To determine the most relevant pathogens for CAP in Germany, patients with radiologically confirmed pulmonary infiltrates and at least one clinical sign of lung infection were prospectively recruited within the CAPNETZ cohort from 2004 until 2016. In 990 out of 4.672 patients (21%) receiving complete diagnostics the most prominent change of pathogens was a decrease of S. pneumoniae (58% in 2004 to 37.5% in 2016; p ≤ 0.001, ρ = − 0.148) and an increase of H. influenzae (12.2% to 20.8%; p = 0.001, ρ = 0.104).

Non-typeable Haemophilus influenzae (NTHi) is the most common respiratory pathogen in patients with chronic obstructive disease. Limited data is available investigating the impact of NTHi infections on cellular re-differentiation processes in the bronchial mucosa. The aim of this study was to assess the effects of stimulation with NTHi on the bronchial epithelium regarding cellular re-differentiation processes using primary bronchial epithelial cells harvested from infection-free patients undergoing bronchoscopy. The cells were then cultivated using an air-liquid interface and stimulated with NTHi and TGF-β. Markers of epithelial and mesenchymal cells were analyzed using immunofluorescence, Western blot and qRT-PCR. Stimulation with both NTHi and TGF-ß led to a marked increase in the expression of the mesenchymal marker vimentin, while E-cadherin as an epithelial marker maintained a stable expression throughout the experiments. Furthermore, expression of collagen 4 and the matrix-metallopeptidases 2 and 9 were increased after stimulation, while the expression of tissue inhibitors of metallopeptidases was not affected by pathogen stimulation. In this study we show a direct pathogen-induced trans-differentiation of primary bronchial epithelial cells resulting in a co-localization of epithelial and mesenchymal markers and an up-regulation of extracellular matrix components.

Non-typeable Haemophilus influenzae (NTHi) is the most common respiratory pathogen in patients with chronic obstructive disease. Limited data is available investigating the impact of NTHi infections on cellular re-differentiation processes in the bronchial mucosa. The aim of this study was to assess the effects of stimulation with NTHi on the bronchial epithelium regarding cellular re-differentiation processes using primary bronchial epithelial cells harvested from infection-free patients undergoing bronchoscopy. The cells were then cultivated using an air-liquid interface and stimulated with NTHi and TGF-β. Markers of epithelial and mesenchymal cells were analyzed using immunofluorescence, Western blot and qRT-PCR. Stimulation with both NTHi and TGF-ß led to a marked increase in the expression of the mesenchymal marker vimentin, while E-cadherin as an epithelial marker maintained a stable expression throughout the experiments. Furthermore, expression of collagen 4 and the matrix-metallopeptidases 2 and 9 were increased after stimulation, while the expression of tissue inhibitors of metallopeptidases was not affected by pathogen stimulation. In this study we show a direct pathogen-induced trans-differentiation of primary bronchial epithelial cells resulting in a co-localization of epithelial and mesenchymal markers and an up-regulation of extracellular matrix components. Keywords Chronic obstructive pulmonary disease , epithelial-mesenchymal transition , non-typeable , primary bronchial epithelial cells

BACKGROUND:Household air pollution (HAP) is one of the most important environmental risk factors worldwide associated with chronic respiratory diseases.OBJECTIVES:The present study focused on respiratory health in a population with high wood smoke exposure in Nicaragua.METHODS:We employed a cross-sectional study with 213 participants. Data on the prevalence of chronic bronchitis (chronic bronchitis), chronic obstructive pulmonary disease (COPD) and asthma, including respiratory scores and pulmonary function tests, were documented. The role of risk factors for chronic bronchitis was analyzed.RESULTS:We found a high prevalence of chronic airway diseases in the population exposed to wood smoke. A higher prevalence of chronic bronchitis was found in persons serving as primary cooks in households. Further confounding factors for chronic bronchitis included age, a prior diagnosis of asthma, inhalational allergies and lower socioeconomic status. Respiratory scores were elevated in individuals with chronic bronchitis.CONCLUSIONS:This is one of the first studies in a wood smoke-exposed population in Nicaragua showing a high prevalence of chronic bronchitis and COPD with an emphasis on the analysis of personal and environmental risk factors. Further studies are needed to address which combination of interventions is most efficient for ameliorating respiratory health hazards.PARTICIPANT CONSENT:Obtained.ETHICS APPROVAL:The study protocol was approved by the Ethics Committee of the University of Luebeck, Germany (reference number 12-214), and by the Ethics Committee of the Department of Medical Sciences at National Autonomous University of Nicaragua, Managua, Nicaragua.COMPETING INTERESTS:The authors declare no competing financial interests.

Human airways are continuously colonized by microaspiration of microbiota. Less is known about the presence, origin and composition of microbiota in the lung parenchyma. In a study of 13 patients undergoing surgery for peripheral lung cancer microbiota composition was comparatively evaluated in upper airway, lower airway and lung tissue samples using 16S rDNA analysis. Bacterial density decreased stepwise from upper to lower airways and tissue. On a taxonomic level upper and lower airway microbiota were similar whereas lung tissue showed marked dissimilarities compared to lower airways that may reflect different environmental conditions shaping local microbiota and host immunity.

ZUSAMMENFASSUNGDie ambulant erworbene Pneumonie (community-acquired pneumonia, CAP) ist weltweit die häufigste vital bedrohliche Infektion. In Deutschland wird sie mit zunehmender Alterung der Gesellschaft mehr und mehr zu einer geriatrischen Erkrankung. Entscheidend für die Therapie ist die Schweregradbeurteilung, die nach dem CRB65-Score erfolgt. In der Klinik wird zur Abklärung der Ätiologie eine mikrobiologische Basisdiagnostik empfohlen, diese besteht aus respiratorischer Kultur, Blutkulturen, bei mittelschwerer und insbesondere schwerer Pneumonie auch dem Legionellen-Antigentest im Urin. Weitere Tests sind nach anamnestischen Hinweisen gezielt einzusetzen. Die Auswahl der Therapie wird bei der CAP in erster Linie vom Schweregrad bestimmt. Die Therapiedauer sollte bei CAP nicht mehr als 5–7 Tage betragen.Die nosokomiale Pneumonie spielt eine Hauptrolle unter den im Krankenhaus erworbenen Infektionen. Die Mehrzahl der Fälle tritt bei beatmeten Patienten auf. Anders als bei der CAP prägen „Problemkeime“ wie Staphylococcus aureus, Enterobakterien und Pseudomonas aeruginosa das Erregerspektrum der nosokomialen Pneumonie. Eine Zunahme multiresistenter Erreger (MRE) wird weltweit beobachtet. Die Wahl der kalkulierten Therapie erfolgt nach dem MRE-Risiko und dem Schweregrad der Infektion. Eine regelhafte initiale Kombinationstherapie wird nur noch dann empfohlen, wenn sowohl ein erhöhtes MRE-Risiko als auch Schweregradkriterien vorliegen. Deeskalation und Antibiotic Stewardship (ABS) sind integraler Bestandteil des Therapiekonzepts, dabei geht es vorrangig um die Begrenzung des Antibiotikaeinsatzes.

Around 3 billion people worldwide use solid biomass fuels for cooking. Exposure to indoor biomass smoke is an important cause of COPD and therefore a target of many public health interventions, such as usage of improved cookstoves. The aim of our study was to show whether usage of improved cookstoves can lead to relevant improvement in lung function and CAT-score in a well characterized population including a subgroup of this population with preexisting airway obstruction. Interviews and spirometry were performed in Congolese women living in an UNHCR (United Nations High Commissioner for Refugees) refugee camp in Rwanda before (baseline, BL) and 9 months after (follow-up, F9) they received an energy-efficient cookstove (Save80) and were trained how to use it. Two hundred sixty-two women completed both spirometry and interview appropriately at BL and F9 and were included in per protocol (pp) analysis, which showed no change in mean FEV1. The predefined subgroup of this population with airway obstruction at baseline (N = 31) showed a significant FEV1 increase (FEV1F9 = 1.70 L; p < 0.01 vs FEV1BL = 1.58 L, p < 0.01). Median CAT-scores were significantly lower in the F9 assessment. Our data indicate that usage of improved cookstoves has a positive impact on respiratory health especially in individuals with preexisting airway obstruction. Further studies to investigate long-term outcome are warranted.

Etiology The role of multidrug-resistant (MDR) pathogens in nosocomial infections is increasing. However national data in Germany do not show significant changes in the spectrum of pathogens in hospital-acquired pneumonia (HAP). The assessment of individual risk factors for MDR pathogens remains central for the selection of empiric antimicrobial therapy. Diagnostics Thoracic ultrasound may be added as part of the diagnostic work-up and for the detection of complications. Procalcitonin and lactate testing are recommended for the diagnosis of sepsis/septic shock in addition to sepsis scores. Detection of influenza virus by PCR from respiratory samples is recommended during influenza season. Antimicrobial treatment Empiric combination therapy is only recommended for patients with severe HAP (invasive ventilation, septic shock) and high risk of infection with MDR pathogens, since combination therapy has only been shown to be superior in this situation. Deescalation according to clinical and microbiological criteria is highly recommended. In patients with septic organ dysfunction/septic shock antibiotic dosing of adequately choosen betalactams according to Pk/Pd criteria is endorsed. Aerosolised antibiotics adjunctive aerosolised therapy should only be performed in experienced centres. This remains an option for patients with detection of MDR pathogens, who are not deemed successfully treatable with systemic therapy alone.

Nosocomial pneumonia (HAP) is a frequent complication of hospital care. Most data are available on ventilator-associated pneumonia. However, infections on general wards are increasing. A central issue are infections with multidrug resistant (MDR) pathogens which are difficult to treat in the empirical setting potentially leading to inappropriate use of antimicrobial therapy.This guideline update was compiled by an interdisciplinary group on the basis of a systematic literature review. Recommendations are made according to GRADE giving guidance for the diagnosis and treatment of HAP on the basis of quality of evidence and benefit/risk ratio.This guideline has two parts. First an update on epidemiology, spectrum of pathogens and antimicrobials is provided. In the second part recommendations for the management of diagnosis and treatment are given. New recommendations with respect to imaging, diagnosis of nosocomial viral pneumonia and prolonged infusion of antibacterial drugs have been added. The statements to risk factors for infections with MDR pathogens and recommendations for monotherapy vs combination therapy have been actualised. The importance of structured deescalation concepts and limitation of treatment duration is emphasized.

The introduction of electronic cigarettes has led to widespread discussion on the cardiovascular risks compared to conventional smoking. We therefore conducted a randomized cross-over study of the acute use of three tobacco products, including a control group using a nicotine-free liquid. Fifteen active smokers were studied during and after smoking either a cigarette or an electronic cigarette with or without nicotine (eGo-T CE4 vaporizer). Subjects were blinded to the nicotine content of the electronic cigarette and were followed up for 2 hours after smoking a cigarette or vaping an electronic cigarette. Peripheral and central blood pressures as well as parameters of arterial stiffness were measured by a Mobil-O-Graph® device. The peripheral systolic blood pressure rose significantly for approximately 45 minutes after vaping nicotine-containing liquid ( p<0.05) and for approximately 15 minutes after smoking a conventional cigarette ( p<0.01), whereas nicotine-free liquids did not lead to significant changes during the first hour of follow-up. Likewise, heart rate remained elevated approximately 45 minutes after vaping an electronic cigarette with nicotine-containing liquid and over the first 30 minutes after smoking a cigarette in contrast to controls. Elevation of pulse wave velocity was independent from mean arterial pressure as well as heart rate in the electronic cigarette and cigarette groups. In this first of its kind trial, we observed changes in peripheral and central blood pressure and also in pulse wave velocity after smoking a cigarette as well as after vaping a nicotine-containing electronic cigarette. These findings may be associated with an increased long-term cardiovascular risk.

Die ambulant erworbene Pneumonie ist die häufigste ernste Infektionserkrankung in Deutschland. Die Mehrzahl der Fälle wird ambulant behandelt. Die Diagnose wird klinisch durch Zeichen der Infektion, respiratorischen Symptomen und dem Auskultationsbefund gestellt und durch den Nachweis eines pneumonischen Infiltrats in der Röntgenaufnahme bestätigt. Der mit Abstand häufigste Erreger bleibt Streptococcus pneumoniae, der in Deutschland unverändert hohe Penicillinempfindlichkeit zeigt. Daneben werden Haemophilus influenzae, Mykoplasmen, Legionellen und Influenza-Viren regelmäßig nachgewiesen. Eine mikrobiologische Diagnostik ist in der Praxis nicht routinemäßig erforderlich. Zur Einschätzung der Prognose und Entscheidung über die Notwendigkeit einer Hospitalisierung dient der CRB65-Score. Die Auswahl der kalkulierten Therapie richtet sich nach Schweregrad der Infektion und Vorliegen von Komorbiditäten. Aminopenicilline sind Mittel erster Wahl bei unkomplizierten Pneumonien. Bei Verdacht auf Mykoplasmen- und Legionelleninfektion ist ein Makrolid oder ein neueres Fluorchinolon indiziert. Wichtige präventive Maßnahmen sind die jährliche Influenzaimpfung und die Pneumokokkenimpfung.

Loss of epithelial barriers characterized by reduction of E-cadherin is a hallmark of chronic obstructive pulmonary disease (COPD). We investigated the effects of nontypeable Haemophilus influenzae (NTHi) infections, associated with acute exacerbations of chronic bronchitis, on the regulation of E-cadherin in host cells. NTHi infection decreased E-cadherin mRNA and protein-levels in lung epithelial cells. E-cadherin reduction was mediated by activation of the fibroblast growth factor 2 (FGF2), the mammalian target of rapamycin (mTOR) and Slug. These data indicate that epithelial integrity and barrier function is disturbed by NTHi infection. Mainly, the destruction of cell-cell contacts is a prominent feature in NTHi infection.

This phase 2 portion of a phase 1/2 study examined the efficacy and safety of LY2603618, a selective checkpoint kinase 1 inhibitor, combined with pemetrexed and cisplatin (LY+Pem+Cis) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). This multicenter, randomized, controlled, open-label study (NCT01139775) enrolled patients with stage IV nonsquamous NSCLC and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized (2:1) to LY+Pem+Cis or pemetrexed and cisplatin (Pem+Cis). Induction therapy comprised four 21-day cycles of 500 mg/m2 pemetrexed and 75mg/m2 cisplatin on Day 1 (both arms) and 275mg LY2603618 on Day 2 (LY+Pem+Cis arm). Maintenance therapy comprised 500mg/m2 pemetrexed on Day 1 (both arms) and 275mg LY2603618 on Day 2 (LY+Pem+Cis arm) until disease progression. The primary endpoint was progression‐free survival (PFS). Enrollment was permanently halted before target enrollment was met due to a greater number of thromboembolic events in the LY+Pem+Cis arm. Sixty-two patients were enrolled (LY+Pem+Cis, n=39; Pem+Cis, n=23). Bayesian and frequentist analysis demonstrated superior PFS in the LY+Pem+Cis arm vs the Pem+Cis arm (median [90% confidence interval]: LY+Pem+Cis, 4.7 months [4.–7.1]; Pem+Cis, 1.5 months [1.3–2.9]; P=0.022). Seven patients in the LY+Pem+Cis arm (vs 0 in the Pem+Cis arm) experienced serious thromboembolic events: pulmonary embolism (n=5), ischemic stroke (n=1), and cerebrovascular accident (n=1). Although the primary endpoint was met, the combination of LY2603618+Pem+Cis will not be further developed for treating advanced nonsquamous NSCLC due to the potential increased risk of thromboembolic events with this combination. ClinicalTrials.gov Identifier: NCT01139775.

Objective: To guide nosology and classification of patients with eosinophilic granulomatosis with polyangiitis (EGPA) based on phenotype and presence or absence of ANCA. Methods: Organ manifestations and ANCA status were retrospectively analyzed based on the presence or not of predefined definite vasculitis features or surrogates of vasculitis in patients asthma, eosinophilia, and at least one systemic organ manifestation attributable to systemic disease. Results: The study population included 157 patients (mean age 49.4 +/- 14.1), with a follow-up of 7.4 +/- 6.4 years. Patients with ANCA (31%) more frequently had weight loss, myalgias, arthralgias, biopsy-proven vasculitis, glomerulonephritis on biopsy, hematuria, leukocytoclastic capillaritis and/or eosinophilic infiltration of arterial wall on biopsy, and other renal disease. A total of 41% of patients had definite vasculitis manifestations (37%) or strong surrogates of vasculitis (4%), of whom only 53% had ANCA. Mononeuritis multiplex was associated with systemic vasculitis (p = 0.005) and with the presence of ANCA (p < 0.001). Overall, 59% of patients had polyangiitis as defined by definite vasculitis, strong surrogate of vasculitis, mononeuritis multiplex, and/or ANCA with at least one systemic manifestation other than ENT or respiratory. Patients with polyangiitis had more systemic manifestations including arthralgias (p = 0.02) and renal disease (p = 0.024), had higher peripheral eosinophilia (p = 0.027), and a trend towards less myocarditis (p = 0.057). Using predefined criteria of vasculitis and surrogates of vasculitis, ANCA alone were found to be insufficient to categorise patients with vasculitis features. Conclusion: We suggest a revised nomenclature and definition for EGPA and a new proposed entity referred to as hypereosinophilic asthma with systemic (non vasculitic) manifestations. (C) 2016 Elsevier B.V. All rights reserved.

The present guideline provides a new and updated concept of treatment and prevention of adult patients with community-acquired pneumonia. It replaces the previous guideline dating from 2009.The guideline was worked out and agreed on following the standards of methodology of a S3-guideline. This includes a systematic literature search and grading, a structured discussion of recommendations supported by the literature as well as the declaration and assessment of potential conflicts of interests.The guideline has a focus on specific clinical circumstances, an update on severity assessment, and includes recommendations for an individualized selection of antimicrobial treatment as well as primary and secondary prevention.

The respiratory manifestations of eosinophilic granulomatosis with polyangiitis (EGPA) have not been studied in detail. In this retrospective multicentre study, EGPA was defined by asthma, eosinophilia and at least one new onset extra-bronchopulmonary organ manifestation of disease. The study population included 157 patients (mean± sd age 49.4±14.1 years), with a mean± sd blood eosinophil count of 7.4±6.4×10 9 L −1 at diagnosis. There was a mean± sd of 11.8±18.2 years from the onset of asthma to the diagnosis of EGPA, of 1.4±8.4 years from the first onset of peripheral eosinophilia to the diagnosis of EGPA, and of 7.4±6.4 years from EGPA diagnosis to the final visit. Despite inhaled and oral corticosteroid treatment, the severity of asthma increased 3–6 months before the onset of the systemic manifestations. Asthma was severe in 57%, 48%, and 56% of patients at diagnosis, at 3 years, and at the final visit, respectively. Persistent airflow obstruction was present in 38%, 30%, and 46% at diagnosis, at 3 years, and at the final visit, respectively. In EGPA, asthma is severe, antedates systemic manifestations by a mean of 12 years, and progresses to long-term persistent airflow obstruction despite corticosteroids in a large proportion of patients, which affects long-term management and morbidity.

The present guideline provides a new and updated concept of treatment and prevention of adult patients with community-acquired pneumonia. It replaces the previous guideline dating from 2009.The guideline was worked out and agreed on following the standards of methodology of a S3-guideline. This includes a systematic literature search and grading, a structured discussion of recommendations supported by the literature as well as the declaration and assessment of potential conflicts of interests.The guideline has a focus on specific clinical circumstances, an update on severity assessment, and includes recommendations for an individualized selection of antimicrobial treatment as well as primary and secondary prevention.