Gut-derived short-chain fatty acids modulate skin barrier integrity by promoting keratinocyte metabolism and differentiation.

Barrier integrity is central to the maintenance of healthy immunological homeostasis. Impaired skin barrier function is linked with enhanced allergen sensitization and the development of diseases such as atopic dermatitis (AD), which can precede the development of other allergic disorders, for example, food allergies and asthma. Epidemiological evidence indicates that children suffering from allergies have lower levels of dietary fibre-derived short-chain fatty acids (SCFA). Using an experimental model of AD-like skin inflammation, we report that a fermentable fibre-rich diet alleviates systemic allergen sensitization and disease severity. The gut-skin axis underpins this phenomenon through SCFA production, particularly butyrate, which strengthens skin barrier function by altering mitochondrial metabolism of epidermal keratinocytes and the production of key structural components. Our results demonstrate that dietary fibre and SCFA improve epidermal barrier integrity, ultimately limiting early allergen sensitization and disease development.The Graphical Abstract was designed using Servier Medical Art images ( https://smart.servier.com ).

Swiss Recommendations for the Follow-Up and Treatment of Pulmonary Long COVID.

INTRODUCTION: Emerging evidence suggests that long-term pulmonary symptoms and functional impairment occurs in a proportion of individuals following SARS-CoV-2 infection. Although the proportion of affected patients remains to be determined, physicians are increasingly being confronted with patients reporting respiratory symptoms and impairment beyond the acute phase of COVID-19. In face of limited evidence, the Swiss Society for Pulmonology established a working group to address this area of unmet need and formulated diagnostic and treatment recommendations for the care of patients with pulmonary long COVID (LC). METHOD: The Swiss COVID Lung Study group and Swiss Society for Pulmonology (SSP) formulated 13 questions addressing the diagnosis and treatment of pulmonary LC. A survey within the SSP special interest groups involved in care of LC patients was conducted in Switzerland. A CORE process/Delphi-like process was used to formulate recommendations. Forty experienced pulmonologists replied to the first survey and 22 completed the second follow-up survey. Agreement of ≥70% consensus led to formulation of a recommendation. RESULTS: The participants in the survey reached consensus and formulated a strong recommendation for regarding the following points. Patients hospitalized for COVID-19 should have a pulmonary assessment including pulmonary function tests. Symptomatic subjects affected by COVID-19, including those with mild disease, should benefit from a pulmonary follow-up. Persistent respiratory symptoms after COVID-19 should be investigated by a pulmonary follow-up including plethysmography, diffusion capacity measurement, and blood gases analysis. Individuals having suffered from COVID-19 and who present with persistent respiratory symptoms should be offered a rehabilitation. Additional questions were given moderateor weak recommendations for. The panel did not reach sufficient consensus for pharmacological therapy (e.g., therapy specifically targeting lung fibrosis) to formulate recommendations for LC drug treatment. CONCLUSION: The formulated recommendations should serve as an interim guidance to facilitate diagnosis and treatment of patients with pulmonary LC. As new evidence emerges, these recommendations may need to be adapted.

A prevalent and culturable microbiota links ecological balance to clinical stability of the human lung after transplantation.

There is accumulating evidence that the lower airway microbiota impacts lung health. However, the link between microbial community composition and lung homeostasis remains elusive. We combine amplicon sequencing and bacterial culturing to characterize the viable bacterial community in 234 longitudinal bronchoalveolar lavage samples from 64 lung transplant recipients and establish links to viral loads, host gene expression, lung function, and transplant health. We find that the lung microbiota post-transplant can be categorized into four distinct compositional states, 'pneumotypes'. The predominant 'balanced' pneumotype is characterized by a diverse bacterial community with moderate viral loads, and host gene expression profiles suggesting immune tolerance. The other three pneumotypes are characterized by being either microbiota-depleted, or dominated by potential pathogens, and are linked to increased immune activity, lower respiratory function, and increased risks of infection and rejection. Collectively, our findings establish a link between the lung microbial ecosystem, human lung function, and clinical stability post-transplant.

Microbiome-induced antigen-presenting cell recruitment coordinates skin and lung allergic inflammation.

BACKGROUND: Allergic skin inflammation often presents in early childhood; however, little is known about the events leading to its initiation and whether it is transient or long-term in nature. OBJECTIVE: We sought to determine the immunologic rules that govern skin inflammation in early life. METHODS: Neonatal and adult mice were epicutaneously sensitized with allergen followed by airway allergen challenge. Epicutaneous application of labeled allergen allowed for determination of antigen uptake and processing by antigen-presenting cells. RNAseq and microbiome analysis was performed on skin from neonatal and adult specific pathogen-free and germ-free mice. RESULTS: A mixed TH2/TH17 inflammatory response in the skin and the lungs of adult mice was observed following sensitization and challenge. Comparatively, neonatal mice did not develop overt skin inflammation, but exhibited systemic release of IL-17a and a TH2-dominated lung response. Mechanical skin barrier disruption was not sufficient to drive allergic skin inflammation, although it did promote systemic immune priming. Skin of neonatal mice and adult germ-free mice was seeded with low numbers of antigen-presenting cells and impaired chemokine and alarmin production. Enhanced chemokine and alarmin production, and seeding of the skin with antigen-presenting cells capable of instructing recruited cells to elicit their effector function, was, at least in part, dependent on formation of the microbiome, and consequently contributed to the development of overt skin disease. CONCLUSIONS: These data shed light on the principles that underlie allergic inflammation in different tissues and highlight a window of opportunity that might exist for early-life prevention of allergic diseases.

PneumoLaus: Prévalence de troubles respiratoires fonctionnels dans un échantillon de la population lausannoise.

PneumoLaus: Prevalence of Lung Function Abnormalities in a Sample of the General Population of Lausanne Abstract. Reduced lung function predicts increased mortality. The prevalence of spirometric abnormalities depends on their definition, the references values used and the use or not of bronchodilation. In the PneumoLaus study, conducted between 2014 and 2017 in a sample of the general population of Lausanne, prevalence of chronic obstruction was 3,8 %, of reversible obstruction 2,5 % and of possible restriction 2,2 %. These numbers are lower than in other population studies. Men had more abnormal spirometry results than women, and ever-smokers more than never-smokers. Two thirds of participants with chronic obstruction, most of which without respiratory symptoms, were not aware of any lung disease.

Résumé. Une fonction pulmonaire réduite s'associe à une mortalité accrue. La prévalence de troubles respiratoires fonctionnels dépend de sa définition, des références employées et de l'utilisation ou non de bronchodilatateur. Dans l'étude PneumoLaus, conduite entre 2014 et 2017 dans un échantillon de la population de Lausanne, la prévalence d'obstruction chronique était de 3,8 %, d'obstruction réversible de 2,5 % et de possible restriction de 2,2 %, proportions plus basses que dans d'autres études populationnelles. Les hommes présentaient plus souvent des anomalies spirométriques comparé aux femmes et les fumeurs plus souvent que les non-fumeurs. Deux tiers des sujets avec obstruction chronique, pour la plupart sans symptômes respiratoires, ne se connaissaient pas de maladie pulmonaire.

Immunotherapy-Induced Airway Disease: A New Pattern of Lung Toxicity of Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) have been shown to improve overall and progression-free survival in various cancers but have been associated with various immune-related adverse events (IRAEs), including interstitial lung disease, especially organizing pneumonia. We report 2 cases of isolated severe airway disease attributable to ICIs, a rarely reported pattern of lung toxicity. The first patient received nivolumab with or without ipilimumab in a randomized double-blind trial for locoregional metastatic melanoma. The second patient was treated with nivolumab for lung adenocarcinoma. An IRAE was suspected in both cases due to a temporal relationship between ICI initiation and symptom onset. ICIs were stopped, and high-dose prednisone, inhaled corticosteroids, and bronchodilators were administered, allowing a rapid clinical and functional improvement in Patient 1. In Patient 2, despite prolonged high-dose prednisone, only a stabilization of forced expiratory volume in 1 s could be achieved, and the disease course was complicated by respiratory infections resulting in further loss of lung function. The patient died 1 year later due to progression of metastatic disease. These 2 cases suggest that pulmonary IRAEs secondary to ICIs may present as isolated bronchitis or bronchiolitis, with variable outcomes following ICI withdrawal and systemic corticosteroids.

Early-Life Formation of the Microbial and Immunological Environment of the Human Airways.

Crosstalk between immune cells and the microbiota in mucosal tissues can set an individual on a trajectory toward health or disease. Little is known about these early-life events in the human respiratory tract. We examined bacterial colonization and immune system maturation in the lower airways over the first year of life. The lower respiratory tract microbiota forms within the first 2 postnatal months. Within the first weeks, three microbial profiles are evident, broadly distinguished as dysbiotic or diverse, and representing different microbial virulence potentials, including proteolysis of immunoglobulin A (IgA) that is critical for mucosal defense. Delivery mode determines microbiota constituents in preterm, but not term, births. Gestational age is a key determinant of immune maturation, with airway cells progressively increasing expression of proallergic cytokine interleukin-33 and genes linked with IgA. These data reveal microbial and immunological development in human airways, and may inform early-life interventions to prevent respiratory diseases.

GLI 2012 equations define few spirometric anomalies in the general population: the PneumoLaus study.

BACKGROUND: Reduced lung function predicts increased mortality, but its prevalence may vary depending on definition considered, use of bronchodilation and applied reference values. We aimed to assess lung function abnormalities in Lausanne, Switzerland, and their association with clinical history. METHODS: In a general population sample, spirometry was performed and bronchodilation applied if the ratio forced expiratory volume in 1 s (FEV1) / forced vital capacity (FVC) or the FVC was below the lower limit of normal (LLN) according to Global Lung Function Initiative 2012 references. Results for FEV1/FVC according to the LLN were compared to the 0.7 fixed ratio. Respiratory risk factors, symptoms and self-reported respiratory diagnoses were recorded through a questionnaire. RESULTS: Out of the 3342 included subjects, 3.8% had chronic obstruction and 2.5% reversible obstruction when using the LLN; possible lung restriction alone was present in 1.8%, and associated with chronic obstruction in 0.4%. Ever smokers had a higher prevalence of abnormal spirometry, chronic obstruction and reversible obstruction; there was no difference with regard to possible restriction. Overall, chronic airway obstruction was found in 8.9% of current smokers, 4.6% of former smokers and 1.5% of never smokers. Only one third of participants with chronic obstruction were aware of a respiratory disease. CONCLUSION: Prevalence of abnormal lung function in the population of Lausanne is low. This may be due to a low rate of ever-smokers, the application of a full bronchodilation dose, but also to inherent characteristics of this population.

[When home become breathtaking]. / Quand la maison nous coupe le souffle.

We spend most of our time indoor and mainly at home. Thermal insulation has greatly improved in the last decades, thus leading to deficiency in ventilation and poor indoor air quality. Many studies suggest that there is a link between respiratory diseases and various indoor air pollutants such as moulds, allergens, volatile organic compounds, combustible smoke, house dust mite, radon or asbestos. This article reviews the most common pathogenic pollutants at home as well as their sources and related respiratory diseases. Preventive measures are further presented for every category of contaminant.

Nous passons la plupart de notre temps à l'intérieur et le plus souvent à notre domicile. Durant les dernières décennies, l'amélioration de l'isolation thermique des habitats a entraîné une diminution de la ventilation des espaces clos et un appauvrissement de la qualité de l'air intérieur. Plusieurs études suggèrent une association entre des symptômes ou pathologies respiratoires et différents contaminants de l'air intérieur comme les moisissures, les animaux domestiques, les composés organiques volatiles, les produits de combustion, les acariens, le radon ou l'amiante. Cet article passe en revue les substances pathogènes les plus fréquentes dans le milieu domestique, ainsi que leurs sources et les pathologies respiratoires associées. Des recommandations sont proposées pour chaque catégorie de contaminant.

[Noninvasive ventilation for chronic hypercapnic respiratory failure]. / Rôle de la ventilation non invasive dans l'insuffisance respiratoire hypercapnique chronique.

Chronic hypercapnic respiratory failure is essentially a ventilatory failure. Noninvasive ventilation (NIV ) reduces the work of breathing, improves pulmonary compliance and alveolar ventilation, corrects gas exchange disorders and improves dyspnoea. However, treatment efficacy depends on the underlying pathology, on correct timing and on patient compliance. In this context, the principal role of the primary care physician is to search for, at every visit of at risk patients, signs and symptoms of ventilatory failure and to refer the patient to a respiratory care specialist. He also plays a role in the follow up of patients under noninvasive ventilation for the detection of clinical parameters suggesting NIV failure.

L'insuffisance respiratoire hypercapnique chronique est essentiellement une défaillance ventilatoire. La ventilation non invasive (VNI) diminue le travail des muscles respiratoires, augmente la compliance thoracique, améliorant ainsi la dyspnée et les troubles des échanges gazeux. Toutefois, l'efficacité du traitement dépend de la pathologie sous-jacente, du bon timing d'initiation et de la compliance du patient. Dans ce contexte, le rôle principal du médecin de premier recours consiste à rechercher, lors de chaque visite médicale de patients à risque, des signes et symptômes de défaillance ventilatoire qui nécessitent de référer le patient à un pneumologue. Son rôle est aussi important dans le suivi des patients ventilés pour la détection précoce des paramètres cliniques suggérant un échec de VNI.

[Systemic biomarkers in respiratory tract infections]. / Biomarqueurs systèmiques pour les infections respiratoires.

Respiratory tract infections represent a major cause of morbidity and mortality despite the progress made in their diagnosis and treatment. Since the clinical presentation of a viral or bacterial infection is often similar, the identification of a biomarker that could guide the clinician whether or not to introduce an antibiotic therapy is crucial. C-reactive protein and procalcitonin are the most commonly used biomarkers as a diagnostic tool for respiratory tract infections. New biomarkers show promising results for assessing the severity of infection and identifying patients at risk for complications. However, the use of biomarkers has limitations and the diagnosis of a bacterial infection should not be based solely on the measurement of a biomarker.

Malgré le progrès effectué pour le diagnostic et le traitement des infections respiratoires, ces dernières représentent une cause de morbidité et mortalité importante. La présentation clinique d'une infection virale ou bactérienne étant souvent identique, l'identification d'un biomarqueur qui pourrait aider le clinicien à la décision d'introduire ou pas un traitement antibiotique est cruciale. La protéine C-réactive et la procalcitonine sont les biomarqueurs les plus fréquemment utilisés comme aide au diagnostic. Des nouveaux biomarqueurs montrent des résultats prometteurs pour évaluer la sévérité de l'infection et les patients à risque de complication. Toutefois, l'utilisation des biomarqueurs présente des limitations et le diagnostic d'une infection bactérienne ne doit en aucun cas être basé uniquement sur la mesure d'un biomarqueur.

Dietary Fiber Confers Protection against Flu by Shaping Ly6c- Patrolling Monocyte Hematopoiesis and CD8+ T Cell Metabolism.

Dietary fiber protects against chronic inflammatory diseases by dampening immune responses through short-chain fatty acids (SCFAs). Here we examined the effect of dietary fiber in viral infection, where the anti-inflammatory properties of SCFAs in principle could prevent protective immunity. Instead, we found that fermentable dietary fiber increased survival of influenza-infected mice through two complementary mechanisms. High-fiber diet (HFD)-fed mice exhibited altered bone marrow hematopoiesis, characterized by enhanced generation of Ly6c- patrolling monocytes, which led to increased numbers of alternatively activated macrophages with a limited capacity to produce the chemokine CXCL1 in the airways. Blunted CXCL1 production reduced neutrophil recruitment to the airways, thus limiting tissue immunopathology during infection. In parallel, diet-derived SCFAs boosted CD8+ T cell effector function by enhancing cellular metabolism. Hence, dietary fermentable fiber and SCFAs set an immune equilibrium, balancing innate and adaptive immunity so as to promote the resolution of influenza infection while preventing immune-associated pathology.

Diagnosis and Management of Asthma - The Swiss Guidelines.

The Global Initiative for Asthma (GINA) is a network of individuals, organizations, and public health officials that was established to disseminate information about the care of patients with asthma and to improve asthma care. The GINA ("Global Strategy for Asthma Management and Prevention") report has been updated annually since 2002. Due to new knowledge and therapeutic development in the field, the Swiss Respiratory Society felt the need to provide a new document that is based on both the available literature and the recommendations of the 2016 GINA report. Key new features of the 2016 GINA report include a "new" definition of asthma, underscoring its heterogeneous nature, and the core elements of variable symptoms and variable expiratory airflow limitation; the importance of confirming the diagnosis of asthma in order to minimize both under- and overtreatment; practical tools for the assessment of symptom control and risk factors for adverse outcomes; a comprehensive approach to asthma management that acknowledges the foundational role of inhaled corticosteroid therapy, but also provides a framework for individualizing patient care; an emphasis on maximizing the benefit of available medications by addressing common problems such as incorrect inhaler technique and poor adherence; a continuum of care for worsening asthma, starting with early self-management and progressing to primary care or acute care management; and diagnosis of the asthma/chronic obstructive pulmonary disease overlap syndrome. This document is meant to advice the key stakeholders on the diagnosis and management of asthma and highlights the need to individualize the care of each and every asthmatic patient.

Airway microbiota signals anabolic and catabolic remodeling in the transplanted lung.

BACKGROUND: Homeostatic turnover of the extracellular matrix conditions the structure and function of the healthy lung. In lung transplantation, long-term management remains limited by chronic lung allograft dysfunction, an umbrella term used for a heterogeneous entity ultimately associated with pathological airway and/or parenchyma remodeling. OBJECTIVE: This study assessed whether the local cross-talk between the pulmonary microbiota and host cells is a key determinant in the control of lower airway remodeling posttransplantation. METHODS: Microbiota DNA and host total RNA were isolated from 189 bronchoalveolar lavages obtained from 116 patients post lung transplantation. Expression of a set of 11 genes encoding either matrix components or factors involved in matrix synthesis or degradation (anabolic and catabolic remodeling, respectively) was quantified by real-time quantitative PCR. Microbiota composition was characterized using 16S ribosomal RNA gene sequencing and culture. RESULTS: We identified 4 host gene expression profiles, among which catabolic remodeling, associated with high expression of metallopeptidase-7, -9, and -12, diverged from anabolic remodeling linked to maximal thrombospondin and platelet-derived growth factor D expression. While catabolic remodeling aligned with a microbiota dominated by proinflammatory bacteria (eg, Staphylococcus, Pseudomonas, and Corynebacterium), anabolic remodeling was linked to typical members of the healthy steady state (eg, Prevotella, Streptococcus, and Veillonella). Mechanistic assays provided direct evidence that these bacteria can impact host macrophage-fibroblast activation and matrix deposition. CONCLUSIONS: Host-microbes interplay potentially determines remodeling activities in the transplanted lung, highlighting new therapeutic opportunities to ultimately improve long-term lung transplant outcome.