8%; p<0.001). There were no significant differences in eosinophil counts, exacerbations in preceding year or maintenance oral steroid use.Data on biologic response was available in 620 patients (of whom 76% were composite responders). There was no significant difference in mean KCO between those that did or did not meet the composite response threshold (95.3% vs. 97.4%, p=0.21).Similarly, the proportion of patients achieving a composite response was not significantly different in the subgroups stratified by baseline KCO (KCO <70%, 72.7% composite responders; KCO 70–120%, 75.9% responders; KCO >120%, 78.9% responders; p=0.81).ConclusionsAlthough there was a trend towards an increased composite response rate in patients with increased alveolar gas transfer measurements, alveolar gas transfer does not significantly affect biologic response.

Introduction and ObjectivesThe UK Severe Asthma Registry (UKSAR) was established to facilitate research and quality improvement including performance monitoring across UK severe asthma centres. We here describe its development and refinement for the latter of those objectives. The selection of performance outcomes measures for severe asthma clinical quality improvement from clinician and patient perspectives, data collection, and assessment of clinical variation across severe asthma centres is presented.MethodsAfter relevant stakeholder consultation (patients, commissioners and clinicians), outcomes measures relating to exacerbations, oral corticosteroid exposure, asthma-related ED attendances and hospital admissions, asthma control and quality of life were selected with appropriate case-mix adjustment to help identify unexplained clinical variation. Over 2018–2025, the number of participating centres increased from 17 to 42. To date, baseline data has been entered for 18,473 patients, with data meeting the agreed quality threshold for 12,792 patients.ResultsCompared to 2018, in 2024 patients were older when first reviewed (54.0 vs 50.3 years), less likely to be never smokers (58.7% vs 65.8%) and to be on mOCS at baseline (25.5% vs 47.1%).Analysis of variation in outcomes between centres, after case-mix adjustment and allowing for effect of centre size, shows relatively few examples of significant variation in outcomes between centres. Where variation was evident, for example in improvement in asthma control ACQ6 score from baseline to follow-up (see figure 1) high-performing centres could be identified to share best-practice.Abstract P75 Figure 1Proportion of patients with positive outcomes for the above metrics, by hospital size, for patients with baseline records on or after 1 January 2022[Image Omitted. See PDF.]ConclusionsRegular discussion at UKSAR registry meetings, at which representatives from each severe asthma centre are present, of outcome measures and related latest research, including UKSAR research, together with sharing of best practice may explain why there is relatively little evidence of variation in clinical outcomes between centres. UKSAR shows that there are an increasing number year-on-year of patients on severe asthma biologic treatments and of hospitals both prescribing biologics and entering data for quality improvement. However, a limitation of UKSAR is that it cannot evaluate the presence of ‘hidden’ severe asthma not known to specialist services, a continuing issue given the harm that results from delays in appropriate diagnosis and management, and accompanying oral corticosteroid associated comorbidities.

IntroductionObese patients with severe asthma have a distinct clinical phenotype. These patients are more likely to have low T2 biomarkers (T2low) so are less likely to meet criteria to be treated with most biologics. Use of Tezepelumab does not require raised eosinophils or FeNO so it may be able to reach this population. Here we present real world outcomes for patients treated with Tezepelumab comparing obese and non obese groups.MethodsData from our service registry were used to study asthma outcomes from Tezepelumab comparing the obese (BMI≥30 kg/m2 ) and the non obese population.ResultsA total of 142 patients were analysed (60% were obese). The cohort median BMI was 31.0 (27.2–37.2). At baseline, obese patients had non-significant trend of higher exacerbation frequency (5 vs 4.5 p=0.371), median ACQ (3.83 vs 3.5 p= 0.16) and mOCS use (8.4% vs 19.7% n=40 p =0.124) compared to non obese. 31.2% of patients had been treated with another biologic previously. Overall, 34.5% of patients were T2low.Outcomes for patients who completed 12 month trials are described in table 1.Trials were discontinued for adverse effects in 9.2% (n= 13/142 including rash and joint pains. 2.8% (n=4/142) of patients felt no improvement in their symptoms and so trials were discontinued early at their request. A further 2.1% (n=3) of patients did not attend (DNA) multiple appointments and so were unable to complete trials. There were no significant differences in the responses of obese and non obese in this regard.Abstract P205 Table 1Outcomes for patients who completed 12 month trialsConclusionTezepelumab improves asthma outcomes for both obese and non obese patients. However, obese patients still have significantly higher exacerbation frequency. Symptoms remain uncontrolled in the obese group though this did not reach statistical significance. However, this may be affected by the number of patients who did not complete a 12-month trial because of adverse effects or non improvement in symptoms. There is a need for other management options in obesity related severe asthma.

IntroductionRandomised clinical trials confirmed efficacy of Tezepelumab in treatment of severe asthma, but real-world data on its performance remains limited. This study evaluated its effectiveness in routine clinical practice across our networkMethodologyThis retrospective, observational study was conducted across nine hospital sites in central England. Eligible patients under NICE guidance were initiated on Tezepelumab following regional MDT approval. Treatment outcomes at 12 months were classified as positive (≥50% reduction in exacerbation frequency or maintenance oral corticosteroid [mOCS] dose) or negative, with early discontinuation of treatment recorded. Clinical remission was defined as: no severe exacerbations, off mOCS, and asthma control questionnaire (ACQ-6) score <1.5. Data was extracted from structured proformas. Standard and descriptive statistics were performed.ResultsA total of 145 patients with severe asthma initiated on Tezepelumab were included in the analysis. Baseline clinical and phenotypical characteristics are summarised in table 1. Positive outcomes were seen in 67% (n=97/145), 7% (n=10/145) had borderline responses requiring review at 18 months, and 26% (n=38) discontinued due to negative response, which included adverse effects such as rash, arthralgia and myalgia, neurological symptoms, and fatigue (10%, n=13/145).In patients with paired baseline and 12-month data (n=125), median annual exacerbations fell from 5.0 (4.0–7.0) to 1.0 (0.0–2.25) (p<0.0001), and maintenance OCS from 10.0 (7.50–15.0) to 5.0 (0.0–10.0) mg/day (p<0.0001) among those on OCS at baseline (n=44). ACQ-6 significantly improved from 3.67 (2.67–4.64) to 2.17 (1.00–4.05) (p<0.0001), and proportion of well-controlled asthma (ACQ-6 <1.5) rose from 3.5% (n=4/116) to 38% (n=44/116) (p=0.03). FEV1significantly increased from 2.22 (1.44–2.71) to 2.44L (1.76–3.02) (p<0.0001). FeNO declined from 25.0 (12.0–59.8) to 18.0 (11.0–29.0) ppb (p<0.0001), blood eosinophil count from 0.23 (0.11–0.45) to 0.14 (0.07–0.24) x109/L (p<0.0001), and total IgE (n=26) from 192.0 (34.0–410.1) to 67.5 (18.0–169.0) (p=0.0002).The proportion who achieved clinical remission at 12 months were 22% (n=27/125).Abstract P206 Table 1Baseline clinical and phenotypical characteristics. *Data missing for 3 patientsConclusionsTezepelumab led to significant improvements in OCS use, asthma control, and T2 markers in a real-world setting. Two-thirds of patients had a positive response, with a subset (22%) achieving clinical remission, demonstrating clinical benefits of Tezepelumab in managing severe asthma in routine care.

Abstract Rationale Respiratory virus infections are associated with chronic obstructive pulmonary disease (COPD) exacerbations, but a causative relationship has not been proven. Studies of naturally occurring exacerbations are difficult and the mechanisms linking virus infection to exacerbations are poorly understood. We hypothesized that experimental rhinovirus infection in subjects with COPD would reproduce the features of naturally occurring COPD exacerbations and is a valid model of COPD exacerbations. Objectives To evaluate experimental rhinovirus infection as a model of COPD exacerbation and to investigate the mechanisms of virus-induced exacerbations. Methods We used experimental rhinovirus infection in 13 subjects with COPD and 13 nonobstructed control subjects to investigate clinical, physiologic, pathologic, and antiviral responses and relationships between virus load and these outcomes. Measurements and Main Results Clinical data; inflammatory mediators in blood, sputum, and bronchoalveolar lavage; and viral load in nasal lavage, sputum, and bronchoalveolar lavage were measured at baseline and after infection with rhinovirus 16. After rhinovirus infection subjects with COPD developed lower respiratory symptoms, airflow obstruction, and systemic and airway inflammation that were greater and more prolonged compared with the control group. Neutrophil markers in sputum related to clinical outcomes and virus load correlated with inflammatory markers. Virus load was higher and IFN production by bronchoalveolar lavage cells was impaired in the subjects with COPD. Conclusions We have developed a new model of COPD exacerbation that strongly supports a causal relationship between rhinovirus infection and COPD exacerbations. Impaired IFN production and neutrophilic inflammation may be important mechanisms in virus-induced COPD exacerbations.

Most asthma exacerbations are triggered by virus infections, the majority being caused by human rhinoviruses (RV). In mouse models, γδT cells have been previously demonstrated to influence allergen-driven airways hyper-reactivity (AHR) and can have antiviral activity, implicating them as prime candidates in the pathogenesis of asthma exacerbations. To explore this, we have used human and mouse models of experimental RV-induced asthma exacerbations to examine γδT-cell responses and determine their role in the immune response and associated airways disease. In humans, airway γδT-cell numbers were increased in asthmatic vs. healthy control subjects during experimental infection. Airway and blood γδT-cell numbers were associated with increased airways obstruction and AHR. Airway γδT-cell number was also positively correlated with bronchoalveolar lavage (BAL) virus load and BAL eosinophils and lymphocytes during RV infection. Consistent with our observations of RV-induced asthma exacerbations in humans, infection of mice with allergic airways inflammation increased lung γδT-cell number and activation. Inhibiting γδT-cell responses using anti-γδTCR (anti-γδT-cell receptor) antibody treatment in the mouse asthma exacerbation model increased AHR and airway T helper type 2 cell recruitment and eosinophilia, providing evidence that γδT cells are negative regulators of airways inflammation and disease in RV-induced asthma exacerbations.