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Background: Pulmonary alveolar proteinosis (PAP) is a rare syndrome caused by several distinct diseases leading to progressive dyspnoea, hypoxaemia, risk of respiratory failure and early death due to accumulation of proteinaceous material in the lungs. Diagnostic strategies may include computed tomography (CT) of the lungs, bronchoalveolar lavage (BAL), evaluation of antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), genetic testing and, eventually, lung biopsy. The management options are focused on removing the proteinaceous material by whole lung lavage (WLL), augmentation therapy with GM-CSF, rituximab, plasmapheresis and lung transplantation. The presented diagnostic and management guidelines aim to provide guidance to physicians managing patients with PAP., Methods: A European Respiratory Society Task Force composed of clinicians, methodologists and patients with experience in PAP developed recommendations in accordance with the ERS Handbook for Clinical Practice Guidelines and the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach. This included a systematic review of the literature and application of the GRADE approach to assess the certainty of evidence and strength of recommendations. The Task Force formulated five PICO (Patients, Intervention, Comparison, Outcomes) questions and two narrative questions to develop specific evidence-based recommendations., Results: The Task Force developed recommendations for the five PICO questions. These included management of PAP with WLL, GM-CSF augmentation therapy, rituximab, plasmapheresis and lung transplantation. Also, the Task Force made recommendations regarding the use of GM-CSF antibody testing, diagnostic BAL and biopsy based on the narrative questions. In addition to the recommendations, the Task Force provided information on the hierarchy of diagnostic interventions and therapy., Conclusions: The diagnosis of PAP is based on CT and BAL cytology or lung histology, whereas the diagnosis of specific PAP-causing diseases requires GM-CSF antibody testing or genetic analysis. There are several therapies including WLL and augmentation therapy with GM-CSF available to treat PAP, but supporting evidence is still limited., Competing Interests: Conflict of interest: C. McCarthy, F. Bonella, B.C. Trapnell and M. Griese report membership of a scientific advisory board of Savara Inc. B.C. Trapnell reports grants from the NHLBI (HL085453) and Savara, consultancy fees from Savara, and support for attending meetings from Savara. T. Wang reports grants from Savara, consultancy fees from Partner Therapeutics and Savara, payment or honoraria for lectures, presentations, manuscript writing or educational events from Partner Therapeutics and Savara, support for attending meetings from the PAP Foundation, participation on a data safety monitoring board or advisory board with Partner Therapeutics and Savara Inc., and a leadership role with the PAP Foundation (Clinical Director and Vice President). C. McCarthy reports grants from Health Research Board, Ireland, Enterprise Ireland and The LAM Foundation, consultancy fees from Theravance Inc., Savara Inc. and AI Therapeutics, support for attending meetings from Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board with Savara Inc. F. Bonella reports consultancy fees from Boehringer Ingelheim, Sanofi, BMS and Savara Inc., payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim and Sanofi, support for attending meetings from Boehringer Ingelheim, AstraZeneca, Atyr and Savara Pharma, and participation on a data safety monitoring board or advisory board with Boehringer Ingelheim, Sanofi and BMS. M. Fally reports leadership roles with the European Respiratory Society (Member of the Clinical Practice Guidelines Methodology Network and Secretary of Assembly 10, Group 1) and Danish Medical Journal (Associate Editor). A. Hadchouel reports patent issued (PCT/EP2022/064179). S. Jouneau reports the following financial (or non-financial) interests: PI for IMPALA and IMPALA-2 studies (Savara Inc.). R. Borie reports honoraria from Boehringer Ingelheim, Sanofi and Ferrer, support for attending meetings from Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board with Savara. I. Campo reports consultancy fees from Partner's Therapeutics, and participation on a data safety monitoring board or advisory board with Savara. E. Manali reports grants from Savara, consulting fees from Boehringer Ingelheim, CLS Behring and Hoffman-La Roche, payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim, CLS Behring and Hoffman-La Roche, support for attending meetings from Boehringer Ingelheim, CLS Behring, Hoffman-La Roche and Elpen, and a leadership role with the European Respiratory Society (Chair in ERS Task Force for Transition of chILD). H. Prosch reports grants from Boehringer Ingelheim, AstraZeneca, Siemens Healthineers, the Christian Doppler Research Association and EU Commission (EU4Health, Horizon Europe Health), consultancy fees from Boehringer Ingelheim and Sanofi, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, BMS, Boehringer Ingelheim, Bracco, Daiichi Sankyo, Janssen, MSD, Novartis, Roche, Sanofi, Siemens Healthineers and Takeda, support for attending meetings from Boehringer Ingelheim, participation on a data safety monitoring board or advisory board with Boehringer Ingelheim, and a leadership role with the European Society of Thoracic Imaging (Vice President). M. Veltkamp reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim and Chiesi, and participation on a data safety monitoring board or advisory board with Boehringer Ingelheim and Xentria. E. Bendstrup reports honoraria from Boehringer Ingelheim, AstraZeneca and Daichii Sankyo, support for attending meetings from Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board with Boehringer Ingelheim and Simbec-Orion. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Idiopathic pulmonary fibrosis (IPF) with coexistent emphysema, termed combined pulmonary fibrosis and emphysema (CPFE) may associate with reduced forced vital capacity (FVC) declines compared to non-CPFE IPF patients. We examined associations between mortality and functional measures of disease progression in two IPF cohorts., Methods: Visual emphysema presence (>0% emphysema) scored on computed tomography identified CPFE patients (CPFE/non-CPFE: derivation cohort n=317/n=183, replication cohort n=358/n=152), who were subgrouped using 10% or 15% visual emphysema thresholds, and an unsupervised machine-learning model considering emphysema and interstitial lung disease extents. Baseline characteristics, 1-year relative FVC and diffusing capacity of the lung for carbon monoxide ( D LCO ) decline (linear mixed-effects models), and their associations with mortality (multivariable Cox regression models) were compared across non-CPFE and CPFE subgroups., Results: In both IPF cohorts, CPFE patients with ≥10% emphysema had a greater smoking history and lower baseline D LCO compared to CPFE patients with <10% emphysema. Using multivariable Cox regression analyses in patients with ≥10% emphysema, 1-year D LCO decline showed stronger mortality associations than 1-year FVC decline. Results were maintained in patients suitable for therapeutic IPF trials and in subjects subgrouped by ≥15% emphysema and using unsupervised machine learning. Importantly, the unsupervised machine-learning approach identified CPFE patients in whom FVC decline did not associate strongly with mortality. In non-CPFE IPF patients, 1-year FVC declines ≥5% and ≥10% showed strong mortality associations., Conclusion: When assessing disease progression in IPF, D LCO decline should be considered in patients with ≥10% emphysema and a ≥5% 1-year relative FVC decline threshold considered in non-CPFE IPF patients., Competing Interests: Conflict of interest: J. Jacob reports fees from Boehringer Ingelheim, Roche, NHSX, Takeda and GlaxoSmithKline, unrelated to the submitted work, and was supported by Wellcome Trust Clinical Research Career Development Fellowship 209553/Z/17/Z and the NIHR Biomedical Research Centre at University College London. N. Mogulkoc reports grant TUBITAK (EJP Rare Disease project “COCOS-IPF”), fees from Boehringer Ingelheim, Roche, and Nobel Turkey unrelated to the submitted work, and received support for travel to meetings from Roche and Actelion. T.J. Corte reports unrestricted educational grants from Boehringer Ingelheim, Roche, Biogen and Galapagos, fees from Roche, BMS, Boehringer Ingelheim, Vicore and DevPro, assistance for travel to meetings from Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board for Roche, BMS, Boehringer Ingelheim, Vicore, Ad Alta, Bridge Biotherapeutics and DevPro. P. Vasudev reports financial interests from Blackford Analysis. T. Goos is supported by Research Foundation Flanders (1S73921N). L.J. De Sadeleer is supported by Marie Sklodowska-Curie actions postdoctoral fellowship within the European Union's Horizon Europe research and innovation programme. H. Jo reports fees from Boehringer Ingelheim and Roche, and received assistance for travel to meetings from Boehringer Ingelheim and Roche. S. Verleden reports consultancy fees from Boehringer Ingelheim and Sanofi. M. Vermant is supported by an FWO (Research Flanders Foundation) fellowship. S.M. Janes reports fees from AstraZeneca, Bard1 Bioscience, Achilles Therapeutics and Jansen unrelated to the submitted work, received assistance for travel to meetings from AstraZeneca and Takeda, and is the investigator lead on grants from GRAIL Inc., GlaxoSmithKline plc and Owlstone. A.U. Wells reports personal fees and non-financial support from Boehringer Ingelheim, Bayer and Roche Pharmaceuticals, and personal fees from Blade, outside of the submitted work. The remaining authors report no relevant conflicts of interest., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)