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Jérémy Laroche,1 Geneviève Pelletier,1 Marie-Ève Boulay,1 Andréanne Côté,1,2 Krystelle Godbout1,2 1Department of Pulmonology and Thoracic Surgery, Quebec Heart and Lung Institute, Laval University, Quebec City, QC, Canada; 2Department of Medicine, Faculty of Medicine, Laval University, Quebec City, QC, CanadaCorrespondence: Krystelle Godbout, Department of Pulmonology and Thoracic Surgery, Quebec Heart and Lung Institute, 2725 Chemin Sainte-Foy, Quebec, QC, G1V 4G5, Canada, Tel +1 418 656 4747, Fax +1 418 656 4762, Email krystelle.godbout@criucpq.ulaval.caIntroduction: Monoclonal antibodies targeting interleukin 5 (IL5) or its receptor (IL5R) are frequently used in severe asthma, in which they reduce exacerbations rate and oral corticosteroids (OCS) exposure. Anti-IL5/IL5Rs have been studied in patients with chronic obstructive pulmonary disease (COPD) without convincing benefits. However, these therapies have been used in clinical practice in COPD with apparently good results.Purpose: To describe the clinical characteristics and therapeutic response of COPD patients treated with anti-IL5/IL5R in a real-world setting.Patients and Methods: This is a retrospective case series of patients followed at the Quebec Heart and Lung Institute COPD clinic. Men or women, with an established diagnosis of COPD, and treated either with Mepolizumab or Benralizumab were included. Demographics, disease and exacerbation-related data, airway comorbidities, lung function, and inflammatory profile were extracted from patients’ hospital files at baseline visit and 12 months post-treatment. Therapeutic response to biologics was assessed by measuring change in annual exacerbation rate and/or OCS daily dose.Results: Seven COPD patients treated with biologics were identified (5M:2F). All were found to be OCSdependent at baseline. Radiological evidence of emphysema was found in all patients. One case was diagnosed with asthma before age 40. Residual eosinophilic inflammation was found in 5/6 patients (blood eosinophils count 237 ± 225× 106 cells/L) despite chronic OCS use. After 12 months of anti-IL5 treatment, mean OCS dose dropped from 12.0 ± 7.6 to 2.6 ± 4.3 mg/day, representing a 78% decrease. Annual exacerbations rate was reduced by 88%, from 8.2 ± 3.3 to 1.0 ± 1.2 per year.Conclusion: Chronic OCS use is a common characteristic of patients treated with anti-IL5/IL5R biological therapies in this real-world setting. In this population, it may be effective in decreasing OCS exposure and exacerbation.Keywords: COPD, treatment, anti-IL5, monoclonal antibodies, exacerbations, oral corticosteroids

The alarmin cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL)-33 and IL-25 and are epithelial cell-derived mediators that contribute to the pathobiology and pathophysiology of asthma. Released from airway epithelial cells exposed to environmental triggers, the alarmins drive airway inflammation through the release of predominantly T2 cytokines from multiple effector cells. The upstream positioning of the alarmins is an attractive pharmacological target to block multiple T2 pathways important in asthma. Blocking the function of TSLP inhibits allergen-induced responses including bronchoconstriction, airway hyperresponsiveness and inflammation, and subsequent clinical trials of an anti-TSLP monoclonal antibody, tezepelumab, in asthma patients demonstrated improvements in lung function, airway responsiveness, inflammation, and importantly, a reduction in the rate of exacerbations. Notably, these improvements were observed in patients with T2-high and with T2-low asthma. Clinical trials blocking IL-33 and its receptor ST2 have also shown improvements in lung function and exacerbation rates, however the impact of blocking the IL-33/ST2 axis in T2-high versus T2-low asthma is unclear. To date there is no evidence that IL-25 blockade is beneficial in asthma. Despite considerable overlap in the cellular functions of IL-25, IL-33 and TSLP, they appear to have distinct roles in the immunopathology of asthma.

Chronic rhinosinusitis with nasal polyposis (CRSwNP) affects a significant number of asthmatic patients and is notably associated with a more difficult-to-control asthma and marked inflammation. We need more studies on this specific asthma phenotype and its possible subphenotypes, in order to better individualize treatments.The aim of this study is to identify and characterize subphenotypes of asthma patients with CRSwNP using clinical, physiological and inflammatory variables.K-means cluster analysis was performed on 17 clinical, physiological, and inflammatory variables from 1263 patients of all asthma severity and on a subpopulation of patients with asthma and CRSwNP. Study was registered on ClinicalTrials.gov (NCT03694847).On the overall population, three groups were identified. Cluster T1 (n = 708) are young, have a short asthma duration and a low prevalence of CRSwNP. Cluster T2 (n = 263) have the longest asthma duration and Cluster T3 (n = 292) are older with the shortest asthma duration. Patients in Clusters T2 and T3 have similar prevalences of CRSwNP. On the subpopulation of asthma with CRSwNP, three clusters were also identified. Cluster S1 (n = 83) have mild-to-moderate asthma with normal lung function. Clusters S2 (N = 53) and S3 (N = 42) include patients with severe asthma and decreased lung function, but those in Cluster S2 have a longer asthma duration, whereas those Cluster S3 have late-onset asthma.Despite coexistence of asthma and CRSwNP, not all patients have the same evolution of their asthma. Different phenotypes of asthma with CRSwNP can be identified and exploration of the characteristics of these subgroups could lead to a better individualized, targeted management.

The effect of serial incremental concentrations of methacholine is only slightly cumulative when assessed by spirometry. This limited cumulative effect may be attributed to the bronchodilator effect of deep inspirations that are required between concentrations to measure lung function. Using oscillometry, the response to methacholine can be measured without deep inspirations. Conveniently, oscillometry can also dissociate the contribution of large versus small airways. Herein, oscillometry was used to assess the cumulative effect of methacholine in the absence of deep inspirations on large and small airways.Healthy and asthmatic volunteers underwent a multiple-concentration methacholine challenge on visit 1 and a single-concentration challenge on visit 2 using the highest concentration of visit 1. The maximal response was compared between visits to assess the cumulative effect of methacholine. The lung volume was also measured after the final concentration to assess hyperinflation.In both healthy and asthmatic subjects, increases in resistance at 19 Hz (RWithout deep inspirations, the effect of methacholine is cumulative on small airways but not on large airways. Lung hyperinflation and derecruitment may partially explain these different responses.

BackgroundLevels of medical intervention (LMI) are legal documents in which physicians record patient preferences, or those of their designated substitute decision-makers, concerning end-of-life care. Studies suggest that, although LMI are intended to orient clinical practice, their function tends to be limited to logistical aspects of care. How LMI shapes or guides patient-centred, end-of-life care remains unclear. The aim of this study was to examine possible associations between LMI and certain aspects of end-of-life care practices in LTCC, such as nurse-documented patient experiences of pain, and prescription and administration of medication. MethodsA retrospective descriptive study of 100 files retrieved from a clinical database of deceased patients in LTCCs located in an urban integrated health and social service organization in Québec, Canada, was conducted. ResultsSignificant associations between last documented LMI and frequency of narcotic prescription and administration, at either regular intervals or PRN, are highlighted. The time delay between last LMI assessment and patient death was one week or less for 39.4% of cases. ConclusionThese results suggest that LMI assessment practices may not correspond to their intended use. A short time frame between last LMI (L-LMI) assessment and patient death may suggest less-than-optimal patient comfort in end-of-life care.

Objective: Bronchial thermoplasty is an effective intervention to improve respiratory symptoms and to reduce the rate of exacerbations in uncontrolled severe asthma. A reduction in airway smooth muscle is arguably the most widely discussed mechanisms accounting for these clinical benefits. Yet, this smooth muscle reduction should also translate into an impaired response to bronchodilator drugs. A pilot study was designed to address this question. Hypothesis: Thermoplasty decreases the response to a bronchodilator. Methods: Lung functions measured by spirometry and respiratory mechanics measured by oscillometry (tremoFlo, Thorasys) were examined pre- and post-bronchodilator (salbutamol, 400 μg) before and after at least 1 year of thermoplasty in 8 patients (7 women) with uncontrolled severe asthma. For each readout, a two-way ANOVA was used to assess the effect of thermoplasty, salbutamol, and their interaction. All procedures were approved by the IUCPQ Ethics Committee. Data: Consistent with previous studies, thermoplasty yielded no benefits in terms of baseline lung function and respiratory mechanics, despite improving symptoms based on two questionnaires assessing the level of asthma control (Asthma Control Questionnaire – ACQ-5, and Asthma Control Test – ACT-5). The response to salbutamol was not affected by thermoplasty based on spirometric readouts, including forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio. However, a significant interaction was observed between thermoplasty and salbutamol for two oscillometric readouts. The reactance of the respiratory system at 5 Hz (Xrs5) increased from -3.2 ±2.6 to -1.9 ± 1.9 cmH2O ·s/L in response to salbutamol pre-thermoplasty, versus from -2.8 ± 2.3 to -2.2 ± 1.9 cmH2O·s/L post-thermoplasty (interaction, p=0.04). Similarly, the reactance area (Ax) decreased from 32.6 ± 29.0 to 12.8 ±18.2 cmH2O/L in response to salbutamol pre-thermoplasty, versus 27.2 ± 29.4 to 15.7 ± 20.1 cmH2O/L post-thermoplasty (interaction, p=0.02). The salbutamol-induced changes in resistance at 5 Hz (Rrs5), resistance at 19 Hz (Rrs19), Rrs5 minus Rrs19, and resonant frequency were not significantly affected by thermoplasty. Summary of results: While spirometry was unable to detect changes in the response to salbutamol caused by thermoplasty, two oscillometric readouts, namely Xrs5 and Ax, confirmed that the bronchodilator response is attenuated post-thermoplasty. Conclusion: Despite its small size, this study demonstrates that thermoplasty attenuates the response to a bronchodilator. We argue that this result is a physiological proof of therapeutic efficacy, consistent with the well-described effect of thermoplasty in reducing the amount of airway smooth muscle. FQSR (Fondation Quebecoise en Sante Respiratoire); Canadian Institutes of Health Research (PJT-387910); FRQS (Fonds de recherche du Quebec - Sante); and Boston Scientific Inc This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Objectives: Suffering is intimately linked to the experience of illness, and its relief is a mandate of medicine. Advances in knowledge around terminal illness have enabled better management of the somatic dimension. Nevertheless, there is what can be called “non-somatic” suffering which in some cases may take precedence. Inspired by Paul Ricoeur's thinking on human suffering, our aim in this qualitative study was to better understand the experience of non-somatic suffering. Methods: Semi-structured interviews were conducted with 19 patients. The results were qualitatively analyzed following a continuous comparative analysis approach inspired by grounded theory. Results: Three key themes synthesize the phenomenon: “the being enduring the suffering”, “the being whose agency is constrained”, and “the being in relationship with others.” The first describes what patients endure, the shock and fears associated with their own finitude, and the limits of what can be tolerated. The second refers to the experience of being restricted and of mourning the loss of their capacity to act. The last describes a residual suffering related to their interactions with others, that of loneliness and of abandoning their loved ones, two dimensions that persist even when they have accepted their own death. Conclusions: Non-somatic suffering can be multifarious, even when minimized by the patient. When evaluating suffering, we must keep in mind that patients can reach a “breaking point” that signals the state of unbearable suffering. In managing it, we probably need to make more room for family and friends, as well as a posture of caring based more on presence and listening.

The objective of this study was to understand the factors associated with "passing through suffering" in terminal illness. We interviewed 19 adults diagnosed with terminal disease in palliative stage. Interviews were analyzed using thematic analysis. Four axes of understanding were generated. In the first, participants discussed the will to "feel alive" despite the disease. The second, the process of acceptance, is based on lucidity and on letting go. The third highlights the importance of relationships with others. The fourth axis describes the consequences of this passage through suffering. This study highlights a phenomenon of adapting to suffering.

BackgroundSubjects without a previous history of asthma, presenting with unexplained respiratory symptoms and normal spirometry, may exhibit airway hyperresponsiveness (AHR) in association with underlying eosinophilic (type 2 (T2)) inflammation, consistent with undiagnosed asthma. However, the prevalence of undiagnosed asthma in these subjects is unknown.MethodsIn this observational study, inhaled corticosteroid-naïve adults without previously diagnosed lung disease reporting current respiratory symptoms and showing normal pre- and post-bronchodilator spirometry underwent fractional exhaled nitric oxide (FENO) measurement, methacholine challenge testing and induced sputum analysis. AHR was defined as a provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 s (PC20) −1and T2 inflammation was defined as sputum eosinophils >2% and/orFENO>25 ppb.ResultsOut of 132 subjects (mean±sdage 57.6±14.2 years, 52% female), 47 (36% (95% CI 28–44%)) showed AHR: 20/132 (15% (95% CI 9–21%)) with PC20−1and 27/132 (21% (95% CI 14–28%)) with PC204–15.9 mg·mL−1. Of 130 participants for whom sputum eosinophils,FENOor both results were obtained, 45 (35% (95% CI 27–43%)) had T2 inflammation. 14 participants (11% (95% CI 6–16%)) had sputum eosinophils >2% and PC20≥16 mg·mL−1, suggesting eosinophilic bronchitis. The prevalence of T2 inflammation was significantly higher in subjects with PC20−1(12/20 (60%)) than in those with PC204–15.9 mg·mL−1(8/27 (30%)) or ≥16 mg·mL−1(25/85 (29%)) (p=0.01).ConclusionsAsthma, underlying T2 airway inflammation and eosinophilic bronchitis may remain undiagnosed in a high proportion of symptomatic subjects in the community who have normal pre- and post-bronchodilator spirometry.

Aim To summarize lung function characteristics of athletic swimmers and discuss mechanisms explaining these changes while puting forward the lack of a clear understanding of the precise physiological factors implicated. Methods Literature search until 07.2021 on Medline and EMBASE using key words swimming, athletes, respiratory physiology, lung development, lung function tests. Relevant articles in french and english were reviewed. Results We found insufficient data to perform a meta-analysis. However, there are evidences that swimmers have better expiratory flows and increased baseline lung volumes than non-athletes or non-swimmers. Although these features can result from changes in lung development following intense training over the years, the contribution of a genetic predisposition and positive selection cannot be totally excluded. Conclusion Disentangling the participation of constitutional factors and years of hard training to explain the larger lung volumes of athletic swimmers is in favour of an adaptative response of the lungs to early swim training through modification of the pathway of lung development. There seems to be an optimal window of opportunity before the end of growth for these adaptational changes to occur. Precise mechanisms, and contribution of adaptative change on lung physiology, remain to be further studied.

Background Clinicians are increasingly recognizing severe asthma patients in whom biologics and other add-on therapies lead to dramatic improvement. Currently, there is no agreed-upon super-responder (SR) definition. Objective To survey severe asthma experts using a modified Delphi process, to develop an international consensus-based definition of a severe asthma SR. Methods The Delphi panel was composed of 81 participants (94% specialist pulmonologists or allergists) from 24 countries and consisted of three iterative online voting rounds. Consensus on individual items, whether acceptance or rejection, required at least 70% agreement by panel members. Results Consensus was achieved that the SR definition should be based on improvement across three or more domains assessed over 12 months. Major SR criteria included exacerbation elimination, a large improvement in asthma control (two or more times the minimal clinically important difference), and cessation of maintenance of oral steroids (or weaning to adrenal insufficiency). Minor SR criteria were composed of a 75% exacerbation reduction, having well-controlled asthma, and 500 mL or greater improvement in FEV1. The SR definition requires improvement in at least two major criteria. In the future, the SR definition should be expanded to incorporate quality of life measures, although current tools can be difficult to implement in a clinical setting and further research is needed. Conclusions This international consensus-based definition of severe asthma SRs is an important prerequisite for better understanding SR prevalence, predictive factors, and the mechanisms involved. Further research is needed to understand the patient's perspective and to measure quality of life more precisely in SRs.

Version 1.0 – September 9, 2020 This document complements the Canadian Thoracic Society (CTS) Position Statement on “Addressing therapeutic questions to help Canadian physicians optimize asthma man...

In 2019, the GINA committee asserted what is arguably one of the most profound changes in the management of asthma in the last 30 years: treatment of asthma with short acting beta agonists (SABA) a...

Severe acute respiratory syndrome coronavirus 2 is responsible for coronavirus disease 2019 (COVID‐19). While COVID‐19 is often benign, a subset of patients develops severe multilobar pneumonia that can progress to an acute respiratory distress syndrome. There is no cure for severe COVID‐19 and few treatments significantly improved clinical outcome. Dexamethasone and possibly aspirin, which directly/indirectly target the biosynthesis/effects of numerous lipid mediators are among those options. Our objective was to define if severe COVID‐19 patients were characterized by increased bioactive lipids modulating lung inflammation. A targeted lipidomic analysis of bronchoalveolar lavages (BALs) by tandem mass spectrometry was done on 25 healthy controls and 33 COVID‐19 patients requiring mechanical ventilation. BALs from severe COVID‐19 patients were characterized by increased fatty acids and inflammatory lipid mediators. There was a predominance of thromboxane and prostaglandins. Leukotrienes were also increased, notably LTB4, LTE4, and eoxin E4. Monohydroxylated 15‐lipoxygenase metabolites derived from linoleate, arachidonate, eicosapentaenoate, and docosahexaenoate were also increased. Finally yet importantly, specialized pro‐resolving mediators, notably lipoxin A4 and the D‐series resolvins, were also increased, underscoring that the lipid mediator storm occurring in severe COVID‐19 involves pro‐ and anti‐inflammatory lipids. Our data unmask the lipid mediator storm occurring in the lungs of patients afflicted with severe COVID‐19. We discuss which clinically available drugs could be helpful at modulating the lipidome we observed in the hope of minimizing the deleterious effects of pro‐inflammatory lipids and enhancing the effects of anti‐inflammatory and/or pro‐resolving lipid mediators.

MPOC; Asma; Pronòstic EPOC; Asma; Pronóstico COPD; Asthma; Prognosis Although chronic obstructive pulmonary disease (COPD) and asthma are well-characterized diseases, they can coexist in a given patient. The term asthma–COPD overlap (ACO) was introduced to describe patients that have clinical features of both diseases and may represent around 25% of COPD patients and around 20% of asthma patients. Despite the increasing interest in ACO, there are still substantial controversies regarding its definition and its position within clinical guidelines for patients with obstructive lung disease. In general, most definitions indicate that ACO patients must present with non-reversible airflow limitation, significant exposure to smoking or other noxious particles or gases, together with features of asthma. In patients with a primary diagnosis of COPD, the identification of ACO has therapeutic implication because the asthmatic component should be treated with inhaled corticosteroids and some studies suggest that the most severe patients may respond to biological agents indicated for severe asthma. This manuscript aims to summarize the current state-of-the-art of ACO. The definitions, prevalence, and clinical manifestations will be reviewed and some innovative aspects, such as genetics, epigenetics, and biomarkers will be addressed. Lastly, the management and prognosis will be outlined as well as the position of ACO in the COPD and asthma guidelines.

PURPOSE OF REVIEW: Allergen bronchoprovocation test (ABT) has been used to study asthma pathophysiology and as a disease-modelling tool to assess the properties and efficacy of new asthma drugs. In view of the complexity and heterogeneity of asthma, which has driven the definition of several phenotypes and endotypes, we aim to discuss the role of ABT in the era of precision medicine and provide guidance for clinicians how to interpret and use available data to understand the implications for the benefits of asthma treatment. RECENT FINDINGS: In this review, we summarize background knowledge and applications of ABT and provide an update with recent publications on this topic. In the past years, several studies have been published on ABT in combination with non-invasive and invasive airway samplings and innovative detection techniques allowing to study several inflammatory mechanisms linked to Th2-pathway and allergen-induced pathophysiology throughout the airways. SUMMARY: ABT is a valuable research tool, which has strongly contributed to precision medicine by helping to define allergen-triggered key inflammatory pathways and airway pathophysiology, and thus helped to shape our understanding of allergen-driven asthma phenotypes and endotypes. In addition, ABT has been instrumental to assess the interactions and effects of new-targeted asthma treatments along these pathways. (Less)

To identify susceptibility loci and candidate causal genes of asthma, we performed a genome-wide association study (GWAS) in UK Biobank on a broad asthma definition (n = 56,167 asthma cases and 352,255 controls). We then carried out functional mapping through transcriptome-wide association studies (TWAS) and Mendelian randomization in lung (n = 1,038) and blood (n = 31,684) tissues. The GWAS revealed 72 asthma-associated loci from 116 independent significant variants (PGWAS 20) including a stop-gain mutation in the filaggrin (FLG) gene. The top lung TWAS gene on 17q12-q21 was GSDMB (PTWAS=1.42E-54). Other TWAS genes of interest include TSLP on 5q22, RERE on 1p36, CLEC16A on 16p13, and IL4R on 16p12, which all replicated in GTEx lung (n = 515). A novel risk locus was also revealed by the lung asthma TWAS on 1q23.3 with the putative gene encoding the gamma chain of the high-affinity IgE receptor (FCER1G, PTWAS=2.13E-6), which was also replicated in GTEx lung (PTWAS=3.71E-7). By testing a comprehensive set of cells and tissues, we then demonstrated that the largest fold enrichment of regulatory and functional annotations among asthma-associated variants was in the blood. We mapped 485 eQTL-regulated genes associated with asthma in the blood and 50 of them were shown to be causally associated with asthma by Mendelian randomization. Prioritization of druggable genes revealed known (IL4R, TSLP, IL6, TNFSF4) and potentially new therapeutic targets for asthma.

To identify candidate causal genes of asthma, we performed a genome-wide association study (GWAS) in UK Biobank on a broad asthma definition (n = 56,167 asthma cases and 352,255 controls). We then carried out functional mapping through transcriptome-wide association studies (TWAS) and Mendelian randomization in lung (n = 1,038) and blood (n = 31,684) tissues. The GWAS reveals 72 asthma-associated loci from 116 independent significant variants (PGWAS, Kim Valette et al. perform a genomic study on asthma integrating genome-wide association study, functional mapping using lung and blood transcriptome-wide profiles, as well as Mendelian randomization. They show candidate causal genes expressed in lung and blood tissues that are putative therapeutic targets for asthma.

This position statement aims to provide rapid guidance for Canadian physicians treating patients with asthma during the COVID-19 pandemic. The recommendations are informed by a very limited body of...

Asthma is a chronic inflammatory disease of the airways affecting more than 300 million patients worldwide. The disease can be of various severity ranging from very mild to severe. The severe form of the disease only affects about 5% of patients but is responsible for a large component of the overall disease burden and results in about half of direct asthma-related costs. This led to important investments in research, which allowed better understanding of its pathophysiology and the development of new therapeutic strategies. Despite those breakthroughs, recent guidelines still emphasize the need to distinguish uncontrolled or difficult-to-control asthma from severe asthma. Indeed, a significant number of patients referred to severe asthma clinics are non-severe uncontrolled patients. However, the basics of asthma management such as ensuring that the patient has the right diagnosis, recognition of contributing comorbidities, avoidance of exposure to sensitizing agents in allergic individuals, regular assessment of control, and patient education should not be forgotten. The major improvements in pathophysiology arose from the evidences that asthma is of heterogeneous nature. Such heterogeneity has been particularly studied in severe asthma, leading to the recognition of more homogeneous groups referred to as phenotypes. Appropriate phenotyping of individual patients allows enforcing more specific treatment plans for patients, which is a step toward precision medicine. The high morbidity and socioeconomic burden of severe asthma has led to the development of optimized therapeutic strategies in addition to the commercialization of new drugs. Many of these have targeted the eosinophilic component of inflammatory asthma phenotypes while there is still a need to develop new therapies for non-eosinophilic asthma. When asthma is not controlled by optimal therapy, including a high-dose of inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA), a long acting anticholinergic agent can be added and if insufficient, a variety of biologic agents is now available in many countries. When biologics are not an option, thermoplasty and macrolides have also become available. Despite many recent breakthroughs in severe asthma, much research needs to be done. Improvement in availability of targeted asthma medications and asthma prevention should be top priorities.

Transient airway narrowing can occur during or following exercise, a phenomenon called exercise-induced bronchoconstriction (EIB). The main mechanism of EIB is considered to be airway dehydration, resulting from increased ventilation during exercise. In asthma, such water loss causes an increase in airway fluid osmolarity, inducing airway smooth muscle contraction following the release of mediators from airway inflammatory cells. Asthmatics frequently experience EIB, but it may also be observed in others not reporting asthma symptoms, particularly elite endurance athletes. Individuals with asthma often refrain from performing physical exercise because they fear troublesome respiratory symptoms. However, in addition to its well-known cardiovascular and metabolic benefits, physical training has been shown to be beneficial for asthmatic adults and children in improving asthma control and asthma-related quality of life. Exercise training also reduces the risk of asthma exacerbations, improves exercise capacity, and decreases frequency and severity of EIB. To minimize the risk of EIB, asthma must be well controlled, and specific pharmacological and nonpharmacological preventative measures can be taken. Counterintuitively, in high-level athletes, the development of asthma, airway hyperresponsiveness, and EIB can be promoted by intense training over many years following exposure to environmental conditions, such as cold air, pollutants, and allergens. As for nonathletes, athletes must have optimal asthma control and apply preventative measures against EIB, taking into account antidoping regulations for asthma medications. A better understanding of the impact of exercise on asthma should improve the overall care of asthmatic patients.

RATIONALE: While severe asthma affects approximately 5% of all individuals with asthma, this small minority of individuals accounts for a large proportion of the asthma-related costs. Greater understanding of the pathophysiology of asthma combined with the emergence of novel biologic therapies for severe asthma supported the need for a thorough review of the diagnosis, investigation, phenotyping, and management of severe asthma.OBJECTIVES: We aimed to propose a practical approach to distinguish uncontrolled asthma due to inadequate asthma management from severe asthma despite optimal asthma management. Moreover, based on emerging scientific evidence, we sought to provide guidance for characterizing individuals with severe asthma and considering a phenotype-specific management. We also aimed to review other novel new potential therapeutic approaches.METHODS: We systematically reviewed the relevant literature focusing on randomized controlled trials and when available, systematic reviews of randomiz...

Characterization of key biological processes underpinning ARDS and the biological differences between disease subgroups (such as direct and indirect ARDS) can enhance our understanding of ARDS, its heterogeneity and may guide the development of specific therapies. In this study, we sought to explore mechanistic biological processes underlying ARDS using a metabolomics approach based on serum proton nuclear magnetic resonance spectroscopy (1H-NMR) and gas chromatography mass spectrometry (GC-MS) methodologies. Additionally, we sought to benchmark metabolomics ability for ARDS detection and subclassification against those of commonly published protein biomarkers and cytokines. Using 1H-NMR and GC-MS we characterized the metabolites that distinguish ARDS patients (n=68) from ICU ventilated controls (n=34). We further measured IL-6, IL-8, IL-10, TNF-a, Ang-2, RAGE, vWF, TNF-RI, ICAM-1, PAI-1, SP-D and Protein-C in ARDS patients and controls. Similarly, to explore ARDS heterogeneity, we identified metabolites and biomarkers that differentiate direct ARDS (n = 49) from indirect ARDS (n = 51). Pathway analysis was carried out to highlight the pathobiological processes underpinning ARDS development and heterogeneity. To characterize ARDS biomolecular processes, we prospectively tracked the metabolic changes in a cohort of ARDS patients (n = 44) as they progressed through ARDS until recovery. Our data indicates that metabolomics fared better than proteins/cytokines biomarkers, especially in differentiating direct and indirect ARDS. Pathway analysis of ARDS versus controls identified a dominant involvement of serine-glycine metabolism in a pattern suggestive of an encompassing theme of relative folate deficiency. In longitudinal tracking, folate-linked metabolites generally exhibit correction by 7-14 days, which parallels clinical improvements. Funding: This study was partly funded by a team grant from Alberta Innovates-Health Solutions (AIHS) to the Alberta Sepsis Network, Alberta’s Health Research Innovation Strategy grant to Brent W. Winston and Hans J. Vogel, Lung Association of Alberta grant to Brent W. Winston, a grant from the Canadian Intensive Care Foundation to Brent W. Winston, an Emerging Team Grant from Cumming School of Medicine, University of Calgary, Alberta Health Services awarded to Brent W. Winston and Hans J. Vogel. Declaration of Interest: None of the authors has any conflicts of interest or other financial disclosures to make. Ethical Approval: This study has been approved by the Calgary Health Research Ethics Board (REB15-0348).

Information regarding risk factors associated with severe coronavirus disease (COVID-19) is limited. This study aimed to develop a model for predicting COVID-19 severity.Overall, 690 patients with confirmed COVID-19 were recruited between 1 January and 18 March 2020 from hospitals in Honghu and Nanchang; finally, 442 patients were assessed. Data were categorised into the training and test sets to develop and validate the model, respectively.A predictive HNC-LL (Hypertension, Neutrophil count, C-reactive protein, Lymphocyte count, Lactate dehydrogenase) score was established using multivariate logistic regression analysis. The HNC-LL score accurately predicted disease severity in the Honghu training cohort (area under the curve [AUC]=0.861, 95% confidence interval [CI]: 0.800-0.922; P0.001); Honghu internal validation cohort (AUC=0.871, 95% CI: 0.769-0.972; P0.001); and Nanchang external validation cohort (AUC=0.826, 95% CI: 0.746-0.907; P0.001) and outperformed other models, including CURB-65 (confusion, uraemia, respiratory rate, BP, age ≥65 years) score model, MuLBSTA (multilobular infiltration, hypo-lymphocytosis, bacterial coinfection, smoking history, hypertension, and age) score model, and neutrophil-to-lymphocyte ratio model. The clinical significance of HNC-LL in accurately predicting the risk of future development of severe COVID-19 was confirmed.We developed an accurate tool for predicting disease severity among COVID-19 patients. This model can potentially be used to identify patients at risks of developing severe disease in the early stage and therefore guide treatment decisions.This work was supported by the National Nature Science Foundation of China (grant no. 81972897) and Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2015).

Resume Objectifs Valider les recommandations posologiques produites en 2007 par un comite de travail du centre hospitalier universitaire de Montreal (Chum) en regard du propofol dans les cas de sedation palliative et les comparer avec celles proposees dans la litterature medicale. Identifier les caracteristiques communes parmi les patients dans cette situation clinique particuliere. Patients et methodes Etude retrospective de dossiers de patients admis a l’unite de soins palliatifs du Chum pour lesquels une sedation palliative au propofol a ete administree entre le 1 er janvier 2009 et le 15 octobre 2012. Resultats Les dossiers de cinq femmes et trois hommes souffrant de pathologies cancereuses variees ont ete etudies. Les indications sont demeurees semblables a celles rapportees dans la litterature (douleur incoercible, agitation psychomotrice, delirium, detresse respiratoire). Les doses de medication analgesique administree dans les 24 heures precedant l’administration du propofol etaient elevees. La dose moyenne en equivalent morphine sous-cutanee s’elevait a 550,81 mg. La dose moyenne de methadone, requise chez cinq des huit patients, s’elevait a 72,5 mg. L’usage des sedatifs courants (midazolam, methotrimeprazine, phenobarbital) etait limite par la presence de reactions paradoxales, d’interactions medicamenteuses, de tolerance ou d’effets secondaires notables, d’ou le recours au propofol. Le debit initial moyen de perfusion etait de 2 a 3 mg/kg/h et s’est eleve a 5 mg/kg/h en moyenne. Conclusion Lorsque utilisee avec prudence, la sedation palliative a base de propofol represente une avenue therapeutique pouvant apporter un soulagement aux patients souffrant de symptomes refractaires, d’effets secondaires ou de tolerance avec la medication sedative couramment utilisee.

Purpose of review Asthma and exercise-induced bronchoconstriction (EIB) are common in the athlete and can interfere with sport performances. In this review, we report recent findings on the prevalence, diagnosis and evaluation of these conditions, in addition to specific issues regarding their treatment and antidoping regulations. Recent findings Recent studies confirmed the high prevalence of exercise-induced respiratory symptoms, asthma and EIB, in athletes and showed that these conditions are still underdiagnosed and undertreated. Recent studies highlight the suboptimal use of asthma medication in asthmatic and allergic athletes. Regarding the diagnosis and treatment, questions about the role and criteria for positivity of eucapnic voluntary hyperpnea test were raised. It was confirmed that there is a subgroup of athletes with poor response to asthma medication. Finally, regarding antidoping regulations, new methods and changes in criteria for urinary bronchodilator thresholds were suggested. Summary Recent publications confirm that exercise-induced respiratory symptoms, asthma and EIB are common in athletes but often unrecognized and not optimally or successfully treated. It was suggested that current criteria for diagnostic bronchoprovocation test responses could be reassessed, as well as antidoping criteria for β2-agonists urinary levels. There is a need for more research on prevention of airways dysfunction in athletes, identification of different asthma phenotypes and the benefits of standard asthma medication in this population.

Resume L’evaluation de la douleur devient plus difficile pour les soignants et plus mysterieuse pour les familles quand les malades deviennent comateux. C’est une source frequente d’inquietude pour elles. Nous revoyons les outils qui permettent d’evaluer la douleur ressentie par les patients en coma de fin de vie afin de prescrire et d’ajuster l’analgesie pour obtenir le confort. Nous revoyons les etudes neurophysiologiques qui suggerent que le malade en etat de conscience minimale, porteur d’une pathologie presumee proche de la situation observee en fin de vie, demeure affecte par la douleur et qu’il en est tres probablement conscient. Au cours de ces comas, les etudes suggerent que le versant communicationnel est probablement plus affecte que la conscience elle-meme. Cela justifie pleinement de traiter le malade en coma de fin de vie comme une personne a part entiere et de le soulager adequatement.