Associations of depressive and anxiety disorders with pulmonary disorders in the community - the PneumoLaus and PsyCoLaus studies.

INTRODUCTION: Mental health disorders figure among the many comorbidities of obstructive respiratory diseases. The multisystemic characteristics of chronic respiratory disease and its impact on quality of life could affect depressive and/or anxiety disorders. We aimed to evaluate the association of spirometric indices, ventilatory disorders and self-reported respiratory diseases with psychiatric disorders considering potential confounders. METHODS: We analysed data from CoLaus|PsyCoLaus, a Swiss population-based cohort study, consisting of 2'774 participants (56% women; mean age: 62.3 (SD=±9.9) years) who performed spirometry and completed semi-structured psychiatric interviews. We defined ventilatory disorders using GLI-2012 references. Major depressive episode (MDE) and anxiety disorders were defined using the DSM-IV (Diagnostic and Statistical Manual). RESULTS: 630 subjects (22.7%) presented a recent MDE. Reversible obstructive ventilatory disorders were associated with recent MDE (OR=1.94, 95% CI95 1.10-3.43) and recent anxiety disorders (2.21 [1.16-4.22]) only in unadjusted model. Self-reported COPD and asthma were associated with MDE with ORs of 2.49 (95%CI, 1.19-5.27) and 1.56 (95% CI, 1.04-2.35) after adjustment, respectively. Possible restrictive ventilatory impairment was positively associated with recent anxiety disorders (OR=2.46, 1.10-5.51). Z-scores of FEV1, FVC and maximum mid expiratory flow (MMEF) were not associated with psychiatric disorders. There was no association between ventilatory disorders and MDE in adjusted models. CONCLUSIONS: In this cross-sectional population-based study, the association between respiratory disorders and depressive disorders was observed for self-reported COPD and asthma, but not with objective diagnoses based on spirometry. Lung volumes are not associated with psychiatric disorders. Further prospective studies will be necessary to understand the significance of the association.

Systems prediction of chronic lung allograft dysfunction: Results and perspectives from the Cohort of Lung Transplantation and Systems prediction of Chronic Lung Allograft Dysfunction cohorts.

Background: Chronic lung allograft dysfunction (CLAD) is the leading cause of poor long-term survival after lung transplantation (LT). Systems prediction of Chronic Lung Allograft Dysfunction (SysCLAD) aimed to predict CLAD. Methods: To predict CLAD, we investigated the clinicome of patients with LT; the exposome through assessment of airway microbiota in bronchoalveolar lavage cells and air pollution studies; the immunome with works on activation of dendritic cells, the role of T cells to promote the secretion of matrix metalloproteinase-9, and subpopulations of T and B cells; genome polymorphisms; blood transcriptome; plasma proteome studies and assessment of MSK1 expression. Results: Clinicome: the best multivariate logistic regression analysis model for early-onset CLAD in 422 LT eligible patients generated a ROC curve with an area under the curve of 0.77. Exposome: chronic exposure to air pollutants appears deleterious on lung function levels in LT recipients (LTRs), might be modified by macrolides, and increases mortality. Our findings established a link between the lung microbial ecosystem, human lung function, and clinical stability post-transplant. Immunome: a decreased expression of CLEC1A in human lung transplants is predictive of the development of chronic rejection and associated with a higher level of interleukin 17A; Immune cells support airway remodeling through the production of plasma MMP-9 levels, a potential predictive biomarker of CLAD. Blood CD9-expressing B cells appear to favor the maintenance of long-term stable graft function and are a potential new predictive biomarker of BOS-free survival. An early increase of blood CD4 + CD57 + ILT2+ T cells after LT may be associated with CLAD onset. Genome: Donor Club cell secretory protein G38A polymorphism is associated with a decreased risk of severe primary graft dysfunction after LT. Transcriptome: blood POU class 2 associating factor 1, T-cell leukemia/lymphoma domain, and B cell lymphocytes, were validated as predictive biomarkers of CLAD phenotypes more than 6 months before diagnosis. Proteome: blood A2MG is an independent predictor of CLAD, and MSK1 kinase overexpression is either a marker or a potential therapeutic target in CLAD. Conclusion: Systems prediction of Chronic Lung Allograft Dysfunction generated multiple fingerprints that enabled the development of predictors of CLAD. These results open the way to the integration of these fingerprints into a predictive handprint.

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.

Multicenter analysis of sputum microbiota in tuberculosis patients.

The impact of tuberculosis and of anti-tuberculosis therapy on composition and modification of human lung microbiota has been the object of several investigations. However, no clear outcome has been presented so far and the relationship between M. tuberculosis pulmonary infection and the resident lung microbiota remains vague. In this work we describe the results obtained from a multicenter study of the microbiota of sputum samples from patients with tuberculosis or unrelated lung diseases and healthy donors recruited in Switzerland, Italy and Bangladesh, with the ultimate goal of discovering a microbiota-based biomarker associated with tuberculosis. Bacterial 16S rDNA amplification, high-throughput sequencing and extensive bioinformatic analyses revealed patient-specific flora and high variability in taxon abundance. No common signature could be identified among the individuals enrolled except for minor differences which were not consistent among the different geographical settings. Moreover, anti-tuberculosis therapy did not cause any important variation in microbiota diversity, thus precluding its exploitation as a biomarker for the follow up of tuberculosis patients undergoing treatment.

[Diaphragmatic paralysis and paresis†: review]. / Parésies et paralysies diaphragmatiques.

Diaphragmatic paresis/paralysis can be unilateral or bilateral. Its manifestations range from completely asymptomatically to global respiratory failure. Respiratory functional tests will reveal lowered respiratory pressures with a restrictive syndrome, and a decrease in vital capacity when lying in the supine position compared to sitting. Unilateral paresis is most often self-limited and mainly post-surgical. The bilateral dysfunction, observed in neuromuscular diseases, is often permanent. The treatment consists in the management of specific causes, the optimization of the treatment of comorbidities, and in some cases, diaphragmatic plication, ventilatory support or pacing of phrenic nerves.

La parésie/paralysie du diaphragme peut être uni- ou bilatérale. Elle peut se présenter de façon complètement asymptomatique ou aller jusqu'à l'insuffisance respiratoire globale. Les tests fonctionnels respiratoires révéleront des pressions respiratoires abaissées avec un syndrome restrictif, et une diminution de la capacité vitale en position couchée par rapport à assise. La parésie unilatérale est le plus souvent autolimitée et principalement d'étiologie postchirurgicale. L'atteinte bilatérale, principalement observée dans les maladies neuromusculaires, est souvent permanente. Le traitement consiste en une prise en charge des causes spécifiques, une optimisation du traitement des comor bidités, et dans certains cas une plicature diaphragmatique, un support ventilatoire ou un pacing des nerfs phréniques.

Genome sequencing of Mycobacterium tuberculosis clinical isolates revealed isoniazid resistance mechanisms undetected by conventional molecular methods.

A combination of targeted molecular methods and phenotypic drug-susceptibility testing is the most widely used approach to detect drug resistance in Mycobacterium tuberculosis isolates. We report the delay in the introduction of an efficient anti-tuberculous drug regimen because of a M. tuberculosis strain displaying a high level of resistance to isoniazid, in the absence of the common mutations associated with isoniazid-resistance, including katG mutations and inhA promoter mutations. Whole-genome sequencing (WGS) identified a large loss-of-function insertion (>1000 pb) at the end of katG in the isolate together with a -57C>T ahpC mutation, a resistance mechanism that would have remained undetected by a conventional molecular targeted approach. A retrospective search using publicly available WGS data of more than 1200 isoniazid-resistant isolates and a similar sized control dataset of isoniazid-susceptible isolates revealed that most (22/31) isoniazid-resistant, KatG loss-of-function mutants had an associated rare ahpC promoter mutation. In contrast, only 7 of 1411 isoniazid-susceptible strains carried a rare ahpC promoter mutation, including shared mutations with the 31 isoniazid-resistant KatG loss-of-function mutants. These results indicate that rare ahpC promoter mutations could be used as a proxy for investigating simultaneous KatG loss-of-function or missense mutations. In addition, WGS in routine diagnosis would improve drug susceptibility testing in M. tuberculosis clinical isolates and is an efficient tool for detecting resistance mechanisms undetected by conventional molecular methods.

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.

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.

[What's new on asthma in primary care]. / Nouveautés concernant l'asthme en médecine de premier recours.

The international recommendations of the management of asthma have been modified last years. Several therapies used since long time have no place in the management of moderate asthma today. The use of targeted immunotherapies against phenotypes of asthma are used more and more. Inhalant therapies are becoming more targeted towards the patient's wishes. This article specifies the novelties in management of asthma for de general practitioner, including the use of short acting beta2-agonists, which are no longer to be used without inhaled corticosteroid.

Les recommandations internationales de la prise en charge de l'asthme ont été modifiées ces dernières années. Plusieurs thérapies utilisées de longue date n'ont plus leur place dans la prise en charge des asthmes modérés, et l'utilisation d'immunothérapies ciblées envers certains phénotypes d'asthme se répand. Les thérapies inhalées deviennent de plus en plus orientées vers la volonté du patient. Cet article précise les nouveautés dans la prise en charge de l'asthme à destination du praticien, notamment l'utilisation de bêta2-agonistes à courte durée d'action seuls qui n'ont plus leur place sans corticostéroïde inhalé.

[Computer instruments for the management of isolated pulmonary nodule. Detectability and prediction of malignancy]. / Outils informatiques pour la prise en charge du nodule pulmonaire isolé - Détectabilité et prédiction de malignité.

Lung cancer remains the most common cause of cancer deaths in the world, but its mortality can be significantly reduced by diagnosis and early detection. Computerized resources were developed to assist radiologists in their management of the large volume of thoracic images to be analyzed. Their objective is the detection of pulmonary nodules with high sensitivity and a low rate of false-positives and the ability to differentiate benign and malignant nodules. The volume of a pulmonary nodule and its volume doubling time are essential to nodule management. Computer aided detection or diagnosis (CAD) software are not currently used in clinically settings on a routine basis . Significant advances are expected due to the implementation of the artificial intelligence systems who will probably be integrated into the multidisciplinary management of any pulmonary nodule.

Le cancer du poumon reste la principale cause de décès par cancer dans le monde. Sa mortalité peut être significativement réduite par un diagnostic et un dépistage précoce. Des outils informatiques ont été développés afin d'aider les radiologues à gérer la quantité d'images thoraciques à analyser. Ils ont pour objectif la détection des nodules pulmonaires avec une haute sensibilité et un taux faible de faux positifs, mais aussi la différenciation des nodules bénins et malins. Le volume d'un nodule pulmonaire et le temps de doublement déterminent la suite de la prise en charge de ce nodule. Ces deux paramètres sont inclus dans la plupart des recommandations actuelles. Les logiciels de détection assistés par ordinateur (CAD) ne sont pas utilisés en routine clinique actuellement. Des avancées dans ce domaine sont attendues en utilisant l'intelligence artificielle, notamment dans le cadre de la prise de décision multidisciplinaire.

[Obesity hypoventilation syndrome†: 2019's management]. / Syndrome obésité-hypoventilation†: prise en charge 2019.

Obesity hypoventilation syndrome is an underdiagnosed pathology, whose prevalence is increasing due to the progressively higher prevalence of obesity in the general population. Early detection allows early management and lowers the risk of acute exacerbation, hospitalization and mortality. The diagnosis is done by excluding other, pulmonary or extra pulmonary, reasons of hypercapnia; a nocturnal polygraphy is mandatory to diagnose an associated obstructive sleep apnea syndrome. The pneumological treatment is a ventilatory support by CPAP or biPAP (bilevel Positive Airways Pressure).

Le syndrome obésité-hypoventilation (SOH) est une pathologie sous-diagnostiquée, mais de plus en plus fréquente au vu de l'augmentation de la prévalence de l'obésité. Le dépistage précoce au cabinet du généraliste peut permettre une prise en charge rapide diminuant le risque d'exacerbation aiguë, d'hospitalisation et de mortalité. Le diagnostic repose sur l'exclusion d'autres causes - pulmonaires ou extrapulmonaires - d'hypercapnie ; une polygraphie nocturne est utile au diagnostic de syndrome des apnées obstructives du sommeil (SAOS), pathologie souvent associée. Le traitement pneumologique consiste en un support ventilatoire par CPAP ou biPAP (bilevel Positive Airways Pressure).

Added diagnostic value of 16S rRNA gene pan-mycobacterial PCR for nontuberculous mycobacterial infections: a 10-year retrospective study.

The diagnosis of mycobacterial infections has been dramatically improved by the introduction of molecular methods aimed to reduce the time to diagnosis as compared with culture. The broad range pan-mycobacterial PCR can detect all the mycobacterial species directly from clinical specimens. We aimed to evaluate its usefulness and its clinical added value for the diagnosis of nontuberculous mycobacterial (NTM) infections. We performed a retrospective study (2003-2013) including 952 samples taken from 639 patients with clinical suspicion of NTM infection. The performance of smear microscopy, PCR and culture was established using clinical data to investigate discrepant results. We also compared the time to microbial diagnosis between the direct PCR and culture. The sensitivity, specificity, positive and negative predictive values of the PCR were 61.6% (53.5-69.1), 99.1% (98.2-99.6), 92.8% (85.8-96.5) and 93.4% (91.6-94.9), respectively, when considering all specimens. When considering smear-positive specimens and smear-negative specimens, the sensitivity was 81.6% and 40%, respectively. The sensitivity for pulmonary and extra-pulmonary smear-positive specimens was 85.2% versus 72.7%. The median time to identification at species level was 35 days (SD, 17.67) for culture and 6 days (SD, 2.67) for the PCR (when positive), which represents a 29-day shorter time to results (p < 0.0001). The 16S rRNA gene pan-mycobacterial PCR displays a substantial benefit in terms of time to diagnose NTM infections when compared with culture. Despite an excellent specificity, its sensitivity is yet limited in particular for smear-negative specimens, which might be improved by relying onto real-time PCRs.