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.

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.

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.

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.

[Lung and pleural space ultrasonography for pulmonologist]. / L'échographie pleuro-pulmonaire pour le pneumologue.

In the past twenty years ultrasound has been the subject of renewed interest in lung exploration in the broad sense. The necessity of accessing a means of rapid exploration at the bed of the patient in a critical situation has led to the development of a pleuro-pulmonary ultrasound semiology to make it a diagnostic tool of choice which exceeds the strict framework intensive care units and emergency services. With the diagnosis of thoracic tumors or the exploration of interstitial syndromes, it tends to integrate more into the daily practice of the pulmonologist. This article is a review of the possibilities offered by ultrasound in the field with its advantages and limitations.

Depuis une vingtaine d'années, l'échographie fait l'objet d'un regain d'intérêt pour l'exploration pulmonaire au sens large. La nécessité d'accéder à un moyen d'exploration rapide au lit du malade en situation critique a mené au développement d'une sémiologie échographique pleuro-pulmonaire jusqu'à en faire un outil diagnostique de choix dont l'utilisation dépasse désormais le cadre strict des unités de soins intensifs et des services d'urgence. Avec le diagnostic des tumeurs thoraciques ou encore l'exploration des syndromes interstitiels, elle tend à s'intégrer davantage dans la pratique quotidienne du pneumologue. Cet article est une revue des possibilités qu'offre l'échographie dans ce domaine avec ses avantages et ses limites.

Cystic Lung Disease in Genetic Syndromes with Deficient Tumor Suppressor Gene Function.

Cystic lung diseases constitute a distinct group of rare lung disorders, among which two result from monogenic defects affecting tumor suppressor genes: lymphangioleiomyomatosis, either sporadic or associated with tuberous sclerosis complex, and Birt-Hogg-Dubé syndrome. These disorders have similarities in their clinical expression, including occurrence in young adults, multiple pulmonary cysts, recurrent pneumothorax, skin hamartomas, and renal tumors. However, they markedly differ in their gender distribution, pathogenesis, disease course, and prognosis. Our knowledge on these two rare conditions is rapidly expanding. Management of lymphangioleiomyomatosis has substantially improved in the past decade with the understanding of its pathogenic mechanisms, the discovery of an effective therapy, and development of large cohorts and international guidelines. Birt-Hogg-Dubé syndrome has been described more recently and still awaits deeper understanding of its pathophysiology.

Development of a Multivariate Prediction Model for Early-Onset Bronchiolitis Obliterans Syndrome and Restrictive Allograft Syndrome in Lung Transplantation.

BACKGROUND: Chronic lung allograft dysfunction and its main phenotypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), are major causes of mortality after lung transplantation (LT). RAS and early-onset BOS, developing within 3 years after LT, are associated with particularly inferior clinical outcomes. Prediction models for early-onset BOS and RAS have not been previously described. METHODS: LT recipients of the French and Swiss transplant cohorts were eligible for inclusion in the SysCLAD cohort if they were alive with at least 2 years of follow-up but less than 3 years, or if they died or were retransplanted at any time less than 3 years. These patients were assessed for early-onset BOS, RAS, or stable allograft function by an adjudication committee. Baseline characteristics, data on surgery, immunosuppression, and year-1 follow-up were collected. Prediction models for BOS and RAS were developed using multivariate logistic regression and multivariate multinomial analysis. RESULTS: Among patients fulfilling the eligibility criteria, we identified 149 stable, 51 BOS, and 30 RAS subjects. The best prediction model for early-onset BOS and RAS included the underlying diagnosis, induction treatment, immunosuppression, and year-1 class II donor-specific antibodies (DSAs). Within this model, class II DSAs were associated with BOS and RAS, whereas pre-LT diagnoses of interstitial lung disease and chronic obstructive pulmonary disease were associated with RAS. CONCLUSION: Although these findings need further validation, results indicate that specific baseline and year-1 parameters may serve as predictors of BOS or RAS by 3 years post-LT. Their identification may allow intervention or guide risk stratification, aiming for an individualized patient management approach.

Idiopathic Pulmonary Fibrosis in Switzerland: Diagnosis and Treatment.

Idiopathic pulmonary fibrosis (IPF) is a severe progressive and irreversible lung disease. Novel antifibrotic drugs that slow disease progression are now available. However, many issues regarding patient management remain unanswered, such as the choice between available drugs, their use in particular subgroups and clinical situations, time of treatment onset, termination, combination or switch, or nonpharmacologic management. To guide Swiss respiratory physicians in this evolving field still characterized by numerous areas of uncertainty, the Swiss Working Group for interstitial and rare lung diseases of the Swiss Respiratory Society provides a position paper on the diagnosis and treatment of IPF.

Blood Gene Expression Predicts Bronchiolitis Obliterans Syndrome.

Bronchiolitis obliterans syndrome (BOS), the main manifestation of chronic lung allograft dysfunction, leads to poor long-term survival after lung transplantation. Identifying predictors of BOS is essential to prevent the progression of dysfunction before irreversible damage occurs. By using a large set of 107 samples from lung recipients, we performed microarray gene expression profiling of whole blood to identify early biomarkers of BOS, including samples from 49 patients with stable function for at least 3 years, 32 samples collected at least 6 months before BOS diagnosis (prediction group), and 26 samples at or after BOS diagnosis (diagnosis group). An independent set from 25 lung recipients was used for validation by quantitative PCR (13 stables, 11 in the prediction group, and 8 in the diagnosis group). We identified 50 transcripts differentially expressed between stable and BOS recipients. Three genes, namely POU class 2 associating factor 1 (POU2AF1), T-cell leukemia/lymphoma protein 1A (TCL1A), and B cell lymphocyte kinase, were validated as predictive biomarkers of BOS more than 6 months before diagnosis, with areas under the curve of 0.83, 0.77, and 0.78 respectively. These genes allow stratification based on BOS risk (log-rank test p < 0.01) and are not associated with time posttransplantation. This is the first published large-scale gene expression analysis of blood after lung transplantation. The three-gene blood signature could provide clinicians with new tools to improve follow-up and adapt treatment of patients likely to develop BOS.

Radial Ultrasound-Assisted Transbronchial Biopsy: A New Diagnostic Approach for Non-Resolving Pulmonary Infiltrates in Neutropenic Hemato-Oncological Patients.

The role of radial-endobronchial ultrasound (R-EBUS) assisted transbronchial biopsy (TBB) for the diagnosis of peripheral pulmonary lesions is well established. However, no study has addressed its safety and value in hemato-oncological patients presenting with non-resolving infiltrates during persistent febrile neutropenia. To assess safety and feasibility of R-EBUS assisted TBB in severe thrombocytopenic and neutropenic patients. Over a period of 18 months, eight patients were assessed with R-EBUS assisted TBB after adequate platelet transfusion. This technique allowed precise localisation and sampling of the pulmonary lesions in seven of eight patients. In the seven patients, R-EBUS assisted TBB enabled treatment optimization. Invasive fungal infection was diagnosed in four patients, idiopathic acute fibrinous and organising pneumonia in three patients, and a granulomatous inflammation of undetermined origin in one patient. Importantly, no complications, such as bleeding, were observed. R-EBUS assisted TBB is a promising and safe procedure for the evaluation of nonresolving pulmonary infiltrates in febrile neutropenic hemato-oncological patients.

Late Major Hemoptysis After Lung Volume Reduction With Coils Induced by Dual Antiaggregation Therapy.

Lung-volume reduction using coils is an effective and safe treatment for selected patients presenting severe emphysema and hyperinflation. Most complications occur during the first 30 days after the procedure. Although frequent, hemoptysis is usually transient and minor. Antiaggregation therapy is common in patients with emphysema who, very often, have additional tobacco-associated comorbidities. Aspirin is considered safe for most major interventions; however, clopidogrel is mainly contraindicated and considered an exclusion criterion. We present a case of life-threatening hemoptysis caused by dual antiaggregation therapy "accidentally" introduced 3 months after the procedure. So far no recommendations exist on the optimal therapeutic strategy after lung-volume reduction with coils.

[How to handle a non-resolving pneumonia?] / Que faire quand une pneumonie persiste?

Persistent pneumonias are frequent both in hospital and primary care settings. Several parameters have to be taken into account. Firstly the appropriateness of treatment; secondly the immune status of the host; and finally infectious complications need to be ruled out. Several non-infectious diagnoses can mimic a persistent infiltrate, such as neoplastic disorders, organising pneumonias, interstitial disorders and drug - or radiation-induced lung diseases. Uncommon pathogens will not respond to common treatment, for instance atypical bacteria, mycobacteria, fungi including Pneumocystis as well as viruses. Referral to a pulmonologist should be considered to perform a fiberoptic bronchoscopy.

Une pneumonie qui ne guérit pas est un problème fréquent en pratiques hospitalière et ambulatoire. Il faut prendre en compte plusieurs facteurs devant une telle situation. Premièrement, l'adéquation de l'antibiothérapie; deuxièmement, le statut immunitaire du sujet; finalement toute complication infectieuse du foyer de pneumonie doit être exclue. Une série de diagnostics non infectieux seront évoqués, parmi lesquels une néoplasie, une pneumonie en organisation, une pneumopathie interstitielle, médicamenteuse ou radique. Des pathogènes inhabituels doivent être envisagés face à une pneumonie réfractaire, notamment les germes «atypiques¼, les mycobactéries, les champignons y compris le Pneumocystis et les virus. Un avis pneumologique est indiqué afin de réaliser si nécessaire une bronchoscopie avec lavage bronchoalvéolaire.

[Subsolid pulmonary nodules]. / Nodules pulmonaires subsolides.

Subsolid nodules represent almost 20% of all pulmonary nodules found incidentally at chest computed tomography (CT). Their detection is steadily rising, in parallel with the increasing number of CT scans performed. Subsolid nodules differ from solid lung nodules in several ways: morphology, course of progression, risk of malignancy and prognosis. Although they remain a diagnostic challenge, a good correlation has been established between radiological appearance and histopathology. Whilst 75% of persistent subsolid nodules represent a form of adenocarcinoma, their prognosis is generally excellent when resected. Non-resected subsolid nodules require a long follow-up of 3 to 5 years due to their slow-growing nature and high prevalence of malignancy. Specific guidelines have been published in 2013 and in 2015.

Les nodules subsolides représentent près de 20% des nodules pulmonaires découverts fortuitement lors d'un scanner thoracique. Leur détection ne fait qu'augmenter, parallèlement au nombre croissant de scanners réalisés. Ils se distinguent des nodules solides par leur morphologie, leur comportement évolutif, leur risque de malignité et leur pronostic. Ils restent un challenge diagnostique, mais une bonne corrélation entre les présentations radiologiques et histologiques a été démontrée. Bien que 75% des nodules subsolides persistants soient une forme d'adénocarcinome, leur pronostic est en général excellent après résection. Un suivi prolongé de 3 à 5 ans est requis pour les nodules subsolides non opérés, étant donné leur croissance lente et la haute prévalence de malignité. Des recommandations spécifiques ont été publiées en 2013 et 2015.

Chair's Summary: Mechanisms of Exacerbation of Lung Diseases.

This year's conference focused on the origins of exacerbations in chronic lung diseases, such as asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and cystic fibrosis. Common themes emerged, with the role of viral infections being key. In addition, there were data presented supporting the role of the microbiota and microbial dysbiosis either in the gut or in the lung contributing to disease progression and the susceptibility to disease exacerbation. These effects can be amplified by the triggering of biologic cascades that include alterations in oxidative stress and inflammatory mediator release, which can be driven by epithelial cell injury or activation.

A 3-step therapeutic strategy for severe alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of lipoproteinaceous material in the terminal airways. Whole lung lavage (WLL) remains the gold standard treatment but may be particularly challenging in cases of severe hypoxemia. We present a 3-step strategy that was used in a patient with PAP-associated refractory hypoxemia and that combined venovenous extracorporeal membrane oxygenation (vvECMO), double-lumen orotracheal intubation, and bilateral multisegmental sequential lavage (MSL). The procedure was well tolerated and permitted weaning from the ventilator.

Dominant TNF-α+ Mycobacterium tuberculosis-specific CD4+ T cell responses discriminate between latent infection and active disease.

Rapid diagnosis of active Mycobacterium tuberculosis (Mtb) infection remains a clinical and laboratory challenge. We have analyzed the cytokine profile (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2)) of Mtb-specific T cells by polychromatic flow cytometry. We studied Mtb-specific CD4+ T cell responses in subjects with latent Mtb infection and active tuberculosis disease. The results showed substantial increase in the proportion of single-positive TNF-α Mtb-specific CD4+ T cells in subjects with active disease, and this parameter was the strongest predictor of diagnosis of active disease versus latent infection. We validated the use of this parameter in a cohort of 101 subjects with tuberculosis diagnosis unknown to the investigator. The sensitivity and specificity of the flow cytometry-based assay were 67% and 92%, respectively, the positive predictive value was 80% and the negative predictive value was 92.4%. Therefore, the proportion of single-positive TNF-α Mtb-specific CD4+ T cells is a new tool for the rapid diagnosis of active tuberculosis disease.

Monocyte differentiation toward regulatory dendritic cells is not affected by respiratory syncytial virus-induced inflammatory mediators.

Airway epithelial cells were shown to drive the differentiation of monocytes into dendritic cells (DCs) with a suppressive phenotype. In this study, we investigated the impact of virus-induced inflammatory mediator production on the development of DCs. Monocyte differentiation into functional DCs, as reflected by the expression of CD11c, CD123, BDCA-4, and DC-SIGN and the capacity to activate T cells, was similar for respiratory syncytial virus (RSV)-infected and mock-infected BEAS-2B and A549 cells. RSV-conditioned culture media resulted in a partially mature DC phenotype, but failed to up-regulate CD80, CD83, CD86, and CCR7, and failed to release proinflammatory mediators upon Toll-like receptor (TLR) triggering. Nevertheless, these DCs were able to maintain an antiviral response by the release of Type I IFN. Collectively, these data indicate that the airway epithelium maintains an important suppressive DC phenotype under the inflammatory conditions induced by infection with RSV.