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Rationale: Previous studies investigating the impact of comorbidities on the effectiveness of biologic agents have been relatively small and of short duration and have not compared classes of biologic agents. Objectives: To determine the association between type 2-related comorbidities and biologic agent effectiveness in adults with severe asthma (SA). Methods: This cohort study used International Severe Asthma Registry data from 21 countries (2017-2022) to quantify changes in four outcomes before and after biologic therapy-annual asthma exacerbation rate, FEV 1 % predicted, asthma control, and long-term oral corticosteroid daily dose-in patients with or without allergic rhinitis, chronic rhinosinusitis (CRS) with or without nasal polyps (NPs), NPs, or eczema/atopic dermatitis. Measurements and Main Results: Of 1,765 patients, 1,257, 421, and 87 initiated anti-IL-5/5 receptor, anti-IgE, and anti-IL-4/13 therapies, respectively. In general, pre- versus post-biologic therapy improvements were noted in all four asthma outcomes assessed, irrespective of comorbidity status. However, patients with comorbid CRS with or without NPs experienced 23% fewer exacerbations per year (95% CI, 10-35%; P  < 0.001) and had 59% higher odds of better post-biologic therapy asthma control (95% CI, 26-102%; P  < 0.001) than those without CRS with or without NPs. Similar estimates were noted for those with comorbid NPs: 22% fewer exacerbations and 56% higher odds of better post-biologic therapy control. Patients with SA and CRS with or without NPs had an additional FEV 1 % predicted improvement of 3.2% (95% CI, 1.0-5.3; P  = 0.004), a trend that was also noted in those with comorbid NPs. The presence of allergic rhinitis or atopic dermatitis was not associated with post-biologic therapy effect for any outcome assessed. Conclusions: These findings highlight the importance of systematic comorbidity evaluation. The presence of CRS with or without NPs or NPs alone may be considered a predictor of the effectiveness of biologic agents in patients with SA.

Background: Investigation for the presence of asthma comorbidities is recommended by the Global Initiative for Asthma because their presence can complicate asthma management., Objective: To understand the prevalence and pattern of comorbidities and multimorbidity in adults with severe asthma and their association with asthma-related outcomes., Methods: This was a cross-sectional study using data from the International Severe Asthma Registry from 22 countries. A total of 30 comorbidities were identified and categorized a priori as any of the following: (1) potentially type 2-related comorbidities, (2) potentially oral corticosteroid (OCS)-related comorbidities, or (3) comorbidities mimicking or aggravating asthma. The association between comorbidities and asthma-related outcomes was investigated using multivariable models adjusted for country, age at enrollment, and sex (ie male or female)., Results: Of the 11,821 patients, 69%, 67%, and 55% had at least 1 potentially type 2-related, potentially OCS-related, or mimicking or aggravating comorbidities, respectively; 57% had 3 or more comorbidities, and 33% had comorbidities in all 3 categories. Patients with allergic rhinitis, nasal polyposis, and chronic rhinosinusitis experienced 1.12 (P = .003), 1.16 (P < .001), and 1.29 times (P < .001) more exacerbations per year, respectively, than those without. Patients with nasal polyposis and chronic rhinosinusitis were 40% and 46% more likely (P < .001), respectively, to have received long-term (LT) OCS. All assessed potential OCS-related comorbidities (except obesity) were associated with a greater likelihood of LTOCS use (odds ratios [ORs]: 1.23-2.77) and, except for dyslipidemia, with a greater likelihood of uncontrolled asthma (ORs: 1.29-1.68). All mimicking or aggravating comorbidities assessed were associated with more exacerbations (1.24-1.68 times more), all (except bronchiectasis) with increased likelihood of uncontrolled asthma (ORs: 1.57-1.81), and all (except chronic obstructive pulmonary disease) with increased likelihood of LTOCS use (ORs: 1.37-1.57). A greater number of comorbidities was associated with worse outcomes., Conclusion: In a global study, comorbidity or multimorbidity is reported in most adults with severe asthma and is associated with poorer asthma-related outcomes., Clinical Trial Registration: The International Severe Asthma Registry database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization Studies (European Network Centres for Pharmacoepidemiology and Pharmacovigilance [ENCEPP]/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EMA 2014; EUPAS44024) and with all applicable local and international laws and regulations, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=48848). Governance was provided by ADEPT (registration number: ADEPT1121)., Competing Interests: Disclosures Dr Scelo and Dr Murray are consultants for the Observational and Pragmatic Research Institute (OPRI). Dr Torres-Duque has received fees as an advisory board participant and/or speaker from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi-Aventis; has taken part in clinical trials from AstraZeneca, Novartis, and Sanofi-Aventis; and has received unrestricted grants for investigator-initiated studies at Fundacion Neumologica Colombiana from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols, and Novartis. Dr Maspero reports receiving speaker fees, grants, or fees for serving on advisory boards for AstraZeneca, Sanofi, GlaxoSmithKline, Novartis, Inmunotek, Menarini, and Noucor. Dr Tran, Dr Menzies-Gow, and Dr Martin are employees of AstraZeneca and may own stock or stock options in AstraZeneca. Dr Hew reports receiving grants and other advisory board fees (made to his institutional employer) from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, Teva, and Seqirus for unrelated projects. Dr Peters reports receiving personal fees and nonfinancial support from AstraZeneca and GlaxoSmithKline. Dr Gibson has received speaking fees and grants to his institution from AstraZeneca, GlaxoSmithKline, and Novartis. Dr Popov reports receiving relevant research support from Novartis and Chiesi Pharma. Dr Côté reports receiving speaking fees and consultant fees from Sanofi, Regeneron, AstraZeneca, GlaxoSmithKline, and ValeoPharma and reports receiving unrestricted grant support from GlaxoSmithKline; Dr Bergeron reports advisory board participation in Sanofi, AstraZeneca, Takeda, and ValeoPharma and honorarium for presentations for GlaxoSmithKline, AstraZeneca, Amgen, Grifols, Sanofi, Regeneron, and ValeoPharma. Dr Dorscheid is on faculty at the University of British Columbia and is supported by grants from the Canadian Institutes of Health Research, British Columbia Lung Association, and Michael Smith Foundation for Health Research. In addition, he has received speaking fees, travel grants, unrestricted project grants, and writing fees and is a paid consultant for Sanofi-Regeneron, Novartis Canada, AstraZeneca, GlaxoSmithKline, and ValeoPharma and is an active member of the Canadian Thoracic Society, American Thoracic Society, European Respiratory Society, and the Allergen Research Network. Dr FitzGerald previously reported receiving grants from AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron, and Novartis paid directly to UBC and personal fees for lectures and attending advisory boards for AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron, and Teva. Dr Chapman reports receiving grants from AstraZeneca, Boehringer Ingelheim, Bellus, CSL Behring, GlaxoSmithKline, Grifols, Inhibrx, Novartis, Regeneron, Sanofi, Takeda, and Vertex and consulting fees from AstraZeneca, CSL Behring, GlaxoSmithKline, Grifols, Inhibrx, Novartis, Sanofi, and Takeda; he has a leadership or fiduciary role in Alpha-1 Canada, the Canadian Thoracic Society, and Alpha-1 Foundation. Dr Boulet has received grants for participation in clinical studies from Amgen, AstraZeneca, GlaxoSmithKline, Merck, Novartis, Sanofi-Regeneron, and BioHaven; for consulting and advisory boards from AstraZeneca, Novartis, GlaxoSmithKline, Merck, and Sanofi-Regeneron; and lecture fees from AstraZeneca, Covis, Cipla, GlaxoSmithKline, Novartis, Merck, and Sanofi. Dr Bhutani has received speaker and consultant fees for AstraZeneca, GlaxoSmithKline, Sanofi, Covis, Boehringer Ingelheim, and Valeo. Dr Sadatsafavi has received honoraria from AstraZeneca, Boehringer Ingelheim, Teva, and GlaxoSmithKline for purposes unrelated to the content of this manuscript; and has received research funding from AstraZeneca and Boehringer Ingelheim directly into his research account from AstraZeneca for unrelated projects. Dr Jiménez-Maldonado has received fees as an advisory board participant and/or speaker from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi-Aventis and has participated in clinical trials for AstraZeneca, Novartis, and GlaxoSmithKline. Dr Duran-Silva has received fees as an advisory board participant and/or speaker from Boehringer Ingelheim, Novartis, and Sanofi-Aventis and has taken part in clinical trials from AstraZeneca, Novartis, and Sanofi-Aventis. Dr Solarte received fees from GlaxoSmithKline for participation on advisory boards. Dr Fernandez-Sanchez is a part-time employee of GlaxoSmithKline and does not hold shares in the company. Dr Bülow reports receiving speakers fees and consultancy fees from AstraZeneca and Novartis outside the submitted work and has also attended the advisory board for Novartis and AstraZeneca. Dr Bjerrum has received lecture fees from AstraZeneca, GlaxoSmithKline, and Novartis. Dr Ulrik reports receiving personal fees for talks and participation in advisory boards, among others, from AstraZeneca, GlaxoSmithKline, Teva, Boehringer Ingelheim, Orion Pharma, Sanofi-Genzyme, TFF Pharmaceuticals, Covis Pharma, Berlin-Chemie, Takeda, Chiesi, and Pfizer outside the submitted work. Dr Rasmussen declares receiving speaker fees from AstraZeneca, Boehringer Ingelheim, Teva, ALK, and Mundipharma outside the submitted work and attended advisory board for AstraZeneca, Sanofi, and Teva. Dr Altraja has received lecture fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, MSD, Norameda, Novartis, Orion, Sanofi, and Zentiva; sponsorships from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, MSD, Norameda, Novartis, and Sanofi; and has participated in advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi, and Teva. Dr Bourdin has received industry-sponsored grants from AstraZeneca-MedImmune, Boehringer Ingelheim, Cephalon/Teva, GlaxoSmithKline, Novartis, and Sanofi-Regeneron and consultancies with AstraZeneca-MedImmune, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Regeneron-Sanofi, Med-in-Cell, Actelion, Merck, Roche, and Chiesi. Dr Taille has received lecture or advisory board fees and grants to her institution from AstraZeneca, Sanofi, GlaxoSmithKline, Chiesi, and Novartis for unrelated projects. Dr Charriot reports receiving advisory board and lecture fees from AstraZeneca, GlaxoSmithKline, Sanofi; consulting fees for Chiesi; and serving as a trial coinvestigator for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi. Dr Roche reports receiving grants and personal fees from Austral, Biosency, Boehringer Ingelheim, Novartis, and Pfizer and personal fees from MSD, GlaxoSmithKline, AstraZeneca, Chiesi, Sanofi, Menarini, and Zambon. Dr Papaioannou has received fees and honoraria from Menarini, GlaxoSmithKline, Novartis, Elpen, Boehringer Ingelheim, AstraZeneca, and Chiesi. Dr Kostikas received honoraria for presentations and consultancy fees from AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, ELPEN, GILEAD, GlaxoSmithKline, Menarini, Novartis, Sanofi, Specialty Therapeutics, and WebMD; and received funding and grants from AstraZeneca, Boehringer Ingelheim, Chiesi, Innovis, ELPEN, GlaxoSmithKline, Menarini, Novartis, and NuvoAir (paid to the University of Ioannina). Dr Papadopoulos has been a speaker and/or advisory board member for Abbott, AbbVie, ALK, Asit Biotech, AstraZeneca, Biomay, Boehringer Ingelheim, GlaxoSmithKline, HAL, Faes Farma, Medscape, Menarini, MSD, Novartis, Nutricia, OM Pharma, Regeneron, Sanofi, Takeda, and Viatris. Dr Salvi reports receiving research support and speaker fees from Cipla, Glenmark, and GlaxoSmithKline. Dr Mitchell has received speaker fees from GlaxoSmithKline, AstraZeneca, Teva, and Novartis and has received grants from AstraZeneca and Teva. Dr Costello has received honoraria for lectures from Aerogen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Teva; is a member of advisory boards for GlaxoSmithKline and Novartis; has received grant support from GlaxoSmithKline and Aerogen; and has patents in the use of acoustics in the diagnosis of lung disease, assessment of adherence, and prediction of exacerbations. Dr Heffler declares receiving personal fees from Sanofi, Regeneron, GlaxoSmithKline, Novartis, AstraZeneca, Stallergenes, and Circassia. Dr Puggioni reports having received lectures or advisory board fees from Menarini, Mundipharma, Chiesi, Alk Abello, AstraZeneca, Boehringer Ingelheim, Guidotti, Malesci, GlaxoSmithKline, HAL Allergy, Novartis, Sanofi, Regeneron, Stallergenes Greer, Valeas, and Almirall. Dr Canonica has received research grants and lecture or advisory board fees from A. Menarini, Alk-Albello, Allergy Therapeutics, Anallergo, AstraZeneca, MedImmune, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia, Danone, Faes, Genentech, Guidotti Malesci, GlaxoSmithKline, HAL Allergy, Merck, MSD, Mundipharma, Novartis, Orion, Sanofi-Aventis, Sanofi, Genzyme/Regeneron, Stallergenes, UCB Pharma, Uriach Pharma, Teva, Thermo Fisher, and Valeas. Dr Iwanaga received lecture fees from Kyorin, GlaxoSmithKline, Novartis, Boehringer Ingelheim, and AstraZeneca. Dr Mona Al-Ahmad has received advisory board and speaker fees from AstraZeneca, Sanofi, Novartis, and GlaxoSmithKline and received a grant from the Kuwait Foundation for the Advancement of Sciences (KFAS). Dr Linnemann reports receiving personal fees from ALK-Abelló, AstraZeneca national and global, Bayer, Chiesi, Grunenthal, Grin, GlaxoSmithKline national and global, Viatris, Menarini, MSD, Novartis, Pfizer, Sanofi, Siegfried, UCB, and Carnot and grants from AbbVie, Bayer, Lilly, Sanofi, AstraZeneca, Pfizer, Novartis, Circassia, UCB, and GlaxoSmithKline outside the submitted work. Dr Garcia Ramirez received fees as a speaker and advisory board participant from AstraZeneca, GlaxoSmithKline, Sanofi-Genzyme, Chiesi, and Novartis. Dr Kuna reports receiving personal fees from Adamed, AstraZeneca, Berlin-Chemie Menarini, FAES, Glenmark, Novartis, Polpharma, Boehringer Ingelheim, Teva, and Zentiva outside the submitted work. Dr Fonseca reports receiving grants from or has research agreements with AstraZeneca, Mundipharma, Sanofi-Regeneron, and Novartis and has received personal fees for lectures and attending advisory boards for AstraZeneca, GlaxoSmithKline, Mundipharma, Novartis, Sanofi-Regeneron, and Teva. Dr Lehebi has given lectures at meetings supported by AstraZeneca, Boehringer Ingelheim, Novartis, GlaxoSmithKline, and Sanofi and participated in advisory board fees from GlaxoSmithKline, AstraZeneca, Novartis, and Abbott. Dr Koh reports receiving grant support from AstraZeneca and honoraria for lectures and advisory board meetings paid to her hospital (Singapore General Hospital) from GlaxoSmithKline, AstraZeneca, Novartis, Sanofi, and Boehringer Ingelheim outside the submitted work. Dr Kook Rhee received consulting/lecture fees from MSD, AstraZeneca, GlaxoSmithKline, Novartis, Takeda, Mundipharma, Boehringer Ingelheim, Teva, Sanofi, and Bayer. Dr Cosio declares receiving grants from Chiesi and GlaxoSmithKline; personal fees for advisory board activities from Chiesi, GlaxoSmithKline, Novartis, Sanofi, Teva, and AstraZeneca; and payment for lectures/speaking engagements from Chiesi, Novartis, GlaxoSmithKline, Menarini, and AstraZeneca outside the submitted work. Dr de Llano reports receiving grants, personal fees and nonfinancial support from AstraZeneca, Teva, Faes, and Sanofi; personal fees and nonfinancial support from GlaxoSmithKline and Chiesi; personal fees from MSD, Techdow Pharma, GILEAD, and Leo Pharma; and grants and personal fees from GEBRO outside the submitted work. Dr Perng received sponsorship to attend or speak at international meetings, honoraria for lecturing or attending advisory boards, and research grants from the following companies: AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Daiichi Sankyo, Shionogi, and Orient Pharma. Dr Tsai has received grants from Boehringer Ingelheim and has received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Orient EuroPharma. Dr Jackson has received speaker fees and consultancy fees from AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron, and Boehringer Ingelheim and research funding from AstraZeneca. Dr Busby has received research grants from AstraZeneca and personnel fees from NuvoAir outside the submitted work. Dr Heaney 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; has received grants from MedImmune, Novartis UK, Roche/Genentech Inc, GlaxoSmithKline, Amgen, Genentech/Hoffman la Roche, AstraZeneca, Aerocrine, and Vitalograph; has received sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Napp Pharmaceuticals; has taken part in asthma clinical trials sponsored by AstraZeneca, Boehringer Ingelheim, Hoffmann la Roche, and GlaxoSmithKline, for which his institution received remuneration; and 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. Dr Pfeffer has attended advisory boards for AstraZeneca, GlaxoSmithKline, and Sanofi; has given lectures at meetings supported by AstraZeneca and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, GlaxoSmithKline, Novartis, and Sanofi, for which his institution received remuneration; and has a current research grant funded by GlaxoSmithKline. Dr Goddard reports receiving lecture fees from Sanofi. Dr Wang has received honoraria from AstraZeneca, GlaxoSmithKline, and Genentech; and has been an investigator on studies sponsored by AstraZeneca, GlaxoSmithKline, Genentech, Sanofi, Novartis, and Teva, for which her institution has received funding. Dr Hoyte reports receiving honoraria from AstraZeneca and Genentech and has been an investigator on clinical trials sponsored by GlaxoSmithKline, Genentech, Teva, and Sanofi, for which her institution has received funding. Dr Wechsler reports receiving grants and/or personal fees from Novartis, Sanofi, Regeneron, Genentech, Sentien, resTORbio, Equillium, Genzyme, Cohero Health, Teva, Boehringer Ingelheim, AstraZeneca, Amgen, GlaxoSmithKline, Cytoreason, Cerecor, Sound biologic, Incyte, and Kinaset. Ms Carter is an employee of Optimum Patient Care (OPC) (OPC is a cofounder of the International Severe Asthma Registry and a cofounder of the APEX-COPD initiative). Ms Bulathsinhala is an employee of OPRI. Ms Eleangovan and Mr Ariti were employees of OPRI. Dr Lyu was an employee of OPC. Dr Price has advisory board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi-Genzyme, Teva Pharmaceuticals, Thermofisher; consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, Theravance; received grants and unrestricted funding for investigator-initiated studies (conducted through OPRI Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi-Genzyme, Teva Pharmaceuticals, Theravance, and the UK National Health Service; received payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi-Genzyme, Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma, Novartis; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; funding for patient enrollment or completion of research from Novartis; has stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals; owns 74% of the social enterprise OPC Ltd (Australia and UK) and 74% of OPRI Pte Ltd (Singapore); has 5% shareholding in Timestamp, which develops adherence monitoring technology; is a peer reviewer for grant committees of the Efficacy and Mechanism Evaluation program and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. Dr Porsbjerg has attended advisory boards for AstraZeneca, Novartis, Teva, and Sanofi-Genzyme; has given lectures at meetings supported by AstraZeneca, Novartis, Teva, Sanofi-Genzyme, and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, Novartis, MSD, Sanofi-Genzyme, GlaxoSmithKline, and Novartis; and has received educational and research grants from AstraZeneca, Novartis, Teva, GlaxoSmithKline, ALK, and Sanofi-Genzyme. The remaining authors have no conflicts of interest to report., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Severe asthma affects about 10% of the population with asthma and is characterized by low lung function and a high count of blood leukocytes, mainly eosinophils. Various definitions are used in clinical practice and in the literature to identify asthma remission: clinical remission, inflammatory remission, and complete remission. This work highlights a consensus for asthma remission using a Delphi method. In the context of the Severe Asthma Network Italy, which accounts for 57 severe asthma centers and more than 2,200 patients, a board of six experts drafted a list of candidate statements in a questionnaire, which has been revised to minimize redundancies and ensure clear and consistent wording for the first round (R1) of the analysis. Thirty-two statements were included in the R1 questionnaire and then submitted to a panel of 80 experts, which used a 5-point Likert scale to measure agreement regarding each statement. Then, an interim analysis of R1 data was performed, and items were discussed and considered to produce a consistent questionnaire for round 2 (R2) of the analysis. Then, the board set the R2 questionnaire, which included only important topics. Panelists were asked to vote on the statements in the R2 questionnaire afterward. During R2, the criteria of complete clinical remission (the absence of the need for oral corticosteroids, symptoms, exacerbations or attacks, and pulmonary function stability) and those of partial clinical remission (the absence of the need for oral corticosteroids, and two of three criteria: the absence of symptoms, exacerbations or attacks, and pulmonary stability) were confirmed. This Severe Asthma Network Italy Delphi analysis defined a valuable and independent tool that is easy to use, to test the efficacy of different treatments in patients with severe asthma enrolled into the SANI registry., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Patients with severe asthma perceive beneficial effects of biologics and good self-reported adherence to treatment, even when self-administered at home https://bit.ly/48vP70w., Competing Interests: Conflict of interest: C. Crimi reports support for the present manuscript from GlaxoSmithKline (GSK) and Sanofi; honoraria received for lectures from AstraZeneca, GSK, Sanofi, Novartis, ResMed and F&P, outside the submitted work; and patent pending number 102023000013077 not discussed in the present study. Conflict of interest: C. Calabrese reports support for the present manuscript from GlaxoSmithKline (GSK) and Sanofi; honoraria received for lectures from AstraZeneca, GSK, Sanofi and Novartis, outside the submitted work; and support for attending meetings and/or travel received from AstraZeneca, GSK, Sanofi and Novartis, outside the submitted work. Conflict of interest: M. D'Amato reports support for the present manuscript from GlaxoSmithKline and Sanofi. Conflict of interest: F. Blasi reports support for the present manuscript from GlaxoSmithKline (GSK) and Sanofi; financial grants from AstraZeneca, Chiesi Farmaceutici S.p.A and Insmed Inc. outside the submitted work; consulting fees from Menarini and Zambon outside the submitted work; and speaker fees from AstraZeneca, Chiesi Farmaceutici S.p.A, GSK, Guidotti, Grifols, Insmed Inc., Menarini, Novartis AG, Sanofi-Genzyme, Viatris Inc., Vertex Pharmaceuticals and Zambon outside the submitted work. Conflict of interest: G.W. Canonica reports support for the present manuscript from GlaxoSmithKline (GSK) and Sanofi; research grants from A. Menarini, Allergy Therapeutics, AstraZeneca, Chiesi Farmaceutici, Faes, Firma, GSK, Guidotti-Malesci, Hal Allergy, Innovacaremd, Novartis, OmPharma, RedMaple, Sanofi-Aventis, Sanofi-Genzyme, Stallergenes-Greer, Uriach Pharma, ThermoFisher and Valeas outside the submitted work; honoraria for lectures from A. Menarini, Allergy Therapeutics, AstraZeneca, Chiesi Farmaceutici, Faes, Firma, GSK, Guidotti-Malesci, Hal Allergy, Innovacaremd, Novartis, OmPharma, RedMaple, Sanofi-Aventis, Sanofi-Genzyme, Stallergenes-Greer, Uriach Pharma, ThermoFisher and Valeas outside the submitted work; and advisory board fees from A. Menarini, Allergy Therapeutics, AstraZeneca, Chiesi Farmaceutici, Faes, Firma, GSK, Guidotti-Malesci, Hal Allergy, Innovacaremd, Novartis, OmPharma, RedMaple, Sanofi-Aventis, Sanofi-Genzyme, Stallergenes-Greer, Uriach Pharma, ThermoFisher and Valeas outside the submitted work. Conflict of interest: G. Guida reports support for the present manuscript from GlaxoSmithKline and Sanofi; and a speaker fee from AstraZeneca outside the submitted work. Conflict of interest: E. Heffler reports support for the present manuscript from GlaxoSmithKline (GSK) and Sanofi; a research grant from GSK outside the submitted work; fees for lectures from Sanofi, Regeneron, GSK, AstraZeneca, Novartis, Chiesi and Stallergenes-Greer outside the submitted work; and fees for advisory boards participation from Sanofi, Regeneron, GSK, AstraZeneca, Novartis, Chiesi and Stallergenes-Greer outside the submitted work. Conflict of interest: P. Paggiaro reports support for the present manuscript from GlaxoSmithKline (GSK) and Sanofi; grants for educational events from AstraZeneca, Chiesi Farmaceutici, GSK, Guidotti and Sanofi outside the submitted work; and grants for participation to Advisory Board from AstraZeneca, Chiesi Farmaceutici, GSK, Guidotti and Sanofi outside the submitted work. Conflict of interest: G.E. Carpagnano reports support for the present manuscript from GlaxoSmithKline (GSK) and Sanofi; and honoraria received for lectures from AstraZeneca, GSK, Sanofi and Chiesi, outside the submitted work., (Copyright ©The authors 2023.)

Objective: Previous studies suggested that distinct phenotypes of eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) could be determined by the presence or absence of antineutrophil cytoplasmic antibodies (ANCA), reflecting predominant vasculitic or eosinophilic processes, respectively. This study explored whether ANCA-based clusters or other clusters can be identified in EGPA., Methods: This study used standardized data of 15 European centers for patients with EGPA fulfilling widely accepted classification criteria. We used multiple correspondence analysis, hierarchical cluster analysis, and a decision tree model. The main model included 10 clinical variables (musculoskeletal [MSK], mucocutaneous, ophthalmological, ENT, cardiovascular, pulmonary, gastrointestinal, renal, central, or peripheral neurological involvement); a second model also included ANCA results., Results: The analyses included 489 patients diagnosed between 1984 and 2015. ANCA were detected in 37.2% of patients, mostly perinuclear ANCA (85.4%) and/or antimyeloperoxidase (87%). Compared with ANCA-negative patients, those with ANCA had more renal ( P < 0.001) and peripheral neurological involvement ( P = 0.04), fewer cardiovascular signs ( P < 0.001), and fewer biopsies with eosinophilic tissue infiltrates ( P = 0.001). The cluster analyses generated 4 (model without ANCA) and 5 clusters (model with ANCA). Both models identified 3 identical clusters of 34, 39, and 40 patients according to the presence or absence of ENT, central nervous system, and ophthalmological involvement. Peripheral neurological and cardiovascular involvement were not predictive characteristics., Conclusion: Although reinforcing the known association of ANCA status with clinical manifestations, cluster analysis does not support a complete separation of EGPA in ANCA-positive and -negative subsets. Collectively, these data indicate that EGPA should be regarded as a phenotypic spectrum rather than a dichotomous disease., (Copyright © 2023 by the Journal of Rheumatology.)

The efficacy mepolizumab in severe asthmatic patients is proven in the literature. Primarily to study the effect of mepolizumab on exacerbations, steroid dependence, and the continuation of efficacy in the long term. Secondarily to evaluate the effect of the drug on nasal polyps. Analyzing data from SANI (Severe Asthma Network Italy) clinics, we observed severe asthmatic patients treated with mepolizumab 100 mg/4 weeks, for a period of 3 years. 157 patients were observed. Exacerbations were reduced from the first year (-84.6%) and progressively to 90 and 95% in the second and third ones. Steroid-dependent patients decreased from 54% to 21% and subsequently to 11% in the second year and 6% in the third year. Patients with concomitant nasal polyps, assessed by SNOT-22, showed a 49% reduction in value from baseline to the third year. The study demonstrated the long-term efficacy of mepolizumab in a real-life setting.

Background: High total IgE levels are weak predictors of T2 High and have been reported in nonallergic asthma. Therefore, the role of total serum IgE (IgE) in the T2 High phenotype is still debated. Objective: This study investigated the reliability of stratifying asthmatics into IgE High and IgE Low within the T2 High and T2 Low phenotypes. Methods: This cross-sectional single-center study investigated the association of clinical, functional, and bio-humoral parameters in a large asthmatic population stratified by IgE ≥ 100 kU/L, allergen sensitization, B-EOS ≥ 300/µL, and F E NO ≥ 30 ppb. Results: Combining T2 biomarkers and IgE identifies (1) T2 Low -IgE Low (15.5%); (2) T2 Low -IgE High (5.1%); (3) T2 High -IgE Low (33.6%); and T2 High -IgE High (45.7%). T2 Low -IgE Low patients have more frequent cardiovascular and metabolic comorbidities, a higher prevalence of emphysema, and higher LAMA use than the two T2 High subgroups. Higher exacerbation rates, rhinitis, and anxiety/depression syndrome characterize the T2 Low -IgE High phenotype vs. the T2 Low -IgE Low phenotype. Within the T2 High , low IgE was associated with female sex, obesity, and anxiety/depression. Conclusions: High IgE in T2 Low patients is associated with a peculiar clinical phenotype, similar to T2 High in terms of disease severity and nasal comorbidities, while retaining the T2 Low features. IgE may represent an additional biomarker for clustering asthma in both T2 High and T2 Low phenotypes rather than a predictor of T2 High asthma " per se ".

The heterogeneity of asthma makes it challenging to unravel the pathophysiologic mechanisms of the disease. Despite the wealth of research identifying diverse phenotypes, many gaps still remain in our knowledge of the disease's complexity. A crucial aspect is the impact of airborne factors over a lifetime, which often results in a complex overlap of phenotypes associated with type 2 (T2), non-T2 and mixed inflammation. Evidence now shows overlaps between the phenotypes associated with T2, non-T2 and mixed T2/non-T2 inflammation. These interconnections could be induced by different determinants such as recurrent infections, environmental factors, T-helper plasticity and comorbidities, collectively resulting in a complex network of distinct pathways generally considered as mutually exclusive. In this scenario, we need to abandon the concept of asthma as a disease characterised by distinct traits grouped into static segregated categories. It is now evident that there are multiple interplays between the various physiologic, cellular and molecular features of asthma, and the overlap of phenotypes cannot be ignored., Competing Interests: Conflict of interest: F.L.M. Ricciardolo reports grants from Chiesi, grants and personal fees from AstraZeneca, GSK and Sanofi, and personal fees from Novartis outside the submitted work. G. Guida reports personal fees from AstraZeneca, outside the submitted work. F. Bertolini and A. Di Stefano have no conflicts of interest. V. Carriero received a grant from Sanofi., (Copyright ©The authors 2023.)

Purpose of Review: Exhaled nitric oxide (FENO) is a noninvasive marker of eosinophilic airway inflammation, therefore, highly informative in asthma. Although FENO measurement is a potentially accessible tool to many physicians, recommendations regarding its clinical utility in diagnosing or tailoring treatment have not reached the expected diffusion. More recently FENO emerged as a biomarker for type-2 asthma phenotyping and a predictor of response to biologics., Recent Findings: The physiological discoveries and relevant acquisitions in clinical practice regarding FENO in asthma are presented. The FENO story draw a wavy path, characterized by promising findings, exciting confirmations and periods of low visibility. FENO emerged as a tool to increase the probability of asthma diagnosis. FENO predicts response to inhaled glucocorticoids (ICS), favoring the development of tailored treatment strategies and unrevealing nonadherence to ICS in difficult-to-treat or uncontrolled asthma. Finally, FENO was associated with a more severe phenotype and became a consolidated biomarker of type-2 inflammation., Summary: FENO demonstrated to be a noninvasive and very reproducible test, encompassing many applications in the field of asthma management. Its routinely use, according to international guidelines, may improve the quality of patient assistance, from difficult-to-treat cases to biologic monitoring., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Pirfenidone and nintedanib are the only two drugs approved for the treatment of idiopathic pulmonary fibrosis (IPF). Both proved to be safe and well-tolerated in clinical trials, but real-world data and direct comparisons are scarce. This real-life study explored the safety profile of pirfenidone and nintedanib with a prolonged follow-up. We retrospectively collected clinical status, adverse events (AEs), and treatment changes from IPF patients who had started an antifibrotic treatment at our centre from December 2011 to December 2020, including 192 patients treated with pirfenidone and 89 with nintedanib. The majority of patients in both groups experienced one or more AEs during the follow-up. A higher proportion of AEs in the nintedanib group were effectively treated with behavioural modifications or additional medications compared with the pirfenidone group (52.5% vs. 40.6%, p = 0.04). Overall, a difference in the impact of AEs due to nintedanib versus pirfenidone resulted in a lower permanent discontinuation of therapy (8.3% vs. 18.3%, p = 0.02), with the latter being associated with a higher risk of drug discontinuation at 48 months after initiation (OR = 2.52, p = 0.03). Our study confirms the safety profile of antifibrotic drugs in IPF but highlights that AEs due to nintedanib are usually easier to manage and lead to fewer cases of permanent discontinuation of therapy.

The advent of personalized medicine has revolutionized the whole approach to the management of asthma, representing the essential basis for future developments. The cornerstones of personalized medicine are the highest precision in diagnosis, individualized prediction of disease evolution, and patient-tailored treatment. To this aim, enormous efforts have been established to discover biomarkers able to predict patients' phenotypes according to clinical, functional, and bio-humoral traits. Biomarkers are objectively measured characteristics used as indicators of biological or pathogenic processes or clinical responses to specific therapeutic interventions. The diagnosis of type-2 asthma, prediction of response to type-2 targeted treatments, and evaluation of the risk of exacerbation and lung function impairment have been associated with biomarkers detectable either in peripheral blood or in airway samples. The surrogate nature of serum biomarkers, set up to be less invasive than sputum analysis or bronchial biopsies, has shown several limits concerning their clinical applicability. Routinely used biomarkers, like peripheral eosinophilia, total IgE, or exhaled nitric oxide, result, even when combined, to be not completely satisfactory in segregating different type-2 asthma phenotypes, particularly in the context of severe asthma where the choice among different biologics is compelling. Moreover, the type-2 low fraction of patients is not only an orphan of biological treatments but is at risk of being misdiagnosed due to the low negative predictive value of type-2 high biomarkers. Sputum inflammatory cell analysis, considered the highest specific biomarker in discriminating eosinophilic inflammation in asthma, and therefore elected as the gold standard in clinical trials and research models, demonstrated many limits in clinical applicability. Many factors may influence the measure of these biomarkers, such as corticosteroid intake, comorbidities, and environmental exposures or habits. Not least, biomarkers variability over time is a confounding factor leading to wrong clinical choices. In this narrative review, we try to explore many aspects concerning the role of routinely used biomarkers in asthma, applying a critical view over the "state of the art" and contemporarily offering an overview of the most recent evidence in this field., Competing Interests: The 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 © 2022 Guida, Bagnasco, Carriero, Bertolini, Ricciardolo, Nicola, Brussino, Nappi, Paoletti, Canonica and Heffler.)

Introduction: Asthma, along with inhaled steroids, was initially considered a risk factor for worse clinical outcomes in COVID-19. This was related to the higher morbidity observed in asthma patients during previous viral outbreaks. This retrospective study aimed at evaluating the prevalence of asthma among patients admitted due to SARS-CoV-2 infection as well as the impact of inhaled therapies on their outcomes. Furthermore, a comparison between patients with asthma, COPD and the general population was made. Methods: All COVID-19 inpatients were recruited between February and July 2020 from four large hospitals in Northwest Italy. Data concerning medical history, the Charlson Comorbidity Index (CCI) and the hospital stay, including length, drugs and COVID-19 complications (respiratory failure, lung involvement, and the need for respiratory support) were collected, as well as the type of discharge. Results: patients with asthma required high-flow oxygen therapy (33.3 vs. 14.3%, p = 0.001) and invasive mechanical ventilation (17.9 vs. 9.5%, p = 0.048) more frequently when compared to the general population, but no other difference was observed. Moreover, asthma patients were generally younger than patients with COPD (59.2 vs. 76.8 years, p < 0.001), they showed both a lower mortality rate (15.4 vs. 39.4%, p < 0.001) and a lower CCI (3.4 vs. 6.2, p < 0.001). Patients with asthma in regular therapy with ICS at home had significantly shorter hospital stay compared to those with no treatments (25.2 vs. 11.3 days, p = 0.024). Discussion: Our study showed that asthma is not associated with worse outcomes of COVID-19, despite the higher need for respiratory support compared with the general population, while the use of ICS allowed for a shorter hospital stay. In addition, the comparison of asthma with COPD patients confirmed the greater frailty of the latter, according to their multiple comorbidities.

Nasal cytology is a diagnostic tool that can be used in precision rhinology medicine. Particularly in non-allergic rhinitis and chronic rhinosinusitis forms it can be useful to evaluate biomarkers of both surgical or biological therapy and especially in the follow-up it must be used to predict the prognostic index of recurrence of nasal polyposis. All inflammatory cytokines are also linked to the presence of cells such as eosinophils and mastcells and nasal cytology is a non-invasive and repeatable method to assess the situation in real life., Competing Interests: The 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 © 2022 Caruso, Giancaspro, Guida, Macchi, Landi, Heffler and Gelardi.)

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex inflammatory disease highly impacting patient's quality of life, and associated with lower airway inflammation often evolving into asthma. Exhaled nitric oxide (FE NO ) is a non-invasive tool to assess Type 2 airway inflammation and its extended analysis allows to differentiate between alveolar concentration (CalvNO) and bronchial output (JawNO). It is also possible to assess the sino-nasal production of nitric oxide (nNO). We studied extended nitric oxide production in patients with CRSwNP with or without associated asthma. Consecutive adult patients with CRSwNP, with or without asthma, and 15 healthy controls were enrolled. Exclusion criteria were: smoking, uncontrolled asthma, recent upper or lower airway infections and oral corticosteroid therapy in the 4 weeks preceding clinical evaluation. Patients' demographic and clinical data were collected; patients underwent pulmonary function tests and extended nitric oxide analysis including nasal nNO assessment. A total of 125 subjects were enrolled (15 healthy controls; 69 with CRSwNP and asthma, and 41 with CRSwNP only). FE NO , JawNO and CalvNO values were higher, while nNO was lower, in all patients with CRSwNP compared to healthy controls; no difference was found in CalvNO between patients with concomitant asthma and non-asthmatic subjects; in asthmatic patients, FE NO and JawNO were significantly higher, while nNO values was lower, compared to patients with CRSwNP only. These results suggest that CRSwNP could be the first manifestation of a more complex systemic inflammatory pathology driven by Type 2 inflammation. An 'inflammatory gradient' hypothesis could describe a pattern of inflammation in CRSwNP patients that starts distally in the alveoli. Finally, our study indirectly reinforces the concept that novel biological drugs could become valid therapeutic options for nasal polyposis.

According to the data derived from several national and international registries, including SANI (Severe Asthma Network Italy), and considering the strong impact that frequent or regular use of oral corticosteroid has on quality of life (QoL) of severe asthmatics, as well as on the costs for managing corticosteroid-related diseases, oral corticosteroid sparing up to withdrawal should be considered a primary outcome in the management of severe asthma. New biologics have clearly demonstrated that this effect is possible, with concomitant reduction in the rate of exacerbations and in symptom control. Then, there is no reason for using so frequently oral corticosteroid before having explored all alternatives currently available for a large part of severe asthmatics., Competing Interests: GW Canonica received in the last three years research grants as well as lecture or advisory board fees from: A. Menarini, Alk-Abello, Allergy Therapeutics, AstraZeneca, Boehringer-Ingelheim, Chiesi Farmaceutici, Genentech, Guidotti-Malesci, Glaxo Smith Kline, Hal Allergy, Mylan, Merck, Mundipharma, Novartis, Regeneron, Sanofi-Aventis, Sanofi-Genzyme, StallergenesGreer, UCB pharma, Uriach Pharma, Valeas, ViborPharma. F Blasi received grants and/or personal fees from: AstraZeneca, Bayer, Chiesi, Guidotti, Glaxo Smith Kline, Grifols, Insmed, Menarini, Mundifarma, Novartis, Pfizer, Zambon. PL Paggiaro received grants and/or personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, Guidotti, Mundipharma, Novartis, Sanofi. S Aliberti received grants and/or personal fees from Actavis UK Ltd, Aradigm Corporation, AstraZeneca, Basilea, Bayer Healthcare, Chiesi, Grifols, Horizon, INSMED, Novartis, Raptor, Zambon. L Cosmi received personal fees from Glaxo Smith Kline and Novartis. S Centanni received grants and/or personal fees from AstraZeneca, Boheringer Ingelheim, Chiesi, Glaxo Smith Kline, Guidotti, Menarini, Novartis, Valeas. ME Conte received personal fees from Glaxo Smith Kline. S D’Alò received fees for clinical trials from Glaxo Smith Kline. S Del Giacco received grants and/or personal fees from AstraZeneca, Chiesi, Glaxo Smith Kline, Menarini. Novartis. F Puggioni received personal fees from Allergy therapeutics, Almirall, AstraZeneca, Chiesi, Glaxo Smith Kline, Guidotti, Menarini, Mundipharma, Novartis, Sanofi, Valeas. FLM Ricciardolo received grants, personal fees and/or other supports from AstraZeneca, Boehringer Ingelheim, Chiesi, Glaxo Smith Kline, Guidotti, Lusofarmaco, Menarini, Neopharmed, Novartis, Sanofi, Teva. L Richeldi received personal fees from Bayer, Boehringer Ingelheim, Celgene, FibroGen, Promedior, RespiVant, Roche, Sanofi-Aventis. P Santus received grants and/or personal fees from ALK Abellò, AstraZeneca, Berlin Chemie, Boheringer Ingheleim, Menarini International, Novartis, Sanofi, Valeas, Zambon. E Heffler received personal fees from AstraZeneca, Boheringer Ingheleim, Circassia, Glaxo Smith Kline, Nestlè Purina, Novartis, Sanofi, Teva, Valeas. GE Senna, G Passalacqua, A Spanevello, D Bagnasco, M Bonavia, M Bonini, L Brussino, C Bucca, MF Caiaffa, C Calabresi, G Camiciottoli, M Caminati, GE Carpagnano, C Caruso, AG Corsico, MT Costantino, N Crimi, M D'Amato, A Farsi, E Favero, MP Foschino Barbato, G Guarneri, G Guida, M Latorre, S Lo Cicero, C Lombardi, L Macchia, F Mazza, F Menzella, M Milanese, M Montagni, P Montuschi, E Nucera, R Parente, V Patella, G Pelaia, L Pini, L Ricciardi, E Ridolo, G Rolla, N Scichilone, G Spadaro, A Vianello, V Viviano, MR Yacoub, MC Zappa have nothing to disclose., (© 2020 The Authors.)

Introduction: Severe asthma occurs in 5-10% of asthmatic patients, with nasal polyposis as one of the most frequent comorbidity. Benralizumab was recently marketed, thus we could analyse its effects in real-life in severe asthma, and compare the effects of the drug in patients with and without polyposis., Methods: Patients with severe asthma, receiving Benralizumab were enrolled in Italian asthma centres. The efficacy criteria for asthma (exacerbation rate, oral corticosteroid intake, hospitalizations, pulmonary function, exhaled nitric oxide) were evaluated at baseline and after 24 weeks of treatment. Patients were then sub-analysed according to the presence/absence of nasal polyposis., Results: Fifty-nine patients with severe uncontrolled asthma (21 males, age range 32-78) and treated with benralizumab for at least 24 weeks has been evaluated, showing significant improvements in asthma-related outcomes, except for pulmonary function and exhaled nitric oxide. This included a reduction in the sino-nasal outcome-22 score versus baseline of 13.7 points (p = .0037) in the 34 patients with nasal polyposis. Anosmia disappeared in 31% patients (p = .0034). When comparing the groups with and without nasal polyposis, a similar reduction of exacerbations was seen, with a greater reduction of the steroid dependence in patients with polyposis (-72% vs -53%; p < .0001), whereas lung function was significantly more improved (12% vs 34%, p = .0064) without polyposis patients., Conclusions: Benralizumab, after 6 months of treatment, confirmed its efficacy in severe asthma, and also in nasal polyposis, which is the most frequent comorbidity. The efficacy of Benralizumab in reducing steroid dependence was even higher in patients with polyposis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Asthma prevalence in Italy is on the rise and is estimated to be over 6% of the general population. The diagnosis of asthma can be challenging and elusive, especially in children and the last two decades has brought evidences that asthma is not a single disease but consists of various phenotypes. Symptoms can be underestimated by the patient or underreported to the clinician and physical signs can be scanty. Usual objective measures, like spirometry, are necessary but sometimes not significant. Despite proper treatment, asthma can be a very severe condition (even leading to death), however new drugs have recently become available which can be very effective in its control. Since asthma is currently thought to be caused by inflammation, a direct measure of the latter can be of paramount importance. For this purpose, the measurement of Fractional Exhaled Nitric Oxide (FE NO ) has been used since the early years of the current century as a non-invasive, easy-to-assess tool useful for diagnosing and managing asthma. This SIP-IRS/SIAAIC Position Paper is a narrative review which summarizes the evidence behind the usefulness of FE NO in the diagnosis, management and phenotypization of asthma., Competing Interests: Conflict of interest: EH, SN are consultants of Circassia AB; SN is Coordinator of the Associate Editors of the Editorial Board of Multidisciplinary Respiratory Medicine. The remaining authors have no conflict of interest to declare., (©Copyright: the Author(s), 2020.)

Airway remodeling is accepted to be a determining component within the natural history of asthma. It is a phenomenon characterized by changes in the airways structures that marches in parallel with and can be influenced by airway inflammation, floating at the interface between both natural and adaptive immunity and physical and mechanical cells behavior. In this review we aimed to highlight the comprehensive, yet not exhaustive, evidences of how immune cells induce, regulate and adapt to the recognized markers of airway remodeling. Mucous cell hyperplasia, epithelial dysfunction and mesenchymal transition, extracellular matrix protein synthesis and restructuration, fibroblast to myofibroblast transition, airway smooth muscle proliferation, bioactive and contractile properties, and vascular remodeling encompass complex physiopathological mechanisms that can be induced, suppressed or regulated by different cellular and molecular pathways. Growth factors, cytokines, chemokines and adhesion molecules expressed or derived either from the immune network of cells infiltrating the asthmatic airways and involving T helper lymphocytes, immune lymphoid cells, dendritic cells, eosinophils, neutrophils, mast cells or by the structural components such as epithelial cells, fibroblasts, myocytes, airway smooth muscle cells concur with protein cellular matrix component and metalloproteases in modifying the airway structure in a detrimental way. The consequences in lung function decline, fixed airway obstruction and clinical severity of the disease suggest the possibility of identify among the immune molecular pathway of remodeling some biological parameters or signal pathway to be either a good tracer for monitoring the disease evolution or a target for hypothetical phenotypes and endotypes. In the era of personalized medicine, a biomarker of remodeling might predict a response to small-molecule inhibitors or biologicals potentially targeting a fundamental aspect of asthma pathogenesis that impacts on the low responsiveness to airway inflammation directed treatments., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: Trials that accrue participants on the basis of genetic biomarkers are a powerful means of testing targeted drugs, but they are often complicated by the rarity of the biomarker-positive population. Umbrella trials circumvent this by testing multiple hypotheses to maximize accrual. However, bigger trials have higher chances of conflicting treatment allocations because of the coexistence of multiple actionable alterations; allocation strategies greatly affect the efficiency of enrollment and should be carefully planned on the basis of relative mutation frequencies, leveraging information from large sequencing projects., Methods: We developed software named Precision Trial Drawer (PTD) to estimate parameters that are useful for designing precision trials, most importantly, the number of patients needed to molecularly screen (NNMS) and the allocation rule that maximizes patient accrual on the basis of mutation frequency, systematically assigning patients with conflicting allocations to the drug associated with the rarer mutation. We used data from The Cancer Genome Atlas to show their potential in a 10-arm imaginary trial of multiple cancers on the basis of genetic alterations suggested by the past Molecular Analysis for Personalised Therapy (MAP) conference. We validated PTD predictions versus real data from the SHIVA (A Randomized Phase II Trial Comparing Therapy Based on Tumor Molecular Profiling Versus Conventional Therapy in Patients With Refractory Cancer) trial., Results: In the MAP imaginary trial, PTD-optimized allocation reduces number of patients needed to molecularly screen by up to 71.8% (3.5 times) compared with nonoptimal trial designs. In the SHIVA trial, PTD correctly predicted the fraction of patients with actionable alterations (33.51% [95% CI, 29.4% to 37.6%] in imaginary v 32.92% [95% CI, 28.2% to 37.6%] expected) and allocation to specific treatment groups (RAS/MEK, PI3K/mTOR, or both)., Conclusion: PTD correctly predicts crucial parameters for the design of multiarm genetic biomarker-driven trials. PTD is available as a package in the R programming language and as an open-access Web-based app. It represents a useful resource for the community of precision oncology trialists. The Web-based app is available at https://gmelloni.github.io/ptd/shinyapp.html.

Background: One of the main concerns for archaeo-metallurgists and archaeologists is to determine to what extent ancient craftsmen understood the effect of metal alloy composition and were able to control it in order to produce objects with the most suitable features. This problem can be investigated by combining compositional analyses of a high number of ancient artefacts with correlation analyses of the objects' age, production site, destination of usage etc. - and thus chemometric data treatment is carried out. In this study, multivariate analyses were performed on a matrix composed of elemental compositional data from 134 archaeological bronze objects, obtained by XRF analyses. Analysed objects have been dated back from the Eneolithic Period to the end of the Bronze Age including the early Iron Age and were excavated in Central Italy (mainly Abruzzo Region)., Results: Chemometric analysis was performed attempting to visualise clouds of objects through PCA. In parallel and independently, object grouping was attempted using several different approaches, based on object characteristics (e.g. shape, weight, type of use - cutting or hitting and age) following indications given by archaeologists (or derived from the archaeological context). Furthermore, case-tailored data pretreatment (logratio-centred scaling) was used, but no homogeneous groups could be identified., Conclusions: By using chemometric data analysis, homogeneous groups of objects could not be detected, meaning that compositional data of alloys is not correlated with the considered objects' characteristics. This favours the conclusion that - without discussing the ascertained ability of ancient foundry-men - they had also already discovered the convenience of recycling broken objects thus producing a more or less similar bronze alloy each time, depending on materials' availability; necessary mechanical characteristics could then be obtained by post processing. Graphical AbstractScores PCA plot in 3D space with 3 different bronze objects.

Although it is well known that any material degrades faster when exposed to an aggressive environment as well as that "aggressive" cannot be univocally defined as depending also on the chemical-physical characteristics of material, few researches on the identification of the most significant parameters influencing the corrosion of metallic object are available.A series of ancient coins, coming from the archaeological excavation of Palazzo Valentini (Rome) were collected together with soils, both near and far from them, and then analysed using different analytical techniques looking for a correlation between the corrosion products covering the coins and the chemical-physical soil characteristics. The content of soluble salts in the water-bearing stratum and surfacing in the archaeological site, was also measured.The obtained results stress the influence of alkaline soils on formation of patina. Cerussite, probably due to the circulation of water in layers rich in marble and plaster fragments, was the main corrosion product identified by X-ray Diffraction (XRD). Copper, lead and vanadium were found in soil surrounding coins. By measuring conductivity, pH and soluble salts content of the washing solutions from both coins and soils, we could easily separate coins coming from different stratigraphic units of the site.Data were treated by cluster and multivariate analysis, revealing a correlation between part of the coins and the nearby soil samples.

Objectives: Churg-Strauss syndrome (CSS) is a necrotising vasculitis of small vessels in which oligoclonally expanded TCR Vβ CD8+ effector memory T cells populations (TEM) may be involved in vasculitic damage. The aim of this study was to assess the functional role of CD8+ T cells in CSS patients by flow cytometry analysis of membrane expression of cytotoxic markers NKG2D and CD107a., Methods: Immunostaining of peripheral T cells and effector memory lymphocytes (TEM) from CSS patients and controls was performed by gating CD28 and CD45RA in the CD8+NKG2D+ and CD4+NKG2D+ populations. CD107a expression was evaluated in both whole CD8+ and CD4+ and the TEM cells by gating CD62 and CD45RA following polyclonal stimulation., Results: NKG2D expression was shifted toward the CD8+CD28- fraction of T cells in CSS patients compared to healthy controls (56.1±25.8% versus 17.2±7.3%, respectively, p=0.002). CD8+Vβ+ expanded T cells showed a significantly increased expression of NKG2D compared to the whole CD8+ T cell population (91.4±1.9% versus 79.7±3.8%, respectively, p=0.015). Moreover the CD8+ population from CSS upregulates CD107a on its surface upon polyclonal stimulation in a significantly higher proportion than healthy subjects (26.2±10.8% versus 8.2±2.9%, p=0.0031) and the majority CD8+ CD107+ cells from CSS patients showed a TEM phenotype compared to controls (64.8±4.9% vs. 19.8±2.9, respectively, p<0.001)., Conclusions: In CSS, CD8+ TEM lymphocytes show markers of cytotoxic activity, which suggests a role for these cells in vasculitic damage.

The development of Orthopedics and Traumatology in the last 50 years have been characterized by the concurrence of several milestone events, such as the disappearance of polio and osteoarticular tuberculosis, the progress of some disciplines such as Anesthesia and Intensive Care, Diagnostic Imaging and technology development. As for other common diseases, also for osteoporosis the evolution of knowledge about pathophysiology and treatment represents a "must" to know for the orthopaedic surgeons.

Background: Chronic cough is characterized by sensory neuropathy. Vitamin B-12 (cobalamin) deficiency (Cbl-D) causes central and peripheral nervous system damage and has been implicated in sensory neuropathy and autonomic nervous system dysfunction., Objective: We evaluated whether Cbl-D has a role in chronic, unexplained cough., Design: Laryngeal threshold (histamine concentration that provokes a 25% decrease in the midinspiratory flow), bronchial threshold (histamine concentration that provokes a 20% decrease in the forced expiratory volume in 1 s), and cough threshold (histamine concentration that causes ≥5 coughs) in response to an inhaled histamine were assessed in 42 patients with chronic, unexplained cough [27 Cbl-D patients and 15 patients without Cbl-D (Cbl-N)] before and after intramuscular injections of cobalamin for 2 mo. Laryngeal, bronchial, and cough hyperresponsiveness was diagnosed when histamine concentration thresholds were ≤8 mg/mL. Seven Clb-D and 3 Cbl-N patients underwent an oropharyngeal biopsy before treatment., Results: Cbl-D patients had a higher prevalence of laryngeal hyperresponsiveness than did Cbl-N patients (92.6% compared with 66.7%; P = 0.03), a thinner oropharyngeal epithelium [133.7 μm (95% CI: 95, 172 μm) compared with 230.8 μm (95% CI: 224, 237 μm); P = 0.002], a lower number of myelinated nerve fibers [2.25/mm(2) (95% CI: 1.8, 2.7/mm(2)) compared with 3.44/mm(2) (95% CI: 3, 3.8/mm(2)); P = 0.05], and a higher immunoreactive score for nerve growth factor (NGF) [6.7 (95% CI: 6, 7.3) compared with 2.8 (95% CI: 2.5, 3.1); P = 0.02]. After cobalamin supplementation, symptoms and laryngeal, bronchial, and cough thresholds were significantly improved in Cbl-D but not in Cbl-N patients., Conclusions: This study suggests that Cbl-D may contribute to chronic cough by favoring sensory neuropathy as indicated by laryngeal hyperresponsiveness and increased NGF expression in pharyngeal biopsies of Cbl-D patients. Cbl-D should be considered among factors that sustain chronic cough, particularly when cough triggers cannot be identified.

Background: Perennial rhinitis (PR), chronic rhinosinusitis (CRS), or both, asthma, and gastroesophageal reflux disease (GERD) are the most frequent triggers of chronic cough (CC). Extrathoracic airway receptors might be involved in all 3 conditions because asthma is often associated with PR/CRS and gastroesophageal refluxate might reach the upper airway. We previously found that most patients with rhinosinusitis, postnasal drip, and pharyngolaryngitis show laryngeal hyperresponsiveness (LHR; ie, vocal cord adduction on histamine challenge) that is consistent with an irritable larynx., Objective: We sought to evaluate the role of LHR in patients with CC., Methods: LHR and bronchial hyperresponsiveness (BHR) to histamine were assessed in 372 patients with CC and in 52 asthmatic control subjects without cough (asthma/CC-). In 172 patients the challenge was repeated after treatment for the underlying cause of cough., Results: The primary trigger of CC was PR/CRS in 208 (56%) patients, asthma in 41 (11%) patients (asthma/CC+), GERD in 62 (17%) patients, and unexplained chronic cough (UNEX) in 61 (16%) patients. LHR prevalence was 76% in patients with PR/CRS, 77% in patients with GERD, 66% in patients with UNEX, 93% in asthma/CC+ patients, and 11% in asthma/CC- patients. Upper airway disease was found in most (95%) asthma/CC+ patients and in 6% of asthma/CC- patients. BHR discriminated asthmatic patients and atopy discriminated patients with PR/CRS from patients with GERD and UNEX. Absence of LHR discriminated asthmatic patients without cough. After treatment, LHR resolved in 63% of the patients and improved in 11%, and BHR resolved in 57% and improved in 18%., Conclusions: An irritable larynx is common in patients with CC and indicates upper airway involvement, whether from rhinitis/sinusitis, gastric reflux, or idiopathic sensory neuropathy., (Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Chronic rhinosinusitis (CRS) has been reported to be associated with increased values of exhaled nitric oxide (ENO), which could not be entirely explained by the association between CRS and asthma. The aim of this study was to investigate the variables associated with increased ENO in patients with CRS., Methods: This was a prospective cross-sectional descriptive study of 93 consecutive patients with CRS. The effect on ENO of age, gender, atopy, asthma, respiratory symptoms without bronchial hyperresponsiveness (BHR), and nasal polyps was evaluated by multiple regression analysis., Results: Nasal polyps (P = .01), asthma (P < .001), and respiratory symptoms without BHR (P = .01) were the only independent variables associated with increased ENO. The prevalence of asthma was significantly higher in subjects with nasal polyps (61% vs 29.4%), P = .005, whereas the prevalence of respiratory symptoms without BHR was higher in those without nasal polyps (44.1% vs 15.3%, P = .003). Respiratory symptoms without BHR were associated with significantly higher ENO and prevalence of sputum eosinophilia (eosinophils > 3%) in patients with nasal polyps compared with those without nasal polyps (68.2 vs 24.0 ppb, P = .001; 60% vs 8.3%, P = .03, respectively)., Conclusions: The presence of nasal polyps in patients with CRS was associated with increased asthma prevalence as well as increased ENO levels. Respiratory symptoms without BHR were associated with eosinophilic airway inflammation and increased ENO only in patients with nasal polyps. These findings suggest important clinical and biologic differences between the two types of CRS, with and without nasal polyps.

Background: Reliable clinical or laboratory markers of chronic idiopathic urticaria (CIU) duration are not available. Angioedema, autologous serum skin test (ASST) results, and antithyroid antibodies have been inconsistently associated with longer urticaria duration., Objective: To investigate the association of clinical and laboratory parameters with CIU duration, including systemic hypertension, because activation of the coagulation cascade pathway may contribute to the pathogenesis of CIU., Methods: We performed a prospective study of a cohort of 228 consecutive adult patients with CIU of moderate to severe intensity referred to 2 outpatient allergy clinics and followed up for a 3- to 5-year period. The association of clinical and laboratory parameters (sex, atopy, markers of autoimmunity, antithyroid antibodies, positive ASST result, Helicobacter pylori infection, and hypertension) with urticaria duration was analyzed using semiparametric multivariable proportional hazards models (Cox regression) using remission as main outcome measure., Results: Apart from systemic hypertension (hazard ratio, 0.71; 95% confidence interval, 0.53-0.95; P = .02), none of the considered parameters influenced CIU remission of our patients; 74% and 54% of our patients with and without hypertension, respectively, still had CIU after 5 years., Conclusions: Our results show, for the first time to our knowledge, that hypertension is associated with extended duration of CIU. This observation, together with the previous findings that point to vascular and coagulation involvement in CIU, may suggest a new approach to antihistamine-refractory CIU treatment, including adequate treatment of hypertension.

Background: The role that nasal nitric oxide (nNO) plays in sinonasal diseases is increasingly appreciated., Objective: To test the diagnostic value of measuring nNO levels in a symptomatic population undergoing evaluation for potential chronic rhinosinusitis (CRS)., Methods: Of the patients referred to an outpatient allergy clinic for persistent nasal symptoms, those reporting nasal blockage plus 1 or more additional symptoms (discolored discharge, anterior or postnasal drip, facial pain or pressure, and reduction or loss of smell) were categorized as having CRS according to sinus computed tomography scores, with (CRSwNP) and without (CRSsNP) nasal polyps on the basis of endoscopic signs. All the included patients underwent nNO measurement and skin prick tests for common inhalant allergens. Healthy individuals served as controls for nNO measurement., Results: Levels of nNO were significantly lower in patients with CRSwNP (median, 340 ppb; 25th-75th percentile, 145-390 ppb) compared with patients with CRSsNP (762 ppb; 620-1,013 ppb), patients without CRS (917 ppb; 647-1,159 ppb), and controls (843 ppb; 762-962 ppb) (P < .001). Low values of nNO separated very well patients with CRSwNP, and the nNO cutoff value of less than 442 ppb was associated with the best combination of specificity (91%) and sensitivity (87%), resulting in a negative predictive value of 91% and a positive predictive value of 87%. A significant inverse relationship was observed between nNO level and sinus computed tomography score (r2 = -0.39, P < .001)., Conclusion: Testing for nNO is highly predictive of CRSwNP in a selected population of patients with symptoms suggestive of CRS.

Since the last years the better knowledge of immunologic mechanisms underlying autoimmune phenomena and rejection of allotransplants has been accompanied by an impressive production of new drugs: new inhibitors of purine and pyrimidine synthesis, as mycophenolate mofetil and leflunomide respectively, new inhibitors of calcineurin, such as tacrolimus, and target of rapamycine, such as sirolimus. Moreover, the tremendous advance in the methodology of producing monoclonal antibodies and the genetic engineering of proteins has led to a wide variety of biological agents, many of them have been approved as important new therapies for autoimmune diseases and against graft rejection. Monoclonal antibodies targeting IL-2 cytokine receptor have been shown to be useful in decrease the incidence of rejection. Moreover, monoclonal antibodies are available which target inflammatory cytokines, such as TNFalpha and IL-1, while other monoclonal antibodies may cause immune cell depletion, such as anti CD20 rituximab, or cause disruption of co-stimuli, like CTLA4Ig abatacept in the treatment of rheumatoid arthritis and anti CD11 efalizumab in the treatment of psoriasis. The new biologic agents have induced salutary clinical effects and extended the therapeutic option of patients not responding to existing treatments. The future looks brighter than ever as the recorded success fuels efforts to optimize the use of the biologic agents and extend their use in other diseases.

We studied immunoglobulin variable heavy-chain (IGHV) repertoire and mutational status in 553 patients with chronic lymphocytic leukemia (CLL) from the Mediterranean area to gain insight into the potential pathogenetic role of antigenic stimulation. The most commonly represented IGHV genes mirrored the usage of normal B cells, with the exception of IGHV1-18, IGHV3-30.3, and IGHV4-59 that were underrepresented. The IGHV3-21 gene, frequently expressed in Northern European CLL, was present only in 16 cases (2.9%). Based on HCDR3 cluster analysis, cases using IGHV3-21 could be grouped in 2 subsets of similar frequency. The first one (7 of 16 cases) carried a similar HCDR3 amino acid sequence (common-HCDR3 subset), virtually identical to the Scandinavian IGHV3-21 CLL. These cases used the IGHJ6 gene; 4 of 7 were unmutated; 6 of 7 carried the V(lambda)2-14 (IGLV3-21) light-chain gene with a similar LCDR3. All expressed CD38 and had a progressive disease. The second subset (9 of 16) was characterized by heterogeneous HCDR3 rearrangements (nonhomogeneous-HCDR3 subset), diverse IGHJ and IGV light-chain gene usage, variable IGHV mutational status (5 of 9 unmutated), variable CD38 expression, and variable clinical course (4 of 9 progressed). The first subset suggests a potential antigenic element rarely encountered in the Mediterranean area, possibly responsible for a negative outcome. The second subset may reflect the physiologic heterogeneity of expression of IGHV3-21 rearrangements in the normal repertoire and is characterized by a variable clinical outcome.