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Over the past years, eosinophils have become a focus of scientific interest, especially in the context of their recently uncovered functions (e.g. antiviral, anti-inflammatory, regulatory). These versatile cells display both beneficial and detrimental activities under various physiological and pathological conditions. Eosinophils are involved in the pathogenesis of many diseases which can be classified into primary (clonal) and secondary (reactive) disorders and idiopathic (hyper)eosinophilic syndromes. Depending on the biological specimen, the eosinophil count in different body compartments may serve as a biomarker reflecting the underlying pathophysiology and/or activity of distinct diseases and as a therapy-driving (predictive) and monitoring tool. Personalized selection of an appropriate therapeutic strategy directly or indirectly targeting the increased number and/or activity of eosinophils should be based on the understanding of eosinophil homeostasis including their interactions with other immune and non-immune cells within different body compartments. Hence, restoring as well as maintaining homeostasis within an individual's eosinophil pool is a goal of both specific and non-specific eosinophil-targeting therapies. Despite the overall favourable safety profile of the currently available anti-eosinophil biologics, the effect of eosinophil depletion should be monitored from the perspective of possible unwanted consequences., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Competing Interests: Declaration of competing interest ZD: received consultancy fees/lecture fees/fees for attending advisory boards from ALK, Antabio, Foresee Pharmaceuticals, GlaxoSmithKline, Hippo-Dx, QPS-Netherlands, Sanofi-Genzyme; she served as Director Respiratory & Allergy at QPS-NL and this CRO received research grants for clinical trials from HAL Allergy, Janssen Research & Development LLC, Patara pharma, Cerbios, Merck Sharp & Dohme, Novartis, Foresee Pharmaceuticals and ERA4TB (IMI-project). MJ: ALK, Stallergenes-Greer, Chiesi, GSK, Pfizer, Novartis, AstraZeneca and SANOFI. NH: Received honoraria for serving as advisor or consultant for GSK, AstraZeneca, Sanofi, Regeneron, Amgen, Genentech, Novartis and Teva. His institution received research grant support of his behalf from GSK, Genentech, Sanofi, Teva, Novartis, and AstraZeneca. LH: Has received grant funding, participated in advisory boards and given lectures at meetings supported by Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Hoffmann la Roche, GlaxoSmithKline, Novartis, Theravance, Evelo Biosciences, Sanofi, and Teva; he has received grants from MedImmune, Novartis UK, Roche/ Genentech Inc, and Glaxo Smith Kline, Amgen, Genentech/Hoffman la Roche, Astra Zeneca, MedImmune, Glaxo Smith Kline, Aerocrine and Vitalograph; he has received sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK and Napp Pharmaceuticals; he has also taken part in asthma clinical trials sponsored by AstraZeneca, Boehringer Ingelheim, Hoffmann la Roche, and GlaxoSmithKline for which his institution received remuneration; he is the Academic Lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma which involves industrial partnerships with a number of pharmaceutical companies including Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann la Roche, and Janssen. RD: Declares consulting fees from Synairgen, Sanofi and Galapagos, lecture fees from GSK, AZ and Airways Vista and he holds shares from Synairgen. DR: No COIs related to this work. SQ: ALK, Allergy Therapeutics, AstraZeneca, Chiesi, GSK, Leti, Mundipharma, Novartis, Sanofi-Genzyme, Teva. VB: Has worked as advisor, supervisor, investigator of pharmaceutical studies, unrestricted grants, and others with: AstraZeneca, GSK, MSD & Shering Plough, ALK-Abello; Chiesi,Novartis, Pharmaxis, Pfizer, Boehringer Ingelheim, Aerocrine, Teva, Sanofi, Birk NPC as. MG: No COIs related to this work. IP: In the last 5 years IDP has received speaker’s honoraria for speaking at sponsored meetings from Astra Zeneca, Boehringer Ingelheim, Aerocrine, Almirall, Novartis, Teva, Chiesi, Sanofi/Regeneron, Menarini and GSK and payments for organising educational events from AZ, GSK, Sanofi/Regeneron and Teva. He has received honoraria for attending advisory panels with Genentech, Sanofi/ Regeneron, Astra Zeneca, Boehringer Ingelheim, GSK, Novartis, Teva, Merck, Circassia, Chiesi and Knopp and payments to support FDA approval meetings from GSK. He has received sponsorship to attend international scientific meetings from Boehringer Ingelheim, GSK, AstraZeneca, Teva and Chiesi. He has received a grant from Chiesi to support a phase 2 clinical trial in Oxford. DAA: Has received honoraria as grants/contracts from Sociedad Española de Alergología e Inmunología Clínica (SEAIC), as consulting fees from ALK-Abelló, AstraZeneca, Chiesi and Gebro, as speaker from AstraZeneca, Chiesi, Gebro, GSK, Leti Pharma, Mundipharma, Novartis, Roxall, Sanofi. AS: GSK support for an asthma biologic clinical trial 2021-ongoing. PB: Has received honoraria for presentations and consultancy fees from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, GSK, Menarini, Novartis, Sanofi, and Gilead. AB: Takeda, Novartis, Viatris, ALK, Zentiva, MERCK, Stallergenes Greer, Ewopharma, Astra Zeneca, Chiesi, S&D Pharma, Mundipharma, Berlin Chemie. WB: GlaxoSmithKline, Sanofi, Regeneron. JK: Grants and/or personal fees from ALK, Chiesi, GSK, Novartis, AstraZeneca, Sanofi, Boerhinger, Teva, Viatris, Stallergen, Abbot, all outside the submitted work. SL: Honorarium AstraZeneka, GSK, Chiesi Hellas, Sanofi, Elpen, Menarini, Guidoti. MVM: No COIs related to this work. PP: ALK, AstraZeneca, Stallergenes. HP: No COIs related to this work. AS: Reports lecture fees and/or consultancies from AstraZeneca, Chiesi, B.I., GSK, Merck, Novartis, Zambon, Sanofi. HS: No COIs related to this work. IS: No COIs related to this work. BT: No COIs related to this work. MKV: GlaxoSmithKline, AstraZeneca. Diego Conti: No COIs related to this work. WF: The department of Otorhinolaryngology of the Amsterdam University Medical centre, location AMC received grants for research in Rhinology from: ALK, AllergyTherapeutics, Novartis, EU, GSK, MYLAN, Sanofi-Aventis, and Zon-MW; personal COIs: for consultation and/or speaker fees from Dianosic, GSK, Novartis and Sanofi-Aventis/Regeneron. SL: Advisory Board Sanof-Aventis, GSK and Leo-Pharma. Honoraria by DBV Technologies, Allergopharma, Leti, Nutricia, Sanofi-Aventis. GKS: Honoraria for articles, speaker and advisory boards: ALK, AstraZeneca, Capnia, Church & Dwight, Circassia, Noucor, GSK, Meda/Mylan/Viatris, Merck, Sanofi- Regeneron, Stallergenes. Scientific Chief Editor, Rhinology Section, Frontiers in Allergy. Board Member, Lead for Allergic Rhinitis, EUFOREA. Chair of Data Monitoring Board for Paediatric AR trials of HDM SLIT. EVS: No COIs related to this work. PH: Recipient of research grants, honoraria and/or lecture fees of Sanofi, Regeneron, Viatris, GSK, and Novartis. LB: No COIs related to this work.

Transbronchial cryobiopsy (TBCB) is increasingly used for the diagnosis of fibrosing interstitial pneumonias, but there are few detailed descriptions of the pathologic findings in such cases. It has been proposed that a combination of patchy fibrosis and fibroblast foci with an absence of alternative features is diagnostic of usual interstitial pneumonia (UIP; ie, idiopathic pulmonary fibrosis [IPF]) in TBCB. In this study, we reviewed 121 TBCB in which a diagnosis of fibrotic hypersensitivity pneumonitis (FHP; n = 83) or IPF (n = 38) was made by multidisciplinary discussion and evaluated a range of pathologic features. Patchy fibrosis was found in 65 of 83 (78%) biopsies from FHP and 32of 38 (84%) biopsies from UIP/IPF cases. Fibroblast foci were present in 47 of 83 (57%) FHP and 27 of 38 (71%) UIP/IPF cases. Fibroblast foci/patchy fibrosis combined did not favor either diagnosis. Architectural distortion was seen in 54 of 83 (65%) FHP and 32 of 38 (84%) UIP/IPF cases (odds ratio [OR] for FHP, 0.35; P = .036) and honeycombing in 18 of 83 (22%) and 17 of 38 (45%), respectively (OR, 0.37; P = .014). Airspace giant cells/granulomas were present in 13 of 83 (20%) FHP and 1 of 38 (2.6%) UIP/IPF cases (OR for FHP, 6.87; P = .068), and interstitial giant cells/granulomas in 20 of 83 (24%) FHP and 0 of 38 (0%) UIP/IPF (OR, 6.7 x 10 6 ; P = .000). We conclude that patchy fibrosis plus fibroblast foci can be found in TBCB from both FHP and UIP/IPF. The complete absence of architectural distortion/honeycombing favors a diagnosis of FHP, as does the presence of airspace or interstitial giant cells/granulomas, but these measures are insensitive, and many cases of FHP cannot be separated from UIP/IPF on TBCB., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants, genome-wide, may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ⩽0.01) within genes or regions. We also identified individual rare variants that are influential within genes and estimated the heritability of IPF on the basis of rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP heritability of IPF was estimated to be 32% (SE = 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or the development of therapies for IPF that focus on TERT , RTEL1 , common variants, and environmental risk factors are likely to have the largest impact on this complex disease.