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Abstract In less than half a century, allergy, originally perceived as a rare disease, has become a major public health threat, today affecting the lives of more than 60 million people in Europe, and probably close to one billion worldwide, thereby heavily impacting the budgets of public health systems. More disturbingly, its prevalence and impact are on the rise, a development that has been associated with environmental and lifestyle changes accompanying the continuous process of urbanization and globalization. Therefore, there is an urgent need to prioritize and concert research efforts in the field of allergy, in order to achieve sustainable results on prevention, diagnosis and treatment of this most prevalent chronic disease of the 21st century. The European Academy of Allergy and Clinical Immunology (EAACI) is the leading professional organization in the field of allergy, promoting excellence in clinical care, education, training and basic and translational research, all with the ultimate goal of improving the health of allergic patients. The European Federation of Allergy and Airways Diseases Patients’ Associations (EFA) is a non-profit network of allergy, asthma and Chronic Obstructive Pulmonary Disorder (COPD) patients’ organizations. In support of their missions, the present EAACI Position Paper, in collaboration with EFA, highlights the most important research needs in the field of allergy to serve as key recommendations for future research funding at the national and European levels. Although allergies may involve almost every organ of the body and an array of diverse external factors act as triggers, there are several common themes that need to be prioritized in research efforts. As in many other chronic diseases, effective prevention, curative treatment and accurate, rapid diagnosis represent major unmet needs. Detailed phenotyping/endotyping stands out as widely required in order to arrange or re-categorize clinical syndromes into more coherent, uniform and treatment-responsive groups. Research efforts to unveil the basic pathophysiologic pathways and mechanisms, thus leading to the comprehension and resolution of the pathophysiologic complexity of allergies will allow for the design of novel patient-oriented diagnostic and treatment protocols. Several allergic diseases require well-controlled epidemiological description and surveillance, using disease registries, pharmacoeconomic evaluation, as well as large biobanks. Additionally, there is a need for extensive studies to bring promising new biotechnological innovations, such as biological agents, vaccines of modified allergen molecules and engineered components for allergy diagnosis, closer to clinical practice. Finally, particular attention should be paid to the difficult-to-manage, precarious and costly severe disease forms and/or exacerbations. Nonetheless, currently arising treatments, mainly in the fields of immunotherapy and biologicals, hold great promise for targeted and causal management of allergic conditions. Active involvement of all stakeholders, including Patient Organizations and policy makers are necessary to achieve the aims emphasized herein.

Abstract Background There is a growing body of evidence to suggest that CD8+ T lymphocytes contribute to local allergen-induced eosinophilic inflammation. Since bone marrow (BM) responses are intricately involved in the induction of airway eosinophilia, we hypothesized that CD8+ T lymphocytes, as well as CD4+ T lymphocytes, may be involved in this process. Methods Several approaches were utilized. Firstly, mice overexpressing interleukin-5 (IL-5) in CD3+ T lymphocytes (NJ.1638; CD3IL-5+ mice) were bred with gene knockout mice lacking either CD4+ T lymphocytes (CD4-/-) or CD8+ T lymphocytes (CD8-/-) to produce CD3IL-5+ knockout mice deficient in CD4+ T lymphocytes (CD3IL-5+/CD4-/-) and CD8+ T lymphocytes (CD3IL-5+/CD8-/-), respectively. Secondly, CD3+, CD4+ and CD8+ T lymphocytes from naïve CD3IL-5+ and C57BL/6 mice were adoptively transferred to immunodeficient SCID-bg mice to determine their effect on BM eosinophilia. Thirdly, CD3IL-5+, CD3IL-5+/CD8-/- and CD3IL-5+/CD4-/- mice were sensitized and allergen challenged. Bone marrow and blood samples were collected in all experiments. Results The number of BM eosinophils was significantly reduced in CD3IL-5+/CD8-/- mice compared to CD3IL-5+ mice and CD3IL-5+/CD4-/- mice. Serum IL-5 was significantly higher in CD3IL-5+/CD4-/- mice compared to CD3IL-5+ mice but there was no difference in serum IL-5 between CD3IL-5+/CD4-/- and CD3IL-5+/CD8-/- mice. Adoptive transfer of CD8+, but not CD4+ T lymphocytes from naïve CD3IL-5+ and C57BL/6 mice restored BM eosinophilia in immunodeficient SCID-bg mice. Additionally, allergen challenged CD3IL-5+/CD8-/- mice developed lower numbers of BM eosinophils compared to CD3IL-5+ mice and CD3IL-5+/CD4-/- mice. Conclusion This study shows that CD8+ T lymphocytes are intricately involved in the regulation of BM eosinophilopoiesis, both in non-sensitized as well as sensitized and allergen challenged mice.

Inflammation, structural, and functional abnormalities within the airways are key features of asthma. Although these processes are well documented, their expression varies across the heterogeneous spectrum of asthma. Type 2 inflammatory responses are characterized by increased levels of eosinophils, FeNO, and type 2 cytokines in blood and/or airways. Presently, type 2 asthma is the best‐defined endotype, typically found in patients with allergic asthma, but surprisingly also in nonallergic patients with (severe) asthma. The etiology of asthma with non‐type 2 inflammation is less clear. During the past decade, targeted therapies, including biologicals and small molecules, have been increasingly integrated into treatment strategies of severe asthma. These treatments block specific inflammatory pathways or single mediators. Single or composite biomarkers help to identify patients who will benefit from these treatments. So far, only a few inflammatory biomarkers have been validated for clinical application. The European Academy of Allergy & Clinical Immunology Task Force on Biomarkers in Asthma was initiated to review different biomarker sampling methods and to investigate clinical applicability of new and existing inflammatory biomarkers (point‐of‐care) to support diagnosis, targeted treatment, and monitoring of severe asthma. Subsequently, we discuss existing and novel targeted therapies for asthma as well as applicable biomarkers. [ABSTRACT FROM AUTHOR]

Abstract: Sonic hedgehog signaling pathway is important in developmental processes like dorsoventral neural tube patterning, neural stem cell proliferation and neuronal and glial cell survival. Shh is also implicated in the regulation of the adult hippocampal neurogenesis. Recently, nonpeptidyl Smoothened activators of the Shh pathway have been identified. The aim of this study was to investigate the effects of chlorobenzothiophene-containing molecule, Smo agonist (SAG), which has been shown to activate Shh signaling pathway, in neurogenesis and neuronal survival in in vitro and in vivo models. Our in vitro experiments showed that SAG induces increased expression of Gli1 mRNA, transcriptional target and mediator of Shh signal. In vitro experiments also demonstrated that SAG in low-nanomolar concentrations induces proliferation of neuronal and glial precursors without affecting the differentiation pattern of newly produced cells. In contrast to Shh, SAG did not induce neurotoxicity in neuronal cultures. The SAG and Shh treatment also promoted the survival of newly generated neural cells in the dentate gyrus after their intracerebroventricular administration to adult rats. We propose that SAG and similar compounds represent attractive molecules to be developed for treatment of disorders where stimulation of the generation and survival of new neural cells would be beneficial. [ABSTRACT FROM AUTHOR]

Background: There is a growing body of evidence to suggest that CD8+ T lymphocytes contribute to local allergen-induced eosinophilic inflammation. Since bone marrow (BM) responses are intricately involved in the induction of airway eosinophilia, we hypothesized that CD8+ T lymphocytes, as well as CD4+ T lymphocytes, may be involved in this process. Methods: Several approaches were utilized. Firstly, mice overexpressing interleukin-5 (IL-5) in CD3+ T lymphocytes (NJ.1638; CD3IL-5+ mice) were bred with gene knockout mice lacking either CD4+ T lymphocytes (CD4-/-) or CD8+ T lymphocytes (CD8-/-) to produce CD3IL-5+ knockout mice deficient in CD4+ T lymphocytes (CD3IL-5+/CD4-/-) and CD8+ T lymphocytes (CD3IL-5+/CD8-/-), respectively. Secondly, CD3+, CD4+ and CD8+ T lymphocytes from naïve CD3IL-5+ and C57BL/6 mice were adoptively transferred to immunodeficient SCID-bg mice to determine their effect on BM eosinophilia. Thirdly, CD3IL-5+, CD3IL-5+/CD8-/- and CD3IL-5+/CD4-/- mice were sensitized and allergen challenged. Bone marrow and blood samples were collected in all experiments. Results: The number of BM eosinophils was significantly reduced in CD3IL-5+/CD8-/- mice compared to CD3IL-5+ mice and CD3IL-5+/CD4-/- mice. Serum IL-5 was significantly higher in CD3IL-5+/CD4-/- mice compared to CD3IL-5+ mice but there was no difference in serum IL-5 between CD3IL-5+/CD4-/- and CD3IL-5+/CD8-/- mice. Adoptive transfer of CD8+, but not CD4+ T lymphocytes from naïve CD3IL-5+ and C57BL/6 mice restored BM eosinophilia in immunodeficient SCID-bg mice. Additionally, allergen challenged CD3IL-5+/CD8-/- mice developed lower numbers of BM eosinophils compared to CD3IL-5+ mice and CD3IL-5+/CD4-/- mice. Conclusion: This study shows that CD8+ T lymphocytes are intricately involved in the regulation of BM eosinophilopoiesis, both in non-sensitized as well as sensitized and allergen challenged mice. [ABSTRACT FROM AUTHOR]

We evaluated whether bone marrow (BM) inflammatory cells have capacity to traffic into the airways following allergen exposure in a mouse model of allergen-induced airway inflammation. We also evaluated the effect of IL-5 overexpression on (i) the production of eosinophils in BM, (ii) the accumulation of eosinophils, neutrophils and lymphocytes in blood and airways and (iii) the changes in CD34 cell numbers in BM, blood and airways. Bromodeoxyuridine (BrdU) was used to label cells produced during the exposure period. Furthermore, CD3 splenocytes were adoptively transferred to investigate the BM inflammatory response. Allergen exposure induced traffic of BM eosinophils, neutrophils and lymphocytes to the airways and increased the number of BrdU eosinophils, neutrophils, lymphocytes and CD34 cells in BALf. IL-5 overexpression enhanced the eosinophilopoiesis and increased the presence of BrdU eosinophils and CD34 cells in airways and enhanced the number of CD34 cells in BM and blood after allergen exposure. Adoptive transfer of CD3 lymphocytes overexpressing IL-5 caused increased BM eosinophilia. In conclusion, allergen exposure induces traffic of not only newly produced eosinophils but also newly produced neutrophils and lymphocytes into the airways. [ABSTRACT FROM AUTHOR]

Currently, there is no effective pharmacotherapy against exaggerated mobilisation of neutrophils in human airway diseases such as chronic obstructive pulmonary disease and asthma. We evaluated the effect of two synthetic vasoactive intestinal peptide (VIP)-like analogues on cytokine-induced neutrophil recruitment in airways in vivo.Recombinant interleukin (IL)-1β was administered intratracheally (i.t.) to intubated, spontaneously breathing Sprague–Dawley rats. The rats were pretreated either with a VIP synthetic peptide analogue, a pituitary adenylate cyclase-activating peptide (PACAP)-1–27 synthetic analogue, the β2-adrenoceptor agonist salbutamol or vehicle, systemically or locally. Differential cell counts were performed on bronchoalveolar lavage fluid (BALf) cytospins. Effects on mean arterial blood pressure (MAP) were monitored in separate experiments.Systemic administration of the VIP analogue, the PACAP analogue and salbutamol attenuated the cytokine-induced increase in BALf neutrophil number. Local administration of the VIP analogue and salbutamol, but not the PACAP analogue, also decreased the neutrophil number in BALf. Local administration of the VIP analogue and salbutamol caused a transient decrease in MAP.Systemic or local administration of a synthetic VIP peptide analogue inhibits cytokine-induced neutrophil recruitment in airways in vivo. This action is exerted without severe, sustained cardiovascular side effects, and deserves to be further evaluated in obstructive pulmonary diseases in human. [Copyright &y& Elsevier]

Introduction: Treatment with biologics for severe asthma is informed by international and national guidelines and defined by national regulating bodies, but how these drugs are used in real-life is unknown., Materials and Methods: The European Respiratory Society (ERS) SHARP Clinical Research Collaboration conducted a three-step survey collecting information on asthma biologics use in Europe. Five geographically distant countries defined the survey questions, focusing on seven end-points: biologics availability and financial issues, prescription and administration modalities, inclusion criteria, continuation criteria, switching biologics, combining biologics and evaluation of corticosteroid toxicity. The survey was then sent to SHARP National Leads of 28 European countries. Finally, selected questions were submitted to a broad group of 263 asthma experts identified by national societies., Results: Availability of biologics varied between countries, with 17 out of 28 countries having all five existing biologics. Authorised prescribers (pulmonologists and other specialists) also differed. In-hospital administration was the preferred deliverance modality. While exacerbation rate was used as an inclusion criterion in all countries, forced expiratory volume in 1 s was used in 46%. Blood eosinophils were an inclusion criterion in all countries for interleukin-5 (IL-5)-targeted and IL-4/IL-13-targeted biologics, with varying thresholds. There were no formally established criteria for continuing biologics. Reduction in exacerbations represented the most important benchmark, followed by improvement in asthma control and quality of life. Only 73% (191 out of 263) of surveyed clinicians assessed their patients for corticosteroid-induced toxicity., Conclusion: Our study reveals important heterogeneity in the use of asthma biologics across Europe. To what extent this impacts on clinical outcomes relevant to patients and healthcare services needs further investigation., Competing Interests: Conflict of interest: L.G. Heaney reports the following relationships outside the submitted work: academic lead for the UK MRC Consortium for Stratified Medicine in Severe Asthma (industrial pharma partners: Amgen, AstraZeneca, Medimmune, Janssen, Novartis, Roche/Genentech, GlaxoSmithKline and Boehringer Ingelheim); project grant funding from Medimmune, Novartis UK, Roche/Genentech and GlaxoSmithKline; travel funding support to international respiratory meetings received from AstraZeneca, Chiesi, Novartis, Boehringer Ingelheim, Teva and GlaxoSmithKline; participated on advisory boards for AstraZeneca, Novartis, GlaxoSmithKline, Chiesi, Teva, Theravance and Vectura. Conflict of interest: B. Dahlén reports the following relationships outside the submitted work: grant received from GSK and Novartis to support Karolinska Severe Asthma Centre; personal consulting fees received from GSK, Novartis, Teva and AstraZeneca; consulting fees, paid to the institution, received from Region Stockholm; personal honoraria received from GSK, Novartis, Teva and AstraZeneca. Conflict of interest: S. Popović-Grle reports the following relationships outside the submitted work: payment for educational events from Abbot, Alkaloid, AstraZeneca, BerlinChemie Menarini, Boehringer Ingelheim, Medis, Novartis, Pliva-Teva, PharmaS, Providens, Salvus, Sandoz, Sanofi-Aventis and SwixxPharma; participation on advisory boards for AstraZeneca, Boehringer Ingelheim, BerlinChemie Menarini, GSK, Novartis, Pliva-Teva, PharmaS, Sanofi-Aventis and SwixxPharma. Conflict of interest: V. Sedlák reports the following relationships outside the submitted work: payment for presentations received from AstraZeneca, Novartis, GlaxoSmithKline, TEVA and Sanofi; payment for expert testimony payments received from AstraZeneca, Novartis, GlaxoSmithKline, TEVA and Sanofi; payment for participation on a data safety monitoring board or advisory board received from AstraZeneca, Novartis, GlaxoSmithKline, TEVA and Sanofi. Conflict of interest: L. Lehtimäki reports the following relationships outside the submitted work: fees for lectures or advisory board meetings received from ALK, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, GSK, Mundipharma, Novartis, Orion Pharma and Sanofi; owner of shares for Ausculthing OY. Conflict of interest: A. Bourdin reports the following relationships outside the submitted work: unrestricted grants received from AstraZeneca and Boehringer Ingelheim; consulting fees received from Astra Zeneca, GSK, Novartis, Sanofi Regeneron, Boehringer Ingelheim and Chiesi; payment or honoraria received for lectures, presentations, speakers bureaus, manuscript writing or educational events received from AstraZeneca, GSK, Novartis, Sanofi Regeneron, Boehringer Ingelheim and Chiesi; support for attending meetings and/or travel received from Astra Zeneca, GSK, Novartis, Sanofi Regeneron, Boehringer Ingelheim and Chiesi. Conflict of interest: S. Korn reports the following relationships outside the submitted work: consulting fees received from AstraZeneca, Novartis, GlaxoSmithKline and Sanofi; payment or honoraria received for lectures and presentations from AstraZeneca, Novartis, GlaxoSmithKline and Sanofi; participation on a data safety monitoring board or advisory board for AstraZeneca, Novartis and GlaxoSmithKline. Conflict of interest: M.W. Butler reports the following relationships outside the submitted work: payment or honoraria received for lectures and presentations from AstraZeneca, Novartis and GlaxoSmithKline; support received for international meeting attendance received from AstraZeneca; participation on Advisory Boards for ALK Abello, AstraZeneca, GlaxoSmithKline and Novartis; Chair of Medical Advisory Group, board member of Asthma Society of Ireland, Ireland member of GINA Assembly, President of Irish Thoracic Society (2022 to present). Conflict of interest: G.W. Canonica reports the following relationships outside the submitted work: payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from AstraZeneca, GSK, Novartis and Sanofi; participation on a data safety monitoring board or advisory board for AstraZeneca, GSK, Novartis and Sanofi; leadership or fiduciary role in other board, society, committee or advocacy group for EAACI Methodology Committee, REG Vice President and SANI Steering Committee. Conflict of interest: K. Beiksiene reports the following relationships outside the submitted work: payment or honoraria received for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from AstraZeneca and Berlin Chemie. Conflict of interest: A. ten Brinke reports the following relationships outside the submitted work: unrestricted grants received from TEVA, GSK and AstraZeneca; consulting fees paid to the institution from GSK, Sanofi, TEVA, AstraZeneca and Boehringer Ingelheim; payments for lectures, paid to the institution, received from GSK, TEVA, AstraZeneca and Sanofi; participation on research advisory boards for GSK, Sanofi, AstraZeneca, Boehringer Ingelheim and TEVA; Chair of Dutch severe asthma registry RAPSODI. Conflict of interest: P. Kuna reports the following relationships outside the submitted work: personal fees received for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from Adamed, AstraZeneca, Boehringer Ingelheim, Berlin Chemie Menarini, Alvogen, Glenmark, Novartis, GSK, Chiesi, Polpharma and Teva. Conflict of interest: C. Chaves Loureiro reports the following relationships outside the submitted work: Consulting fees received from AstraZeneca and GSK. Payment for r presentations and speakers bureaus received from AstraZeneca, GSK, Novartis and Sanofi-Aventis. Support for attending meetings received from AstraZeneca, Novartis, Nippon, Sanofi-Aventis, Tecnifarma and VitalAire. Participation on Advisory Boards for AstraZeneca, GSK, Novartis and Sanofi-Aventis. Conflict of interest: Z. Lazic reports the following relationships outside the submitted work: payment or honoraria for educational events received from AstraZeneca, BerlinChemie Menarini, Boehringer Ingelheim, Novartis, PharmaS, Providens, Sandoz and Actavis-Teva Serbia; participation on Advisory Boards for AstraZeneca, Boehringer Ingelheim, BerlinChemie Menarini, Novartis and Actavis-Teva Serbia. Conflict of interest: S. Škrgat reports the following relationships outside the submitted work: honoraria received for lectures and educational events from Astra Zeneca, Pliva Teva, Berlin Chemie, Chiesi and Medis; participation on local advisory boards organized by AstraZeneca. Conflict of interest: J. Leuppi reports the following relationships outside the submitted work: J. Leuppi is supported by grants from the Swiss National Science Foundation (SNF 160072 and 185592) and by Swiss Personalised Health Network (SPHN 2018DR108); J. Leuppi has also received unrestricted grants from AstraZeneca AG Switzerland, Boehringer Ingelheim GmbH Switzerland, GSK AG Switzerland, and Novartis AG Switzerland. Conflict of interest: B. Gemicioglu reports the following relationships outside the submitted work: grants or contracts received from AstraZeneca, Novartis, GlaxoSmithKline and Sanofi; payment or honoraria received for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from Novartis; support for attending meetings received from Novartis; participation on a data safety monitoring board or advisory board for GlaxoSmithKline. Conflict of interest: A. Bossios reports the following relationships outside the submitted work: payment or honoraria received for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from Astra Zeneca, GSK and TEVA; support for attending meetings and/or travel received from Novartis; participation on a data safety monitoring board or advisory board for AstraZeneca, Novartis, GlaxoSmithKline, TEVA and Sanofi; member of the steering committee of SHARP, Secretary of Assembly 5 (Airway diseases, asthma, COPD and chronic cough), European Respiratory Society; vice-chair of Nordic Severe Asthma Network (NSAN). Conflict of interest: C.M. Porsbjerg reports the following relationships outside the submitted work: grants or contracts, paid to the institution, received from AZ, GSK, Novartis, TEVA, Sanofi, Chiesi and ALK; consulting fees received from AZ, GSK, Novartis, TEVA, Sanofi, Chiesi and ALK; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from AZ, GSK, Novartis, TEVA, Sanofi, Chiesi and ALK; participation on a data safety monitoring board or advisory board for AZ, GSK, Novartis, TEVA, Sanofi, Chiesi and ALK. Conflict of interest: E.H. Bel reports the following relationships outside the submitted work: research grants received from GSK and Teva; consulting fees received from Teva, Sanofi, AstraZeneca, GSK, Sterna and Chiesi; participation on a data safety monitoring board or advisory board for AstraZeneca. Conflict of interest: R. Djukanovic reports the following relationships outside the submitted work: funding received for the SHARP CRC from ERS, TEVA, GSK, Novartis, Sanofi and Chiesi; consultancy fees paid to the author received from Synairgen plc, Sanofi-Genzyme Corporation and Galapagos; honorarium for lectures paid to the author received from GlaxoSmithKline, Congress of Interasma, AstraZeneca and Airways Vista, Seoul; personal shares owned for Synairgen. Conflict of interest: L. Renaud reports receiving support for the present manuscript from SHARP CRC supported by GSK, Novartis, Sanofi, Chiesi and Teva. The following relationships are reported outside the submitted work: grants or contracts received from GSK, AZ and Chiesi; consulting fees received from AZ and Sanofi; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events, received from AZ, GSK and Chiesi; patents planned, issued or pending WO 2017/050527 A1 “Method for the diagnosis of airway disease inflammatory subtype”. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2022.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has put pressure on healthcare services, forcing the reorganisation of traditional care pathways. We investigated how physicians taking care of severe asthma patients in Europe reorganised care, and how these changes affected patient satisfaction, asthma control and future care., Methods: In this European-wide cross-sectional study, patient surveys were sent to patients with a physician-diagnosis of severe asthma, and physician surveys to severe asthma specialists between November 2020 and May 2021., Results: 1101 patients and 268 physicians from 16 European countries contributed to the study. Common physician-reported changes in severe asthma care included use of video/phone consultations (46%), reduced availability of physicians (43%) and change to home-administered biologics (38%). Change to phone/video consultations was reported in 45% of patients, of whom 79% were satisfied or very satisfied with this change. Of 709 patients on biologics, 24% experienced changes in biologic care, of whom 92% were changed to home-administered biologics and of these 62% were satisfied or very satisfied with this change. Only 2% reported worsening asthma symptoms associated with changes in biologic care. Many physicians expect continued implementation of video/phone consultations (41%) and home administration of biologics (52%)., Conclusions: Change to video/phone consultations and home administration of biologics was common in severe asthma care during the COVID-19 pandemic and was associated with high satisfaction levels in most but not all cases. Many physicians expect these changes to continue in future severe asthma care, though satisfaction levels may change after the pandemic., Competing Interests: Conflict of interest: A. Bourdin reports receiving grants or contracts outside the submitted work from AstraZeneca and Boeringher Ingelheim; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events as well as support for attending meetings and/or travel from AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Chiesi and Amgen, outside the submitted work. Z. Csoma reports receiving honoraria for presentations from Astra/Zeneca, TEVA and Sanofi/Aventis (Hungary) outside the submitted work. E. Heffler reports receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, Sanofi-Genzyme, Regeneron, Novartis, GSK, Circassia; Stallergenes-Greer and Nestlè Purina outside the submitted work. G.W. Canonica reports receiving consulting fees from AstraZeneca GSK, Novartis, Sanofi and Stallergenes Greer; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, GSK, Novartis, Sanofi, Stallergenes Greer, Menarini, Chiesi and Mylan; participation on data safety monitoring or advisory boards for AstraZeneca, GSK, Novartis, Sanofi, Stallergenes Greer and Chiesi; all disclosures made outside the submitted work. G-J. Braunstahl reports grants or contracts from GSK, AstraZeneca and ALK Abello; consulting fees from GSK, Sanofi, ALK Abello, AstraZeneca and Novartis; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from GSK, Sanofi, ALK Abello, AstraZeneca and Novartis; and is on the scientific board of the Dutch Lung Foundation, task force Asthma NVALT and editorial board NTVAAKI; all disclosures made outside the submitted work. S. van der Sar reports receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca and GSK; and support received from ALK for attending meetings and/or travel; all disclosures made outside the submitted work. N. Nenasheva reports receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca plc., Sanofi S.A., Teva Pharmaceuticals, Novartis International AG and Chiesi Farmaceutici S.p.A., outside the submitted work. A. Bossios reports receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AZ, GSK and Teva; support for attending meetings and/or travel received from Novartis; and participation on a data safety monitoring or advisory boards for AZ, GSK, Novartis, Teva and Sanofi; and is a member of the steering Committee of SHARP, Secretary of Assembly 5 (Airway diseases, asthma, COPD and chronic cough) of the European Respiratory Society and vice-chair of Nordic Severe Asthma Network; all disclosures made outside the submitted work. D. Aronsson reports receiving grants or contracts from ALK-Abello outside the submitted work. A. Egesten reports receiving honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, outside the submitted work. L. Ahlbeck reports receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca; and participation on data safety monitoring or advisory boards for AstraZeneca, Sanofi and GSK; all disclosures made outside the submitted work. S. Škrgat reports receiving honoraria for lectures and educational events supported by GSK, AstraZeneca, Sanofi, Chiesi, Pliva Teva and Medis; and participation on advisory boards of GSK, AstraZeneca, Chiesi and Sanofi; all disclosures made outside the submitted work. N. Edelbaher reports receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from GSK, Astra Zeneca, Chiesi, Pliva Teva, Krka, Novartis, Boehringer Ingelheim and Sanofi; and participation on advisory boards of GSK, Astra Zeneca, Chiesi, Novartis and Boehringer Ingelheim; all disclosures made outside the submitted work. J. Rüdiger reports receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from the Education of Swiss Emergency physicians; and participation on a data safety monitoring board or board for Boehringer Ingelheim; and is a member of the Board of the Swiss Society of Pneumology and President of the Thorax section of the Swiss Ultrasound Society; all disclosures made outside the submitted work. N. Pavlov reports receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from GSK, Novartis and OM Pharma; support for attending meetings and/or travel received from Boehringer Ingelheim; participation on data safety monitoring or advisory boards for AstraZeneca, GSK, Novartis and Sanofi; all disclosures made outside the submitted work. P. Gianella reports participation on an advisory board for Novartis about Xolair for nasal polyps, outside the submitted work. F. Charbonnier reports receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Sanofi, Novartis, Mundipharma, AstraZeneca and GSK; participation on data safety monitoring or advisory boards for Sanofi, Novartis, Mundipharma, AstraZeneca and GSK; all disclosures made outside the submitted work. R. Chaudhuri reports receiving grants or contracts from AstraZeneca; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from GSK, AstraZeneca, Teva, Chiesi, Sanofi and Novartis; support for attending meetings and/or travel received from Chiesi, Napp, Sanofi, Boehringer, GSK and AZ; and participation on data safety monitoring or advisory boards for GSK, AstraZeneca, Teva, Chiesi and Novartis; all disclosures made outside the submitted work. S.J. Smith is supported by the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement number 831434 for Taxonomy, Targets, Treatment, and Remission; the JU receives support from the European Union's Horizon 2020 research and innovation programme, and the European Federation of Pharmaceutical Industries and Associates; all disclosures made outside the submitted work. S. Doe reports receiving support for attending meetings and/or travel from GSK and Sanofi, outside the submitted work. L. Heaney reports grants or contracts from Medimmune, Novartis UK, Roche/Genentech Inc., GlaxoSmithKline, Amgen, Genentech/Hoffman la Roche, AstraZeneca, Medimmune, Aerocrine and Vitalograph; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events for Novartis, Hoffman la Roche/Genentech Inc., Sanofi, GlaxoSmithKline, AstraZeneca, Teva and Circassia; support for attending meetings and/or travel from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK and Napp Pharmaceuticals; participation on data safety monitoring or advisory board for Novartis, Hoffman la Roche/Genentech Inc., Sanofi, Evelo Biosciences, GlaxoSmithKline, AstraZeneca, Teva, Theravance and Circassia; all disclosures made outside the submitted work. M. Masoli reports receiving grants or contracts from ERS SHARP to support the study “The burden of severe asthma on HRQoL across Europe”, outside the submitted work. P. Howarth is an employee of GSK. R. Djukanovic reports support for the present manuscript received from ERS, TEVA, GSK, Novartis, Sanofi and Chiesi; consulting fees from Synairgen for which the author is a co-founder and consultant and owns shares, outside the submitted work; and participation on a data safety monitoring or advisory board for Kymab (Cambridge), outside the submitted work. E. Bel reports support for the present manuscript from the ERS; grants or contracts received from GlaxoSmithKline and Teva, outside the submitted work; consulting fees received from AstraZeneca, GlaxoSmithKline, Sanofi, Sterna and Chiesi, outside the submitted work; honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from Teva; participation on a data safety monitoring or advisory board for AstraZeneca, outside the submitted work; and leadership or fiduciary roles, unpaid, for SHARP-CRC and RAPSODI (Dutch registry), outside the submitted work. M. Hyland reports receiving grants or contracts from TEVA; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events for GSK; all disclosures made outside the submitted work. The remaining authors have nothing to disclose., (Copyright ©The authors 2022.)

Sensitization to fungi and long term or uncontrolled fungal infection are associated with poor control of asthma, the likelihood of more severe disease and complications such as bronchiectasis and chronic pulmonary aspergillosis. Modelling suggests that >6.5 million people have severe asthma with fungal sensitizations (SAFS), up to 50% of adult asthmatics attending secondary care have fungal sensitization, and an estimated 4.8 million adults have allergic bronchopulmonary aspergillosis (ABPA). There is much uncertainty about which fungi and fungal allergens are relevant to asthma, the natural history of sensitisation to fungi, if there is an exposure response relationship for fungal allergy, and the pathogenesis and frequency of exacerbations and complications. Genetic associations have been described but only weakly linked to phenotypes. The evidence base for most management strategies in ABPA, SAFS and related conditions is weak. Yet straightforward clinical practice guidelines for management are required. The role of environmental monitoring and optimal means of controlling disease to prevent disability and complications are not yet clear. In this paper we set out the key evidence supporting the role of fungal exposure, sensitisation and infection in asthmatics, what is understood about pathogenesis and natural history and identify the numerous areas for research studies.

This study investigated the expression of MUC5B by AMs in the lungs of cigarette smokers and nonsmokers. We analyzed MUC5B expression by measuring the levels of apomucin and mRNA in human BALF cells from 50 subjects (20 nonsmokers, 17 patients with CB, and 13 patients with COPD). apoMUC5B was observed in BALF mononuclear cells in 60% of all subjects, but a significantly higher frequency of apoMUC5B(+) cells was found in subjects with CB (95% CI, 4.5-24.9) or COPD (95% CI, 6.2-39.6) than in nonsmokers (95% CI, 0.5-2.5). apoMUC5B(+) mononuclear cells showed strong expression of CD163, confirming their identity as AMs. MUC5B mRNA expression was detected by ISH in AMs of subjects investigated, and real-time qPCR analysis confirmed MUC5B mRNA expression. In conclusion, MUC5B is expressed in a subset of lung AMs and long-term cigarette smoking may increase the level of MUC5B produced by these cells.

Abnormal activation of the Sonic hedgehog (Shh) signaling pathway has been demonstrated in a number of human tumors, including prostate cancer. The study aimed to assess the activity of Shh pathway components (Shh, Gli1, Gli2 and Gli3), as well as the proliferation markers FoxA1 and Notch1 during cancer progression in the transgenic adenocarcinoma of the mouse prostate (TRAMP). We evaluated changes in respective proteins by immunohistochemistry at three time points (12, 17 and 21 weeks of age) in the tissue of TRAMP and C57Bl/6 mice. Moreover, the expression of mRNA of these proteins was assessed. The present study shows a significant age-dependent increase in the number of Shh, Gli1, Gli3 and FoxA1-positive prostate cells and a decrease in Gli2-positive cells in TRAMP. The study also supports the hypothesis that the development of prostate cancer and its metastasis is associated with activation of the Shh signaling pathway.

Background: There is a growing body of evidence to suggest that CD8+ T lymphocytes contribute to local allergen-induced eosinophilic inflammation. Since bone marrow (BM) responses are intricately involved in the induction of airway eosinophilia, we hypothesized that CD8+ T lymphocytes, as well as CD4+ T lymphocytes, may be involved in this process., Methods: Several approaches were utilized. Firstly, mice overexpressing interleukin-5 (IL-5) in CD3+ T lymphocytes (NJ.1638; CD3IL-5+ mice) were bred with gene knockout mice lacking either CD4+ T lymphocytes (CD4-/-) or CD8+ T lymphocytes (CD8-/-) to produce CD3IL-5+ knockout mice deficient in CD4+ T lymphocytes (CD3IL-5+/CD4-/-) and CD8+ T lymphocytes (CD3IL-5+/CD8-/-), respectively. Secondly, CD3+, CD4+ and CD8+ T lymphocytes from naïve CD3IL-5+ and C57BL/6 mice were adoptively transferred to immunodeficient SCID-bg mice to determine their effect on BM eosinophilia. Thirdly, CD3IL-5+, CD3IL-5+/CD8-/- and CD3IL-5+/CD4-/- mice were sensitized and allergen challenged. Bone marrow and blood samples were collected in all experiments., Results: The number of BM eosinophils was significantly reduced in CD3IL-5+/CD8-/- mice compared to CD3IL-5+ mice and CD3IL-5+/CD4-/- mice. Serum IL-5 was significantly higher in CD3IL-5+/CD4-/- mice compared to CD3IL-5+ mice but there was no difference in serum IL-5 between CD3IL-5+/CD4-/- and CD3IL-5+/CD8-/- mice. Adoptive transfer of CD8+, but not CD4+ T lymphocytes from naïve CD3IL-5+ and C57BL/6 mice restored BM eosinophilia in immunodeficient SCID-bg mice. Additionally, allergen challenged CD3IL-5+/CD8-/- mice developed lower numbers of BM eosinophils compared to CD3IL-5+ mice and CD3IL-5+/CD4-/- mice., Conclusion: This study shows that CD8+ T lymphocytes are intricately involved in the regulation of BM eosinophilopoiesis, both in non-sensitized as well as sensitized and allergen challenged mice.