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An increasing number of children and adolescents is diving with Self-Contained Underwater Breathing Apparatus (SCUBA). SCUBA diving is associated with health risks such as pulmonary barotrauma, especially in children and in individuals with airflow limitation. As no data has been published on the effects of open-water diving on pulmonary function in children, the objective of this study was to evaluate the effects of SCUBA dives on airflow in children. 16 healthy children aged 10-13 years underwent spirom- etry and a cycle-exercise challenge while breathing cold air. They subsequently performed dives to 1-m and 8-m depth in random order. Pulmo- nary function was measured before and after the exercise challenge and the dives. There were statistically significant decreases in FEV,, FVC, FEV,/ FVC, MEF25 and MEF50 after the cold-air exercise challenge and the dives. Changes in lung function following the exercise challenge did not predict the responses to SCUBA diving. In 3 children the post-dive decrements in FEV, exceeded 10%. These children had a lower body weight and BMI percentile. SCUBA diving in healthy children may be associated with relevant airflow limitation. A low body mass might contribute to diving-associated bronchoconstriction. In the majority of subjects, no clinically relevant airway obstruction could be observed. [ABSTRACT FROM AUTHOR]

Rationale: Epidermal growth factor receptor (EGFR) activation is implicated in mucin hypersecretion in chronic obstructive pulmonary disease (COPD). Objectives: To investigate the safety and efficacy of an inhaled EGFR antagonist (BIBW 2948) in COPD. Methods: Multicenter, double-blind, placebo-controlled trial of 4 weeks of treatment with two doses of BIBW 2948 (15 and 30 mg twice a day) on safety and mucin-related outcomes in 48 patients with COPD. The effect of BIBW 2948 on EGFR activation in airway epithelial cells was assessed using an ex vivo assay. Efficacy measures included the volume of mucin in the airway epithelium (Vs mu,bala) in bronchial biopsies and the expression of mucin genes in bronchial brushings. Measurements and Main Results: Inhaled BIBW 2948 induced a dose-related inhibition of EGFR internalization (reflecting decreased EGFR activation) in epithelial cells from treated subjects. However, BIBW 2948 was associated with a dose-related increase in adverse events, including reversible liver enzyme elevation (n = 2), and reduction in FEV(1). The changes in mucin stores and mucin gene expression were not significantly different in the pooled BIBW 2948 group versus placebo (volume of mucin per surface area of basal lamina = 0.22 +/- 7.11 vs. 0.47 +/- 8.06 mum(3)/mum(2); P = 0.93). However, in the 30 mg twice a day group, the reduction in epithelial mucin stores was greatest in subjects with the greatest degree of EGFR inhibition (Pearson r = 0.98; 95% confidence interval, 0.71-0.99). Conclusions: Four-week treatment with BIBW 2948 did not significantly decrease epithelial mucin stores and was poorly tolerated in patients with COPD. Ex vivo analyses suggest that higher doses may be more effective at both EGFR inhibition and decreases in mucin stores but that adverse events should be expected. Clinical trial registered with www.clinicaltrials.gov (NCT00423137). [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVES: Obstructive changes in lung function have been reported with cumulative scuba diving exposure. The aim of this study was to investigate the decline in FEV(1) in scuba divers over time. DESIGN: Prospective controlled cohort study. SETTING: German Naval Medical Institute. PATIENTS: Four hundred sixty-eight healthy, male, military scuba divers and 122 submariners (control subjects) were entered. MEASUREMENTS AND RESULTS: Pulmonary function tests were performed in all subjects on at least three occasions with a minimum interval of 1 year between first and last measurement. The decline in FEV(1) was investigated fitting a general linear model to FEV(1) across time with a factorial main-effects model for slopes and intercepts with respect to the factors group, smoking status, and baseline FEV(1). Mean baseline age of all subjects was 32 years (SD, 9.1), and mean body mass index was 24.7 kg/m(2) (SD, 2.4). Subjects were followed up for 5 years (range, 1 to 9 years) on average. Baseline FEV(1) exceeded the predicted values in both divers and nondiving control subjects. There was no significant difference in the decline of FEV(1) between divers and control subjects. Over time, FEV(1) declined more rapidly in smokers than in nonsmokers (p = 0.0064) and declined more rapidly also in subjects with a baseline FEV(1) above average compared to subjects below average (p < 0.0001). The annual decline of FEV(1) peaked in smoking divers who had a high FEV(1) at baseline. CONCLUSIONS: The data indicate that scuba diving is not associated with an accelerated decline in FEV(1). Combined exposure to diving and smoking contributes to the fall of FEV(1); therefore, smoking cessation is advised for divers. [ABSTRACT FROM AUTHOR]

Background: Generalized pustular psoriasis (GPP) is a rare, life-threatening, inflammatory skin disease characterized by widespread eruption of sterile pustules. Interleukin-36 signaling is involved in the pathogenesis of this disorder. Spesolimab, a humanized anti-interleukin-36 receptor monoclonal antibody, is being studied for the treatment of GPP flares.Methods: In a phase 2 trial, we randomly assigned patients with a GPP flare in a 2:1 ratio to receive a single 900-mg intravenous dose of spesolimab or placebo. Patients in both groups could receive an open-label dose of spesolimab on day 8, an open-label dose of spesolimab as a rescue medication after day 8, or both and were followed to week 12. The primary end point was a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (range, 0 [no visible pustules] to 4 [severe pustulation]) at the end of week 1. The key secondary end point was a GPPGA total score of 0 or 1 (clear or almost clear skin) at the end of week 1; scores range from 0 to 4, with higher scores indicating greater disease severity.Results: A total of 53 patients were enrolled: 35 were assigned to receive spesolimab and 18 to receive placebo. At baseline, 46% of the patients in the spesolimab group and 39% of those in the placebo group had a GPPGA pustulation subscore of 3, and 37% and 33%, respectively, had a pustulation subscore of 4. At the end of week 1, a total of 19 of 35 patients (54%) in the spesolimab group had a pustulation subscore of 0, as compared with 1 of 18 patients (6%) in the placebo group (difference, 49 percentage points; 95% confidence interval [CI], 21 to 67; P<0.001). A total of 15 of 35 patients (43%) had a GPPGA total score of 0 or 1, as compared with 2 of 18 patients (11%) in the placebo group (difference, 32 percentage points; 95% CI, 2 to 53; P = 0.02). Drug reactions were reported in 2 patients who received spesolimab, in 1 of them concurrently with a drug-induced hepatic injury. Among patients assigned to the spesolimab group, infections occurred in 6 of 35 (17%) through the first week; among patients who received spesolimab at any time in the trial, infections had occurred in 24 of 51 (47%) at week 12. Antidrug antibodies were detected in 23 of 50 patients (46%) who received at least one dose of spesolimab.Conclusions: In a phase 2 randomized trial involving patients with GPP, the interleukin-36 receptor inhibitor spesolimab resulted in a higher incidence of lesion clearance at 1 week than placebo but was associated with infections and systemic drug reactions. Longer and larger trials are warranted to determine the effect and risks of spesolimab in patients with pustular psoriasis. (Funded by Boehringer Ingelheim; Effisayil 1 ClinicalTrials.gov number, NCT03782792.). [ABSTRACT FROM AUTHOR]

Rationale: A COPD Foundation working group sought to identify measures of exercise endurance, a meaningful aspect of physical functioning in everyday life among patients with chronic obstructive pulmonary disease (COPD) that is not fully accepted in regulatory decision making, hampering drug development. Objectives: To demonstrate, as we previously asserted (Casaburi COPD 2022;9:252), that constant work rate cycling endurance time is an appropriate exercise endurance measure in patients with COPD. Methods: To validate this assertion, we assembled an integrated database of endurance time responses, including 8 bronchodilator (2,166 subjects) and 15 exercise training (3,488 subjects) studies (Casaburi COPD 2022;9:520). Results: Construct validity was demonstrated: 1 ) peak physiologic and perceptual responses were similar for constant work rate and incremental cycling; 2 ) after bronchodilator therapy, there were greater increases in endurance time in patients with more severe airflow limitation; 3 ) after exercise training, endurance time increases were similar across airflow limitation severities; and 4 ) there were correlations between changes in endurance time and changes in mechanistically related physiologic and perceptual variables. Test-retest reliability was demonstrated, with consistency of changes in endurance time at two time points after the intervention. Responsiveness was confirmed, with significant increases in endurance time after active (but not placebo) bronchodilator therapy, with greater increases seen with more severe airflow limitation and after exercise training. On the basis of regression analysis using multiple anchor variables, the minimum important difference for endurance time increase is estimated to be approximately 1 minute. Conclusions: Constant work rate cycling endurance time is a valid exercise endurance measure in COPD, suitable for contributing to the evaluation of treatment benefit supporting regulatory decision making and evidence-based therapeutic recommendations.

Pulmonary physiology is significantly altered during underwater exposure, as immersion of the body and increased ambient pressure elicit profound effects on both the cardiovascular and respiratory systems. Thoracic blood pooling, increased breathing gas pressures, and variations in gas volumes alongside ambient pressure changes put the heart and lungs under stress. Normal physiologic function and fitness of the cardiovascular and respiratory systems are prerequisites to safely cope with the challenges of the underwater environment when freediving, or diving with underwater breathing apparatus. Few physicians are trained to understand the physiology and medicine of diving and how to recognize or manage diving injuries. This article provides an overview of the physiologic challenges to the respiratory system during diving, with or without breathing apparatus, and outlines possible health risks and hazards unique to the underwater environment. The underlying pathologic mechanisms of dive-related injuries are reviewed, with an emphasis on pulmonary physiology and pathophysiology., Competing Interests: None declared., (Thieme. All rights reserved.)

Over the past 50 years, outcomes after heart transplantation (HTX) have continuously and significantly improved. In the meantime, many heart transplant recipients live almost normal lives with only a few limitations. In some cases, even activities that actually seemed unreasonable for these patients turn out to be feasible. This article describes the encouraging example of a patient returning to recreational scuba diving after HTX. So far, there were no scientific experiences documented in this area. We worked out the special hemodynamic features and the corresponding risks of this sport for heart transplant recipients in an interdisciplinary manner and evaluated them using the patient as an example. The results show that today, with the appropriate physical condition and compliance with safety measures, a wide range of activities, including scuba diving, are possible again after HTX. They illustrate again the significant development and the enormous potential of this therapy option, which is unfortunately only available to a limited extent. NEW & NOTEWORTHY Example for shared decision-making process for tricky questions: First scientific publication about heart transplantation (HTX)-recipient restarting scuba diving. As exercise physiology after HTX combined with specific diving medicine aspects is challenging, we formed a multidisciplinary team to identify, evaluate, and mitigate the risks involved. The results show that today, with the appropriate physical condition and compliance with safety measures, a wide range of activities are possible again after HTX.

Introduction: The COPD Biomarkers Qualification Consortium (CBQC) was formed under COPD Foundation management, with the goal of qualifying biomarkers and clinical outcome assessments through established regulatory processes for chronic obstructive pulmonary disease (COPD). Within CBQC, a working group evaluated opportunities for qualification of an exercise endurance measure. In a recent publication ( Chronic Obstr Pulm Dis. 2022; 9[2]:252-265), we described a conceptual framework establishing exercise endurance's direct relationship to an individual with COPD's experience of physical functioning in daily life, and that increase in exercise endurance is a patient-centered, meaningful treatment benefit. We further proposed endurance time during constant work rate cycle ergometery (CWRCE) as a useful efficacy endpoint in clinical therapeutic intervention trials. In this current publication, we describe the process of assembling an integrated database of endurance time responses to interventions in COPD., Methods: We sought participant-level data from published studies incorporating CWRCE as an outcome measure. A literature search screened 2993 publications and identified 553 studies for assessment. Two interventions had sufficient data across studies to warrant data extraction: bronchodilators and rehabilitative exercise training. Investigators were contacted and requested to provide participant-by-participant data from their published studies., Results: The final dataset included data from 8 bronchodilator studies (2166) participants and 15 exercise training studies (3488 participants). The database includes 71 variables per participant, comprising demographic, pulmonary function, and detailed physiologic response data. This paper provides a detailed description of the analysis population, while analysis supporting the validation/qualification process and addressing other scientific questions will be described in subsequent publications., (JCOPDF © 2022.)

Acute pulmonary edema is a serious condition that may occur as a result of increased hydrostatic forces within the lung microvasculature or increased microvascular permeability. Heart failure or other cardiac or renal disease are common causes of cardiogenic pulmonary edema. However, pulmonary edema may even occur in young and healthy individuals when exposed to extreme environments, such as immersion in water or at high altitude. Immersion pulmonary edema (IPE) and high-altitude pulmonary edema (HAPE) share some morphological and clinical characteristics; however, their underlying mechanisms may be different. An emerging understanding of IPE indicates that an increase in pulmonary artery and capillary pressures caused by substantial redistribution of venous blood from the extremities to the chest, in combination with stimuli aggravating the effects of water immersion, such as exercise and cold temperature, play an important role, distinct from hypoxia-induced vasoconstriction in high altitude pulmonary edema. This review aims at a current perspective on both IPE and HAPE, providing a comparative view of clinical presentation and pathophysiology. A particular emphasis will be on recent advances in understanding of the pathophysiology and occurrence of IPE with a future perspective on remaining research needs., 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 Tetzlaff, Swenson and Bärtsch.)

Background: The INBUILD trial investigated nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs). We investigated the decline in forced vital capacity (FVC) in subgroups based on the inclusion criteria for ILD progression., Methods: Subjects had a fibrosing ILD other than idiopathic pulmonary fibrosis and met the following criteria for ILD progression within the 24 months before screening despite management deemed appropriate in clinical practice: Group A, relative decline in FVC ≥10% predicted; Group B, relative decline in FVC ≥5-<10% predicted with worsened respiratory symptoms and/or increased extent of fibrosis on high-resolution computed tomography (HRCT); Group C, worsened respiratory symptoms and increased extent of fibrosis on HRCT only., Results: In the placebo group, the rates of FVC decline over 52 weeks in Groups A, B and C, respectively, were -241.9, -133.1 and -115.3 mL per year in the overall population (p=0.0002 for subgroup-by-time interaction) and -288.9, -156.2 and -100.1 mL per year among subjects with a usual interstitial pneumonia (UIP)-like fibrotic pattern on HRCT (p=0.0005 for subgroup-by-time interaction). Nintedanib had a greater absolute effect on reducing the rate of FVC decline in Group A than in Group B or C. However, the relative effect of nintedanib versus placebo was consistent across the subgroups (p>0.05 for heterogeneity)., Conclusions: The inclusion criteria used in the INBUILD trial, based on FVC decline or worsening of symptoms and extent of fibrosis on HRCT, were effective at identifying patients with progressive fibrosing ILDs. Nintedanib reduced the rate of decline in FVC across the subgroups based on the inclusion criteria related to ILD progression., Competing Interests: Conflict of interest: T.M. Maher reports grants and personal fees (for serving as a board member or consultant, or working on clinical trials) from UCB and GlaxoSmithKline, and personal fees (for serving as a board member or consultant, or working on clinical trials) from Apellis, Boehringer Ingelheim, Roche, Bayer, Biogen Idec, Galapagos, Indalo, Galecto, Blade, Bristol-Myers Squibb, Novartis, Respivent and Trevi, outside the submitted work. Conflict of interest: K.K. Brown reports grants from NHLBI, serves on the board of the Open Source Imaging Consoritum (OSIC), and reports personal fees from Biogen, Galecto, Third Pole, Galapagos, Boehringer Ingelheim, Theravance, Lifemax, Pliant, Blade Therapeutics, Huitai Biomedicine, Lilly, Dispersol, DevPro Biopharma and Humanetics, outside the submitted work. Conflict of interest: M. Kreuter reports grants and personal fees from Boehringer Ingelheim and Roche, and personal fees from Galapagos, outside the submitted work. Conflict of interest: A. Devaraj reports personal fees from Boehringer Ingelheim, during the conduct of the study; and personal fees from Boehringer Ingelheim, GSK, Roche, Galapagos and Galecto Biotech, outside the submitted work. Conflict of interest: S.L.F. Walsh reports personal fees for consultancy from Sanofi-Aventis, Galapagos and OSIC, personal fees for advisory board work from Roche, grants and personal fees for steering committee work from Boehringer Ingelheim, and personal fees for lectures from Bracco, outside the submitted work. Conflict of interest: L.H. Lancaster reports grants and other (speaker for disease state education, advisory board) from Genentech, grants and other (speaker for disease state education) from Boehringer Ingelheim, and grants from Novartis, Celgene and Bellerophon, outside the submitted work. Conflict of interest: E.A. Belloli reports grants from Boehringer Ingelheim, during the conduct of the study; and personal fees for consultancy from Boehringer Ingelheim, outside the submitted work. Conflict of interest: M. Padilla reports grants and personal fees for consultancy from Boehringer Ingelheim, and personal fees for lectures from Genentech, Vindico and France Foundation, outside the submitted work. Conflict of interest: J. Behr reports personal fees for consultancy and lectures from Actelion, Bayer, Boehringer Ingelheim and Roche, and personal fees for consultancy from Galapagos, Biogen, BMS and Pliant, outside the submitted work; and is a member of national and international guideline committees for IPF and other interstitial lung diseases. Conflict of interest: R-G. Goeldner is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. Conflict of interest: K. Tetzlaff is an employee of Boehringer Ingelheim International GmbH. Conflict of interest: R. Schlenker-Herceg is an employee of Boehringer Ingelheim Pharmaceuticals, Inc. Conflict of interest: K.R. Flaherty reports grants and personal fees for consultancy from Boehringer Ingelheim and Roche/Genentech, and personal fees for consultancy from FibroGen, Veracyte, Sanofi-Genzyme, Respivant, Bellerophon, Blade Therapeutics and Celgene, outside the submitted work., (Copyright ©The authors 2022.)

Pulmonary fibrosis is a pathologic process associated with scarring of the lung interstitium. Interstitial lung diseases (ILDs) encompass a large and heterogenous group of disorders, a number of which are characterized by progressive pulmonary fibrosis that leads to respiratory failure and death. Idiopathic pulmonary fibrosis (IPF) has been described as an archetype of progressive fibrosing ILD, and the development of pirfenidone and nintedanib has been a major breakthrough in the treatment of patients with this deadly disease. Both drugs principally target scar-forming fibroblasts and have been shown to significantly slow down the accelerated decline of lung function by approximately 50%. In addition, nintedanib has been approved for patients with other progressive fibrosing ILDs and systemic sclerosis-associated ILD. However, there is still no cure for pulmonary fibrosis and no meaningful improvement of symptoms or quality of life has been shown. Advancement in research, such as the advent of single cell sequencing technology, has identified additional pathologic cell populations beyond the fibroblast which could be targeted for therapeutic purposes. The preclinical and clinical development of novel drug candidates is hampered by profound challenges such as a lack of sensitive clinical outcomes or suitable biomarkers that would provide an early indication of patient benefit. With the availability of these anti-fibrotic treatments, it has become even more difficult to demonstrate added efficacy, in particular in short-term clinical studies. Patient heterogeneity and the paucity of biomarkers of disease activity further complicate clinical development. It is conceivable that future treatment of pulmonary fibrosis will need to embrace more precision in treating the right patient at the right time, explore novel measures of efficacy, and likely combine treatment options., Competing Interests: Author EW is employed by the company Boehringer Ingelheim Pharmaceuticals, Inc. Author MT is employed by the company Boehringer Ingelheim Pharma GmbH & Co. KG. Authors SS and KT are employed by the company Boehringer Ingelheim International GmbH. The page processing charges for this article have been paid by Boehringer Ingelheim., (Copyright © 2022 White, Thomas, Stowasser and Tetzlaff.)

Breath-hold diving involves environmental challenges, such as water immersion, hydrostatic pressure, and asphyxia, that put the respiratory system under stress. While training and inherent individual factors may increase tolerance to these challenges, the limits of human respiratory physiology will be reached quickly during deep breath-hold dives. Nonetheless, world records in deep breath-hold diving of more than 214 m of seawater have considerably exceeded predictions from human physiology. Investigations of elite breath-hold divers and their achievements revised our understanding of possible physiological adaptations in humans and revealed techniques such as glossopharyngeal breathing as being essential to achieve extremes in breath-hold diving performance. These techniques allow elite athletes to increase total lung capacity and minimize residual volume, thereby reducing thoracic squeeze. However, the inability of human lungs to collapse early during descent enables respiratory gas exchange to continue at greater depths, forcing nitrogen (N 2 ) out of the alveolar space to dissolve in body tissues. This will increase risk of N 2 narcosis and decompression stress. Clinical cases of stroke-like syndromes after single deep breath-hold dives point to possible mechanisms of decompression stress, caused by N 2 entering the vasculature upon ascent from these deep dives. Mechanisms of neurological injury and inert gas narcosis during deep breath-hold dives are still incompletely understood. This review addresses possible hypotheses and elucidates factors that may contribute to pathophysiology of deep freediving accidents. Awareness of the unique challenges to pulmonary physiology at depth is paramount to assess medical risks of deep breath-hold diving., 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 © 2021 Tetzlaff, Lemaitre, Burgstahler, Luetkens and Eichhorn.)

Childhood interstitial lung disease (chILD) comprises >200 rare respiratory disorders, with no currently approved therapies and variable prognosis. Nintedanib reduces the rate of forced vital capacity (FVC) decline in adults with progressive fibrosing interstitial lung diseases (ILDs). We present the design of a multicentre, prospective, double-blind, randomised, placebo-controlled clinical trial of nintedanib in patients with fibrosing chILD (1199-0337 or InPedILD; ClinicalTrials.gov: NCT04093024). Male or female children and adolescents aged 6-17 years (≥30; including ≥20 adolescents aged 12-17 years) with clinically significant fibrosing ILD will be randomised 2:1 to receive oral nintedanib or placebo on top of standard of care for 24 weeks (double-blind), followed by variable-duration nintedanib (open-label). Nintedanib dosing will be based on body weight-dependent allometric scaling, with single-step dose reductions permitted to manage adverse events. Eligible patients will have evidence of fibrosis on high-resolution computed tomography (within 12 months of their first screening visit), FVC ≥25% predicted, and clinically significant disease (Fan score of ≥3 or evidence of clinical progression over time). Patients with underlying chronic liver disease, significant pulmonary arterial hypertension, cardiovascular disease, or increased bleeding risk are ineligible. The primary endpoints are pharmacokinetics and the proportion of patients with treatment-emergent adverse events at week 24. Secondary endpoints include change in FVC% predicted from baseline, Pediatric Quality of Life Questionnaire, oxygen saturation, and 6-min walk distance at weeks 24 and 52. Additional efficacy and safety endpoints will be collected to explore long-term effects., Competing Interests: Conflict of interest: R. Deterding reports scientific advisory and consulting fees paid to the University of Colorado, and manuscript preparation assistance from Boehringer Ingelheim Pharmaceuticals Inc., during the conduct of the study. Conflict of interest: M. Griese reports personal fees from Boehringer Ingelheim during the conduct of the study and grants from Boehringer Ingelheim outside the submitted work. Conflict of interest: G. Deutsch reports consulting fees paid to Seattle Children's Hospital by Boehringer Ingelheim during the conduct of the study. Conflict of interest: D. Warburton serves in an advisory role for Boehringer Ingelheim on the evaluation of nintedanib as a potential treatment for childhood ILD, and has received reimbursement for travel and consultation in this role. Conflict of interest: E.M. DeBoer reports consulting fees from Boehringer Ingelheim and Parexel, and consulting fees from and stock in EvoEndoscopy, outside the submitted work. Conflict of interest: S. Cunningham reports consultancy fees paid to the University of Edinburgh by Boehringer Ingelheim during the conduct of the study. Conflict of interest: A. Clement has nothing to disclose. Conflict of interest: N. Schwerk reports consulting fees from Boehringer Ingelheim outside the submitted work. Conflict of interest: K.R. Flaherty reports grants and personal fees from Boehringer Ingelheim, and personal fees from Roche/Genentech, Bellerophan, Respivant and Blade Therapeutics, outside the submitted work. Conflict of interest: K.K. Brown reports, outside the submitted work, grants from NHLBI, personal fees from Biogen and advisory board participation for Blade, Boehringer Ingelheim, Galapagos, Galecto, Genoa, Lifemax, MedImmune, OSIC (Open Source Imaging Consortium), Pliant, ProMetic, Third Pole, Theravance, Three Lakes Partners and Veracyte. Conflict of interest: F. Voss is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. Conflict of interest: U. Schmid is an employee of Boehringer Ingelheim. Conflict of interest: R. Schlenker-Herceg is an employee of Boehringer Ingelheim. Conflict of interest: D. Verri is an employee of Boehringer Ingelheim Italia S.p.A. Conflict of interest: M. Dumistracel is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. Conflict of interest: M. Schiwek is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. Conflict of interest: S. Stowasser is an employee of Boehringer Ingelheim International GmbH. Conflict of interest: K. Tetzlaff is an employee of Boehringer Ingelheim International GmbH. Conflict of interest: E. Clerisme-Beaty is an employee of Boehringer Ingelheim. Conflict of interest: L.R. Young reports personal fees for advisory board participation from Boehringer Ingelheim, and grants from the NIH, during the conduct of the study. All authors disclose third-party writing assistance contracted and funded by Boehringer Ingelheim International GmbH., (Copyright ©The authors 2021.)

Introduction: Generalized pustular psoriasis (GPP) is a rare, potentially life-threatening disease characterised by recurrent flares of widespread neutrophilic aseptic skin pustular eruption. Despite the availability of approved biologics for GPP in Japan, Taiwan and Thailand, associated evidence is largely based on uncontrolled studies in which acute flares were not directly assessed. Therefore, there is a high unmet need to investigate new rapid-acting effective treatments that resolve symptoms associated with acute GPP flares. A prior Phase I proof-of-concept study showed rapid improvements in skin and pustule clearance with a single intravenous dose of spesolimab, a novel anti-interleukin-36 receptor antibody, in patients presenting with an acute GPP flare. Here, we present the design and rationale of Effisayil 1, a global, Phase II, placebo-controlled study to evaluate the efficacy, safety and tolerability of spesolimab in patients presenting with an acute GPP flare., Methods and Analysis: At least 51 patients with an acute GPP flare will be randomised 2:1 to receive a single 900 mg intravenous dose of spesolimab or placebo and followed for up to 28 weeks. The primary endpoint is a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (pustule clearance) at Week 1. The key secondary endpoint is a GPPGA score of 0 or 1 (clear or almost clear) at Week 1. Safety will be assessed over the study duration by the occurrence of treatment-emergent adverse events. Blood and skin biopsies will be collected to assess biomarkers. Superiority of spesolimab over placebo in the proportion of patients achieving the primary and key secondary endpoints will be evaluated., Ethics and Dissemination: The study complies with the ethical principles of the Declaration of Helsinki, the International Council for Harmonisation's Good Clinical Practice and local regulations. Ethics committee approvals have been obtained for each centre from all participating countries and are listed in online supplementary file 1. Primary results will be published in a peer-reviewed journal., Trial Registration Details: ClinicalTrials.gov identifier: NCT03782792; Pre-results., Competing Interests: Competing interests: SR is an employee of Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut, USA. HD is an employee of Boehringer Ingelheim Investment Co Ltd, Shanghai, China. KT is an employee of Boehringer Ingelheim GmbH, Ingelheim, Germany. CT is an employee of Boehringer Ingelheim International GmbH, Biberach, Germany. SEC declares paid activities as advisor, speaker or consultant for AbbVie, Boehringer Ingelheim, Eli Lilly, Janssen, Leo Pharma, MSD, Novartis, Pfizer, Sanofi and UCB. MGL declares paid consulting activities for Aditum Bio, Allergan, Almirall, Arcutis, Inc, Avotres Therapeutics, BirchBioMed Inc, BMD skincare, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Evelo, Facilitate International Dermatologic Education, Foundation for Research and Education in Dermatology, Inozyme Pharma, Kyowa Kirin, LEO Pharma, Meiji Seika Pharma, Menlo, Mitsubishi, NeuroDerm, Pfizer, Promius (Dr Reddy’s Laboratories Ltd), Serono, Theravance and Verrica, and research funds from AbbVie, Amgen, Arcutis, Boehringer Ingelheim, Dermavant, Eli Lilly, Incyte, Janssen Research & Development, LLC, LEO Pharma, Ortho Dermatologics, Pfizer and UCB. SM and HT declare paid consulting activities for Boehringer Ingelheim. ADB declares paid consulting activities for AbbVie, Almirall, Boehringer Ingelheim, Celgene, Janssen, LEO Pharma, Lilly, Novartis and UCB. TFT declares conducting clinical trials or paid consulting activities for AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Galderma, GlaxoSmithKline, Janssen-Cilag, LEO Pharma, Merck Sharp & Dohme, Novartis International, Pfizer and UCB Pharma. AM declares receiving research grants, consulting fees and/or speaker’s fees from AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly, Eisai, Janssen, Kyowa Hakko Kirin, LEO Pharma, Maruho, Mitsubishi Tanabe, Nichi-Iko, Nippon Kayaku, Novartis, Sun Pharmaceutical Industries, Taiho Pharmaceutical and Torii Pharmaceutical and Ushio. AAN declares being a consultant and advisor and/or receiving speaking fees and/or grants and/or served as an investigator in clinical trials for AbbVie, Almirall, Amgen, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, GSK, LEO Pharma, Janssen-Cilag, MSD, Novartis, Pfizer, Sandoz, Sanofi, Serono and UCB. MZ declares receiving grants, consulting fees, and/or speaker’s fees from AbbVie, Boehringer Ingelheim, Janssen-Cilag, LEO Pharma China, Novartis, Pfizer Inc and Xian-Janssen. JX declares receiving grants, consulting fees, and/or speaker’s fees from AbbVie, Boehringer Ingelheim, Novartis, Pfizer Inc and Sanofi. HB declares paid consulting activities for AbbVie, Almirall, BIOCAD, Boehringer Ingelheim, Celgene, Janssen, Kyowa-Kirin, LEO Pharma, Lilly, Mylan, Novartis and UCB, and grant support from Boehringer Ingelheim, Janssen, LEO Pharma, Novartis and Pfizer., (© 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.)

We used data from the INBUILD and INPULSIS trials to investigate the natural history of progressive fibrosing interstitial lung diseases (ILDs).Subjects in the two INPULSIS trials had a clinical diagnosis of idiopathic pulmonary fibrosis (IPF) while subjects in the INBUILD trial had a progressive fibrosing ILD other than IPF and met protocol-defined criteria for ILD progression despite management. Using data from the placebo groups, we compared the rate of decline in forced vital capacity (FVC) (mL·year -1 ) and mortality over 52 weeks in the INBUILD trial with pooled data from the INPULSIS trials.The adjusted mean annual rate of decline in FVC in the INBUILD trial (n=331) was similar to that observed in the INPULSIS trials (n=423) (-192.9 mL·year -1 and -221.0 mL·year -1 , respectively; nominal p-value=0.19). The proportion of subjects who had a relative decline in FVC >10% predicted at Week 52 was 48.9% in the INBUILD trial and 48.7% in the INPULSIS trials, and the proportion who died over 52 weeks was 5.1% in the INBUILD trial and 7.8% in the INPULSIS trials. A relative decline in FVC >10% predicted was associated with an increased risk of death in the INBUILD trial (hazard ratio 3.64) and the INPULSIS trials (hazard ratio 3.95).These findings indicate that patients with fibrosing ILDs other than IPF, who are progressing despite management, have a subsequent clinical course similar to patients with untreated IPF, with a high risk of further ILD progression and early mortality., Competing Interests: Conflict of interest: K.K. Brown reports grants from NHLBI; personal fees from Biogen, Blade Therapeutics, Galapagos, Galecto Biotech, Huitai Biomedicine, Lifemax, Lilly, MedImmune, monARC Bionetworks, Pliant Therapeutics, ProMetic, Third Pole Therapeutics, Theravance, Three Lakes Partners, and Veracyte; personal fees and non-financial support from Boehringer Ingelheim; and other support from Genoa and the Open Source Imaging Consortium (OSIC). Conflict of interest: F.J. Martinez reports grants, personal fees, non-financial support and other support from Boehringer Ingelheim; personal fees, nonfinancial support and other support from AstraZeneca; non-financial support and other support from ProterixBio; personal fees and non-financial support from the Canadian Respiratory Network, Chiesi, CME Outfitters, Dartmouth, Genentech, GlaxoSmithKline, Inova Fairfax Health System, Miller Communications, the National Association for Continuing Education, Novartis, Pearl Pharmaceuticals, PeerView Communications, Physicians Education Resource, Potomac, Prime Communications, the Puerto Rican Respiratory Society, Sunovion, Teva, Theravance, the University of Alabama Birmingham, and Vindico; personal fees and other support from Patara/Respivant; grants from NIH; personal fees from the American Thoracic Society, Columbia University, France Foundation, MD Magazine, Methodist Hospital Brooklyn, New York University, Physicians Education Resource, Rare Disease Healthcare Communications, Rockpointe, UpToDate, and WebMD/Medscape; other support from Afferent/Merck, Bayer, Biogen, Bridge Biotherapeutics, Gala Pharmaceutical, Promedior, Wolters Kluwer, and Veracyte; and non-financial support from Gilead, Nitto, Prometic, and Zambon. Conflict of interest: S.L.F. Walsh reports personal fees for consultancy from Sanofi-Aventis, Galapagos and OSIC, personal fees for advisory board work from Roche, grants and personal fees for steering committee work from Boehringer Ingelheim, personal fees for lectures from Bracco, outside the submitted work. Conflict of interest: V.J. Thannickal reports personal fees for consultancy from Boehringer Ingelheim Pharmaceuticals, Inc., Kadmon Corporation, Pliant, Glenmark, Covance, Blade, Versant Venture, Mistral and Translate Bio, grants from Genkyotex, outside the submitted work. Conflict of interest: A. Prasse reports that Hannover Medical School received a fee for patient randomisation into the INBUILD study from Boehringer Ingelheim; personal fees for consultancy and lectures and non-financial support (travel expenses) from Boehringer Ingelheim and Roche, personal fees for lectures and non-financial support (travel expenses) from Novartis, AstraZeneca and Chiesi, personal fees for consultancy and non-financial support (travel expenses) from Nitto Denko and Pliant, outside the submitted work. Conflict of interest: R. Schlenker-Herceg is an employee of Boehringer Ingelheim Pharmaceuticals, Inc. Conflict of interest: R-G. Goeldner is an employee of Boehringer Ingelheim Pharma GmbH & Co., KG. Conflict of interest: E. Clerisme-Beaty is an employee of Boehringer Ingelheim International GmbH. Conflict of interest: K. Tetzlaff is an employee of Boehringer Ingelheim International GmbH. Conflict of interest: V. Cottin reports personal fees for advisory board work and lectures, and non-financial support for meeting attendance from Actelion, grants, personal fees for advisory board work and lectures, and non-financial support for meeting attendance from Boehringer Ingelheim and Roche, personal fees for advisory board work and data monitoring committee work from Bayer/MSD, Promedior and Galapagos, personal fees for adjudication committee work from Gilead, personal fees for advisory board work and lectures from Novartis, personal fees for lectures from Sanofi, personal fees for data monitoring committee work from Celgene and Galecto, outside the submitted work. Conflict of interest: A.U. Wells reports personal fees for consultancy and lectures from Boehringer Ingelheim and Roche, personal fees for consultancy from Blade, outside the submitted work., (Copyright ©ERS 2020.)

Background: Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown., Methods: In this double-blind, placebo-controlled, phase 3 trial conducted in 15 countries, we randomly assigned patients with fibrosing lung disease affecting more than 10% of lung volume on high-resolution computed tomography (CT) to receive nintedanib at a dose of 150 mg twice daily or placebo. All the patients met criteria for progression of interstitial lung disease in the past 24 months despite treatment and had a forced vital capacity (FVC) of at least 45% of the predicted value and a diffusing capacity of the lung for carbon monoxide ranging from 30 to less than 80% of the predicted value. Randomization was stratified according to the fibrotic pattern (a pattern of usual interstitial pneumonia [UIP] or other fibrotic patterns) on high-resolution CT. The primary end point was the annual rate of decline in the FVC, as assessed over a 52-week period. The two primary populations for analysis were the overall population and patients with a UIP-like fibrotic pattern., Results: A total of 663 patients were treated. In the overall population, the adjusted rate of decline in the FVC was -80.8 ml per year with nintedanib and -187.8 ml per year with placebo, for a between-group difference of 107.0 ml per year (95% confidence interval [CI], 65.4 to 148.5; P<0.001). In patients with a UIP-like fibrotic pattern, the adjusted rate of decline in the FVC was -82.9 ml per year with nintedanib and -211.1 ml per year with placebo, for a difference of 128.2 ml (95% CI, 70.8 to 185.6; P<0.001). Diarrhea was the most common adverse event, as reported in 66.9% and 23.9% of patients treated with nintedanib and placebo, respectively. Abnormalities on liver-function testing were more common in the nintedanib group than in the placebo group., Conclusions: In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo. Diarrhea was a common adverse event. (Funded by Boehringer Ingelheim; INBUILD ClinicalTrials.gov number, NCT02999178.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD., Methods: We conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud's symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 52., Results: A total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was -52.4 ml per year in the nintedanib group and -93.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P = 0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of -0.21 (95% CI, -0.94 to 0.53; P = 0.58) and 1.69 (95% CI, -0.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group., Conclusions: Among patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo. (Funded by Boehringer Ingelheim; SENSCIS ClinicalTrials.gov number, NCT02597933.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: The symptoms of acute carbon monoxide (CO) poisoning are unspecific, ranging from headaches to unconsciousness and death. In addition to acute symptoms, delayed severe neurological sequelae may occur. While a total of 440 deaths by CO poisoning were registered in Germany in 1999, a total of 594 patients died (0.73 per 100,000 inhabitants) in 2014 and in 2015 the number even increased to 648 deaths. A national database on clinical symptoms, course of illness or quality of care concerning CO poisoning does not yet exist., Methods: The treatment data of patients admitted to the Hyperbaric Emergency Centre Wiesbaden (HEC) from 2013 to 2017 with CO poisoning formed the basis of the study. This was a comparative evaluation of patient demographics, poisoning sources, symptom spectrum, course of treatment and time intervals registered on the preclinical and clinical levels., Results: From 2013 to 2017 a total of 476 patients (282 men and 194 women) with an average non-invasively measured CO-Hb of 15% (Q 0.25  = 7.6%, Q 0.75  = 22.3%) were treated with hyperbaric oxygen. Heaters (n = 131), charcoal barbecues (n = 93), fires (n = 90), hookahs (n = 78) and combustion engines (n = 37) were the most frequent CO sources identified. Headaches, vertigo, nausea and syncope were the most prevalent symptoms. A median of 91 min (Q 0.25  = 53 min; Q 0.75  = 147 min) passed between first medical contact and BGA-validated diagnosis. In total, 151 patients were transferred directly to the HEC, whereas 325 patients were secondarily transferred. The delay in this subgroup took 183 min (median Q 0.25  = 138 min; Q 0.75  = 248 min). After receiving the first hyperbaric treatment, 80% were free of symptoms. Remaining symptoms included headache (10%), fatigue (8%), vertigo (5%) and nausea (3%) and 45 patients terminated further treatment. Of the patients 417 received a second hyperbaric treatment and 370 patients were treated 3 times. After the third treatment, 89% were free of symptoms and 5% still reported headaches, 3% vertigo and 2% fatigue. In total, 6 patients died and 430 patients were symptom-free after treatment., Conclusion: Commonly known sources (fire, charcoal grills) aside, many poisonings by smoking a hookah were observed. This study highlights the importance of considering CO poisoning as a differential diagnosis when encountering patients, especially of younger age, with non-specific neurological symptoms, as well as the importance of early initiation of treatment. A direct correlation between CO-Hb values (whether measured noninvasively or by invasive BGA) and the initial symptoms could not be demonstrated. In total, substantial time expired between the diagnosis and start of treatment of patients transported to a primary care hospital compared to those transported directly to the HEC. Although analysis showed adequate treatment with oxygen in the preclinical interval, administration of oxygen during primary hospital stay showed room for improvement. Introducing a national CO poisoning register and uniform treatment guidelines could improve in-house clinical processes. Multicenter studies are needed to close the gaps identified in the quality of care in Germany.

This short review focuses on pulmonary injury in breath-hold (BH) divers. When practicing their extreme leisure sport, they are exposed to increased pressure on pulmonary gas volumes, hypoxia, and increased partial gas pressures. Increasing ambient pressures do present a serious problem to BH deep divers, because the semi-rigid thorax prevents the deformation required by the Boyle-Mariotte law. As a result, a negative-pressure barotrauma (lung squeeze) with acute hemoptysis is not uncommon. Respiratory maneuvers such as glossopharyngeal insufflation (GI) and glossopharyngeal exsufflation (GE) are practiced to prevent lung squeeze and to permit equalizing the paranasal sinuses and the middle ear. GI not only impairs venous return, thereby provoking hypotension and even fainting, but also produces intrathoracic pressures likely to induce pulmonary barotrauma that is speculated to induce long-term injury. GE, in turn, further increases the already negative intrapulmonary pressure, thereby favoring alveolar collapse (atelectasis). Finally, hypoxia seemingly not only induces brain injury but initiates the opening of intrapulmonary shunts. These pathways are large enough to permit transpulmonary passage of venous N2 bubbles, making stroke-like phenomena in deep BH divers possible., (© 2019 S. Karger AG, Basel.)

Background: Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with loss of lung function and poor outcomes for patients. However, there are limited data on the time course of changes in forced expiratory volume in 1 s (FEV 1 ) preceding the first reported symptom and after the start of an exacerbation., Methods: WISDOM was a multinational, randomized, double-blind, active-controlled, 52-week study in patients with severe-to-very severe COPD. Patients received triple therapy (long-acting muscarinic antagonist and long-acting β 2 -agonist/inhaled corticosteroid [ICS]) for 6 weeks, and were randomized to continue triple therapy or stepwise withdrawal of the ICS (dual bronchodilator group). After suitable training, patients performed daily spirometry at home using a portable, battery-operated spirometer. In the present post hoc analysis, patients who continued to perform daily home spirometry and completed at least one measurement per week for a 56-day period before and after the start of a moderate or severe exacerbation were included. Missing values were imputed by linear interpolation (intermittent), backfilling (beginning) or carry forward (end). Exacerbation onset was the first day of a reported symptom of exacerbation., Results: Eight hundred and eighty-eight patients in the WISDOM study had a moderate/severe exacerbation after the complete ICS withdrawal visit; 360 of them contributed at least one FEV 1 measure per week for the 8 weeks before and after the event and are included in this analysis. Mean daily FEV 1 began to decline from approximately 2 weeks before the onset of symptoms of an exacerbation, dropping from 0.907 L (mean Days - 56 to - 36 before the exacerbation) to 0.860 L on the first day of the exacerbation. After the exacerbation, mean FEV 1 improved but did not return to pre-exacerbation levels (mean Days 36-56 after the exacerbation, 0.875 L). The pattern of FEV 1 changes around exacerbations was similar in the triple therapy and dual bronchodilator groups, and a similar pattern was seen in moderate and severe exacerbations when analysed separately., Conclusions: Mean lung function starts to decline prior to the first reported symptoms of an exacerbation, and does not recover to pre-exacerbation levels 8 weeks after the event., Trial Registration: WISDOM (ClinicalTrials.gov number, NCT00975195 ).

Objective: Waterpipe smoking may increasingly account for unintentional carbon monoxide poisoning, a serious health hazard with high morbidity and mortality. We aimed at identifying waterpipe smoking as a cause for carbon monoxide poisoning in a large critical care database of a specialty care referral center., Methods: This retrospective cohort study included patients with a history of exposure to waterpipe smoking and carbon monoxide blood gas levels >10% or presence of clinical symptoms compatible with CO poisoning admitted between January 2013 and December 2016. Patients' initial symptoms and carbon monoxide blood levels were retrieved from records and neurologic status was assessed before and after hyperbaric oxygen treatment., Results: Sixty-one subjects with carbon monoxide poisoning were included [41 males, 20 females; mean age 23 (SD ± 6) years; range 13-45] with an initial mean carboxyhemoglobin of 26.93% (SD ± 9.72). Most common symptoms included syncope, dizziness, headache, and nausea; 75% had temporary syncope. Symptoms were not closely associated with blood COHb levels., Conclusion: CO poisoning after waterpipe smoking may present in young adults with a wide variability of symptoms from none to unconsciousness. Therefore diagnosis should be suspected even in the absence of symptoms.