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The allergen provocation test is an established model of allergic airway diseases, including asthma and allergic rhinitis, allowing the study of allergen-induced changes in respiratory physiology and inflammatory mechanisms in sensitised individuals as well as their associations. In the upper airways, allergen challenge is focused on the clinical and pathophysiological sequelae of the early allergic response, and is applied both as a diagnostic tool and in research settings. In contrast, bronchial allergen challenge has almost exclusively served as a research tool in specialised research settings with a focus on the late asthmatic response and the underlying type 2 inflammation. The allergen-induced late asthmatic response is also characterised by prolonged airway narrowing, increased nonspecific airway hyperresponsiveness and features of airway remodelling including the small airways, and hence allows the study of several key mechanisms and features of asthma. In line with these characteristics, allergen challenge has served as a valued tool to study the cross-talk of the upper and lower airways and in proof-of-mechanism studies of drug development. In recent years, several new insights into respiratory phenotypes and endotypes including the involvement of the upper and small airways, innovative biomarker sampling methods and detection techniques, refined lung function testing as well as targeted treatment options further shaped the applicability of the allergen provocation test in precision medicine. These topics, along with descriptions of subject populations and safety, in line with the updated Global Initiative for Asthma 2021 document, will be addressed in this review., Competing Interests: G.M. Gauvreau declares grants from AstraZeneca, Biohaven, Novartis and Genentech; consulting fees from AstraZeneca, Biohaven, Novartis, Sterna Biologicals and Certior Consulting; and payment or honoraria from AstraZeneca, Genzyme and Genentech, all in the 36 months prior to manuscript submission. B.E. Davis declares no competing interests. G. Scadding declares support from ALK-Abelló (provision of active and placebo medication for the GRASS clinical trial referenced in the article) and the Immune Tolerance Network (NIAID, NIH, USA; sponsor of the GRASS clinical trial) related to the present manuscript; as well as payment for lectures from ALK-Abelló in 2020 and 2021; and support from GlaxoSmithKline for attendance at the 2021 European Academy of Allergy and Clinical Immunology meeting. L-P. Boulet declares research grants for participation in multicentre studies or research projects proposed by the investigator from Amgen, AstraZeneca, GlaxoSmithKline, Merck, Novartis and Sanofi-Regeneron; royalties from UptoDate and Taylor & Francis; lecture fees from AstraZeneca, Covis, GlaxoSmithKline, Novartis, Merck and Sanofi, all in the 36 months prior to manuscript submission; and the following unpaid contributions: Chair of the Global Initiative for Asthma (GINA) Board of Directors; President of the Global Asthma Organisation (Interasma); Member of the Canadian Thoracic Society Respiratory Guidelines Committee; and Laval University Chair on Knowledge Transfer, Prevention and Education in Respiratory and Cardiovascular Health. L. Bjermer declares no competing interests. A. Chaker declares grants or contracts, via Technical University Munich, from EIT Health (European Institute of Technology), BMBF (German Federal Ministry of Education and Research), AstraZeneca, Sanofi-Genzyme, Roche, GlaxoSmithKline and ALK-Abelló; payments or honoraria, via Technical University Munich, from ALK-Abelló, Allergopharma, AstraZeneca, GlaxoSmithKline, Immunotek, Novartis, Regeneron, Sanofi-Genzyme, Leti, Zeller and Bencard; travel reimbursement to attend European Academy of Allergy and Clinical Immunology meetings (2018 and 2021 from the European Academy of Allergy and Clinical Immunology; 2019 from ALK-Abelló); patents, via Technical University Munich, relating to allergen-specific immunotherapy and treatment of SARS-CoV-2 infection; participation, via Technical University Munich, on a data safety monitoring board or advisory board for ALK-Abelló, Allergopharma, AstraZeneca, GlaxoSmithKline, Immunotek, Novartis, Regeneron and Sanofi-Genzyme; and the following unpaid roles: Past Chair of the Allergy, Clinical Immunology and Environmental Medicine Section of the German ENT Society; board member at large of the German Allergy Society (DGAKI); scientific advisor/board member to the German Society for Applied Allergy (AeDA); board member of the Allergen Immuntherapy Interest Group, European Academy of Allergy and Clinical Immunology. D.W. Cockcroft reports the following research grants in the 36 months prior to manuscript submission: research grant Dept of Medicine University of Saskatchewan (Effect of tiotropium on airway response to allergen); Canadian Society of Allergy and Clinical Immunology (The effect of deep inhalation on mannitol responsiveness); AstraZeneca (A phase 2a double blind randomised parallel group placebo controlled multicentre study to evaluate the effect of AZD8154 administered via nebuliser once daily on allergen-induced inflammation in subjects with mild allergic asthma challenged with inhaled allergen); AllerGen NCE (Methacholine challenge comparison of a jet nebuliser and vibrating mesh nebuliser); Novartis (Inhaled CSJ117 in adult asthmatics with mild atopic asthma). B. Dahlén declares payment to their institution in 2004 for a clinical trial by AstraZeneca, related to the present work; and grants to support the Karolinska Severe Asthma Centre from GlaxoSmithKline and Novartis; consulting fees from Teva, AstraZeneca and Sanofi; and payment for lectures from AstraZeneca and Sanofi, all in the 36 months prior to manuscript submission. W. Fokkens declares grants to their institution from ALK, Mylan, Allergy Therapeutics, GlaxoSmithKline, Sanofi, Novartis and Chordate; consulting fees from Sanofi and Bioinspire; payment or honoraria from Sanofi, GlaxoSmithKline and Novartis; and participation on a data safety monitoring board or advisory board for Lyra, Sanofi and GlaxoSmithKline, all in the 36 months prior to manuscript submission; and that they are Secretary General of the European Rhinologic Society. P. Hellings declares no competing interests. N. Lazarinis declares no competing interests. P.M. O'Byrne reports grants from AstraZeneca, GlaxoSmithKline, Biohaven, Merck, Bayer and Novartis; consulting fees from AstraZeneca, Covis, GlaxoSmithKline, Amgen and Novartis; and payment or honoraria from AstraZeneca, Covis and Novartis, all in the 36 months prior to manuscript submission; and that they are a Section Editor of the European Respiratory Journal. E. Tufvesson declares no competing interests. S. Quirce declares consulting fees and payment or honoraria from GlaxoSmithKline, Sanofi and AstraZeneca; and payment or honoraria from Novartis, Chiesi, Mundipharma and Teva, all in the 36 months prior to manuscript submission. M. Van Maaren declares payment or honoraria from ALK-Abelló, Takeda and CSL Behring, in the 36 months prior to manuscript submission; and an unpaid role as Chairman of the Dutch Society of Allergology and Clinical Immunology since 2020. F. H. de Jongh declares an unpaid role as European Respiratory Society Assessment Director. Z. Diamant reports that until May 2020 they worked as Research Director Respiratory & Allergy at a CRO (QPS-NL), which received funding from biotech and several pharma companies for conduct of phase I–II clinical studies (drug development); and declares consulting fees from ALK-Abelló, AstraZeneca, Antabio, GlaxoSmithKline, HAL Allergy, QPS-NL and Sanofi-Genzyme; and payment or honoraria from BMR, Boehringer Ingelheim, European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA), Merck Sharp & Dohme and Sanofi-Genzyme, all in the 36 months prior to manuscript submission; and unpaid roles as the European Academy of Allergy and Clinical Immunology Asthma Section Chair (2017–2019) and EUFOREA Asthma Expert Panel Chair (since 2020)., (Copyright ©The authors 2022.)

Background: A subset of individuals with allergic asthma develops a late phase response (LPR) to inhaled allergens, which is characterized by a prolonged airway obstruction, airway inflammation and airway hyperresponsiveness. The aim of this study was to identify changes in the plasma proteome and circulating hematopoietic progenitor cells associated with the LPR following inhaled allergen challenge., Methods: Serial plasma samples from asthmatics undergoing inhaled allergen challenge were analyzed by mass spectrometry and immunosorbent assays. Peripheral blood mononuclear cells were analyzed by flow cytometry. Mass spectrometry data were analyzed using a linear regression to model the relationship between airway obstruction during the LPR and plasma proteome changes. Data from immunosorbent assays were analyzed using linear mixed models., Results: Out of 396 proteins quantified in plasma, 150 showed a statistically significant change 23 h post allergen challenge. Among the most upregulated proteins were three protease inhibitors: alpha-1-antitrypsin, alpha-1-antichymotrypsin and plasma serine protease inhibitor. Altered levels of 13 proteins were associated with the LPR, including increased factor XIII A and decreased von Willebrand factor. No relationship was found between the LPR and changes in the proportions of classical, intermediate, and non-classical monocytes., Conclusions: Allergic reactions to inhaled allergens in asthmatic subjects were associated with changes in a large proportion of the measured plasma proteome, whereof protease inhibitors showed the largest changes, likely to influence the inflammatory response. Many of the proteins altered in relation to the LPR are associated with coagulation, highlighting potential mechanistic targets for future treatments of type-2 asthma., (© 2022. The Author(s).)

Introduction: Clinical recommendations for childhood asthma are often based on data extrapolated from studies conducted in adults, despite significant differences in mechanisms and response to treatments. The Paediatric Asthma in Real Life (PeARL) Think Tank aspires to develop recommendations based on the best available evidence from studies in children. An overview of systematic reviews (SRs) on paediatric asthma maintenance management and an SR of treatments for acute asthma attacks in children, requiring an emergency presentation with/without hospital admission will be conducted., Methods and Analysis: Standard methodology recommended by Cochrane will be followed. Maintenance pharmacotherapy of childhood asthma will be evaluated in an overview of SRs published after 2005 and including clinical trials or real-life studies. For evaluating pharmacotherapy of acute asthma attacks leading to an emergency presentation with/without hospital admission, we opted to conduct de novo synthesis in the absence of adequate up-to-date published SRs. For the SR of acute asthma pharmacotherapy, we will consider eligible SRs, clinical trials or real-life studies without time restrictions. Our evidence updates will be based on broad searches of Pubmed/Medline and the Cochrane Library. We will use A MeaSurement Tool to Assess systematic Reviews, V.2, Cochrane risk of bias 2 and REal Life EVidence AssessmeNt Tool to evaluate the methodological quality of SRs, controlled clinical trials and real-life studies, respectively.Next, we will further assess interventions for acute severe asthma attacks with positive clinical results in meta-analyses. We will include both controlled clinical trials and observational studies and will assess their quality using the previously mentioned tools. We will employ random effect models for conducting meta-analyses, and Grading of Recommendations Assessment, Development and Evaluation methodology to assess certainty in the body of evidence., Ethics and Dissemination: Ethics approval is not required for SRs. Our findings will be published in peer reviewed journals and will inform clinical recommendations being developed by the PeARL Think Tank., Prospero Registration Numbers: CRD42020132990, CRD42020171624., Competing Interests: Competing interests: AGM reports grants from Boehringer Ingelheim outside the submitted work. AC reports personal fees from Novartis, Regeneron / Sanofi, Thermo Fisher Scientific, Boehringer Ingelheim and Philips, outside the submitted work. LB reports personal fees from Aerocrine, GlaxoSmithKline, Genentech/Novartis, Merck, DBV Technologies, Teva, Boehringer Ingelheim, AstraZeneca, WebMD/Medscape, Sanofi/Regeneron, Vectura and Circassia outside the submitted work. TC reports grants and personal fees CSL Behring, Dyax, Takeda, BioCryst, Pharming, personal fees from Grifols, grants and non-financial support from GSK, Regeneron, Novartis/Genetech outside the submitted work. AD reports grants and personal fees from Stallergenes Greer, personal fees from Novartis, ALK, TEVA, GSK, MEDA-MYLAN, CHIESI, AImmune, DBV technologies and Astra Zeneca, outside the submitted work. ZD reports personal fees from academic affiliations, ZD acts as Executive and Scientific Medical Director at a phase I/II pharmacological unit (QPS-NL), which performs clinical studies for pharmaceutical companies. ZD reports personal fees from Astrazeneca, ALK, Aquilon, Boehringer Ingelheim, CSL, HAL Allergy, MSD, and Sanofi-Genzyme outside the submitted work. FMD reports grants from Thorasys; personal fees from Jean-Coutu Pharmaceuticals, unrestricted research funds from Novartis Canada, Teva and Trudell Medical, research grants from GlaxoSmithKline and MEDteq in partnership with Thorasys; honorarium for consultancy work from Covis Pharma and Teva; and honorarium as invited speaker from Covis Pharma, Pharmacy Brunet, outside the submitted work. JEG reports grants from NIH/NIAID, personal fees from Regeneron, Ena Theraputics and MedImmune outside the submitted work; personal fees and stock options from Meissa Vaccines Inc outside the submitted work. JG reports personal fees from GSK, Vifor Pharmaceuticals, Novartis, BV Pharma and AstraZeneca outside the submitted work. AK reports personal fees Astra Zeneca, Behring, Boehringer Ingelheim, Covis, GSK, NovoNordisk, Novartis, Griffols, Pfizer, Sanofi, Teva and Trudel, outside the submitted work. RFL reports grants from NIH, non-financial support from GlaxoSmithKline, Boehringer-Ingelheim, Merck, TEVA, American Academy of Allergy, Asthma and Immunology, grants from Clinical and Translational Science Award (NIH), Childhood Origins of ASThma (COAST) grant, AsthmaNet, personal fees from LSU, Elsevier, UpToDate, the University of Kentucky, ThermoFischer, and Food Allergy Research and Education (FARE) Network, outside the submitted work. CM reports personal fees from Novartis, GSK, Astra Zeneca, Thermo Fisher and Boehringer Ingelheim outside the submitted work. NGP reports personal fees from ALK, Novartis, Nutricia, HAL, Menarini/FAES Farma, Sanofi, Mylan/MEDA, Biomay, AstraZeneca, GSK, MSD, ASIT BIOTECH and Boehringer Ingelheim; grants from Gerolymatos International SA and Capricare outside the submitted work. WP reports grants from NIH; grants and personal fees from Genentech/Novartis, Sanofi/Rgeneron; personal fees GSK; non-financial support from Thermo Fisher, Lincoln Diagnostics, Alk Abello, and Monaghen, outside the submitted work. PP reports grants from Astra Zeneca, Chiesi and TEVA; personal fees from Astra Zeneca, TEVA, Novartis, Mundipharma, S&D Pharma, and GlaxoSmithKline outside the submitted work. DP reports grants from AKL Research and Development, British Lung Foundation, Respiratory Effectiveness Group and the UK National Health Service; grants and personal fees from Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Napp, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, TEVA, Theravance and Zentiva (Sanofi Generics); personal fees from Cipla, GlaxoSmithKline, Kyorin and Merck; non-financial support from Efficacy and Mechanism Evaluation programme, Health Technology Assessment, outside the submitted work; DP also reports stock/stock options from AKL Research and Development which produces phytopharmaceuticals; and owns 74% of the social enterprise Optimum Patient Care (Australia and UK) and 74% of Observational and Pragmatic Research Institute (Singapore), outside the submitted work. GR reports personal fees from ALK, Allergen Therapeutics, Meda Plus, Merck; and a patent for the use of sublingual immunotherapy to prevent the development of allergy in at-risk infants, outside the submitted work. IT reports personal fees from Novartis, GSK, Boehringer Ingelheim and Astra Zeneca; grants from GSK Hellas, outside the submitted work. PX reports personal fees from Nutricia, Nestle, Friesland, Uriach, Novartis Pharma AG, and GlaxoSmithkline outside the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Despite the use of effective medications to control asthma, severe exacerbations in asthma are still a major health risk and require urgent action on the part of the patient and physician to prevent serious outcomes such as hospitalisation or death. Moreover, severe exacerbations are associated with substantial healthcare costs and psychological burden, including anxiety and fear for patients and their families. The European Academy of Allergy and Clinical Immunology (EAACI) and the European Respiratory Society (ERS) set up a task force to search for a clear definition of severe exacerbations, and to also define research questions and priorities. The statement includes comments from patients who were members of the task force., Competing Interests: Conflict of interest: A. Bourdin reports personal and institutional fees for advisory board work from AstraZeneca, Novartis, GSK, Boehringher Ingelheim, Chiesi, Actelion, Pfizer and Teva, outside the submitted work. Conflict of interest: L. Bjermer has nothing to disclose. Conflict of interest: C. Brightling reports grants and personal fees for consultancy from GlaxoSmithKline, AstraZeneca/Medimmune, Novartis, Chiesi, Roche/Genentech and Boehringer Inglheim, personal fees for consultancy from Vectura, Theravance, PreP, Gilead, Sanofi/Regeneron, Teva, Gossamer and 4DPharma, grants from Pfizer and Mologic, outside the submitted work. Conflict of interest: G.G. Brusselle reports personal fees for advisory board work and lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Teva, personal fees for advisory board work from Sanofi, outside the submitted work. Conflict of interest: P. Chanez reports research grants and personal fees for consultancy, advisory board work and lectures from ALK, Almirall, Boehringer Ingelheim, GSK, AstraZeneca, Novartis, TEVA and Chiesi, grants from AMU, outside the submitted work. Conflict of interest: K.F. Chung has received honoraria for participating in advisory board meetings of GSK, AZ, Novartis, Merck, BI and TEVA regarding treatments for asthma and COPD, and has also been renumerated for speaking engagements. Conflict of interest: A. Custovic reports personal fees for consultancy from Novartis, Regeneron/Sanofi, Boehringer Ingelheim and Philips, personal fees for lectures from Thermo Fisher Scientific and Novartis, outside the submitted work. Conflict of interest: Z. Diamant reports personal fees from AstraZeneca and Sanofi-Genzyme, during the conduct of the study; personal fees from Aquilon, ALK, Boehringer Ingelheim, Gilead, Hal Allergy and MSD, outside the submitted work; and in addiction to academic affiliations, also works at a phase I/II unit performing clinical studies for different biotech and pharma companies. Conflict of interest: S. Diver has nothing to disclose. Conflict of interest: R. Djukanovic reports receiving fees for lectures at symposia organised by Novartis, AstraZeneca and TEVA, consultation for TEVA and Novartis as member of advisory boards, and participation in a scientific discussion about asthma organised by GlaxoSmithKline; in addition, is a co-founder and current consultant, and has shares in, Synairgen, a University of Southampton spin out company. Conflict of interest: D. Hamerlijnck has nothing to disclose. Conflict of interest: I. Horvath reports personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GSK, Novartis, CSL-Behring and Roche, outside the submitted work. Conflict of interest: S.L. Johnston reports personal fees for advisory board work from Therapeutic Frontiers and Virtus Respiratory Research, personal fees for consultancy from Myelo Therapeutics GmbH, Concert Pharmaceuticals, Bayer, Gerson Lehrman Group, resTORbio, Bioforce, Materia Medical Holdings, PrepBio Pharma, Pulmotect, Virion Health and Lallemand Pharma, personal and insititutional fees for consultancy from Synairgen, Novartis, Boehringer Ingelheim and Chiesi; and has received personal fees for the following patents planned, issued or pending: transgenic animal models of HRV with human ICAM-1 sequences (UK patent application number 02 167 29.4, and international patent application number PCT/EP2003/007939); anti-virus therapy for respiratory diseases (UK patent application number GB 0405634.7); interferon-beta for anti-virus therapy for respiratory diseases (international patent application number PCT/GB05/50031); interferon lambda therapy for the treatment of respiratory disease (UK patent application number 6779645.9, granted); induction of cross-reactive cellular response against rhinovirus antigens (European patent number 13305152), outside the submitted work. Conflict of interest: F. Kanniess reports personal fees for lectures and advisory board work from AstraZeneca, Novartis, Mundipharma and TEVA, outside the submitted work. Conflict of interest: N. Papadopoulos reports personal fees for advisory board work and lectures from Novartis, Nutricia, HAL, personal fees from Menarini/Faes Farma and Mylan/Meda, personal fees for lectures from Sanofi, Biomay, MSD, ASIT Biotech and Boehringer Ingelheim, personal fees for advisory board work from AstraZeneca and GSK, grants from Gerolymatos International SA and Capricare, outside the submitted work. Conflict of interest: A. Papi reports grants, personal fees for lectures, advisory board work and consultancy, and travel expenses reimbursement from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline and Teva, personal fees for advisory board work and consultancy from Sanofi/Regeneron, personal fees for lectures and travel expenses reimbursement from Zambon and Novartis, personal fees for lectures, advisory board work and consultancy, and travel expenses reimbursement from Mundipharma, personal fees for lectures and advisory board work, and travel expenses reimbursement Almirall, grants, personal fees for lectures and travel expenses reimbursement from Menarini, grants from Fondazione Maugeri, grants from Fondazione Chiesi Farmaceutici, outside the submitted work. Conflict of interest: R.J. Russell has nothing to disclose. Conflict of interest: D. Ryan reports personal fees for advisory board work from GSK and Trudell Medical, personal fees for advisory board work and lectures from AZ, personal fees for lectures from Mylan and Chiesi, personal fees for consultancy from Optimum Patient Care, outside the submitted work. Conflict of interest: K. Samitas has nothing to disclose. Conflict of interest: T. Tonia acts as ERS methodologist. Conflict of interest: E. Zervas reports personal fees consultancy and lectures from Astra, Bristol-Myers Squibb, Chiesi, GSK, Elpen, Merck, MSD, Novartis, Menarini and Pfizer, non-financial support for travel, accommodation and meeting expenses from Astra, Bristol-Myers Squibb, Galenica, Chiesi, Elpen, Novartis, Menarini and Roche, outside the submitted work. Conflict of interest: M. Gaga reports grants and personal fees from AZ, grants from BI, Elpen, Novartis and Menarini, personal fees from BMS, MSD, Chiesi and Pharmaten, outside the submitted work., (Copyright ©ERS 2019.)

Recently, this international task force reported the general considerations for bronchial challenge testing and the performance of the methacholine challenge test, a "direct" airway challenge test. Here, the task force provides an updated description of the pathophysiology and the methods to conduct indirect challenge tests. Because indirect challenge tests trigger airway narrowing through the activation of endogenous pathways that are involved in asthma, indirect challenge tests tend to be specific for asthma and reveal much about the biology of asthma, but may be less sensitive than direct tests for the detection of airway hyperresponsiveness. We provide recommendations for the conduct and interpretation of hyperpnoea challenge tests such as dry air exercise challenge and eucapnic voluntary hyperpnoea that provide a single strong stimulus for airway narrowing. This technical standard expands the recommendations to additional indirect tests such as hypertonic saline, mannitol and adenosine challenge that are incremental tests, but still retain characteristics of other indirect challenges. Assessment of airway hyperresponsiveness, with direct and indirect tests, are valuable tools to understand and to monitor airway function and to characterise the underlying asthma phenotype to guide therapy. The tests should be interpreted within the context of the clinical features of asthma., Competing Interests: Conflict of interest: T.S. Hallstrand has nothing to disclose. Conflict of interest: J.D. Leuppi has nothing to disclose. Conflict of interest: G. Joos reports grants and personal fees for advisory board work and lecturing from AstraZeneca and Novartis, grants from Boehringer Ingelheim and Chiesi, grants and personal fees for advisory board work from GlaxoSmithKline, and personal fees for lecturing from Teva, outside the submitted work. Conflict of interest: G.L. Hall has nothing to disclose. Conflict of interest: K.H. Carlsen has nothing to disclose. Conflict of interest: D.A. Kaminsky has received honoraria for teaching at an annual Cardiorespiratory Diagnostics Course from MGC Diagnostics, Inc., outside the submitted work. Conflict of interest: A.L. Coates has nothing to disclose. Conflict of interest: D.W. Cockcroft is a member of a medical advisory board for Methapharm, as has received products for research purposes from Aerogen and Pharmaxis, outside the submitted work. Conflict of interest: B.H. Culver has nothing to disclose. Conflict of interest: Z. Diamant reports personal fees from Aerocrine, ALK, Aquilon, AstraZeneca, Boehringer Ingelheim, Gilead, HAL Allergy, MSD and Sanofi Genzyme-Regeneron, outside the submitted work. Conflict of interest: G.M. Gauvreau has nothing to disclose. Conflict of interest: I. Horvath reports personal fees and non-financial support from AstraZeneca, Berlin-Chemie, Chiesi, Boehringer Ingelheim, Novartis, CSL Behring and Roche, personal fees from Sandoz, GSK, Sager Pharma, Affidea, Orion Pharma and Teva, and non-financial support from MSD, outside the submitted work. Conflict of interest: F.H.C. de Jongh has nothing to disclose. Conflict of interest: B.L. Laube has nothing to disclose. Conflict of interest: P.J. Sterk has nothing to disclose. Conflict of interest: J. Wanger has nothing to disclose., (Copyright ©ERS 2018.)

Asthma is a common disease, and although its clinical manifestations may be similar among patients, recent research discoveries have shown that it consists of several distinct clinical clusters or phenotypes, each with different underlying molecular pathways yielding different treatment responses. Based on these observations, an alternative approach - known as 'precision medicine' - has been proposed for the management of patients with severe asthma. Precision medicine advocates identification of treatable traits, linking them to therapeutic approaches targeting genetic, immunological, environmental, and/or lifestyle factors in individual patients. The main "goal" of this personalised approach is to enable choosing a treatment which will be more likely to produce a beneficial response in the individual patient rather than a 'one size fits all' approach. The aim of the present review is to discuss different ways of phenotyping asthma and to provide a rationale for treatment algorithms based on principles of precision medicine., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In recent years, it has become increasingly important to get as much as possible information on clinical efficacy already in the early phases of drug development. For proof of concept (POC) studies testing novel anti-inflammatory drugs in asthma, there are several validated exacerbation models, inducing various aspects of the airway inflammation and airway responsiveness. The choice of the appropriate asthma model depends on the drug's targets within the inflammatory process. For adequate assessment of the drug's anti-inflammatory potential, it is crucial to choose adequate (surrogate) biomarkers. Ideally, these should include measures of airway response, central and peripheral airway inflammation and airway hyperresponsiveness. Overall, there are validated non-invasive sampling techniques for the measurement of inflammatory markers in asthma that can be applied as outcome parameters in early clinical trials. If adequately implemented, these measurements can provide early indication of proof of pharmacological and potential therapeutic efficacy-even in first administration to humans.

In this review, we aim to lead the readers through the historical highlights of pathophysiological concepts and treatment of asthma. Understanding the nature and links of asthma has modeled our diagnostic, pathophysiological and therapeutic thinking and acting. The recognition of its heterogeneous nature in combination with several refined and sophisticated technologies will mark a new era of phenotype-specific approach and treatment of asthma.

Rationale: The tachykinins substance P and neurokinin A (NKA) are implicated in the pathophysiology of asthma., Objective: We tested the safety, tolerability, and pharmacologic and biological efficacy of a tachykinin NK(1)/NK(2) receptor antagonist, AVE5883, in patients with asthma in two double-blind, placebo-controlled crossover studies., Methods: The pharmacologic efficacy of a single inhaled dose (4.8 mg) of AVE5883 was tested against inhaled NKA in 20 patients with asthma. Subsequently, we studied the biological efficacy of the pharmacologically effective dose on inhaled allergen in a multiple-dose trial (4.8 mg three times per day, 9 d) in 12 patients with asthma with dual responses to inhaled house dust mite. On Day 8, an allergen challenge was conducted, and airway response was measured by FEV(1) until 9 hours postallergen. Exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and induced sputum were performed on Days 1, 7, and 9., Results: AVE5883 had a bad taste, and transient bronchospasm occurred in some subjects. A single inhaled dose shifted the dose response to NKA by 1.2 doubling doses. Pretreatment with multiple doses of AVE5883 enhanced the allergen-induced early and late airway responses. There were no significant differences in the allergen-induced changes in exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and sputum cell differentials between placebo and AVE5883., Conclusions: Despite its demonstrated pharmacologic activity against inhaled NKA, multiple doses of AVE5883 increased the allergen-induced airway responses without affecting markers of airway hyperresponsiveness and airway inflammation. Our data question the prominent role of neurogenic inflammation in asthma and, consequently, the therapeutic potential of dual tachykinin antagonists.

Asthma is a chronic disorder, characterized by airway hyperresponsiveness (AHR), airway inflammation and airway remodelling. Evidence has been provided for a relationship between pathophysiology, airway inflammation and remodelling. Moreover, these asthma features have been shown to respond to anti-inflammatory therapy. According to current guidelines, monitoring of asthma is predominantly based on symptoms and lung function data. However, these parameters appeared as poor indices for asthma control. Alternatively, asthma control relates well to exacerbations and (anamnestic) surrogate biomarkers of airway inflammation. Hence, appropriate treatment of asthma should primarily target the airway inflammation. According to current guidelines for asthma management, anti-inflammatory therapy with inhaled corticosteroids (ICS) is the cornerstone in the treatment of persistent asthma. To further optimize asthma control, add-on therapy with long-acting beta2-agonists (LABA) or leukotriene receptor antagonists (LTRA) should be combined with low to high doses of ICS. While the first combination focuses on optimal control of symptoms and lung function, the second provides a more complete suppression of the airway inflammation. In this paper we discuss treatment of asthma according to current guidelines versus new insights, addressing practical issues.

Background: The fractional exhaled nitric oxide (FENO) test is a point-of-care test that is used in the assessment of asthma. Objective: To provide evidence-based clinical guidance on whether FENO testing is indicated to optimize asthma treatment in patients with asthma in whom treatment is being considered. Methods: An international, multidisciplinary panel of experts was convened to form a consensus document regarding a single question relevant to the use of FENO. The question was selected from three potential questions based on the greatest perceived impact on clinical practice and the unmet need for evidence-based answers related to this question. The panel performed systematic reviews of published randomized controlled trials between 2004 and 2019 and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework to develop recommendations. All panel members evaluated and approved the recommendations. Main Results: After considering the overall low quality of the evidence, the panel made a conditional recommendation for FENO-based care. In patients with asthma in whom treatment is being considered, we suggest that FENO is beneficial and should be used in addition to usual care. This judgment is based on a balance of effects that probably favors the intervention; the moderate costs and availability of resources, which probably favors the intervention; and the perceived acceptability and feasibility of the intervention in daily practice. Conclusions: Clinicians should consider this recommendation to measure FENO in patients with asthma in whom treatment is being considered based on current best available evidence.