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Background: Idiopathic pulmonary fibrosis (IPF) is a progressive condition associated with a variable prognosis. The relationship between socioeconomic status or distance travelled to respiratory clinics and prognosis is unclear., Research Question: To determine whether socioeconomic status, distance to hospital and time to referral affects survival in patients with IPF., Study Design and Methods: In this retrospective cohort study, we used data collected from the British Thoracic Society Interstitial Lung Diseases Registry, between 2013 and 2021 (n = 2359) and calculated the quintile of Index of Multiple Deprivation 2019 score, time from initial symptoms to hospital attendance and distance as the linear distance between hospital and home post codes. Survival was assessed using Cox proportional hazards models., Results: There was a significant association between increasing quintile of deprivation and duration of symptoms prior to hospital presentation, Gender Age Physiology (GAP) index and receipt of supplemental oxygen and antifibrotic therapies at presentation. The most deprived patients had worse overall survival compared to least deprived after adjusting for smoking status, GAP index, distance to hospital and time to referral (HR = 1.39 [1.11, 1.73]; p = 0.003). Patients living furthest from a respiratory clinic also had worse survival compared to those living closest (HR = 1.29 [1.01, 1.64]; p = 0.041)., Interpretation: The most deprived patients with IPF have more severe disease at presentation and worse outcomes. Living far from hospital was also associated with poor outcomes. This suggests inequalities in access to healthcare and requires consideration in delivering effective and equitable care to patients with IPF., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AMW: Institutional research funding from Aseptika, Brainomix, Celgene Corporation, GlaxoSmithKline and Insmed. Speaker fees from Boehringer Ingelheim. Support to attend meeting from Chiesi. NC: Institutional research funding from Boehringer Ingelheim. Consultancy fees from Boehringer Ingelheim, Vicor and Bridge therepeutics. Speaker fees from Boehringer Ingelheim and Astra Zeneca. LS: Member of an advisory board for Daichi Sankyo. Support to attend meeting from Chiesi. RS, CH, AC, HA – None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Eosinophilic gastrointestinal disorder (EGID) is an umbrella term encompassing a group of chronic, immune-mediated disorders characterized by eosinophil-rich inflammation affecting one or more segments of the gastrointestinal tract. A recent consensus in nomenclature and emerging data made possible through multi-center consortia are beginning to unravel the molecular and cellular underpinnings of EGIDs below the esophagus. These emerging findings are revealing both overarching commonalities related to a food allergen-driven, chronic, Th2-mediated immune response as well as location-specific nuances in the pathophysiology of the collective EGIDs. Altogether, these advances offer promise for improved diagnoses and more efficacious interventional strategies., Competing Interests: Disclosure None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Interstitial lung disease (ILD) is a significant complication of many systemic autoimmune rheumatic diseases (SARDs), although the clinical presentation, severity and outlook may vary widely between individuals. Despite the prevalence, there are no specific guidelines addressing the issue of screening, diagnosis and management of ILD across this diverse group. Guidelines from the ACR and EULAR are expected, but there is a need for UK-specific guidelines that consider the framework of the UK National Health Service, local licensing and funding strategies. This article outlines the intended scope for the British Society for Rheumatology guideline on the diagnosis and management of SARD-ILD developed by the guideline working group. It specifically identifies the SARDs for consideration, alongside the overarching principles for which systematic review will be conducted. Expert consensus will be produced based on the most up-to-date available evidence for inclusion within the final guideline. Key issues to be addressed include recommendations for screening of ILD, identifying the methodology and frequency of monitoring and pharmacological and non-pharmacological management. The guideline will be developed according to methods and processes outlined in Creating Clinical Guidelines: British Society for Rheumatology Protocol version 5.1., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease, with most patients reporting cough. Currently, there are no proven treatments. We examined the use of low dose controlled-release morphine compared with placebo as an antitussive therapy in individuals with idiopathic pulmonary fibrosis., Methods: The PACIFY COUGH study is a phase 2, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial done in three specialist centres in the UK. Eligible patients aged 40-90 years had a diagnosis of idiopathic pulmonary fibrosis within 5 years, self-reported cough (lasting >8 weeks), and a cough visual analogue scale (VAS) score of 30 mm or higher. Patients were randomly assigned (1:1) to placebo twice daily or controlled-release morphine 5 mg orally twice daily for 14 days followed by crossover after a 7-day washout period. Patients were randomised sequentially to a sequence group defining the order in which morphine and placebo were to be given, according to a computer-generated schedule. Patients, investigators, study nurses, and pharmacy personnel were masked to treatment allocation. The primary endpoint was percentage change in objective awake cough frequency (coughs per h) from baseline as assessed by objective digital cough monitoring at day 14 of treatment in the intention-to-treat population, which included all randomised participants. Safety data were summarised for all patients who took at least one study drug and did not withdraw consent. This study was registered at ClinicalTrials.gov, NCT04429516, and has been completed., Findings: Between Dec 17, 2020, and March 21, 2023, 47 participants were assessed for eligibility and 44 were enrolled and randomly allocated to treatment. Mean age was 71 (SD 7·4) years, and 31 (70%) of 44 participants were male and 13 (30%) were female. Lung function was moderately impaired; mean forced vital capacity (FVC) was 2·7 L (SD 0·76), mean predicted FVC was 82% (17·3), and mean predicted diffusion capacity of carbon monoxide was 48% (10·9). Of the 44 patients who were randomised, 43 completed morphine treatment and 41 completed placebo treatment. In the intention-to-treat analysis, morphine reduced objective awake cough frequency by 39·4% (95% CI -54·4 to -19·4; p=0·0005) compared with placebo. Mean daytime cough frequency reduced from 21·6 (SE 1·2) coughs per h at baseline to 12·8 (1·2) coughs per h with morphine, whereas cough rates did not change with placebo (21·5 [SE 1·2] coughs per h to 20·6 [1·2] coughs per h). Overall treatment adherence was 98% in the morphine group and 98% in the placebo group. Adverse events were observed in 17 (40%) of 43 participants in the morphine group and six (14%) of 42 patients in the placebo group. The main side-effects of morphine were nausea (six [14%] of 43 participants) and constipation (nine [21%] of 43). One serious adverse event (death) occurred in the placebo group., Interpretation: In patients with cough related to idiopathic pulmonary fibrosis, low dose controlled-release morphine significantly reduced objective cough counts over 14 days compared with placebo. Morphine shows promise as an effective treatment to palliate cough in patients with idiopathic pulmonary fibrosis, and longer term studies should be the focus of future research., Funding: The Jon Moulton Charity Trust., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Nintedanib slows progression of lung function decline in patients with progressive fibrosing (PF) interstitial lung disease (ILD) and was recommended for this indication within the United Kingdom (UK) National Health Service in Scotland in June 2021 and in England, Wales and Northern Ireland in November 2021. To date, there has been no national evaluation of the use of nintedanib for PF-ILD in a real-world setting., Methods: 26 UK centres were invited to take part in a national service evaluation between 17 November 2021 and 30 September 2022. Summary data regarding underlying diagnosis, pulmonary function tests, diagnostic criteria, radiological appearance, concurrent immunosuppressive therapy and drug tolerability were collected via electronic survey., Results: 24 UK prescribing centres responded to the service evaluation invitation. Between 17 November 2021 and 30 September 2022, 1120 patients received a multidisciplinary team recommendation to commence nintedanib for PF-ILD. The most common underlying diagnoses were hypersensitivity pneumonitis (298 out of 1120, 26.6%), connective tissue disease associated ILD (197 out of 1120, 17.6%), rheumatoid arthritis associated ILD (180 out of 1120, 16.0%), idiopathic nonspecific interstitial pneumonia (125 out of 1120, 11.1%) and unclassifiable ILD (100 out of 1120, 8.9%). Of these, 54.4% (609 out of 1120) were receiving concomitant corticosteroids, 355 (31.7%) out of 1120 were receiving concomitant mycophenolate mofetil and 340 (30.3%) out of 1120 were receiving another immunosuppressive/modulatory therapy. Radiological progression of ILD combined with worsening respiratory symptoms was the most common reason for the diagnosis of PF-ILD., Conclusion: We have demonstrated the use of nintedanib for the treatment of PF-ILD across a broad range of underlying conditions. Nintedanib is frequently co-prescribed alongside immunosuppressive and immunomodulatory therapy. The use of nintedanib for the treatment of PF-ILD has demonstrated acceptable tolerability in a real-world setting., Competing Interests: Conflict of interest: A.J. Simpson has received funding to his institution from Boehringer Ingelheim (BI) to undertake an educational meeting. A. West has received support from BI for speaking at or chairing educational events, and attendance and travel to educational meetings; and is part of an advisory board for BI and Avalyn Pharmaceuticals. A. John has received funding from BI to attend an educational event. A.M. Wilson has received grants from Aseptika, Brainomix and BASF, has received speakers’ fees from BI, has received support for attending meetings by Chiesi, and has institutional interests with Celgene Corporation, GSK and Insmed Inc. A. Crawshaw has received speakers’ fees from BI and AstraZeneca (AZ). A.U. Wells has undertaken advisory board activity and consultant work for BI, Roche and Veracyte. C.C. Huntley has received an honorarium for educational content from BI and sponsorship for conference attendance. D. Dosanjh has received a speaker's fee from BI, meeting attendance costs from AZ and is part of the advisory board for AZ, Gilead, BI and Synairgen. E. Renzoni has received institutional funding, honoraria for educational events and funding for conference attendance from BI, and is member of the advisory board for BI and Roche. F. Chua has received consulting fees, honoraria, support for conference attendance and is an advisory board member for BI. G. Saini has received institutional payment for educational presentation from BI. G. Dixon, H. Stone, L.M. Nicol and I.A. Forrest have received support for educational event attendance from BI. J.C.L. Rodrigues has received grant funding from NIHR, consulting fees from NHSx and HeartFlow, honoraria from Sanofi, Aidence and 4-C Research market research, meeting attendance support from Aidence and HeartFlow, leadership role in Heart and Lung Imaging LTD (HLH), stock in Radnet and shares in HLH. K. Tsaneva-Atanasova has financial support from EPSRC grant. M. Naqvi has received a grant from NHS Digital, honoraria from BI, AZ and Roche, support for meeting attendance from BI and advisory board membership for BI, and is ILD Pharmacist Network Chair and ILD-IN Co-chair. M.G. Jones has received grants from Royal Society, BI, NC3Rs, MRC, AAIR Charity and the British Lung Foundation. P.M. George has received an institutional grant from BI, honoraria from BI, Roche, Teva, Cipla and Brainomix, meeting attendance support from BI and Roche and has stock in Brainomix. P. Molyneaux has grant funding from AZ, consulting fees from Roche, BI, AZ, Trevi and Qureight, and honoraria from BI and Roche; and is an associate editor of this journal. P. Rivera-Ortega has received grant funding from MRC, institutional grant funding from BI, Roche, CSL Behring, Fibrogen, Vicore Pharma AB, Gilead Sciences and Galecto, consulting fees from BI and Roche, honoraria from BI, Roche and Respiratory Effectiveness Group (REG), support for meeting attendance from BI and REG, is a chair of the REG and member of the Global Writing Group Committee for REMAP-ILD. R.K. Coker has received honoraria from BI. S. Agnew has received honoraria from BI, support for meeting attendance from BI and is member of the BTS ILD registry advisory board. S.L. Barratt has received consulting fees and honoraria from BI. S. Hart has received research grant from BI, consulting fees from Trevi Therapeutics, honoraria and support for meeting attendance from BI and Chiesi, was Chair of the BTS Standard of Care Committee 2019–2022, and is a Trustee of Action for Pulmonary Fibrosis and an associate editor of this journal. S. Barth received honoraria from BI for educational meeting facilitating. T. Garfoot received support to attend the ILD IN annual conference. T. Gatheral has received speakers’ fees from BI. Conflict of interest: The remaining authors have no competing interests., (Copyright ©The authors 2024.)

Policy diffusion is the process in which an innovation is communicated over time through various channels among the members of a social system. It is a special type of communication, in that the messages are concerned with new ideas. Diffusion theory or diffusion of innovations is the theoretical framework utilized in this study to compare successful programs aimed at providing health care for the homeless population. This study examines the Crisis Outreach Response and Engagement (CORE) program in Hawaii and explains how the diffusion innovation theory and programs in other states can be used to develop policies and processes to successfully address the medical and crisis intervention needs of the homeless on O'ahu. The study also includes suggested recommendations and strategies for the CORE program.

Introduction: Sarcoidosis is a highly variable disease in terms of organ involvement, type of onset and course. Associations of genetic polymorphisms with sarcoidosis phenotypes have been observed and suggest genetic signatures., Methods: After obtaining a positive vote of the competent ethics committee we genotyped 1909 patients of the deeply phenotyped Genetic-Phenotype Relationship in Sarcoidosis (GenPhenReSa) cohort of 31 European centers in 12 countries with 116 potentially disease-relevant single-nucleotide polymorphisms (SNPs). Using a meta-analysis, we investigated the association of relevant phenotypes (acute vs. sub-acute onset, phenotypes of organ involvement, specific organ involvements, and specific symptoms) with genetic markers. Subgroups were built on the basis of geographical, clinical and hospital provision considerations., Results: In the meta-analysis of the full cohort, there was no significant genetic association with any considered phenotype after correcting for multiple testing. In the largest sub-cohort (Serbia), we confirmed the known association of acute onset with TNF and reported a new association of acute onset an HLA polymorphism. Multi-locus models with sets of three SNPs in different genes showed strong associations with the acute onset phenotype in Serbia and Lublin (Poland) demonstrating potential region-specific genetic links with clinical features, including recently described phenotypes of organ involvement., Discussion: The observed associations between genetic variants and sarcoidosis phenotypes in subgroups suggest that gene-environment-interactions may influence the clinical phenotype. In addition, we show that two different sets of genetic variants are permissive for the same phenotype of acute disease only in two geographic subcohorts pointing to interactions of genetic signatures with different local environmental factors. Our results represent an important step towards understanding the genetic architecture of sarcoidosis., Competing Interests: FB received from Boehringer Ingelheim, Fujirebio, Galapagos NV and Roche; personal travel support from Boehringer Ingelheim and Roche, board membership fees from Boehringer Ingelheim, Bristol Myers Squibb, Fujirebio, Galapagos, GlaxoSmithKline, Roche and Takeda. DB grants paid to the institution from Synairgen and Sanofi; personal honoraria received from Chiesi, Norvatis and Sanofi; personal honoraria for lectures received from Astra Zeneca, Eli Lilly and Norvatis; not for profit activities for ministry of health, Romania. AF received a grant from the German Research Foundation. BF: received grants from Bristol Myers Squibb and AdVita Lifescience paid to the institution; personal honoraria for lectures from Boehringer Ingelheim, Astra Zeneca and Roche, personal travel support from Boehringer Ingelheim; reports a pending patient WO2020225246A1 and stocks from Relief Therapeutics. CG received lecture fees from Astra Zeneca paid to the institution. MK received consulting fees from Boehringer Ingelheim. JM-Q grants from German Research Council, Bristol Myers Squibb and AdVita Lifesciences paid to the institution, received personal honoria from AdVita Lifesciences and Roche, received lecture fees from Astra Zeneca and Roche, received payments for expert testimony from AdVita Lifescience; received travel support from AdVita Lifescience and Grifols, reports a pending patent WO2020225246A1 and stocks from Relief Therapeutics. MaP received grants from Palacky University paid to the institution. MiP reports fiduciary activities for Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin. VP received personal consulting fees from Ambu and Erbe; lecture honoraria from Boehringer Ingelheim and Roche and participated in a data safety monitoring board for Boehringer Ingelheim. AP received personal consulting fees from Boehringer Ingelheim, Roche, AstraZeneca and Galapagos, lecture fees from Boehringer Ingelheim, Norvatis and Gilead, participated in data safety monitoring boards for Boehringer Ingelheim, Roche and AstraZeneca and reports fiduciary activities for the European Rare Disease Network Interstitial Lung Disease Group and the steering committee of the World Association of Sarcoidosis and Other Granulomtous Disorders. SS reports grants from the German Research Council paid to the institution, personal consulting fees from Abbvie, Arenal, BMS, Biogen, Celltrion, Celgen, IMAB, Gilead, MSD, Mylan, Pfizer, Fresinius, Janssen, Takeda, Theravance, Provention Bio, Protagonist, Falk, Ferring, UCB, Amgen, Sandoz Hexal, Lilly, Galapagos. JCS grants from the German Research Council, Else Kröner-Fresenius Foundation, and Fritz Thyssen-Foundation paid to the institution; received personal lecture honoraria from Boehringer Ingelheim. LS received personal honoraria from Boehringer Ingelheim for educational events. D received personal honoraria from Boehringer Ingelheim for activities in advisory boards and lecture fees from Boehringer Ingelheim and AstraZeneca and reports travel support from Boehringer Ingelheim. WW grants from Roche, Boehringer Ingelheim, and Galapagos, consulting fees from Sanofi, Boehringer Ingelheim and Roche, honoraria for lectures from Roche and Beohdringer Ingelheim and payments for activities in data safety monitoring boards from Boehringer Ingelheim and Roche all paid to the institution. GZ reports a pending patent (EP 2585089 A1) and stock options for Moderna, Biontech and Relief Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Freitag-Wolf, Schupp, Frye, Fischer, Anwar, Kieszko, Mihailović-Vučinić, Milanowski, Jovanovic, Zissel, Bargagli, Rottoli, Bumbacea, Jonkers, Ho, Gaede, Dubaniewicz, Marshall, Günther, Petrek, Keane, Haraldsdottir, Bonella, Grah, Peroš-Golubičić, Kadija, Pabst, Grohé, Strausz, Safrankova, Millar, Homolka, Wuyts, Spencer, Pfeifer, Valeyre, Poletti, Wirtz, Prasse, Schreiber, Dempfle and Müller-Quernheim.)

Rationale: Shared symptoms and genetic architecture between coronavirus disease (COVID-19) and lung fibrosis suggest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to progressive lung damage. Objectives: The UK Interstitial Lung Disease Consortium (UKILD) post-COVID-19 study interim analysis was planned to estimate the prevalence of residual lung abnormalities in people hospitalized with COVID-19 on the basis of risk strata. Methods: The PHOSP-COVID-19 (Post-Hospitalization COVID-19) study was used to capture routine and research follow-up within 240 days from discharge. Thoracic computed tomography linked by PHOSP-COVID-19 identifiers was scored for the percentage of residual lung abnormalities (ground-glass opacities and reticulations). Risk factors in linked computed tomography were estimated with Bayesian binomial regression, and risk strata were generated. Numbers within strata were used to estimate posthospitalization prevalence using Bayesian binomial distributions. Sensitivity analysis was restricted to participants with protocol-driven research follow-up. Measurements and Main Results: The interim cohort comprised 3,700 people. Of 209 subjects with linked computed tomography (median, 119 d; interquartile range, 83-155), 166 people (79.4%) had more than 10% involvement of residual lung abnormalities. Risk factors included abnormal chest X-ray (risk ratio [RR], 1.21; 95% credible interval [CrI], 1.05-1.40), percent predicted Dl CO less than 80% (RR, 1.25; 95% CrI, 1.00-1.56), and severe admission requiring ventilation support (RR, 1.27; 95% CrI, 1.07-1.55). In the remaining 3,491 people, moderate to very high risk of residual lung abnormalities was classified at 7.8%, and posthospitalization prevalence was estimated at 8.5% (95% CrI, 7.6-9.5), rising to 11.7% (95% CrI, 10.3-13.1) in the sensitivity analysis. Conclusions: Residual lung abnormalities were estimated in up to 11% of people discharged after COVID-19-related hospitalization. Health services should monitor at-risk individuals to elucidate long-term functional implications.

Background: Interstitial lung disease is a known complication of rheumatoid arthritis, with a lifetime risk of developing the disease in any individual of 7·7%. We aimed to assess the safety, tolerability, and efficacy of pirfenidone for the treatment of patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD)., Methods: TRAIL1 was a randomised, double-blind, placebo-controlled, phase 2 trial done in 34 academic centres specialising in interstitial lung disease in four countries (the UK, the USA, Australia, and Canada). Adults aged 18-85 years were eligible for inclusion if they met the 2010 American College of Rheumatology and European Alliance of Associations for Rheumatology criteria for rheumatoid arthritis and had interstitial lung disease on a high-resolution CT scan imaging and, when available, lung biopsy. Exclusion criteria include smoking, clinical history of other known causes of interstitial lung disease, and coexistant clinically significant COPD or asthma. Patients were randomly assigned (1:1) to receive 2403 mg oral pirfenidone (pirfenidone group) or placebo (placebo group) daily. The primary endpoint was the incidence of the composite endpoint of a decline from baseline in percent predicted forced vital capacity (FVC%) of 10% or more or death during the 52-week treatment period assessed in the intention-to-treat population. Key secondary endpoints included change in absolute and FVC% over 52 weeks, the proportion of patients with a decline in FVC% of 10% or more, and the frequency of progression as defined by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02808871., Findings: From May 15, 2017, to March 31, 2020, 231 patients were assessed for inclusion, of whom 123 patients were randomly assigned (63 [51%] to the pirfenidone group and 60 [49%] to the placebo group). The trial was stopped early (March 31, 2020) due to slow recruitment and the COVID-19 pandemic. The difference in the proportion of patients who met the composite primary endpoint (decline in FVC% from baseline of 10% or more or death) between the two groups was not significant (seven [11%] of 63 patients in the pirfenidone group vs nine [15%] of 60 patients in the placebo group; OR 0·67 [95% CI 0·22 to 2·03]; p=0·48). Compared with the placebo group, patients in the pirfenidone group had a slower rate of decline in lung function, measured by estimated annual change in absolute FVC (-66 vs -146; p=0·0082) and FVC% (-1·02 vs -3·21; p=0·0028). The groups were similar with regards to the decline in FVC% by 10% or more (five [8%] participants in the pirfenidone group vs seven [12%] in the placebo group; OR 0·52 [95% CI 0·14-1·90]; p=0·32) and the frequency of progression as defined by OMERACT (16 [25%] in the pirfenidone group vs 19 [32%] in the placebo group; OR 0·68 [0·30-1·54]; p=0·35). There was no significant difference in the rate of treatment-emergent serious adverse events between the two groups, and there were no treatment-related deaths., Interpretation: Due to early termination of the study and underpowering, the results should be interpreted with caution. Despite not meeting the composite primary endpoint, pirfenidone slowed the rate of decline of FVC over time in patients with RA-ILD. Safety in patients with RA-ILD was similar to that seen in other pirfenidone trials., Funding: Genentech., Competing Interests: Declaration of interests SKD reports grants and salary support from Brigham and Women's Hospital, during the study; grants, personal fees, and non-financial support from Boehringer Ingelheim; personal fees and non-financial support from Galaplagos; personal fees from Galecto, and Lupin Pharma; grants from Bristol Meyers Squibb; salary support from the Pulmonary Fibrosis Foundation, and Royalties for Topics on systemic erythematous pneumonia- interstitial lung disease and myositis- interstitial lung disease from UpToDate, outside the submitted work. IG reports personal fees from Boehringer Ingelheim and personal fees from Ad Alta, Amplia, Accendatech, and Lassen, outside the submitted work. PFD served on an unpaid advisory committee at Boehringer Ingleheim, and reports receiving non-financial support for serving as a site-principal investigator for Bristol Myers and Genentech, outside the submitted work. RV reports grants from Bristol Myers Squibb, Pfizer, and Sun Pharma, outside the submitted work. PGC reports grants from InterMune, outside the submitted work. KRF reports grants and personal fees from Boehringer Ingelheim; personal fees from Roche/Genentech, Bellerophon, Respivant, Shionogi, DevPro, AstraZeneca, Pure Health, Horizon, Fibrogen, Sun Pharmaceuticals, Pliant, United Therapeutics, Arrowhead, Lupin, Polarean, Pure Tech, Trevi Pharmaceuticals, CSL Behring, Daewong, DevPro, Dispersol, Immumet, and NeRRe Therapeutics, outside the submitted work. LT reports personal fees from Boehringer Ingelheim outside the submitted work. MBS reports grants from Boehringer Ingelheim, Veracyte, and Genentech; financial support from Genentech, United Therapeutics, Veracyte; honoraria from Boehringer Ingelheim, United Therapeutics, and Veracyte, and meeting and travel support from Genentech and the American College of Chest Physicians. NC reports personal fees from Boehringer Ingelheim, Redex, Novartis, Liminal Biosciences, Vicor Pharma, Bridge Biotherapeutics, and Roche, outside the submitted work. DAL reports grants from Boehringer Ingelheim and grants and personal fees from Calyx, outside the submitted work; DAL has a patent issued on systems and methods for automatic detection and quantification of pathology using dynamic feature classification (US10706533B2). DCC reports that Roche/Genentech provided the investigational medicinal product free of charge during the study; and that he served as principal investigator for a trial site in a Roche sponsored study outside the submitted work, in which per patient fees were paid to the site. MK reports grants from Genentech, during the study; grants from Canadian Pulmonary Fibrosis Foundation and Canadian Institute for Health Research; an allowance as chief editor from European Respiratory Journal; grants and personal fees from Boehringer Ingelheim and Roche Canada; and personal fees from Horizon, Algernon, CSL Behring, and DevPro; and served as a site principal investigator for industry sponsored clinical trials (Roche and Boehringer Ingelheim); outside the submitted work. GR served as a consultant/steering committee member for IPF and PPF studies for Roche/Genentech and served on a data safety monitoring board for an IPF study (Avalyn), outside the submitted work. HJG reports receiving support to participate as a member of the Clinical Coordinating Center and coprincipal investigator, from Genentech, during the study. FAW is currently an employee at Avalyn. IOR reports grants from Genentech/Roche, during the conduct of the study and personal fees from Genentech/Roche, Boehringer Ingelheim, and Immunomet, outside the submitted work. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Recent studies have shown that IgG4 is increased in the esophageal tissue of eosinophilic esophagitis patients, including the presence of IgG4+ plasma cells., Aims: Our aim was to determine whether IgG4 is elevated in the gastric or duodenal tissue of pediatric patients with eosinophilic gastritis or duodenitis (EoG or EoD)., Methods: This was a retrospective single center study. Pediatric patients were characterized as having active EoG, EoD, or as controls based on clinical symptoms and histologic features. Immunohistochemistry for IgG4 was performed in gastric and duodenal tissue, and peak IgG4+ cells were compared between groups and after treatment., Results: The frequency of IgG4+ cells was significantly higher in patients with EoG and EoD compared to controls in the stomach [EoG 6.5 cells/hpf (3.6-10.9), control 0 cells/hpf (0-0.7), p<0.0001] and duodenum [EoD 7.5 cells/hpf (2.8-37), control 0.5 cells/hpf (0.3-1.3), p<0.001)] respectively, and positively correlated with eosinophil counts (stomach: r 0.74, p<0.0001; duodenum: r 0.57, p<0.0001). The amount of tissue IgG4 was significantly decreased in patients in remission but not in persistently active disease., Conclusions: These data suggest local tissue production of IgG4 may be a universal feature of eosinophilic gastrointestinal disease that tracks with disease activity., Competing Interests: Conflict of Interest None declared., (Copyright © 2022. Published by Elsevier Ltd.)

Intestinal eosinophils are implicated in the inflammatory pathology of eosinophilic gastrointestinal diseases and inflammatory bowel diseases. Eosinophils also contribute to intestinal immunologic and tissue homeostasis and host defense. Recent studies in allergic airway disease suggest functional subphenotypes of eosinophils may underly their pathogenic versus protective roles. However, subphenotypes of intestinal eosinophils have not been defined and are complicated by their constitutive expression of the putative eosinophil inflammatory marker CD11c. Here, we propose a framework for subphenotype characterization of intestinal eosinophils based on relative intensity of surface CD11c expression. Using this flow cytometry framework in parallel with histology and BrdU tracing, we characterize intestinal eosinophil subphenotypes and monitor their plasticity at baseline and within the context of acute allergic and chronic systemic inflammation. Data reveal a conserved continuum of CD11c expression amongst intestinal eosinophils in health and acute disease states that overall tracked with other markers of activation. Oral allergen challenge induced recruitment of eosinophils into small intestinal lamina propria surrounding crypts, followed by in situ induction of CD11c expression in parallel with eosinophil redistribution into intestinal villi. Allergen challenge also elicited eosinophil transepithelial migration and the appearance of CD11c lo CD11b hi eosinophils in the intestinal lumen. Chronic inflammation driven by overexpression of TNFα led to a qualitative shift in the relative abundance of CD11c-defined eosinophil subphenotypes favoring CD11c hi -expressing eosinophils. These findings provide new insights into heterogeneity of intestinal tissue eosinophils and offer a framework for measuring and tracking eosinophil subphenotype versatility in situ in health and disease., (©2022 Society for Leukocyte Biology.)

Background: The unique characteristics of the millennial generation has promulgated changes in the workplace and in academia. A lack of national standards necessitates that anesthesia faculty create educational content for anesthesia clerkships. Assessing expectations before an anesthesia rotation would provide data to accommodate millennial medical students' needs and preferences for learning., Methods: A 16-question survey using Qualtrics software was created, with input from millennial medical students, to query preclinical medical students at the Oakland University William Beaumont School of Medicine on their educational expectations of an anesthesia clerkship., Results: Seventy-four surveys were completed, with 34 (46%) of 74 from first-year and 40 (54%) of 74 from second-year medical students. Daily feedback (44 [59%] of 74) and written exams (43 [58%] of 74) were preferred methods of evaluation. No lectures, observing in an operating room, and performing procedures on real patients were the preferred format for instruction. Two (23 [31%] or 74) to 3 (33 [45%] of 74) weeks was the preferred duration of an anesthesia rotation., Conclusions: This study demonstrates that millennial medical students have preconceived educational expectations of an anesthesia clerkship, and identifies learning preferences that differ from the implemented anesthesia curriculum currently described in the literature., (© 2021 Society for Education in Anesthesia.)

Introduction: The COVID-19 pandemic has led to over 100 million cases worldwide. The UK has had over 4 million cases, 400 000 hospital admissions and 100 000 deaths. Many patients with COVID-19 suffer long-term symptoms, predominantly breathlessness and fatigue whether hospitalised or not. Early data suggest potentially severe long-term consequence of COVID-19 is development of long COVID-19-related interstitial lung disease (LC-ILD)., Methods and Analysis: The UK Interstitial Lung Disease Consortium (UKILD) will undertake longitudinal observational studies of patients with suspected ILD following COVID-19. The primary objective is to determine ILD prevalence at 12 months following infection and whether clinically severe infection correlates with severity of ILD. Secondary objectives will determine the clinical, genetic, epigenetic and biochemical factors that determine the trajectory of recovery or progression of ILD. Data will be obtained through linkage to the Post-Hospitalisation COVID platform study and community studies. Additional substudies will conduct deep phenotyping. The Xenon MRI investigation of Alveolar dysfunction Substudy will conduct longitudinal xenon alveolar gas transfer and proton perfusion MRI. The POST COVID-19 interstitial lung DiseasE substudy will conduct clinically indicated bronchoalveolar lavage with matched whole blood sampling. Assessments include exploratory single cell RNA and lung microbiomics analysis, gene expression and epigenetic assessment., Ethics and Dissemination: All contributing studies have been granted appropriate ethical approvals. Results from this study will be disseminated through peer-reviewed journals., Conclusion: This study will ensure the extent and consequences of LC-ILD are established and enable strategies to mitigate progression of LC-ILD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and terminal interstitial lung disease (ILD) with a median survival of 3-5 years. The British Thoracic Society (BTS) established the UK IPF Registry in 2013 as a platform to collect data on clinical characteristics, treatments and outcomes for this cohort in the UK. Between 1 January 2013 and 31 October 2019, 2474 cases were registered. Most patients were male (79%) with a mean±sd age of 74±8.3 years and 66% were ex-smokers. Over time we observed an increase in the number of patients aged over 70 years. However, we have not seen a trend towards earlier presentation as symptoms of breathless and/or cough were present for >12 months in 63% of the cohort. At presentation, mean±sd % predicted forced vital capacity (FVC) was 78.2±18.3%, median 76.2% (interquartile range (IQR) 22.4%) and transfer factor of the lung for carbon monoxide ( T LCO ) 48.4±16.0, median 47.5 (IQR 20.1). Most cases were discussed at an ILD multidisciplinary meeting, with an increase over this time in the number of cases reported as having possible usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HRCT) thorax. We noted a reduction in the number of patients undergoing surgical lung biopsy or bronchoalveolar lavage. Although more patients were prescribed anti-fibrotic therapies from 2013 to 2019, 43% were ineligible for treatment based upon National Institute for Health and Care Excellence (NICE) prescribing criteria. Hypertension, ischaemic heart disease, diabetes mellitus and gastro-oesophageal reflux were the most common comorbidities. In conclusion, we have presented baseline demographics as well as diagnostic and treatment strategies from the largest single-country IPF registry, reflecting changes in UK practices over this period., Competing Interests: Conflict of interest: L.G. Spencer reports a small, one-off start grant from HQIP in 2013, and small, one-off grants for software from Boehringer Ingelheim and InterMune in 2014, during the conduct of the study; and in the last 12 months has given one lecture paid for by Roche, facilitated one 2-day leadership course paid for by Boehringer Ingelheim, and received travel support and a registration fee to attend ERS Congress 2019 from Roche. Conflict of interest: M. Loughenbury reports a small, one-off start grant from HQIP in 2013, and small, one-off grants for software from Boehringer Ingelheim and InterMune in 2014, during the conduct of the study. Conflict of interest: N. Chaudhuri reports a small, one-off starter grant from HQIP in 2013, and small, one-off grants for software from Boehringer Ingelheim and InterMune in 2014, during the conduct of the study; and in the last 12 months: Roche funding for attending ATS 2019, participation in advisory boards, presenting at UK Advances in IPF meeting, presenting at Roche European AIR meeting and presenting at international meetings, and Boehringer Ingelheim funding for attending ERS 2019, participation in advisory boards and a video for a clinical trial. Conflict of interest: M. Spiteri reports a small, one-off start grant from HQIP in 2013, and small, one-off grants for software from Boehringer Ingelheim and InterMune in 2014, during the conduct of the study. Conflict of interest: H. Parfrey reports a small, one-off start grant from HQIP in 2013, and small, one-off grants for software from Boehringer Ingelheim and InterMune in 2014, during the conduct of the study; an educational grant and costs for conference attendance from Boehringer Ingelheim, and an educational grant, lecture fees and costs for conference attendance from Roche, outside the submitted work; and she is founding trustee for Action for Pulmonary Fibrosis., (Copyright ©ERS 2021.)

Eosinophils are primarily tissue-dwelling leukocytes. Utilization of flow cytometry techniques applied to digested tissues is expanding the scope of organs within which eosinophils are identified at baseline and is providing deeper insights into categorizing phenotypically and functionally distinct tissue-resident eosinophil subpopulations in health and disease. Here we describe a tissue digestion protocol and flow cytometry gating strategy for identification and isolation of tissue eosinophils from the small intestine of mice. This protocol is also amenable to the isolation and characterization of colonic eosinophils, and of intestinal eosinophils from human resected tissues.

Background: Common variable immunodeficiency (CVID) is a group of heterogeneous primary immunodeficiencies characterised by a dysregulated and impaired immune response. In addition to an increased susceptibility to infection, it is also associated with noninfectious autoimmune and lymphoproliferative complications. CVID is rarely associated with neurological complications. Pulmonary involvement is more common, and patients can develop an interstitial lung disease known as granulomatous-lymphocytic interstitial lung disease (GLILD)., Case Presentation: A 50-year-old Caucasian female with a history of Evans syndrome (idiopathic thrombocytopaenic purpura and autoimmune haemolytic anaemia) and hypogammaglobulinaemia initially presented to the neurology clinic with marked cerebellar ataxia and headaches. Following extensive investigation (which included brain biopsy), she was diagnosed with neuro-sarcoidosis and her symptoms resolved following treatment with immunosuppressive therapy. Over the following 10 years, she was extensively investigated for recurrent pulmonary infections and abnormal radiological findings, which included pulmonary nodules, infiltrates and splenomegaly. Subsequently, she was referred to an immunology clinic, where immunoglobulin replacement treatment was started for what was ultimately considered to be CVID. Shortly afterwards, evaluation of her clinical, radiological and histological findings at a specialist interstitial lung disease clinic led to a diagnosis of GLILD., Conclusion: CVID is a condition which should be suspected in patients with immunodeficiency and recurrent infections. Concomitant autoimmune disorders such as haemolytic anaemia and immune thrombocytopenia may further support the diagnosis. As illustrated in this case, there is a rare association between CVID and inflammatory involvement of the neurological system. Respiratory physicians should also suspect CVID with associated GLILD in patients with apparent pulmonary granulomatous disease and recurrent infections. In addition, this case also highlights the challenge of diagnosing CVID and its associated features, and how the definitive exclusion of other pathologies such as malignancy, mycobacterial infection and lymphoma is required as part of this diagnostic process.

Purpose of Review: Charcot-Leyden crystals (CLCs), slender bipyramidal hexagonal crystals, were first described by Jean-Martin Charcot in 1853, predating Paul Ehrlich's "discovery" of eosinophils by 26 years. To date, CLCs are known as a classical hallmark of eosinophilic inflammation. CLC protein expresses palmitate cleaving lysophospholipase activity and is a member of the family of S-type lectins, galectin-10. We summarize current knowledge regarding the pathological observations of CLCs and their mechanism of generation focusing on eosinophil cell death., Recent Findings: The presence of CLCs in vivo has been consistently associated with lytic eosinophils. Recent evidence revealed that cytolysis represents the occurrence of extracellular trap cell death (ETosis), an active non-apoptotic cell death process releasing filamentous chromatin structure. Galectin-10 is a predominant protein present within the cytoplasm of eosinophils but not stored in secretory granules. Activated eosinophils undergo ETosis and loss of galectin-10 cytoplasmic localization results in intracellular CLC formation. Free galectin-10 released following plasma membrane disintegration forms extracellular CLCs. Of interest, galectin-10-containing extracellular vesicles are also released during ETosis. Mice models indicated that CLCs could be a novel therapeutic target for Th2-type airway inflammation. The concept of ETosis, which represents a major fate of activated eosinophils, expands our current understanding by which cytoplasmic galectin-10 is crystalized/externalized. Besides CLCs and free galectin-10, cell-free granules, extracellular chromatin traps, extracellular vesicles, and other alarmins, all released through the process of ETosis, have novel implications in various eosinophilic disorders.

Background: In fibrotic interstitial lung diseases, exertional breathlessness is strongly linked to health-related quality of life (HRQOL). Breathlessness is often associated with oxygen desaturation, but few data about the use of ambulatory oxygen in patients with fibrotic interstitial lung disease are available. We aimed to assess the effects of ambulatory oxygen on HRQOL in patients with interstitial lung disease with isolated exertional hypoxia., Methods: AmbOx was a prospective, open-label, mixed-method, crossover randomised controlled clinical trial done at three centres for interstitial lung disease in the UK. Eligible patients were aged 18 years or older, had fibrotic interstitial lung disease, were not hypoxic at rest but had a fall in transcutaneous arterial oxygen saturation to 88% or less on a screening visit 6-min walk test (6MWT), and had self-reported stable respiratory symptoms in the previous 2 weeks. Participants were randomly assigned (1:1) to either oxygen treatment or no oxygen treatment for 2 weeks, followed by crossover for another 2 weeks. Randomisation was by a computer-generated sequence of treatments randomly permuted in blocks of constant size (fixed size of ten). The primary outcome, which was assessed by intention to treat, was the change in total score on the King's Brief Interstitial Lung Disease questionnaire (K-BILD) after 2 weeks on oxygen compared with 2 weeks of no treatment. General linear models with treatment sequence as a fixed effect were used for analysis. Patient views were explored through semi-structured topic-guided interviews in a subgroup of participants. This study was registered with ClinicalTrials.gov, number NCT02286063, and is closed to new participants with all follow-up completed., Findings: Between Sept 10, 2014, and Oct 5, 2016, 84 patients were randomly assigned, 41 randomised to ambulatory oxygen first and 43 to no oxygen. 76 participants completed the trial. Compared with no oxygen, ambulatory oxygen was associated with significant improvements in total K-BILD scores (mean 55·5 [SD 13·8] on oxygen vs 51·8 [13·6] on no oxygen, mean difference adjusted for order of treatment 3·7 [95% CI 1·8 to 5·6]; p<0·0001), and scores in breathlessness and activity (mean difference 8·6 [95% CI 4·7 to 12·5]; p<0·0001) and chest symptoms (7·6 [1·9 to 13·2]; p=0·009) subdomains. However, the effect on the psychological subdomain was not significant (2·4 [-0·6 to 5·5]; p=0·12). The most common adverse events were upper respiratory tract infections (three in the oxygen group and one in the no-treatment group). Five serious adverse events, including two deaths (one in each group) occurred, but none were considered to be related to treatment., Interpretation: Ambulatory oxygen seemed to be associated with improved HRQOL in patients with interstitial lung disease with isolated exertional hypoxia and could be an effective intervention in this patient group, who have few therapeutic options. However, further studies are needed to confirm this finding., Funding: UK National Institute for Health Research., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose Racial variation in the financial impact of cancer may contribute to observed differences in the use of guideline-recommended treatments. We describe racial differences with regard to the financial impact of breast cancer in a large population-based prospective cohort study. Methods The Carolina Breast Cancer Study oversampled black women and women younger than age 50 years with incident breast cancer in North Carolina from 2008 to 2013. Participants provided medical records and data regarding demographics, socioeconomic status, and financial impact of cancer at 5 and 25 months postdiagnosis. We report unadjusted and adjusted financial impact at 25 months postdiagnosis by race. Results The sample included 2,494 women who completed follow-up surveys (49% black, 51% white). Since diagnosis, 58% of black women reported any adverse financial impact of cancer ( v 39% of white women; P < .001). In models adjusted for age, stage at diagnosis, and treatment received, black women were more likely to report adverse financial impact attributable to cancer (adjusted risk difference [aRD], +14 percentage points; P < .001), including income loss (aRD, +10 percentage points; P < .001), health care-related financial barriers (aRD, +10 percentage points; P < .001), health care-related transportation barriers (aRD, +10 percentage points; P < .001), job loss (aRD, 6 percentage points; P < .001), and loss of health insurance (aRD, +3 percentage points; P < .001). The effect of race was attenuated when socioeconomic factors were included but remained significant for job loss, transportation barriers, income loss, and overall financial impact. Conclusion Compared with white women, black women with breast cancer experience a significantly worse financial impact. Disproportionate financial strain may contribute to higher stress, lower treatment compliance, and worse outcomes by race. Policies that help to limit the effect of cancer-related financial strain are needed.

Background: Diagnostic evaluation of eosinophilic esophagitis (EoE) remains difficult, particularly the assessment of the patient's allergic status., Objective: This study sought to establish an automated medical algorithm to assist in the evaluation of EoE., Methods: Machine learning techniques were used to establish a diagnostic probability score for EoE, p(EoE), based on esophageal mRNA transcript patterns from biopsies of patients with EoE, gastroesophageal reflux disease and controls. Dimensionality reduction in the training set established weighted factors, which were confirmed by immunohistochemistry. Following weighted factor analysis, p(EoE) was determined by random forest classification. Accuracy was tested in an external test set, and predictive power was assessed with equivocal patients. Esophageal IgE production was quantified with epsilon germ line (IGHE) transcripts and correlated with serum IgE and the T h 2-type mRNA profile to establish an IGHE score for tissue allergy., Results: In the primary analysis, a 3-class statistical model generated a p(EoE) score based on common characteristics of the inflammatory EoE profile. A p(EoE) ≥ 25 successfully identified EoE with high accuracy (sensitivity: 90.9%, specificity: 93.2%, area under the curve: 0.985) and improved diagnosis of equivocal cases by 84.6%. The p(EoE) changed in response to therapy. A secondary analysis loop in EoE patients defined an IGHE score of ≥37.5 for a patient subpopulation with increased esophageal allergic inflammation., Conclusions: The development of intelligent data analysis from a machine learning perspective provides exciting opportunities to improve diagnostic precision and improve patient care in EoE. The p(EoE) and the IGHE score are steps toward the development of decision trees to define EoE subpopulations and, consequently, will facilitate individualized therapy., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The traditional paradigm of eosinophils as end-stage damaging cells has mainly relied on their release of cytotoxic proteins. Cytokine-induced cell survival and secretion of granular contents from tissue-dwelling eosinophil are thought to be important mechanisms for eosinophilic inflammatory disorders, although the occurrence of cytolysis and its products (i.e., free extracellular granules) has been observed in affected lesions. Recent evidence indicates that activated eosinophils can exhibit a non-apoptotic cell death pathway, namely extracellular trap cell death (ETosis) that mediates the eosinophil cytolytic degranulation. Here, we discuss the current concept of eosinophil ETosis which provides a new look at eosinophilic inflammation. Lessons from eosinophilic chronic rhinosinusitis revealed that ETosis-derived DNA traps, composed of stable web-like chromatin, contribute to the properties of highly viscous eosinophilic mucin and impairments in its clearance. Intact granules entrapped in DNA traps are causing long-lasting inflammation but also might have immunoregulatory roles. Eosinophils possess a way to have post-postmortem impacts on innate immunity, local immune response, sterile inflammation, and tissue damage.

Aims: To understand the perceptions, needs and experiences of patients with Idiopathic Pulmonary Fibrosis., Background: Idiopathic pulmonary fibrosis is a progressive interstitial lung disease, with a mean life expectancy similar to some forms of cancer of 2-4 years from diagnosis. Unlike the cancer literature, which is rich with studies exploring the needs of their disease group, few publications exist on patient needs with this severe fibrotic lung disease., Design: A Qualitative study which took place between 2007-2012., Methods: Seventeen patients with a multidisciplinary team confirmed diagnosis of Idiopathic Pulmonary Fibrosis, with moderate to advanced disease severity and six of their informal carers were interviewed. An interview topic guide was developed by the researchers and service user group. The interviews were audio-recorded, semi-structured and took place at a regional respiratory and lung transplant centre in North West England. Interviews were transcribed verbatim and data analysed using Framework Analysis., Findings: Three main themes were identified: 'Struggling to get a diagnosis'; 'Loss of the life I previously had'; and 'Living with Idiopathic Pulmonary Fibrosis'. Patients reported struggling to get a diagnosis and coping with a life-limiting, rapidly progressive illness with no good treatment and few support structures., Conclusions: There is an urgent need for a better understanding of the difficulties faced by people with Idiopathic Pulmonary Fibrosis and their carers. This can be used to develop better supportive care in the United Kingdom and ultimately improve the quality of life of these patients., (© 2014 The Authors. Journal of Advanced Nursing published by John Wiley & Sons Ltd.)

Major basic protein (MBP), the predominant cationic protein of human eosinophil specific granules, is stored within crystalloid cores of these granules. Secretion of MBP contributes to the immunopathogenesis of varied diseases. Prior electron microscopy (EM) of eosinophils in sites of inflammation noted losses of granule cores in the absence of granule exocytosis and suggested that eosinophil granule proteins might be released through piecemeal degranulation (PMD), a secretory process mediated by transport vesicles. Because release of eosinophil granule-derived MBP through PMD has not been studied, we evaluated secretion of this cationic protein by human eosinophils. Intracellular localizations of MBP were studied within nonstimulated and eotaxin-stimulated human eosinophils by both immunofluorescence and a pre-embedding immunonanogold EM method that enables optimal epitope preservation and antigen access to membrane microdomains. In parallel, quantification of transport vesicles was assessed in eosinophils from a patient with hypereosinophilic syndrome (HES). Our data demonstrate vesicular trafficking of MBP within eotaxin-stimulated eosinophils. Vesicular compartments, previously implicated in transport from granules to the plasma membrane, including large vesiculotubular carriers termed eosinophil sombrero vesicles (EoSVs), were found to contain MBP. These secretory compartments were significantly increased in numbers within HES eosinophils. Moreover, in addition to granule-stored MBP, even unstimulated eosinophils contained appreciable amounts of MBP within secretory vesicles, as evidenced by immunonanogold EM and immunofluorescent colocalizations of MBP and CD63. These data suggest that eosinophil MBP, with its multiple extracellular activities, can be mobilized from granules by PMD into secretory vesicles and both granule- and secretory vesicle-stored pools of MBP are available for agonist-elicited secretion of MBP from human eosinophils. The recognition of PMD as a secretory process to release MBP is important to understand the pathological basis of allergic and other eosinophil-associated inflammatory diseases.

Eosinophil chemotaxis and survival within tissues are key components in the development of tissue eosinophilia and subsequent effector responses. In this study, we demonstrate a novel mechanism of eosinophil autoregulation affecting migration and survival mediated through Notch signaling. We show for the first time that human blood eosinophils express Notch receptors and Notch ligands, expressions of which are influenced by the presence of eosinophil-activating granulocyte-macrophage colony-stimulating factor (GM-CSF). Evidence of Notch receptor activation and subsequent transcription of the Notch-responsive gene HES1 were observed in GM-CSF-stimulated eosinophils, confirming functionality of eosinophil-expressed Notch-signaling components. Moreover, by inhibiting Notch signaling with gamma-secretase inhibitors or Notch receptor-specific neutralizing antibodies, we demonstrate that autocrine Notch signaling enhances stimulus-mediated actin rearrangement and eosinophil chemokinesis, and impairs eosinophil viability. Taken together, these data suggest autocrine Notch signaling, enhanced in response to tissue- or inflammatory-derived signals, influences eosinophil activity and longevity, which may ultimately contribute to the development of tissue eosinophilia and exacerbation or remediation of eosinophil effector functions.

Although leukocytes of the innate immune system, including eosinophils, contain within their granules preformed stores of cytokines available for selective and rapid release, little is known about the mechanisms governing the mobilization and secretion of these cytokines. Here we show that a cytokine receptor, the IL-4 receptor alpha chain, mediates eotaxin-stimulated mobilization of preformed IL-4 from eosinophil granules into secretory vesicles. Eosinophils contain substantial intracellular quantities of several granule- and vesicle-associated cytokine receptors, including IL-4, IL-6, and IL-13 receptors as well as CCR3. Both IL-4 and IL-4 receptor alpha chain colocalized in eosinophil granules; and after eotaxin-stimulation, IL-4 receptor alpha chain, bearing bound IL-4, was mobilized into secretory vesicles. These findings indicate that intracellular cytokine receptors within secretory vesicles transport their cognate cytokines requisite for the secretion of cytokines preformed in innate immune leukocytes.