Purpose:Time to biologic initiation for the treatment of severe asthma (SA) is affected by many factors, including ease of access to biologics, which is often subject to approval by regulatory authorities and reimbursement criteria by relevant agencies. We investigated the association between ease of biologic access (using the biologic accessibility score [BACS] as a proxy) and post-biologic asthma outcomes, including remission. Methods:This ecological study, using data from CHRONICLE (a US severe asthma registry), the International Severe Asthma Registry (ISAR), and the Optimum Patient Care Research Database (OPCRD), included patients with SA from 21 countries. Associations at the country level, between BACS, a composite score of prescription criteria for biologics in SA, and the proportion of patients with a favorable asthma outcome 1-year post-biologic in each setting (ie ISAR country or in the CHRONICLE or OPCRD datasets) were tested. Several definitions of favorable outcome were used, including proportion of patients who achieved clinical remission (defined using 2, 3 and 4 domains), experienced no exacerbations, had well- or partly controlled asthma, a percent predicted forced expiratory volume in 1 second (ppFEV1) or percent predicted peak expiratory flow rate (ppPEFR) ≥80%, and no long-term oral corticosteroid (LTOCS) use. Results:A total of 9,183 patients were included. A higher BACS (as a proxy of easier access to biologics) was associated with a higher likelihood of achieving clinical remission (p≤0.001), no exacerbations (p<0.001), well- or partly controlled asthma (p=0.047), a ppFEV1 or ppPEFR ≥80% (p=0.004), and no need for LTOCS (p=0.045) 1 year post-biologic initiation. Conclusion:Easier access to biologics for patients with SA, a prerequisite for shorter time-to-initiation, was associated with a greater probability of achieving clinical remission and other favorable asthma outcomes. Initiating biologics earlier in the asthma disease course may help unlock greater therapeutic potential in SA. These findings warrant confirmation in additional studies to further establish the causal relationship between biologic accessibility, timing of initiation, and clinical outcomes in SA.

BACKGROUND:Severe asthma affects a minority of patients with asthma; however, it substantially impacts morbidity, health-care use, and systemic corticosteroid-related harm. Despite the increasing use of biological treatments, achievement of severe asthma remission remains elusive. Notably, real-world data on the disease burden and remission potential of severe asthma in Europe remain limited. We aimed to close this knowledge gap, offering insights with global relevance. METHODS:Using data from 13 455 adults with severe asthma enrolled in the European Severe Heterogeneous Asthma Registry, Patient-centred Clinical Research Collaboration (SHARP CRC), this cross-sectional observational study evaluated the burden of severe asthma and remission-related clinical domains (exacerbations, asthma control, airflow limitation, and maintenance oral corticosteroid use) across Europe and examined their relationship with disease duration, biological therapy, and type 2 biomarkers (blood eosinophils, fractional exhaled nitric oxide [FeNO], and total IgE). Patients with severe asthma had been enrolled in national registries according to local principles and guidelines and in accordance with the European Respiratory Society/American Thoracic Society guidelines; 3% (430 of 13 885) of patients were excluded due to no consent for the international study and/or missing medication data. FINDINGS:Patients were predominantly female (59%; 7999 of 13 453), with adult-onset asthma (82%; 8751 of 10 711), and a median disease duration of 23 years (95% CI 20-26 years). 59% (4148 of 7006) of patients had FEV1/FVC of 0·7 or less, 62% (4680 of 7568) had FEV1 lower than 80% predicted, and 89% (3519 of 3968) had at least one active disease domain. Despite 79% (10 632 of 13 453) receiving biological therapy, more than 66% (2621 of 3968) still had at least two active domains. Elevation of type 2 biomarkers persisted (89% [2806 of 3153] with at least one elevated biomarker) despite widespread biological and maintenance oral corticosteroid treatment. A subset of biologic-naive patients (35%; 1069 of 3018) exhibited a rapid accumulation of disease burden within less than 10 years, suggesting a potentially accelerated progression trajectory. INTERPRETATION:This pan-European analysis of severe asthma revealed significant clinical heterogeneity and a substantial disease burden despite advanced therapies, highlighting the enduring nature of type 2 inflammation, the potential inadequacy of current remission strategies with available therapeutic approaches, and the necessity for early identification of high-risk patients. FUNDING:SHARP Clinical Research Collaboration and consortium partners: European Respiratory Society, GlaxoSmithKline Research and Development, Chiesi Farmaceutici Società per Azioni, Novartis Pharma Aktiengesellschaft, Sanofi-Genzyme Corporation, and Teva Branded Pharmaceutical Products R&D.

Asthma is characterised by a chronic inflammation and airway remodelling. The functionality of the asthma airway epithelium is altered, suggesting a central role in the pathophysiology. Cilia-associated abnormalities have been reported in the airway epithelium of asthmatic patients, but the mechanisms remain elusive. This study investigated cilia-associated dysregulations in cohorts of patients with severe asthma to identify and characterize key molecular drivers of epithelial airway remodelling. Transcriptomic data from epithelial bronchial brushing samples of three large cohorts of severe asthma patients and non-asthmatic were analysed: U-BIOPRED (GSE76226, n = 105), SARP (GSE63142, n = 81) and IMSA (GSE158752, n = 42). We focused on cilia-associated genes to highlight common differentially expressed genes in all three cohorts, comparing the non-asthmatic and severe asthma groups. Localisation and expression of the three most dysregulated genes were then validated on ex vivo and in vitro samples and correlated to epithelial airway remodelling features and clinical data. Seventeen genes were significantly dysregulated between the non-asthma and severe asthma groups in all three datasets. We identified the three most dysregulated: PHLDB2 (12.7

Background Healthcare administrative databases have many advantages for conducting studies on asthma. However, identifying asthma patients in these databases requires using algorithms based on reimbursement data. Objective The main objective of this study was to describe published algorithms identifying asthma patients in healthcare administrative databases. Methods We performed a systematic review of the studies using an algorithm to identify asthma patients from healthcare administrative databases, and published between 01/01/2016 and 31/12/2020 in Pubmed®. Data related to the characteristics of the studies, the algorithms used, and their validation were extracted using a standardized form. Results Three hundred and three studies were selected totaling 471 algorithms including 266 (56.5%) identifying asthma patients without details regarding severity or control, 41 (8.7%) identifying asthma exacerbations and 99 (21.0%) characterizing asthma severity or control. Among the 266 algorithms identifying asthma patients, we found a total of 138 ”different” algorithms and most of them used only diagnostic codes - from hospital or ambulatory data (n = 64, 46.4%) or combined diagnostic codes with drug dispensations (n = 36, 26.1%). Only 21.1% of the 266 algorithms used were reported as validated. Conclusion Many algorithms for identifying cases of asthma are available; the choice of an algorithm should be based on its relevance according to the objective of the study, the type of asthma, the type of healthcare administrative database, and its validation.

Diagnosing pulmonary diseases caused by non-fumigatus Aspergillus species remains challenging. We conducted a single-center, retrospective observational study in a French Respiratory Medicine Department. Patients with at least one respiratory sample positive for a non-fumigatus Aspergillus species, without concurrent A. fumigatus isolation over a 12-month period, were included. The primary objective was to determine the prevalence of pulmonary events (colonization or pulmonary diseases) associated with non-fumigatus Aspergillus species. Secondary objectives included species characterization and assessment of positive results for available diagnostic tests, including direct examination and fungal culture from respiratory samples, galactomannan in bronchoalveolar lavage, and serum A. fumigatus-specific IgG. Between April 2017 and January 2022, 497 patients (39.6%) had cultures positive for non-fumigatus Aspergillus species. Among them, 52 (10.5%) experienced pulmonary events: 36 were colonized, and 16 had a documented pulmonary disease. Aspergillus niger was the most frequently isolated species (41%), followed by Aspergillus flavus (27%) and Aspergillus nidulans (10%). Positive results were observed in 10/437 (2.3%) samples for direct examination, 75/808 (9.3%) for fungal culture, 7/94 (7.4%) for galactomannan in bronchoalveolar lavage, and 12/49 (24.5%) for serum Aspergillus fumigatus-specific IgG. Among patients with non-fumigatus Aspergillus positive respiratory samples, most were colonized, while nearly one-third had clinically significant pulmonary diseases, underscoring the clinical relevance of these species. Low positivity rates across diagnostic tests underscore the need for repeated respiratory sampling and fungal culture and suggest that assays primarily designed for A. fumigatus may under-detect these pulmonary events. IMPORTANCE:Non-fumigatus Aspergillus species are recognized as pulmonary pathogens, but their diagnosis is poorly documented. In this 5-year, single-center study, 497 of 1,256 patients had at least one positive respiratory culture for a non-fumigatus species, with 36 considered colonized and 16 with documented lung disease. A. niger, A. flavus, and A. nidulans accounted for almost four-fifths of the isolates. Routine tests produced poor results, with positivity rates of 2.3% for microscopy, 9.3% for repeat culture, 7.4% for bronchoalveolar galactomannan, and 24.5% for Aspergillus fumigatus serum IgG. Overall, the study shows that non-fumigatus species can cause treatable chronic lung disease, but that current diagnostics miss most cases. Until more sensitive tests are available, clinicians must rely on repeated respiratory sampling and culture to identify these infections.

Rationale:Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is characterised by diffuse bronchial hyperplasia of pulmonary neuroendocrine cells, which are situated within the walls of bronchi and bronchioles. Presenting symptoms are nonspecific and the clinical course varies, making diagnosis challenging. We sought to describe the clinical characteristics of patients with DIPNECH in a large multinational case series to guide and inform future care and research. Methods:Data were collated from 18 international centres. Information collected included disease presentation, pulmonary function testing, histopathology, radiological patterns and outcomes. The relationship between clinical features, radiology and symptoms were explored in parametric and nonparametric group-wise analyses, univariate linear regressions, and multivariate binomial logistic regression. Results:The mean±sd age of the 258 patients in this study was 63.3±10.6 years and 93.4% were female. Diffuse pulmonary nodules (98.8%) and mosaic attenuation (59.1%) were the most common radiological findings and 29.5% had obstructive spirometry with a mean±sdforced expiratory volume in 1 s (FEV1) % pred of 69.0±23.7%. There was a significant association between the number of nodules and a reduction in FEV1 % pred (p<0.001), while the presence of bronchial wall thickening on imaging was most closely associated with cough (OR 4.97, p=0.001) dyspnoea (OR 3.14, p=0.003) and bronchodilator responsiveness (OR 3.09, p=0.013). Approximately half of patients treated with inhaled beta agonist and corticosteroids (46.3%) or somatostatin analogue (54.1%) reported improvement in symptoms. Conclusions:The presence of radiological bronchial wall thickening is associated with the presence of symptoms, while mosaic attenuation is correlated with airflow obstruction; hence, the presence of these radiological findings has the potential to guide possible treatment decisions.

Background Work productivity is impaired in severe asthma; however, its evolution under biologics is poorly known, particularly regarding presenteeism, fact of being present at work while ill. Objective To investigate the evolution and factors associated with presenteeism in severe asthma after treatment with biologics. Methods We conducted a national, multicentric, uncontrolled cohort study. Patients with severe asthma eligible for a biologic and having a professional activity were included. Patients were assessed at baseline and after six months of treatment. Outcomes (percentages of presenteeism, absenteeism and work productivity loss) were measured using the Work Productivity and Activity Impairment (WPAI):Asthma questionnaire. Results A total of 167 patients were included and 122 were analyzed (59.8% women, mean age at 45.7 years). At inclusion, median presenteeism was at 30%. Under biologic, we observed a significant decrease in mean presenteeism (-14.9%, p<0.001) and work productivity loss (-15.4%, p<0.001) but no difference in absenteeism (-1.8%, p=0.41). In the multivariate logistic model, high presenteeism (WPAI:Asthma-Q5 ≥4) at inclusion was associated with uncontrolled asthma (ACQ-6 ≥1.5) (OR=18.9 [2.7; 403]) and hyperventilation symptoms (Nijmegen >17) (OR=4.6 [1.3; 19.8]). In the multivariate linear regression model, we found an association between presenteeism evolution, ACQ-6 score at inclusion (Beta=15.9 [8.6; 23.2], per 1-point increase) and ACQ-6 score evolution (Beta=17.1 [9.9; 24.2], per 1-point increase). Conclusion Although limited by the lack of a control group, our results suggest that biologics can reduce presenteeism and work impairment in severe asthma, and that asthma control is the main factor associated with presenteeism.

Background: Asthma characterization using blood eosinophil count (BEC) (among other biomarkers and clinical indices) is recommended in severe asthma (SA), but the masking effect of oral corticosteroids (OCS), makes this challenging. Aim: Our aim was to explore the effect of OCS use (both intermittent [iOCS] and long-term [LTOCS]) prior to biologic initiation on SA phenotype and biomarker profile in real-life and to characterize the burden of SA among patients prescribed LTOCS by biomarker profile. Methods: This was a registry-based cohort study, including data from 23 countries collected between 2003 and 2023 and shared with the Internatonal Severe Asthma Registry (ISAR). Patients with SA were categorized into 3 cohorts, those with: (i) no prescription for OCS, (ii) prescription(s) for iOCS (ie, ≤90 days in previous 12-months, usually short courses for exacerbations), and (iii) prescriptions for LTOCS (ie, >90 days in previous 12-months). Biomarker distribution (ie, BEC, fractional exhaled nitric oxide [FeNO], and total Immunoglobulin E [IgE]) were quantified in the year prior to biologic initiation in patients with SA according to OCS prescription pattern. Phenotypes were characterized for those prescribed LTOCS according to BEC cut-off (<150 and ≥ 150 cells/μL). Results: Of 4305 patients included, 5.0% (n = 215), 54.1% (n = 2330) and 40.9% (n = 1760) were prescribed no OCS, iOCS, and LTOCS, respectively. The BEC distribution varied by prescription pattern and LTOCS dose (<5 mg to ≥20 mg/day); BEC was <150 cells/μL in 28.6% (n = 369/1288) of LTOCS patients, compared to 19.5% (n = 284/1460) of iOCS patients and 14.0% (n = 21/150) of those in the no OCS group. Median BEC was also significantly lower in the LTOCS versus the iOCS group (310 vs 400 cells/μL; p < 0.001). A similar pattern was noted for IgE, but not FeNO. Among LTOCS patients with BEC <150 cells/μL, 39.9% experienced ≥4 exacerbations, 75.1% had uncontrolled asthma symptoms and 55.9% had evidence of persistent airflow obstruction (compared with 40.9%, 76.2% and 59.5% of those with BEC ≥150 cells/μL, respectively). Conclusions: OCS, whether prescribed intermittently or long term, affect BEC distribution potentially leading to heightened risk of phenotype misclassification and influencing subsequent treatment decisions. FeNO appears to be less susceptible to OCS-induced suppression. Disease burden was high for those in the LTOCS group and was high independent of dose and BEC. Our findings highlight the importance of considering OCS use, even intermittent use, when characterizing SA, and suggests the need for earlier phenotyping and alternative treatment strategies for LTOCS patients with low BEC.

BACKGROUND:Eosinophilic granulomatosis with polyangiitis (EGPA) is an eosinophilic antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Rituximab has emerged as the standard of care in other types of ANCA-associated vasculitis, but controlled studies on its use in EGPA are yet lacking. OBJECTIVE:To compare rituximab with conventional strategy for the induction of remission in patients with EGPA. DESIGN:Phase 3, multicenter, randomized, controlled, double-blind, superiority trial. (ClinicalTrials.gov: NCT02807103). SETTING:France. PARTICIPANTS:Patients with a diagnosis of EGPA, newly diagnosed or relapsing disease at the time of screening, with active disease defined as a Birmingham Vasculitis Activity Score (BVAS) of 3 or greater. INTERVENTION:Glucocorticoids plus rituximab (1 g 2 weeks apart) compared with the conventional strategy (glucocorticoids alone or in combination with cyclophosphamide in severe forms) for induction of remission. MEASUREMENTS:The primary end point was remission defined as a BVAS, version 3, of 0 and a prednisone dose of 7.5 mg/d or less at day 180. Secondary end points included duration of remission during the study, average daily glucocorticoid dose, and safety. RESULTS:A total of 105 participants were randomly assigned. Thirty-three (63.5%) patients in the rituximab group achieved the primary end point compared with 32 (60.4%) in the control group (relative risk, 1.05 [95% CI, 0.78 to 1.42]; P = 0.75). Results were similar at day 360. The mean duration of remission was 48.5 ± 6.51 weeks in the rituximab group and 49.1 ± 7.42 weeks in the conventional strategy group (P = 0.41). All relapse and major relapse rates were similar between the 2 groups. There was no statistically significant difference in the average daily glucocorticoid dose and no statistically significant differences in the rates of adverse events between the treatment groups. LIMITATION:Design not appropriate to answer the question of equivalence between rituximab and cyclophosphamide in patients with severe EGPA. CONCLUSIONS:Rituximab was not superior to a conventional remission induction strategy in EGPA. PRIMARY FUNDING SOURCE:French Ministry of Health.

BACKGROUND:Fungal sensitization has been associated with some features of severe asthma, but whether severe asthma with fungal sensitization (SAFS) requires specific management remains unclear. The long-term outcomes of SAFS remain poorly studied. OBJECTIVE:To assess the impact of fungal sensitization on disease severity using the Asthma Severity Scoring System (ASSESS) score and its evolution over time in a severe asthma cohort. METHODS:This retrospective analysis included adult patients with severe asthma evaluated at Bichat Hospital (Paris, France) between 2017 and 2022. All patients underwent specific IgE testing for Aspergillus, Botrytis, Alternaria, Penicillium, Cladosporium, and Candida. SAFS was defined as the presence of at least 1 positive specific IgE result. RESULTS:Among the 245 patients included, 69 (28.2%) had SAFS. At baseline, the ASSESS score was significantly higher in the SAFS group than in the severe asthma without fungal sensitization (SAwoFS) group (13.7 ± 2.8 vs 12.0 ± 3.0; P < .0001). This greater severity was supported by a lower FEV1 (65.5% vs 76.5% predicted; P = .0007), higher daily oral corticosteroid use (36.2% vs 18.2%; P = .0026), and higher hospitalization rates over the last 6 months (36.2% vs 19.9%; P = .007). At 12 months, the mean ASSESS score significantly decreased in both groups (SAFS: 12.4 ± 3.4; SAwoFS: 10.2 ± 3.6; P = .00015), but remained significantly higher in the SAFS group, driven by persistently lower FEV1 (65% vs 80% predicted; P = .0006), higher exacerbation rate (74.6% vs 55.3%; P = .008), and higher daily oral corticosteroid use (30% vs 14.7%; P = .009). Biologics were initiated in 51% of patients with SAFS and 56% of patients with SAwoFS. Among patients treated with biologics, ASSESS scores remained significantly higher in the SAFS group (12.8 vs 10.0; P = .0015). CONCLUSIONS:Patients with SAFS represent a particularly severe asthma phenotype, even after treatment with biologics. Nonetheless, they show a significant response to standardized care for severe asthma.

AbstractBackgroundChronic rhinosinusitis with nasal polyps (CRSwNP) is a recurrent inflammatory disease associated with several comorbidities and a significant disease burden for patients. Treatments include corticosteroids and sinonasal surgery, but these can be associated with the risk of adverse events and nasal polyp recurrence. Biologic treatments such as mepolizumab can be used as an add‐on treatment and are effective at reducing surgery and corticosteroid use.Main textPatients with CRSwNP may be seen by a specialist in one of several different areas and often experience delayed diagnosis due to the need to see multiple physicians, as well as misdiagnosis resulting from lack of sufficient expertise within any one speciality. Multidisciplinary team (MDT) approaches have been shown to be effective in optimising the treatment and clinical management of other respiratory diseases, such as aspirin‐exacerbated respiratory disease and severe asthma. In CRSwNP, an MDT approach may reduce diagnostic delays, mitigate secondary disease burden, and reduce overprescription of corticosteroids and antibiotics.ConclusionThis article provides an overview of the patient perspective of MDTs, existing approaches and barriers to adoption, lessons learnt from allied and rare diseases, how to address under‐recognised aspects of CRSwNP, and other key considerations for developing an MDT approach.

BACKGROUND:IL-5 is a key mediator of severe eosinophilic asthma (SEA) and also may contribute to airway remodeling. RESEARCH QUESTION:Can mepolizumab, an anti-IL-5 antibody, modify airway remodelling in adult patients with SEA? STUDY DESIGN AND METHODS:Thirty-seven patients who were eligible for mepolizumab were included prospectively. Mepolizumab 100 mg was administered subcutaneously every 4 weeks for 12 months. Bronchial biopsies and bronchoalveolar lavage (BAL) were performed at baseline, 6 months, and 12 months. Clinical and functional outcomes, airway remodeling, and inflammatory markers were assessed at each time point. RESULTS:At 12 months, mepolizumab was shown to improve asthma control and FVC before bronchodilation and reduce the number of exacerbations, oral corticosteroid courses, and hospitalizations. These clinical and functional improvements were associated with a reduction in reticular basement membrane thickness (P < 0.0001), airway smooth muscle (ASM) mass (P = .0066), and proliferating cell nuclear antigen-positive ASM cells (P < .0001) in the bronchial mucosa at both 6 and 12 months. BAL fluid showed reduced levels of tenascin-C at 6 and 12 months and of fibulin-1 at 12 months. Blood eosinophil counts decreased significantly (P < .0001), and eosinophils were almost completely depleted in BAL fluid (P = .023) at 12 months. Submucosal eosinophilia was reduced to a lesser extent (P = .063). INTERPRETATION:In addition to its antiinflammatory effects, mepolizumab also may attenuate structural airway changes in SEA, which could contribute to its clinical benefits. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov; No.: NCT03797404; URL: www. CLINICALTRIALS:gov.

Aim:The impact of sensitization on asthma outcomes in adults is still being discussed. This study aims to describe the sensitization profiles and allergic comorbidities of patients with severe asthma, and to analyze their association with asthma severity. Patients and Methods:This retrospective study included adult patients, evaluated at the Severe Asthma Clinic of Bichat University Hospital (Paris, France) during a 1-day hospital stay between May 2022 and January 2024. Sensitization, defined by a positive skin prick test and/or allergen-specific IgE levels greater than 0.10 kUA/L, was analysed alongside allergic comorbidities. The ASSESS score was used to grade asthma severity. Results:Of the 201 patients included, 142 (70.6%) exhibited at least one sensitization to an aeroallergen, of whom 38 (26.8%) were monosensitized, and 104 (73.2%) were polysensitized. Compared to polysensitized patients, monosensitized patients were older at diagnosis (years: 30.6 ± 20.1 vs 21.7 ± 17.6, p = 0.01), had a higher ASSESS score (median (Q1; Q3); 13 (11; 15) vs 11 (9; 14), p = 0.02), a lower pre-bronchodilator forced expiratory volume in 1 second (%pred: 70.3 ± 23.2 vs 79.3 ± 21.8, p = 0.03), and experienced a greater burden of exacerbations (p = 0.03). There were significantly more polysensitized patients with at least three allergic comorbidities, but the number of allergic comorbidities did not correlate with asthma severity. Conclusion:Monosensitized patients exhibited more severe disease and greater airway obstruction compared to polysensitized individuals. These findings suggest that allergies, especially in cases of late-onset asthma, may not be a significant determinant of asthma severity in adults.

BACKGROUND:Asthma with low levels of type 2 (T2) biomarkers is poorly understood. OBJECTIVE:To characterize severe asthma phenotypes and compare changes in asthma outcomes from pre- to postbiologic treatment along a gradient of T2 involvement. METHODS:This was a registry-based cohort study including data from 24 countries. Biomarker distribution (blood eosinophil count, fractional exhaled nitric oxide, and IgE) was quantified before biologic initiation. Clusters were identified using a 5-component Gaussian finite mixture model and phenotypically characterized. Changes in asthma and health care utilization outcomes between 1-year pre- and postbiologic initiation were compared between clusters and by biologic class. RESULTS:Among 3675 patients, 5 biomarker clusters were identified along a gradient of T2 involvement: cluster A with the lowest T2 involvement (16.4%), cluster B (20.4%), cluster C (22.9%), cluster D (30.3%), and cluster E with the highest T2 involvement (10.0%). In multivariable analysis, biologic use was associated with improved outcomes in all clusters but tended to be better at the higher end of the T2 spectrum. For example, patients in cluster C had a significantly greater increase in forced expiratory volume in 1 second compared with cluster A (difference 0.16 L [95% confidence interval: 0.08, 0.25]; P < .001). The odds of uncontrolled asthma were approximately 0.6 for all clusters compared with cluster A. Overall, exacerbation rates were lower, and greater improvements in lung function and asthma control were noted for anti-IL-5/5 receptor (R) (but not anti-IgE or anti-IL-4Rα) for all clusters compared with cluster A. CONCLUSION:T2-targeting biologics have utility in the management of asthma with low T2 involvement, but more effective therapies are needed. Further research is warranted to identify specific pathogenic pathways at the lower end of the T2 spectrum that can be effectively targeted by biologics.

Rationale: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a pulmonary condition characterised by neuroendocrine cell proliferation along respiratory bronchioles resulting in tumourlet formation which may progress to pulmonary carcinoid. DIPNECH is a rare and under-recognised condition that predominantly affects females, with an estimated worldwide incidence of 5-6 people per million population. Given it's rarity and the poor understanding around the pathogenesis and treatment of this condition, we undertook the largest international case series to date of DIPNECH patients. We aim to further characterise this patient cohort to better understand the clinical features, identify common pulmonary function test (PFT) patterns and radiographic findings and describe current treatment practices. Methods: We collated data from 17 centres across 8 different countries comprising a total of 258 patients. Data collected included patient demographics, smoking history, symptoms, co-morbidities, pathological diagnosis, imaging findings, PFT pattern and therapies. Results: In total 258 patients were identified. The median age was 65 (SD+/- 10.6). 241 (93%) were female. 39% (n= 94/243) were ex-smokers. 79% (n=186/234) of patients reported pulmonary symptoms with cough being the most common symptom reported in 81% (n=151/186) of patients. Many patients were polysymptomatic, with cough and dyspnoea being the most common combination of symptoms described. (50.54%; n=94/186). Complete spirometry pattern was documented for 180 patients (69.78%) with an obstructive pattern being the most commonly observed (n=76/180; 42%). 27.5% (n=41/139) had clinically significant FEV1 reversibility post bronchodilator administration. Pathology specimens were available in 219 cases. Most common pathological features were neuroendocrine hyperplasia which was observed in 75% (n=165/219) and tumourlets in 74% (n=162/219) of cases. Carcinoid, either typical or atypical, was observed in 64% (n=141/219) of samples. 252 patients had computed tomography (CT) imaging performed. Pulmonary nodules were the most common feature identified in 99.60% of cases (248/250). Mosaic attenuation (69.30%; n=50/173) and airway dilatation (28.90%; n=50/173) were also frequently reported. There was no significant correlation between symptoms (cough, dyspnoea, wheeze) and airway dilatation (p=0.496), mosaic attenuation (p=0.496) and PFT pattern (p=0.837). There was a significant association between presence of symptoms and mosaic attenuation on CT (p=0.003). Conclusions: DIPNECH, while a rare disorder, is understudied. This international case series is the largest performed to date and highlights the complexity in management of these patients.