Validation of Constant Work Rate Cycling Endurance Time for Use in Chronic Obstructive Pulmonary Disease Clinical Trials.

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.

Scuba diving after a heart transplant: excessive daring or calculable risk?

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.

Pulmonary Physiology and Medicine of Diving.

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.

An update on environment-induced pulmonary edema - "When the lungs leak under water and in thin air".

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.

Endurance Time During Constant Work Rate Cycle Ergometry in COPD: Development of an Integrated Database From Interventional Studies.

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.

Challenges for Clinical Drug Development in Pulmonary Fibrosis.

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.

Effects of nintedanib by inclusion criteria for progression of interstitial lung disease.

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.

Trial of Spesolimab for Generalized Pustular Psoriasis.

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.).

Going to Extremes of Lung Physiology-Deep Breath-Hold Diving.

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 (N2) out of the alveolar space to dissolve in body tissues. This will increase risk of N2 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 N2 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.

Study design of a randomised, placebo-controlled trial of nintedanib in children and adolescents with fibrosing interstitial lung disease.

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.

Study protocol of the global Effisayil 1 Phase II, multicentre, randomised, double-blind, placebo-controlled trial of spesolimab in patients with generalized pustular psoriasis presenting with an acute flare.

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.

Effect of Inhaled Corticosteroid Withdrawal on Chronic Obstructive Pulmonary Disease Exacerbations in Patients Taking Triple Therapy at Baseline.

Purpose: In the Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management (WISDOM) trial, inhaled corticosteroid (ICS) withdrawal in patients with chronic obstructive pulmonary disease receiving triple therapy (long-acting ß2-agonist+long-acting muscarinic antagonist+ICS) did not change moderate/severe exacerbation risk. However, many patients were not taking triple therapy before study participation. This analysis was conducted to eliminate the impact of non-ICS users on WISDOM results by re-analyzing the data using only the subset of patients who were taking triple therapy at screening. Patients and Methods: The effect of ICS withdrawal on moderate/severe exacerbation risk in the subgroup of WISDOM patients taking triple therapy before enrolling in the study was evaluated in this post hoc analysis. Additionally, the effect of ICS withdrawal in patients with a history of ≥2 exacerbations in the previous year and various blood eosinophil counts was assessed. Results: Overall, 39.0% (n=970: ICS continuation, 479; ICS withdrawal, 491) of the WISDOM trial population were taking triple therapy at screening. Baseline characteristics were generally similar between groups. Moderate/severe exacerbation risk between the ICS withdrawal and continuation groups (hazard ratio [HR], 1.05; 95% confidence interval [CI]: 0.89-1.25) was not increased in patients taking triple therapy at screening versus the overall trial population (HR [95% CI]: 1.06 [0.94-1.19]). However, in patients with a history of ≥2 exacerbations, exacerbation risk (HR [95% CI]) increased nominally with blood eosinophil count from 1.07 [0.81-1.41] (≥100 cells/µL) to 1.45 [0.58-3.60] (≥400 cells/µL). Conclusion: Consistent with results from the overall WISDOM trial population, ICS withdrawal did not increase exacerbation risk in patients taking triple therapy at screening. Patients with a history of frequent exacerbations and higher blood eosinophil counts could benefit from continuation of ICS-based therapy.

The natural history of progressive fibrosing interstitial lung diseases.

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.

Nintedanib in Progressive Fibrosing Interstitial Lung Diseases.

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.).

Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease.

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.).

Effects of Breath-Hold Deep Diving on the Pulmonary System.

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.

Spirometric changes during exacerbations of COPD: a post hoc analysis of the WISDOM trial.

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 (FEV1) 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 ß2-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 FEV1 measure per week for the 8 weeks before and after the event and are included in this analysis. Mean daily FEV1 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 FEV1 improved but did not return to pre-exacerbation levels (mean Days 36-56 after the exacerbation, 0.875 L). The pattern of FEV1 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 ).