Search

Background: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) Working Group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies., Methods: COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult and paediatric clinicians, pharmaceutical representatives, and health regulators from across Europe. Evidence included a systematic review of development, validity and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients' and carers' views about outcome measures. It was discussed using a modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria., Results: Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV 1 ) as z-scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire and Asthma Control Test or Childhood Asthma Control Test, while the adult COM set includes the Severe Asthma Questionnaire and Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately)., Conclusions: This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma., Competing Interests: Conflict of interest: E. Khaleva and A. Rattu declare funding from 3TR European Union Innovative Medicines Initiative 2 to their institution for the present manuscript. C. Brightling declares grants from GlaxoSmithKline, AstraZeneca, Novartis, Chiesi, Boehringer Ingelheim, Genentech, Roche, Sanofi, Mologic and 4DPharma; consulting fees from GlaxoSmithKline, AstraZeneca, Novartis, Chiesi, Boehringer Ingelheim, Genentech, Roche, Sanofi, Mologic, 4DPharma and Teva; and support from the 3TR project. G.W. Clarke declares that he is an employee of AstraZeneca; and that he holds stock or stock options in AstraZeneca. M. van den Berge declares grants from GlaxoSmithKline, AstraZeneca, Roche, Genentech and Novartis paid to the university. A. Bossios declares honoraria for lectures from GlaxoSmithKline, AstraZeneca, Teva and Novartis; support for attending meetings from AstraZeneca and Novartis; honoraria for advisory board meetings from GlaxoSmithKline, AstraZeneca, Teva, Novartis and Sanofi; being a member of the Steering Committee of SHARP, Secretary of Assembly 5 (Airway Diseases, Asthma, COPD and Chronic Cough) of the European Respiratory Society; Vice-chair of the Nordic Severe Asthma Network (NSAN). V. Ramiconi and S. Romagosa Vilarnau declare unrestricted educational grants paid to the organisation from Novartis, Pfizer, AstraZeneca, Chiesi Farmaceutici, GlaxoSmithKline, AbbVie, LeoPharma, Boehringer Ingelheim, Sanofi, Regeneron, OM Pharma, MSD, Roche and DBV Technologies; support for attending meetings from Novartis. S-E. Dahlén declares a 3TR Innovative Medicines Initiative grant; consulting fees for AstraZeneca, Cayman Co., GlaxoSmithKline, Novartis, Regeneron, Sanofi and Teva; payment for lectures from AstraZeneca and Sanofi. S. Principe declares support for provision of study materials and medical writing. G. Hedlin declares participation in advisory boards of AstraZeneca and Sanofi. F. Singer reports grants from Lung League Bern, grants from the Swiss Cystic Fibrosis Society (CFCH), personal fees from Vertex Pharmaceuticals, personal fees from Novartis, outside the submitted work. A. Deschildre reports personal consulting fees from Sanofi-Regeneron, ALK, Novartis and GlaxoSmithKline; honoraria for lectures from ALK, Boehringer Ingelheim and Novartis; support for attending meetings from AstraZeneca, Stallergènes-Greer, MEDA, Nutricia, Sanofi and Novartis, outside the submitted work; and being on the scientific committee of SFA (Société Française d'Allergologie). L.J. Fleming declares participation in advisory boards and honoraria for lectures from Sanofi, Respiri UK, AstraZeneca, Novartis and Teva, outside of the scope of this publication; all payments were made to her institution. H. Staudinger reports that he is a salaried employee of Sanofi Genzyme and owns company stock of Sanofi and Merck & Co. K.C. Pike declares consultancy fees from Novartis, Adherium and Respiri, and honoraria for a lecture from Novartis. J. Grigg declares payments from GlaxoSmithKline, OM Pharma, Omron and Novartis (advisory boards), Sanofi (for lectures) and AstraZeneca (CI clinical trial). N. Rutjes reports personal fees for advisory board work from Sanofi. G.H. Koppelman reports receiving research grants from the Lung Foundation of the Netherlands, Ubbo Emmius Foundation, H2020 European Union, Teva, GlaxoSmithKline and Vertex, outside this work (money to institution); he reports memberships of advisory boards to GlaxoSmithKline and PURE-IMS, outside this work (money to institution). D. Cunoosamy holds shares in AstraZeneca and Sanofi. A.H. Maitland-van der Zee has received research grants outside the submitted work from GlaxoSmithKline, Boehringer Ingelheim and Vertex, she is the PI of a P4O2 (Precision Medicine for more Oxygen) public private partnership sponsored by Health Holland involving many private partners that contribute in cash and/or in kind (Boehringer Ingelheim, Breathomix, Fluidda, Ortec Logiqcare, Philips, Quantib-U, Roche, Smartfish, SODAQ, Thirona, TopMD and Novartis), and she has served in advisory boards for AstraZeneca, GlaxoSmithKline and Boehringer Ingelheim with money paid to her institution. K.F. Chung has received honoraria for participating in advisory board meetings of GlaxoSmithKline, AstraZeneca, Roche, Novartis, Merck and Shionogi, regarding treatments for asthma, COPD and chronic cough, and has also been remunerated for speaking engagements for Novartis and AstraZeneca; received a MRC grant on Precision Medicine for severe asthma, EPSRC grant on air pollution and asthma, and a GlaxoSmithKline grant on mepolizumab and eosinophils in asthma. P. Nagakumar received speaker fees for talks on severe asthma from GlaxoSmithKline and Novartis. G. Brusselle declares payments from AstraZeneca, Novartis, Boehringer Ingelheim, Chiesi, Sanofi, GlaxoSmithKline and MSD, outside the submitted work. E. Hamelmann declares support from the German Ministry of Education and Research (BMBF) and German Asthma Net (GAN) eV; funding for research in severe asthma in children (CHAMP-01GL1742D) and for Severe Asthma Register. S. Vijverberg is PI of the PERMEABLE consortium. The PERMEABLE consortium is a research consortium focused on severe asthma and allergy and supported by ZonMW (456008004), the Swedish Research Council (2018-05619), the Ministry of Education, Science and Sport of the Republic of Slovenia (C3330-19-252012), and the German Ministry of Education and Research (BMBF) FKZ01KU1909A), under the frame of the ERA PerMed JTC 2018 Call. In addition, S. Vijverberg has received research funding for a project on severe paediatric asthma from the Lung Foundation Netherlands (6.2.18.244JO). A-M.M. Schoos has participated on an advisory board for ALK. B. Dahlén reports personal fees for lectures from AstraZeneca, Novartis and Sanofi; and grants from Novartis and GlaxoSmithKline, outside the submitted work; participation on an advisory board for AstraZeneca and Sanofi. A. Exley declares being a minority shareholder in GlaxoSmithKline Plc. E.A. Gaillard reports consultancy work for Boehringer Ingelheim with money paid to the institution (University of Leicester); investigator-led research grants from Circassia Group, Gilead Sciences, Chiesi Limited and Propeller Health; and has a research collaboration with Medimmune. M. Pijnenburg declares payments to her institution from Sanofi Genzyme (advisory work) and Novartis (speakers fee). E. Melén declares consulting fees from AstraZeneca, Chiesi, Novartis and Sanofi, outside the submitted work. R. Chaudhuri has received lecture fees from GlaxoSmithKline, AstraZeneca, Teva, Chiesi, Sanofi and Novartis; honoraria for advisory board meetings from GlaxoSmithKline, AstraZeneca, Teva, Chiesi and Novartis; sponsorship to attend international scientific meetings from Chiesi, Napp, Sanofi and GlaxoSmithKline, and a research grant to her institute from AstraZeneca for a UK multi-centre study. C. Pilette declares grants, consulting fees and honoraria for lectures (paid to institution) from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, Mundipharma, Teva, Sanofi and ALK. C. Porsbjerg declares grants (paid to institution), consulting fees (paid to institution and personal honoraria) and honoraria for lectures (paid to institution and personal honoraria) from AstraZeneca, GlaxoSmithKline, Novartis, Teva, Sanofi, Chiesi and ALK; participation on an advisory board (paid to institution and personal honoraria) for AstraZeneca, Novartis, Teva, Sanofi and ALK. C. Coleman and C. Williams declare funding received to support this work by the European Lung Foundation (ELF) from the European Commission's Innovative Medicines Initiative 2 Joint Undertaking under grant agreement number 831434 (3TR), and are employees of the ELF. B. Ahrens, S. Kaul, D. Hartenstein and V. Mahler declare no conflict of interest for this article and state that the views expressed in this review are the personal views of the author and may not be understood or quoted as being made on behalf of or reflecting the position of the respective national competent authorities, the European Medicines Agency or one of its committees or working parties. L.G. Heaney declares support from the 3TR; grants from industrial pharma partners Amgen, AstraZeneca, Medimmune, Janssen, Novartis, Roche/Genentech, GlaxoSmithKline and Boehringer Ingelheim; project grant funding from Medimmune, Novartis UK, Roche/Genentech and GlaxoSmithKline, outside the submitted work; payments for lectures by AstraZeneca, Novartis, Roche/Genentech, GlaxoSmithKline, Chiesi and Teva, outside the submitted work; travel funding support to international respiratory meetings by AstraZeneca, Chiesi, Novartis, Boehringer Ingelheim, Teva and GlaxoSmithKline, outside the submitted work; advisory boards for AstraZeneca, Novartis, GlaxoSmithKline, Chiesi, Teva, Theravance and Vectura, outside the submitted work. R. Djukanovic declares funding from the European Respiratory Society, Teva, GlaxoSmithKline, Novartis, Sanofi and Chiesi for the SHARP Clinical Research Collaboration; consulting fees for Synairgen; honorarium for a lecture from GlaxoSmithKline; participation on a data safety monitoring board or advisory board for Kymab (Cambridge) and shares in Synairgen outside of the submitted work. A. Bourdin declares grants from Boehringer and AstraZeneca; consulting fees and payments from Boehringer, AstraZeneca, GlaxoSmithKline, Novartis, Chiesi, Regeneron, Sanofi and Amgen outside of the submitted work. B. Karadag declares participation in a trial conducted by Sanofi (payment to institution) and attending advisory board meetings for GlaxoSmithKline (personal fees). K. Blumchen declares grants from Aimmune Therapeutics, DBV Technologies and Hipp GmbH; consulting fees from Aimmune Therapeutics, DBV Technologies and Allergy Therapeutics; payments for lectures from Aimmune Therapeutics, DBV Technologies, Novartis, Allergy Therapeutics, HAL, ALK, Allergopharma, Nutricia, Thermo Fisher Scientific, and Bausch and Lomb; personal fees for expert discussions from Novartis and Nestle; fees for attending meetings from Aimmune Therapeutics and DBV Technologies; being on data safety monitoring board of Charité, IIT. A. Gupta received speaker/advisory board fees from GlaxoSmithKline, Novartis, AstraZeneca and Boehringer Ingelheim; received research grants from GlaxoSmithKline, Novartis, AstraZeneca and Boehringer Ingelheim, paid to institution. L. Giovannini-Chami declares consulting fees from ALK, AstraZeneca and Novartis; honoraria for lectures, presentations from Novartis, ALK, Stallergènes, Sanofi and AstraZeneca; support for attending meetings from Stallergènes; participation on a data safety monitoring board or advisory board for Sanofi; being head of the Scientific Committee of the French Pediatric Pulmonology and Allergology Society. C.S. Murray has received lecture fees from GlaxoSmithKline and Novartis; received grants from Asthma UK and National Institute for Health Research; and has participated on an advisory board for Boehringer Ingelheim. G. Roberts declares European Union Innovative Medicines Initiative funding and AstraZeneca paid to the institution. Other co-authors declare no conflicts of interest for this article., (Copyright ©The authors 2023.)

Background: Valid outcome measures are imperative to evaluate treatment response, yet the suitability of existing end-points for severe asthma is unclear. This review aimed to identify outcome measures for severe asthma and appraise the quality of their measurement properties., Methods: A literature search was performed to identify "candidate" outcome measures published between 2018 and 2020. A modified Delphi exercise was conducted to select "key" outcome measures within healthcare professional, patient, pharmaceutical and regulatory stakeholder groups. Initial validation studies for "key" measures were rated against modified quality criteria from COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). The evidence was discussed at multi-stakeholder meetings to ratify "priority" outcome measures. Subsequently, four bibliographic databases were searched from inception to 20 July 2020 to identify development and validation studies for these end-points. Two reviewers screened records, extracted data, assessed their methodological quality and graded the evidence according to COSMIN., Results: 96 outcome measures were identified as "candidates", 55 as "key" and 24 as "priority" for severe asthma, including clinical, healthcare utilisation, quality of life, asthma control and composite. 32 studies reported measurement properties of 17 "priority" end-points from the latter three domains. Only the Severe Asthma Questionnaire and Childhood Asthma Control Test were developed with input from severe asthma patients. The certainty of evidence was "low" to "very low" for most "priority" end-points across all measurement properties and none fulfilled all quality standards., Conclusions: Only two outcome measures had robust developmental data for severe asthma. This review informed development of core outcome measures sets for severe asthma., Competing Interests: Conflict of interest: A. Rattu and E. Khaleva declare funding from the European Commission's Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement number 831434 (3TR) for this manuscript. C. Brightling declares grants from GlaxoSmithKline, AstraZeneca, Novartis, Chiesi, Boehringer Ingelheim, Genentech, Roche, Sanofi, Mologic and 4DPharma, consulting fees from GlaxoSmithKline, AstraZeneca, Novartis, Chiesi, Boehringer Ingelheim, Genentech, Roche, Sanofi, Mologic, 4DPharma and Teva, and support from the 3TR project. S-E. Dahlén declares a 3TR IMI grant, consulting fees from AstraZeneca, Cayman Co., GlaxoSmithKline, Novartis, Regeneron, Sanofi and Teva, and payment for lectures from AstraZeneca and Sanofi. A. Bossios declares honoraria for lectures from GlaxoSmithKline, AstraZeneca, Teva and Novartis, support for attending meetings from AstraZeneca and Novartis, honoraria for advisory board meetings from GlaxoSmithKline, AstraZeneca, Teva, Novartis and Sanofi, and being a member of the Steering Committee of SHARP, Secretary of Assembly 5 (Airway Diseases, Asthma, COPD and Chronic Cough) of the European Respiratory Society, and Vice-chair of the Nordic Severe Asthma Network (NSAN). L. Fleming declares participation in advisory boards and honoraria for lectures from Sanofi, Respiri UK, AstraZeneca, Novartis and Teva, outside the submitted work; all payments were made to her institution. K.F. Chung has received honoraria for participating in advisory board meetings of GlaxoSmithKline, AstraZeneca, Roche, Novartis, Merck and Shionogi regarding treatments for asthma, COPD and chronic cough, and has also been remunerated for speaking engagements for Novartis and AstraZeneca; has received an MRC grant on precision medicine for severe asthma, an EPSRC grant on air pollution and asthma, and a GlaxoSmithKline grant on mepolizumab and eosinophils in asthma. E. Melén declares consulting fees from AstraZeneca, Chiesi, Novartis and Sanofi, outside the submitted work. R. Chaudhuri has received lecture fees from GlaxoSmithKline, AstraZeneca, Teva, Chiesi, Sanofi and Novartis, honoraria for advisory board meetings from GlaxoSmithKline, AstraZeneca, Teva, Chiesi and Novartis, sponsorship to attend international scientific meetings from Chiesi, Napp, Sanofi and GlaxoSmithKline, and a research grant to her institute from AstraZeneca for a UK multicentre study. R. Djukanovic declares funding from the European Respiratory Society, Teva, GlaxoSmithKline, Novartis, Sanofi and Chiesi for the SHARP CRC, consulting fees for Synairgen, honorarium for a lecture from GlaxoSmithKline, participation on a data safety monitoring board or advisory board for Kymab (Cambridge), and shares in Synairgen, outside the submitted work. A. Exley declares being a minority shareholder in GlaxoSmithKline PLC. G.H. Koppelman reports receiving research grants from the Lung Foundation of the Netherlands, Ubbo Emmius Foundation, H2020 European Union, Teva, GlaxoSmithKline and Vertex, outside this work (money to institution); he reports memberships of advisory boards to GlaxoSmithKline and PURE-IMS, outside this work (money to institution). A. Bourdin declares unrestricted grants from AstraZeneca and Boehringer Ingelheim to his institute; consulting fees, honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, and support for attending meetings and travel from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis and Sanofi; participation on a data safety monitoring board or advisory board for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi and Abs science. C. Porsbjerg declares grants (paid to institution), consulting fees (paid to institution and personal honoraria) and honoraria for lectures (paid to institution and personal honoraria) from AstraZeneca, GlaxoSmithKline, Novartis, Teva, Sanofi, Chiesi and ALK; participation on an advisory board (paid to institution and personal honoraria) for AstraZeneca, Novartis, Teva, Sanofi and ALK. C. Coleman and C. Williams declare funding received to support this work by the European Lung Foundation (ELF) from the European Commission's Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement number 831434 (3TR), and are employees of the ELF. E. Davin bought and sold shares on the public market during 2021–2022 in Regeneron, Roche and ICON Plc, and declares no current holdings. P. Taverner declares honorarium for being a lay member of Asthma and Lung UK's research funding panel, and chairing a Patient and Community Oversight Group for two NIHR health protection research units on environmental and chemical hazards; and payment for chairing a NICE guideline committee on advocacy services. S. Romagosa Vilarnau declares unrestricted educational grants paid to the organisation from Novartis, Pfizer, AstraZeneca, Chiesi Farmaceutici, GlaxoSmithKline, AbbVie, LeoPharma, Boehringer Ingelheim, Sanofi, Regeneron, OM Pharma, MSD, Roche and DBV Technologies. G. Roberts declares EU IMI funding and consulting fees from AstraZeneca paid to his institution. No other author has any conflict of interest to declare., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Risk stratification and assessment of disease progression in patients with pulmonary arterial hypertension (PAH) are challenged by the lack of accurate disease-specific and prognostic biomarkers. To date, brain natriuretic peptide (BNP) and/or its N-terminal fragment (NT-proBNP) are the only markers for right ventricular dysfunction used in clinical practice, in association with echocardiographic and invasive haemodynamic variables to predict outcome in patients with PAH., Methods: This study was designed to identify an easily measurable biomarker panel in the serum of 80 well-phenotyped PAH patients with idiopathic, heritable or drug-induced PAH at baseline and at first follow-up. The prognostic value of identified cytokines of interest was secondly analysed in an external validation cohort of 125 PAH patients., Results: Among the 20 biomarkers studied with the multiplex Ella platform, we identified a three-biomarker panel composed of β-NGF, CXCL9 and TRAIL that were independently associated with prognosis both at the time of PAH diagnosis and at the first follow-up after initiation of PAH therapy. β-NGF and CXCL9 were predictors of death or transplantation, whereas high levels of TRAIL were associated with a better prognosis. Furthermore, the prognostic value of the three cytokines was more powerful for predicting survival than usual non-invasive variables (New York Heart Association Functional Class, 6-min walk distance and BNP/NT-proBNP). The results were validated in a fully independent external validation cohort., Conclusion: The monitoring of β-NGF, CXCL9 and TRAIL levels in serum should be considered in the management and treatment of patients with PAH to objectively guide therapeutic options., Competing Interests: Conflict of interest: A. Boucly reports grants from Acceleron, Janssen and MSD, lecture honoraria from Janssen and Merck, and travel support from Janssen, outside the submitted work. C. Guignabert reports grants from Acceleron, Janssen, Merck and ShouTi, and lecture honoraria from Merck, outside the submitted work. C. Rhodes reports support for the present manuscript from BHF fellowship (FS/15/59/31839), Academy of Medical Sciences Springboard fellowship (SBF004\1095); consulting fees from United Therapeutics and Janssen, travel support from United Therapeutics, a patent submitted for prognostic protein model from Imperial Innovations, and advisory board participation with United Therapeutics and Janssen, outside the submitted work. P. De Groote reports consulting fees and lecture honoraria from Janssen, outside the submitted work. G. Prévot reports lecture honoraria from Boehringer Ingelheim, Sanofi and Jansen, and travel support from Boehringer Ingelheim, outside the submitted work. E. Bergot reports lecture honoraria and travel support from Janssen, Actelion and GSK, outside the submitted work. A. Bourdin reports grants from AstraZeneca and Boehringer Ingelheim, consulting fees, lecture honoraria and travel support from AstraZeneca, GSK, Novartis, Sanofi Regeneron, Boehringer Ingelheim and Chiesi, and advisory board participation with AB Science; outside the submitted work. A. Beurnier reports lecture honoraria and travel support from Sanofi, outside the submitted work. X. Jaïs reports grants from Acceleron, Janssen and MSD, lecture honoraria from Janssen and MSD, and travel support from Janssen, outside the submitted work. D. Montani reports grants from Acceleron, Janssen and Merck, consulting fees from Acceleron, and lecture honoraria from Bayer, Janssen and Merck, outside the submitted work. M.R. Wilkins reports support for the current manuscript from the British Heart Foundation and National Institute for Health Research; outside the submitted work, consulting fees from MorphogenIX, Actelion and Novartis, a patent under consideration on “Biomarker panel for pulmonary hypertension based on blood biomarkers”, and participation on advisory boards with Acceleron and GSK. M. Humbert reports support for the current manuscript from Programme Hospitalier de Recherche Clinique of the French Ministry of Health (PHRC EFORT) and ANR-15-RHUS-0002 (RHU BIOART-LUNG 2020); outside the submitted work, grants and consulting fees from Acceleron, Janssen and Merck, lecture honoraria from Janssen and Merck, and advisory board participation for Acceleron, Janssen, Merck and United Therapeutics. O. Sitbon reports grants from Acceleron, Janssen, GSK and MSD, consulting fees from Gossamer Bio, Janssen and MSD, lecture honoraria from AOP Orphan, Janssen, Ferrer and MSD, and advisory board participation for Acceleron, Janssen, MSD and Ferrer, outside the submitted work. L. Savale reports grants from Acceleron, Janssen and Merck, and lecture honoraria from GSK and Janssen, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Introduction: Contemporary risk assessment tools categorise patients with pulmonary arterial hypertension (PAH) as low, intermediate or high risk. A minority of patients achieve low risk status with most remaining intermediate risk. Our aim was to validate a four-stratum risk assessment approach categorising patients as low, intermediate-low, intermediate-high or high risk, as proposed by the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) investigators., Methods: We evaluated incident patients from the French PAH Registry and applied a four-stratum risk method at baseline and at first reassessment. We applied refined cut-points for three variables: World Health Organization functional class, 6-min walk distance and N-terminal pro-brain natriuretic peptide. We used Kaplan-Meier survival analyses and Cox proportional hazards regression to assess survival according to three-stratum and four-stratum risk approaches., Results: At baseline (n=2879), the four-stratum approach identified four distinct risk groups and performed slightly better than a three-stratum method for predicting mortality. Four-stratum model discrimination was significantly higher than the three-stratum method when applied during follow-up and refined risk categories among subgroups with idiopathic PAH, connective tissue disease-associated PAH, congenital heart disease and portopulmonary hypertension. Using the four-stratum approach, 53% of patients changed risk category from baseline compared to 39% of patients when applying the three-stratum approach. Those who achieved or maintained a low risk status had the best survival, whereas there were more nuanced differences in survival for patients who were intermediate-low and intermediate-high risk., Conclusions: The four-stratum risk assessment method refined risk prediction, especially within the intermediate risk category of patients, performed better at predicting survival and was more sensitive to change than the three-stratum approach., Competing Interests: Conflict of interest: A. Boucly reports personal fees from Actelion, Bayer and Merck, outside the submitted work. Conflict of interest: J. Weatherald reports grants, personal fees and non-financial support from Janssen Inc., grants, personal fees and non-financial support from Actelion, personal fees and non-financial support from Bayer, personal fees from Novartis, outside the submitted work. Conflict of interest: L. Savale reports personal fees from Actelion, personal fees from MSD, grants and personal fees from GSK, outside the submitted work. Conflict of interest: P. de Groote reports consulting fees from Actelion, Janssen, MSD, Novartis, Servier, Boehringer Ingelheim, Abbott, Boston, AstraZeneca, Bayer; lecture honoraria from Abbott, Vifor, MSD, Servier, Novartis, AstraZeneca, Actelion, Janssen, Medtronic; outside the submitted work. Conflict of interest: V. Cottin reports advisory board fees and non-financial support from Actelion, advisory board fees from Bayer/MSD, outside the submitted work. Conflict of interest: G. Prévot reports personal fees from Actelion and GSK, outside the submitted work. Conflict of interest: A. Chaouat reports consulting fees from GSK, Actelion and Bayer, outside the submitted work. Conflict of interest: F. Picard has nothing to disclose. Conflict of interest: D. Horeau-Langlard reports grants from Acceleron, outside the submitted work. Conflict of interest: A. Bourdin reports grants from AstraZeneca and Boehringer Ingelheim; consulting fees from AstraZeneca, GSK, Novartis, Boehringer Ingelheim, Chiesi, Sanofi Regeneron, Amgen; lecture honoraria from AstraZeneca, GSK, Novartis, Boehringer Ingelheim, Chiesi, Sanofi Regeneron, Roche; travel support from Boehringer Ingelheim, Chiesi, Sanofi Regeneron, AstraZeneca, GSK, Roche; participation on advisory boards at AB science, AstraZeneca, GSK, Sanofi Regeneron, Novartis, Acceleron; and acted as investigator in clinical trials for Vertex, Abbvie, Galapagos, Fibrogen, Nuvaira, PulmonX, Gossamer, Acceleron; outside the submitted work. Conflict of interest: E-M. Jutant has nothing to disclose. Conflict of interest: A. Beurnier has nothing to disclose. Conflict of interest: M. Jevnikar has nothing to disclose. Conflict of interest: X. Jais reports grants from Bayer, Janssen and Merck; lecture honoraria from Janssen and Merck; outside the submitted work. Conflict of interest: G. Simonneau reports grants and personal fees from Janssen (formerly Actelion), Bayer and MSD; personal fees from Acceleron, outside the submitted work. Conflict of interest: D. Montani reports grants from Acceleron, Janssen and Merck; steering committee fees from Acceleron; lecture honoraria from Bayer, Janssen and Merck; outside the submitted work. Conflict of interest: O. Sitbon reports grants from Acceleron, Janssen, GSK and MSD; steering committee fees from Gossamer Bio, Janssen and MSD; lecture honoraria from AOP Orphan, Janssen, Ferrer and MSD; advisory board participation at Acceleron, Janssen and MSD; outside the submitted work. Conflict of interest: M. Humbert reports grants, steering committee consulting fees, and advisory board participation from Acceleron, Janssen and Merck; lecture honoraria from AOP, Janssen and Merck; steering committee participation at United Therapeutics; outside the submitted work., (Copyright ©The authors 2022.)

Background: In allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission., Methods: We performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time to first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters., Results: Among 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) out of 65 patients in the nebulised liposomal amphotericin-B group and 38 (51.3%) out of 74 in the placebo group (absolute difference -0.6%, 95% CI -16.8- +15.6%; OR 0.98, 95% CI 0.50-1.90; p=0.95). The median (interquartile range) time to first severe clinical exacerbation was longer in the liposomal amphotericin-B group: 337 days (168-476 days) versus 177 days (64-288 days). At the end of maintenance therapy, total immunoglobulin-E and Aspergillus precipitins were significantly decreased in the nebulised liposomal amphotericin-B group., Conclusions: In ABPA, maintenance therapy using nebulised liposomal amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research., Competing Interests: Conflict of interest: C. Godet reports having received speaker fees, travel support from Pfizer, MSD; fees for board memberships from SOS Oxygène and Pulmatrix; grant support from Ohre Pharma, Pfizer, MSD, SOS Oxygène, ISIS Medical and AstraZeneca. Conflict of interest: F. Couturaud reports having received research grant support from Bristol-Myers Squibb/Pfizer and fees for board memberships or symposia from Bayer, Bristol-Myers Squibb/Pfizer, Merck Sharp & Dohme and AstraZeneca, and having received travel support from Bayer, Bristol-Myers Squibb/Pfizer, Leo Pharma, Merck Sharp & Dohme and Actelion. Conflict of interest: S. Marchand-Adam reports having received consultancy for board membership, consultancy or speaker fees and travel support from AstraZeneca, Boehringer Ingelheim, Novartis and Roche. Conflict of interest: C. Pison reports having received, outside of the submitted work, consultancy for board membership, consultancy or speaker fees, travel support from AGIR à Dom, Chiesi, Boehringer Ingelheim, GSK, SOS Oxygène, AstraZeneca and Novartis. Conflict of interest: F. Gagnadoux reports having received grants and personal fees from Resmed; personal fees and non-financial support from Boehringer Ingelheim, Nyxoah, Sefam; personal fees from Actelion, Cidelec, Novartis, and non-financial support from Asten, unrelated to the submitted work. Conflict of interest: E. Blanchard reports having received consultancy or speaker fees, travel support from Pfizer, MSD, Novartis, Gilead, Roche, Boehringer Ingelheim, SOS Oxygene and ISIS Medical. Conflict of interest: C. Taillé reports having received consulting or advisory fees from Sanofi, GSK, AstraZeneca, Novartis and Chiesi, and research grants from Sanofi and GSK, outside the submitted work. Conflict of interest: B. Philippe reports having received speaker fees, travel support from Chiesi, Novartis and Oxyvie. Conflict of interest: S. Hirschi reports having received research grant support from CSL Behring and Adiral, and fees for board membership from Boehringer Ingelheim and Roche. Conflict of interest: C. Andréjak reports having received fees for board memberships or symposia and travel support from GSK, AstraZeneca, Zambon and Insmed. Conflict of interest: A. Bourdin reports having received grants from AstraZeneca, Boehringer Ingelheim, Cephalon/TEVA, GlaxoSmithKline, Novartis and Sanofi-Regeneron; has provided consultancy for Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, MedinCell, Merck, Novartis, Roche and Sanofi-Regeneron; and has acted as an investigator or co-investigator for trials sponsored by Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi, Galapagos, GlaxoSmithKline, Merck, Novartis, Roche, Sanofi-Regeneron and Vertex. Conflict of interest: C. Chenivesse reports having received grants from AstraZeneca and Santelys outside the submitted work, personal fees from ALK-Abello, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKlein, Novartis, Sanofi-Regeneron and TEVA outside the submitted work and congress support from ALK-Abello, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pierre Fabre, Pfizer, Roche and TEVA. Conflict of interest: S. Dominique reports having received consultancy for board membership, speaker fees, travel support from Roche, Chiesi, Boehringer Ingelheim, AstraZeneca, Novartis and Actelion, outside the submitted work. Conflict of interest: L. Bassinet has nothing to disclose. Conflict of interest: M. Murris-Espin reports having received consultancy for board membership or speaker fees, or travel support, from Insmed, MSD, Pfizer, Asten, LVL, Vertex, Vivisol and Zambon. Conflict of interest: F. Rivière reports having received consultancy fees from Roche and Boehringer Ingelheim. Conflict of interest: G. Garcia reports having received grants from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi-Regeneron and Chiesi; has provided consultancy for AstraZeneca, GlaxoSmithKline, Novartis and Sanofi-Regeneron; and has acted as an investigator or co-investigator for trials sponsored by AstraZeneca, GlaxoSmithKline and Sanofi-Regeneron. Conflict of interest: D. Caillaud reports having received consultancy or speaker fees, travel support from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Menarini and Novartis. Conflict of interest: F-X. Blanc has nothing to disclose. Conflict of interest: F. Goupil reports having received travel support from Aliseo/Asten Santé, GSK, Chiesi, Novartis and Actelion. Conflict of interest: A. Bergeron reports having received consultancy or speaker fees, from Pfizer, Gilead, MSD, AstraZeneca and Takeda, and grants from SOS Oxygene. Conflict of interest: A. Gondouin reports having received consultancy or speaker fees, or travel support from Roche, Boehringer Ingelheim, Vitalaire, Actelion, LFB, GSK and Pfizer. Conflict of interest: J-P. Frat reports having received grants from the French Ministry of Health, outside the submitted work; grants, personal fees and non-financial support from Fisher & Paykel HealthCare, outside the submitted work; personal fees and non-financial support from SOS Oxygène, outside the submitted work. Conflict of interest: T. Flament has nothing to disclose. Conflict of interest: B. Camara reports having received outside of the submitted work, consultancy for speaker fees, travel supports from AGIR à Dom. Conflict of interest: P. Priou received travel support from Asten Santé. Conflict of interest: A-L. Brun has nothing to disclose. Conflict of interest: F. Laurent reports having received consultancy for board membership, consultancy or speaker fees, travel support from Bayer, Roche, Chiesi, Boehringer Ingelheim, SOS Oxygène, AstraZeneca, Basilea, Novartis and Actelion. Conflict of interest: S. Ragot has nothing to disclose. Conflict of interest: J. Cadranel reports having received speaker fees from MSD and Pfizer., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Heritable forms of pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis (PVOD/PCH) diverge by lung histopathological lesions, clinical and para-clinical presentation, their responsible genes, and mode of transmission. Since the identification of the BMPR2 gene in families affected by PAH, mutations in several other genes have been discovered for both forms. The mutation landscape in these new genes is not yet well known., Methods: We set up a next-generation sequencing-based targeted sequencing gene panel allowing known genes for PAH and PVOD/PCH to be analysed simultaneously . Genetic analysis was prospectively performed on 263 PAH and PVOD/PCH patients (adult and paediatric cases)., Results: Pathogenic mutations were identified in 19.5% of sporadic PAH patients (n=180), 54.5% of familial PAH patients and 13.3% of PVOD/PCH patients. BMPR2 was the most frequently mutated gene, followed by TBX4 in both paediatric and adult PAH. BMP9 mutations were identified in 1.2% of adult PAH cases. EIF2AK4 biallelic mutations were restricted to PVOD/PCH. A truncating mutation and a predicted loss-of-function variant were also identified in BMP10 in two severely affected sporadic PAH female patients., Conclusion: Our results confirm that mutations are found in genes beyond BMPR2 in heritable PAH, emphasise the role of TBX4 and BMP9 , and designate BMP10 as a new PAH gene., Competing Interests: Conflict of interest: M. Eyries reports personal fees from Roche Diagnostics France, during the conduct of the study. Conflict of interest: D. Montani reports personal fees from Actelion, GSK, MSD and Pfizer, outside the submitted work. Conflict of interest: S. Nadaud has nothing to disclose. Conflict of interest: B. Girerd has nothing to disclose. Conflict of interest: M. Levy has nothing to disclose. Conflict of interest: A. Bourdin reports grants, personal fees for speaking and nonfinancial support from GSK, grants, personal fees for speaking and advisory board work, and nonfinancial support from AstraZeneca and Boehringer Ingelheim, personal fees for speaking and advisory board work, and nonfinancial support from Novartis, grants from MSD, grants and personal fees for speaking from Actelion, and personal fees for speaking and nonfinancial support from Chiesi Farmaceuticals, outside the submitted work. Conflict of interest: R. Trésorier has nothing to disclose. Conflict of interest: A. Chaouat has nothing to disclose. Conflict of interest: V. Cottin reports personal fees for consultancy, lectures and travel to medical meetings from Actelion and Roche, personal fees for development of educational presentations, consultancy, lectures and travel to medical meetings from Boehringer Ingelheim, personal fees for consultancy from Bayer, personal fees for adjudication committee work from Gilead, personal fees for consultancy and travel to medical meetings from MSD, personal fees for consultancy and lectures from Novartis and Sanofi, institutional grants from Boehringer Ingelheim and Roche, personal fees for data and safety monitoring board work from Promedior and Celgene, and personal fees for consultancy and data and safety monitoring board work from Galapagos, outside the submitted work. Conflict of interest: C. Sanfiorenzo has nothing to disclose. Conflict of interest: G. Prevot has nothing to disclose. Conflict of interest: M. Reynaud-Gaubert has nothing to disclose. Conflict of interest: C. Dromer has nothing to disclose. Conflict of interest: A. Houeijeh has nothing to disclose. Conflict of interest: K. Nguyen has nothing to disclose. Conflict of interest: F. Coulet has nothing to disclose. Conflict of interest: D. Bonnet reports personal fees for advisory board work from Actelion Pharmaceuticals, Bayer Health Care and Novartis, outside the submitted work. Conflict of interest: M. Humbert reports personal fees from Actelion, Bayer, GSK, Johnson & Johnson, Merck and United Therapeutics, outside the submitted work. Conflict of interest: F. Soubrier has nothing to disclose., (Copyright ©ERS 2019.)