[Progressive pulmonary Fibrosis]. / Progressive Pulmonale Fibrose PPF.

INTRODUCTION: Progressive pulmonary Fibrosis Abstract: Cough and dyspnea on excertion are common and early symptoms of interstitial lung diseases (ILD). Thoracic imaging (particularly computed tomography) detects such lung structural alterations early in the disease course. Knowledge of these diseases and their management is necessary in the daily business. The term "progressive pulmonary fibrosis" subsumes a heterogene group of interstitial lung diseases with a similar course of progressive fibrosis. The management of these diseases should be discussed interdisciplinary, similar to the management of the Idiopathic pulmonary fibrosis (IPF). Antifibrotic drugs are new therapeutic options.

Strain-Resolved Dynamics of the Lung Microbiome in Patients with Cystic Fibrosis.

In cystic fibrosis, dynamic and complex communities of microbial pathogens and commensals can colonize the lung. Cultured isolates from lung sputum reveal high inter- and intraindividual variability in pathogen strains, sequence variants, and phenotypes; disease progression likely depends on the precise combination of infecting lineages. Routine clinical protocols, however, provide a limited overview of the colonizer populations. Therefore, a more comprehensive and precise identification and characterization of infecting lineages could assist in making corresponding decisions on treatment. Here, we describe longitudinal tracking for four cystic fibrosis patients who exhibited extreme clinical phenotypes and, thus, were selected from a pilot cohort of 11 patients with repeated sampling for more than a year. Following metagenomics sequencing of lung sputum, we find that the taxonomic identity of individual colonizer lineages can be easily established. Crucially, even superficially clonal pathogens can be subdivided into multiple sublineages at the sequence level. By tracking individual allelic differences over time, an assembly-free clustering approach allows us to reconstruct multiple lineage-specific genomes with clear structural differences. Our study showcases a culture-independent shotgun metagenomics approach for longitudinal tracking of sublineage pathogen dynamics, opening up the possibility of using such methods to assist in monitoring disease progression through providing high-resolution routine characterization of the cystic fibrosis lung microbiome.IMPORTANCE Cystic fibrosis patients frequently suffer from recurring respiratory infections caused by colonizing pathogenic and commensal bacteria. Although modern therapies can sometimes alleviate respiratory symptoms by ameliorating residual function of the protein responsible for the disorder, management of chronic respiratory infections remains an issue. Here, we propose a minimally invasive and culture-independent method to monitor microbial lung content in patients with cystic fibrosis at minimal additional effort on the patient's part. Through repeated sampling and metagenomics sequencing of our selected cystic fibrosis patients, we successfully classify infecting bacterial lineages and deconvolute multiple lineage variants of the same species within a given patient. This study explores the application of modern computational methods for deconvoluting lineages in the cystic fibrosis lung microbiome, an environment known to be inhabited by a heterogeneous pathogen population that complicates management of the disorder.

Bosentan for patients with steroid-resistant pulmonary sarcoidosis: a randomised controlled trial.

BACKGROUND: Sarcoidosis is a disorder of unknown aetiology. Most patients have steroid-responsive disease, but side effects and steroid resistance may necessitate alternative treatments. Endothelin has in-vitro fibrogenic activity and the endothelin system is activated in sarcoidosis. OBJECTIVES: We studied the efficacy and safety of the endothelin receptor antagonist bosentan in sarcoidosis patients. METHODS: In a prospective 12-month, double-blind, 1:1-randomised, placebo-controlled phase II trial, we assessed the effect of bosentan in patients with steroid-resistant sarcoidosis and with impaired exercise capacity and/or resting lung function. Primary endpoints were safety and overall response rate of total lung capacity, diffusion capacity, peak oxygen uptake, 6-minute walking distance and chest computed tomography score. Secondary endpoints included adverse events and quality of life. MAIN RESULTS: Twenty patients were randomised. Three patients discontinued the study medication prematurely. No serious drug-related adverse events occurred. At 12 months no statistically significant differences were observed in the primary endpoints including total lung capacity, diffusion capacity, 6-minute walking distance, peak oxygen uptake, and computed tomography-score. Sixty-three percent of the patients treated with bosentan showed an increase of 10% in at least one of the primary endpoints, compared with 67% in the placebo group (p = 1). CONCLUSIONS: There is no evidence to support efficacy of bosentan as an antifibrotic treatment for patients with steroid-resistant pulmonary sarcoidosis. Bosentan was well tolerated and no drug-related adverse effects were observed within the study population. TRIAL REGISTRATION: ISRCTN registry, ISRCTN73579020.

Sputum DNA sequencing in cystic fibrosis: non-invasive access to the lung microbiome and to pathogen details.

BACKGROUND: Cystic fibrosis (CF) is a life-threatening genetic disorder, characterized by chronic microbial lung infections due to abnormally viscous mucus secretions within airways. The clinical management of CF typically involves regular respiratory-tract cultures in order to identify pathogens and to guide treatment. However, culture-based methods can miss atypical or slow-growing microbes. Furthermore, the isolated microbes are often not classified at the strain level due to limited taxonomic resolution. RESULTS: Here, we show that untargeted metagenomic sequencing of sputum DNA can provide valuable information beyond the possibilities of culture-based diagnosis. We sequenced the sputum of six CF patients and eleven control samples (including healthy subjects and chronic obstructive pulmonary disease patients) without prior depletion of human DNA or cell size selection, thus obtaining the most unbiased and comprehensive characterization of CF respiratory tract microbes to date. We present detailed descriptions of the CF and healthy lung microbiome, reconstruct near complete pathogen genomes, and confirm that the CF lungs consistently exhibit reduced microbial diversity. Crucially, the obtained genomic sequences enabled a detailed identification of the exact pathogen strain types, when analyzed in conjunction with existing multi-locus sequence typing databases. We also detected putative pathogenicity islands and indicators of antibiotic resistance, in good agreement with independent clinical tests. CONCLUSIONS: Unbiased sputum metagenomics provides an in-depth profile of the lung pathogen microbiome, which is complementary to and more detailed than standard culture-based reporting. Furthermore, functional and taxonomic features of the dominant pathogens, including antibiotics resistances, can be deduced-supporting accurate and non-invasive clinical diagnosis.

Pulmonary hypertension associated with left-sided heart disease.

Pulmonary hypertension associated with left-sided heart disease (PH-LHD) is the most common type of pulmonary hypertension. In patients with left-sided heart disease, the presence of pulmonary hypertension is typically a marker of more advanced disease, more severe symptoms, and worse prognosis. In contrast to pulmonary arterial hypertension, PH-LHD is characterised by an elevated pulmonary artery wedge pressure (postcapillary pulmonary hypertension) without or with an additional precapillary component (isolated postcapillary versus combined postcapillary and precapillary pulmonary hypertension). Transthoracic echocardiography is the primary nonin-vasive imaging tool to estimate the probability of pulmonary hypertension and to establish a working diagnosis on the mechanism of pulmonary hyperten-sion. However, right heart catheterisation is always required if significant pulmonary hypertension is sus-pected and exact knowledge of the haemodynamic constellation is necessary. The haemodynamic con-stellation (mean pulmonary artery pressure, mean pulmonary artery wedge pressure, left ventricular end-diastolic pressure) in combination with clinical infor-mation and imaging findings (mainly echocardiog-raphy, coronary angiography and cardiac magnetic resonance imaging) will usually allow the exact mech-anism underlying PH-LHD to be defined, which is a prerequisite for appropriate treatment. The general principle for the management of PH-LHD is to treat the underlying left-sided heart disease in an optimal man-ner using drugs and/or interventional or surgical ther-apy. There is currently no established indication for pulmonary arterial hypertension-specific therapies in PH-LHD, and specific therapies may even cause harm in patients with PH-LHD.

[Sarcoidosis--a multisystem disorder with variable prognosis]. / Sarkoidose--klinische Aspekte.

Sarcoidosis is a pneumotropic granulomatous inflammatory multisystem disorder of unknown origin and heterogeneous outcome. In most cases the disease is self-limited, others progress or die from organ involvement, which is often associated with extensive pulmonary scarring or relevant extrapulmonary organ involvement. Therefore, patients with sarcoidosis must be staged for multiorgan involvement. Modern treatment strategies appraise a critical awareness for the effect to side-effect-ratio of long-term immunosuppressive medication.