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Background: Idiopathic pulmonary fibrosis (IPF) is an incurable disease characterized by progressive lung fibrosis ultimately resulting in respiratory failure and death. Recurrent micro-injuries to the alveolar epithelium and aberrant alveolar wound healing with impaired re-epithelialization define the initial steps of the pathogenic trajectory. Failure of timely alveolar epithelial repair triggers hyper-proliferation of mesenchymal cells accompanied by increased deposition of extracellular matrix into the lung interstitium.Methods: We previously isolated fibrosis-specific mesenchymal stem cell (MSC)-like cells from lung tissue of patients with interstitial lung diseases. These cells produced factors bearing anti-fibrotic potential and changed their morphology from mesenchymal to epithelial upon culture in an epithelial cell (EC)-specific growth medium. Here, we set out to molecularly characterize these MSC-like cell-derived ECs using global gene expression profiling by RNA-sequencing. Moreover, we aimed at characterizing disease-specific differences by comparing the transcriptomes of ECs from IPF and non-IPF sources.Results: Our results suggest that differentially expressed genes are enriched for factors related to fibrosis, hypoxia, bacterial colonization and metabolism, thus reflecting many of the hallmark characteristics of pulmonary fibrosis. IPF-ECs showed enrichment of both pro- and anti-fibrotic genes, consistent with the notion of adaptive, compensatory regulation.Conclusions: Our findings support the hypothesis of a functional impairment of IPF-ECs, which could possibly explain the poor clinical outcome of IPF that roughly compares to those of advanced-stage cancers. Our study provides a valuable resource for downstream mechanistic investigation and the quest for novel therapeutic IPF targets. [ABSTRACT FROM AUTHOR]

Background: Type II alveolar epithelial cells (AT2) play a pivotal role in maintaining the integrity and function of the alveoli. Only recently, the role of impaired epithelial repair mechanisms after injury in the pathogenesis of idiopathic pulmonary fibrosis has been demonstrated, and has shifted the AT2 cell in the focus of interest. Therefore, using primary human AT2 cells instead of cell lines for in vitro experiments has become desirable. Several groups have developed methods to isolate human AT2 cells applying tissue digestion and consecutive filtration in their protocols. Here we present a technique to isolate primary human AT2 cells by sprouting directly from peripheral human lung tissue.Methods: Epithelial cell cultures were established from lung tissue obtained from patients undergoing diagnostic or therapeutic video-assisted thoracoscopic surgery or undergoing flexible bronchoscopy with transbronchial biopsy. Lung tissue was cut into small pieces and those were placed into cell culture flasks containing supplemented epithelial growth medium for cell sprouting. Cells were characterized by immunofluorescence stainings for E-cadherin, pan-cytokeratin, surfactant protein C (SP-C), and for lysotracker; fluorescent surfactant associated protein B (SP-B) uptake and secretion was assessed by live cell imaging; RNA levels of SP-A, SP-B, SP-C, and SP-D were determined by real-time PCR; Electron microscopy was used to search for the presence of lamellar bodies.Results: Sprouting of cells started two to four days after the start of culture. Epithelial differentiation was confirmed by positive staining for E-cadherin and pan-cytokeratin. Further characterization demonstrated positivity for the AT2 cell marker SP-C and for lysotracker which selectively labels lamellar bodies in cultured AT2 cells. The up-take and release of SP-B, a mechanism described for AT2 cells only, was demonstrated by live cell imaging. Real-time RT-PCR showed mRNA expression of all four surfactant proteins with highest levels for SP-B. The presence of lamellar bodies was demonstrated by electron microscopy.Conclusions: This study describes a novel method for isolating AT2 cells from human adult lung tissue by sprouting. The characterization of the cultured AT2 cells complies with current criteria for an alveolar type 2 cell phenotype. Compared to current protocols for the culture of AT2 cells, isolating the cells by sprouting is simple, avoids proteolytic tissue digestion, and has the advantage to be successful even from as few tissue as attained from a transbronchial forceps biopsy. [ABSTRACT FROM AUTHOR]

Clinical practice guidelines are ubiquitous and are developed to provide recommendations for the management of many diseases, including chronic obstructive pulmonary disease. The development of these guidelines is burdensome, demanding a significant investment of time and money. In Europe, the majority of countries develop their own national guidelines, despite the potential for overlap or duplication of effort. A concerted effort and consolidation of resources between countries may alleviate the resource-intensity of maintaining individual national guidelines. Despite significant resource investment into the development and maintenance of clinical practice guidelines, their implementation is suboptimal. Effective strategies of guideline dissemination must be given more consideration, to ensure adequate implementation and improved patient care management in the future. [ABSTRACT FROM AUTHOR]

Background: Trichosporon mycotoxinivorans is a recently described yeast-like fungal organism and its association as a pathogen for patients with cystic fibrosis (CF) was reported previously. We show the clinical course of a CF patient over 9 years as well as the applications of modern molecular and proteomic identification techniques of this rare fungus. Case presentation: We present the case of a 32-year-old male CF patient with sputum cultures continuously positive with the anamorphic yeast T. mycotoxinivorans during 9 years. Furthermore, susceptibility testing of T. mycotoxinivorans to different antifungals were performed. In addition, a rapid identification method of this novel fungal pathogen with matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) was applied using a simple extraction protocol. Conclusions: Our case presentation confirms T. mycotoxinivorans as a potential emerging pathogen in patients with CF. However, our CF patient showed mild symptoms over a very long time period of 9 years. A short MALDI-TOF MS procedure allows reliable and rapid identification of T. mycotoxinivorans and therefore should facilitate further study on the clinical relevance and epidemiology of this unusual fungal organism. [ABSTRACT FROM AUTHOR]

Background: Sarcoidosis is a granulomatous disease that may affect any organ of the body. The most frequent loci of manifestation are the lungs. However, there are individual cases where bones are affected. The literature describes cases in which swelling or fistula were the first findings of a bone lesion. This is the first case reporting an osteolysis in both angles of the mandibles which led to the diagnosis of sarcoidosis with multi-organ involvement. Case presentation: The authors present a 74 years old European female patient without previous diagnosis of sarcoidosis who presented with pain in the area of the jaw angles. There were no further clinical symptoms. Bone biopsy following radiological investigation demonstrated non-caseating granulomas consistent with sarcoidosis of the bone. Further evaluation confirmed multi-organ disease with involvement of lungs, intrathoracic lymph nodes, and the central nervous system. Conclusion: This case report shows that diagnosis of a severe disease can be missed if systematic clinical signs are not given. Furthermore, an accurate anamnesis and examination is required to receive an early diagnosis which often needs an interdisciplinary approach. [ABSTRACT FROM AUTHOR]

Background: Functional deficiency of mannose-binding lectin (MBL) may contribute to the pathogenesis of chronic obstructive pulmonary disease. We hypothesized that specific MBL2 gene polymorphisms and circulating MBL protein levels are associated with clinically relevant outcomes in the Predicting Outcome using systemic Markers In Severe Exacerbations of COPD PROMISE-COPD cohort.Methods: We followed 277 patients with stable COPD GOLD stage II-IV COPD over a median period of 733 days (IQR 641-767) taking survival as the primary outcome parameter. Patients were dichotomized as frequent (≥ 2 AECOPD/year) or infrequent exacerbators. Serum MBL levels and single nucleotide polymorphisms of the MBL2 gene were assessed at baseline.Results: The MBL2-HYPD haplotype was significantly more prevalent in frequent exacerbators (OR: 3.33; 95% CI, 1.24-7.14, p = 0.01). The median serum MBL concentration was similar in frequent (607 ng/ml, [IQR; 363.0-896.0 ng/ml]) and infrequent exacerbators (615 ng/ml, [IQR; 371.0-942.0 ng/ml]). Serum MBL was not associated with lung function characteristics or bacterial colonization in sputum. However, high serum MBL at stable state was associated with better survival compared to low MBL (p = 0.046, log rank test).Conclusions: In COPD, the HYPD haplotype of MBL2 gene is associated with frequent exacerbations and high serum MBL is linked to increased survival. The PROMISE-COPD study was registered at www.controlled-trials.com under the identifier ISRCTN99586989. [ABSTRACT FROM AUTHOR]

Background: Acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) are associated with accelerated aggravation of clinical symptoms and deterioration of pulmonary function. The mechanisms by which exacerbations may contribute to airway remodeling and declined lung function are poorly understood. In this study, we investigated if AE-COPD are associated with differential expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in bronchoalveolar lavage (BAL). Methods: COPD patients undergoing diagnostic bronchoscopy, with either stable disease (n = 53) or AE-COPD (n = 44), matched for their demographics and lung function parameters were included in this study. Protein levels of MMP-2,-9,-12 and of TIMP-1 and -2 in BAL were measured by ELISA. Enzymatic activity of MMP-2 and -9 was assessed by gelatin zymography. Results: We observed that MMP-9, TIMP-1 and TIMP-2 were significantly increased in BAL during AE-COPD. Furthermore, there was a significant negative correlation of MMP-9, TIMP-1 and TIMP-2 with FEV1% predicted and a significant positive correlation of TIMP-1 and TIMP-2 with RV% predicted in AE-COPD. None of MMPs and TIMPs correlated with DLCO% predicted, indicating that they are associated with airway remodeling leading to obstruction rather than emphysema. In AE-COPD the gelatinolytic activity of MMP-2 was increased and furthermore, MMP-9 activation was significantly up-regulated irrespective of lung function, bacterial or viral infections and smoking. Conclusions: The results of this study indicate that during AE-COPD increased expression of TIMP-1, TIMP-2, and MMP-9 and activation of MMP-9 may be persistent aggravating factors associated with airway remodeling and obstruction, suggesting a pathway connecting frequent exacerbations to lung function decline. [ABSTRACT FROM AUTHOR]

Background: Concerns about postcessational weight gain might hamper rather than encourage smokers to quit smoking. Methods: We conducted a comprehensive multi-institutional smoking cessation program for health care and industrial workers (n = 654) employed at University Hospital Basel (Switzerland) and two local health industry companies (Novartis International AG, F. Hoffmann-La Roche AG). The program contained counselling with an option of pharmacological support. Changes in body weight were observed during 24 months of follow-up. Factors associated with longitudinal weight gain (>5 % of baseline weight) were identified by cox-regression analysis. Results: In 51 % of permanent quitters no significant changes of mean body weight were observed after 12 (0.52 kg, SD ±2.87 kg) and 24 months (0.40 kg, SD ± 2.99 kg). Marked weight gain following smoking cessation was characterized by a wide margin of changes. In more than a half of former smokers (58 %) weight increases were moderate (<5 kg), whereas excessive increases (>10 kg) were seen in only 10 % of quitters. Lower baseline BMI (HR 0.60, 95 % CI 0.40- 0.80, p = 0.03), daily consumption of less than ten cigarettes (HR 0.53, 95 % CI 0.27- 0.63, p = 0.04) and ischemic cardiopathy (HR 0.21, 95 % CI 0.07-0.62; p < 0.01) were associated with a lower risk for weight gain. Employees with lower educational levels (HR 2.60, 95 % CI 1.60-5.50, p < 0.01), diabetes mellitus (HR 3.05, 95 % CI 2.20-8.06, p = 0.02) and those smoking to reduce boredom in life (HR 1.68, 95 % CI 1.21-2.33, p < 0.01) were at highest risk. Conclusion: Marked postcessational weight gain occurs less often than expected, but remains difficult to be predicted. Our findings might be helpful to alleviate weight concerns in the average smoker willing to quit. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The kinase inhibitor nintedanib specific for vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) significantly reduced the rate of decline of forced vital capacity versus placebo. Aim: To determine the in vitro effect of nintedanib on primary human lung fibroblasts. Methods: Fibroblasts were isolated from lungs of IPF patients and from non-fibrotic controls. We assessed the effect of VEGF, PDGF-BB and basic FGF (bFGF) ± nintedanib on: (i) expression/activation of VEGFR, PDGFR, and FGFR, (ii) cell proliferation, secretion of (iii) matrix metalloproteinases (MMP), (iv) tissue inhibitor of metalloproteinase (TIMP), and (v) collagen. Results: IPF fibroblasts expressed higher levels of PDGFR and FGFR than controls. PDGF-BB, bFGF, and VEGF caused a pro-proliferative effect which was prevented by nintedanib. Nintedanib enhanced the expression of pro-MMP-2, and inhibited the expression of TIMP-2. Transforming growth factor-beta-induced secretion of collagens was inhibited by nintedanib. Conclusion: Our data demonstrate a significant anti-fibrotic effect of nintedanib in IPF fibroblasts. This effect consists of the drug's anti-proliferative capacity, and on its effect on the extracellular matrix, the degradation of which seems to be enhanced. [ABSTRACT FROM AUTHOR]

Background: The 6-Minute Walk Test (6MWT) is representative of daily-life activities and reflects the functional capacity of patients. The change of oxygen uptake (VO2) in the initial phase of low-intensity exercise (VO2 kinetics) can be used to assess submaximal exercise performance of patients. The objective of the following study was to analyse VO2 kinetics in patients with different pulmonary and cardiovascular diseases. In addition, we investigated the extent to which VO2 kinetics at the onset of the 6MWT were associated with exercise capacity, morbidity and mortality. Methods: VO2 kinetics of 204 patients and 16 healthy controls were obtained using mobile telemetric cardiopulmonary monitoring during a 6MWT. A new mean response time (MRT) index (wMRT) was developed to quantify VO2 kinetics by correcting MRT for work rate. The differences in wMRT between disease categories as well as the association between wMRT and patients’ exercise capacity and outcome - time to hospitalization/ death- were tested. Results: The assessment of a robust wMRT was feasible in 86% (244/284) patients. wMRT was increased in patients compared to healthy controls (p <0.001). wMRT was largest in patients with pulmonary arterial hypertension (PAH). There were significant associations between wMRT and exercise capacity in all patients. High wMRT was found to be associated with a high rate of death and re-hospitalization in patients with CHF (p = 0.024). In patients with pulmonary diseases and pulmonary hypertension wMRT was not associated with outcome (p = 0.952). Conclusions: Submaximal exercise performance of patients is reduced. O2 kinetics at the onset of exercise are associated with exercise capacity in all patients. wMRT was found to be an important prognostic factor in patients with congestive heart failure (CHF), but not with pulmonary diseases. [ABSTRACT FROM AUTHOR]

Introduction Pseudomonas aeruginosa frequently causes nosocomial pneumonia and is associated with poor outcome. The purpose of this study was to assess the prevalence and clinical outcome of nosocomial pneumonia caused by serotype specific Pseudomonas aeruginosa in critically ill patients under appropriate antimicrobial therapy management. Methods A retrospective, non-interventional epidemiological multicenter cohort study involving 143 patients with confirmed nosocomial pneumonia caused by Pseudomonas aeruginosa. Patients were analyzed for a period of 30 days from time of nosocomial pneumonia onset. Fourteen patients fulfilling the same criteria from a Phase IIa study conducted at the same time/centers were included in the prevalence calculations but not in the clinical outcome analysis. Results The prevalence of serotypes was: O6 (29%), O11 (23%), O10 (10%), O2 (9%) and O1 (8%). Serotypes with a prevalence < 5% were found in 13% of patients, 8% were classified as not typeable. Across all serotypes there was 19% mortality, 70% clinical resolution, 11% clinical continuation and 5% clinical recurrence. Age and higher APACHE II were predictive risk factors associated with probability of death and lower clinical resolution for Pseudomonas aeruginosa nosocomial pneumonia. Mortality tends to be higher with O1 (40%) and lower with O2 (0%); clinical resolution tends to be better with O2 (82%) compared to other serotypes. Persisting pneumonia with O6 and O11 was respectively 8% and 21%; clinical resolution with O6 and O11 was respectively 75% and 57%. Conclusions In Pseudomonas aeruginosa nosocomial pneumonia, the most prevalent serotypes were O6 and O11. Further studies including larger group sizes are needed to correlate clinical outcome with virulence factors of Pseudomonas aeruginosa in patients with nosocomial pneumonia caused by various serotypes; and to compare O6 and O11, the 2 serotypes most frequently encountered in critically ill patients. [ABSTRACT FROM AUTHOR]

Background: Invasive fungal disease (IFD) is a frequent and serious infectious complication in immunocompromised patients. Culture and cytology in bronchoalveolar lavage (BAL) have a high specificity but low sensitivity for the diagnosis of IFD as assessed by histology. Molecular methods are expected to allow a rapid diagnosis of IFD with a high sensitivity. We evaluated the diagnostic accuracy of conventional nested PCR in the bronchoalveolar fluid to diagnose IFD in severely immunocompromised patients. Methods: Consecutive immunosuppressed patients undergoing bronchoscopy for suspected pulmonary infection in a tertiary care hospital were included. Patients were classified as having "proven", "probable", "possible", and "no" IFD based on definitions of the European Organization for Research and Treatment of Cancer and National Institute of Allergy and Infectious Diseases (EORTC/NIAID) and on clinical grounds. Conventional nested PCR for aspergillus fumigatus, flavus, niger, glaucus, terreus and tomarrii were applied to 2.5 ml bronchoalveolar fluid. Results: A total of 191 patients were included. Mean age was 51 y, 61% were male. There were 129 patients with hematological conditions, 26 solid organ transplant recipients, 24 auto-immune disorders, and 12 HIV. According to the EORTC/NIAID classification, there were 53 patients with potential IFD: 3 (2%) had proven, 8 (4%) probable, 42 (22%) possible and 138 (72%) no IFD. A total of 111 (58%) of the patients - 10 (90.9%) proven or probable IFD, 32 (76.2%) possible IFD and 69 (50%) "no" IFD) were on anti-fungal therapy at the time of bronchoscopy. Conventional nested PCR for Aspergillus was positive in 55 cases (28.8%). According to these results, sensitivity, specificity, PPV and NPV for "proven" IFD was 0%, 71%, 0%, 98%, respectively and "probable" IFD was 36%, 72%, 7%, 95%, respectively. In 53 (28%) cases there was a strong clinical suspicion of IFD in the chest-x-ray and/or chest-CT irrespective of the EORTC/NIAID classification. However, from those, only 15 (28%) had a positive conventional nested PCR. Conclusion: In our experience, conventional nested Aspergillus PCR in the BAL seems to be of limited usefulness for detection of invasive fungal disease in immunocompromised patients due to the limited sensitivity and specificity of the method. [ABSTRACT FROM AUTHOR]

Background: Airway wall remodelling is an important pathology of asthma. Growth factor induced airway smooth muscle cell (ASMC) proliferation is thought to be the major cause of airway wall thickening in asthma. Earlier we reported that Dimethylfumarate (DMF) inhibits platelet-derived growth factor (PDGF)-BB induced mitogen and stress activated kinase (MSK)-1 and CREB activity as well as IL-6 secretion by ASMC. In addition, DMF altered intracellular glutathione levels and thereby reduced proliferation of other cell types.Methods: We investigated the effect of DMF on PDGF-BB induced ASMC proliferation, on mitogen activated protein kinase (MAPK) activation; and on heme oxygenase (HO)-1 expression. ASMC were pre-incubated for 1 hour with DMF and/or glutathione ethylester (GSH-OEt), SB203580, hemin, cobalt-protoporphyrin (CoPP), or siRNA specific to HO-1 before stimulation with PDGF-BB (10 ng/ml).Results: PDGF-BB induced ASMC proliferation was inhibited in a dose-dependant manner by DMF. PDGF-BB induced the phosphorylation of ERK1/2 and p38 MAPK, but not of JNK. DMF enhanced the PDGF-BB induced phosphorylation of p38 MAPK and there by up-regulated the expression of HO-1. HO-1 induction inhibited the proliferative effect of PDGF-BB. HO-1 expression was reversed by GSH-OEt, or p38 MAPK inhibition, or HO-1 siRNA, which all reversed the anti-proliferative effect of DMF.Conclusion: Our data indicate that DMF inhibits ASMC proliferation by reducing the intracellular GSH level with subsequent activation of p38 MAPK and induction of HO-1. Thus, DMF might reduce ASMC and airway remodelling processes in asthma. [ABSTRACT FROM AUTHOR]

Background: Circulating levels of endothelin-1 are increased in sepsis and correlate with severity of disease. A rapid and easy immunoassay has been developed to measure the more stable ET-1 precursor peptides proET-1. The objective of this study was to assess the diagnostic and prognostic value of proET-1 in a prospective cohort of mainly septic patients with community-acquired pneumonia. Methods: We evaluated 281 consecutive patients with community acquired pneumonia. Serum proET-1 plasma levels were measured using a new sandwich immunoassay. Results: ProET-1 levels exhibited a gradual increase depending on the clinical severity of pneumonia as assessed by the pneumonia severity index (PSI) and the CURB65 scores (p < 0.001 and p < 0.01). The diagnostic accuracy to predict bacteraemia of procalcitonin (AUC 0.84 [95% 0.74-0.93]) was superior than C-reactive protein (AUC 0.67 [95%CI 0.56-0.78]) and leukocyte count (AUC 0.66 [95%CI 0.55-0.78]) and in the range of proET-1(AUC of 0.77 [95%CI 0.67-0.86]). ProET-1 levels on admission were increased in patients with adverse medical outcomes including death and need for ICU admission. ROC curve analysis to predict the risk for mortality showed a prognostic accuracy of proET-1 (AUC 0.64 [95%CI 0.53-0.74]), which was higher than C-reactive protein (AUC 0.51 [95%CI 0.41-0.61]) and leukocyte count (AUC 0.55 [95%CI 0.44-0.65]) and within the range of the clinical severity scores (PSI AUC 0.69 [95%CI 0.61-0.76] and CURB65 0.67 [95%CI 0.57-0.77]) and procalcitonin (AUC 0.59 [95% 0.51-0.67]). ProET-1 determination improved significantly the prognostic accuracy of the CURB65 score (AUC of the combined model 0.69 [95%CI 0.59-0.79]). In a multivariate logistic regression model, only proET1 and the clinical severity scores were independent predictors for death and for the need for ICU admission. Conclusion: In community-acquired pneumonia, ET-1 precursor peptides correlate with disease severity and are independent predictors for mortality and ICU admission. If confirmed in future studies, proET-1 levels may become another helpful tool for risk stratification and management of patients with community-acquired pneumonia. Trial registration: ISRCTN04176397 [ABSTRACT FROM AUTHOR]

Background: Community-acquired pneumonia (CAP) is the most frequent infection-related cause of death. The reference standard to diagnose CAP is a new infiltrate on chest radiograph in the presence of recently acquired respiratory signs and symptoms. This study aims to evaluate the diagnostic and prognostic accuracy of clinical signs and symptoms and laboratory biomarkers for CAP. Methods: 545 patients with suspected lower respiratory tract infection, admitted to the emergency department of a university hospital were included in a pre-planned post-hoc analysis of two controlled intervention trials. Baseline assessment included history, clinical examination, radiography and measurements of procalcitonin (PCT), highly sensitive C-reactive protein (hsCRP) and leukocyte count. Results: Of the 545 patients, 373 had CAP, 132 other respiratory tract infections, and 40 other final diagnoses. The AUC of a clinical model including standard clinical signs and symptoms (i.e. fever, cough, sputum production, abnormal chest auscultation and dyspnea) to diagnose CAP was 0.79 [95% CI, 0.75-0.83]. This AUC was significantly improved by including PCT and hsCRP (0.92 [0.89-0.94]; p < 0.001). PCT had a higher diagnostic accuracy (AUC, 0.88 [0.84-0.93]) in differentiating CAP from other diagnoses, as compared to hsCRP (AUC, 0.76 [0.69-0.83]; p < 0.001) and total leukocyte count (AUC, 0.69 [0.62-0.77]; p < 0.001). To predict bacteremia, PCT had a higher AUC (0.85 [0.80-0.91]) as compared to hsCRP (p = 0.01), leukocyte count (p = 0.002) and elevated body temperature (p < 0.001). PCT, in contrast to hsCRP and leukocyte count, increased with increasing severity of CAP, as assessed by the pneumonia severity index (p < 0.001). Conclusion: PCT, and to a lesser degree hsCRP, improve the accuracy of currently recommended approaches for the diagnosis of CAP, thereby complementing clinical signs and symptoms. PCT is useful in the severity assessment of CAP. [ABSTRACT FROM AUTHOR]

House dust mite allergens (HDM) cause bronchoconstriction in asthma patients and induce an inflammatory response in the lungs due to the release of cytokines, chemokines and additional mediators. The mechanism how HDM components achieve this is largely unknown. The objective of this study was to assess whether HDM components of Dermatophagoides pteronissinus with protease activity (Der p 1) and unknown enzymatic activity (Der p 2, Der p 5) induce biological responses in a human airway-derived epithelial cell line (A549), and if so, to elucidate the underlying mechanism(s) of action. A549 cells were incubated with HDM extract, Der p 1, recombinant Der p 2 and recombinant Der p 5. Cell desquamation was assessed by microscopy. The proinflammatory cytokines, IL-6 and IL-8, were measured by ELISA. Intracellular Ca2+ levels were assessed in A549 cells and in mouse fibroblasts expressing the human protease activated receptor (PAR)1, PAR2 or PAR4. HDM extract, Der p 1 and Der p 5 dose-dependently increased the production of IL-6 and IL-8. Added simultaneously, Der p 1 and Der p 5 further increased the production of IL-6 and IL-8. The action of Der p 1 was blocked by cysteine-protease inhibitors, while that of Der p 5 couldn't be blocked by either serine- or cysteine protease inhibitors. Der p 5 only induced cell shrinking, whereas HDM extract and Der p1 also induced cell desquamation. Der p 2 had no effect on A549 cells. Der p 1's protease activity causes desquamation and induced the release of IL6 and IL-8 by a mechanism independent of Ca2+ mobilisation and PAR activation. Der p 5 exerts a protease-independent activation of A549 that involves Ca2+ mobilisation and also leads to the production of these cytokines. Together, our data indicate that allergens present in HDM extracts can trigger protease-dependent and protease-independent signalling pathways in A549 cells. [ABSTRACT FROM AUTHOR]

Introduction: Pseudomonas aeruginosa frequently causes nosocomial pneumonia and is associated with poor outcome. The purpose of this study was to assess the prevalence and clinical outcome of nosocomial pneumonia caused by serotype-specific P. aeruginosa in critically ill patients under appropriate antimicrobial therapy management.Methods: A retrospective, non-interventional epidemiological multicenter cohort study involving 143 patients with confirmed nosocomial pneumonia caused by P. aeruginosa. Patients were analyzed for a period of 30 days from time of nosocomial pneumonia onset. Fourteen patients fulfilling the same criteria from a phase IIa studyconducted at the same time/centers were included in the prevalence calculations but not in the clinical outcome analysis.Results: The prevalence of serotypes was: O6 (29%), O11 (23%), O10 (10%), O2 (9%), and O1 (8%). Serotypes with a prevalence of less than 5% were found in 13% of patients, 8% were classified as not typeable. Across all serotypes, 19% mortality, 70% clinical resolution, 11% clinical continuation, and 5% clinical recurrence were recorded. Age and higher APACHE II (Acute Physiology and Chronic Health Evaluation II) were predictive risk factors associated with probability of death and lower clinical resolution for P. aeruginosa nosocomial pneumonia. Mortality tends to be higher with O1 (40%) and lower with O2 (0%); clinical resolution tends to be better with O2 (82%) compared to other serotypes. Persisting pneumonia with O6 and O11 was, respectively, 8% and 21%; clinical resolution with O6 and O11 was, respectively, 75% and 57%.Conclusions: In P. aeruginosa nosocomial pneumonia, the most prevalent serotypes were O6 and O11. Further studies including larger group sizes are needed to correlate clinical outcome with virulence factors of P. aeruginosa in patients with nosocomial pneumonia caused by various serotypes; and to compare O6 and O11, the two serotypes most frequently encountered in critically ill patients. [ABSTRACT FROM AUTHOR]

Background: Late 2019, a new highly contagious coronavirus SARS-CoV-2 has emerged in Wuhan, China, causing within 2 months a pandemic with the highest disease burden in elderly and people with pre-existing medical conditions. The pandemic has highlighted that new and more flexible clinical trial approaches, such as trial platforms, are needed to assess the efficacy and safety of interventions in a timely manner. The two existing Swiss cohorts of immunocompromised patients (i.e., Swiss HIV Cohort Study (SHCS) and Swiss Transplant Cohort Study (STCS)) are an ideal foundation to set-up a trial platform in Switzerland leveraging routinely collected data. Within a newly founded trial platform, we plan to assess the efficacy of the first two mRNA SARS-CoV-2 vaccines that reached market authorization in Switzerland in the frame of a pilot randomized controlled trial (RCT) while at the same time assessing the functionality of the trial platform., Methods: We will conduct a multicenter randomized controlled, open-label, 2-arm sub-study pilot trial of a platform trial nested into two Swiss cohorts. Patients included in the SHCS or the STCS will be eligible for randomization to either receiving the mRNA vaccine Comirnaty® (Pfizer/BioNTech) or the COVID-19 mRNA Vaccine Moderna®. The primary clinical outcome will be change in pan-lg antibody response (pan-Ig anti-S1-RBD; baseline vs. 3 months after first vaccination; binary outcome, considering ≥ 0.8 units/ml as a positive antibody response). The pilot study will also enable us to assess endpoints related to trial conduct feasibility (i.e., duration of RCT set-up; time of patient recruitment; patient consent rate; proportion of missing data). Assuming vaccine reactivity of 90% in both vaccine groups, we power our trial, using a non-inferiority margin such that a 95% two-sided confidence interval excludes a difference in favor of the reference group of more than 10%. A sample size of 380 (190 in each treatment arm) is required for a statistical power of 90% and a type I error of 0.025. The study is funded by the Swiss National Science Foundation (National Research Program NRP 78, "COVID-19")., Discussion: This study will provide crucial information about the efficacy and safety of the mRNA SARS-CoV-2 vaccines in HIV patients and organ transplant recipients. Furthermore, this project has the potential to pave the way for further platform trials in Switzerland., Trial Registration: ClinicalTrials.gov NCT04805125 . Registered on March 18, 2021., (© 2021. The Author(s).)

Background: Sarcoidosis is a granulomatous disease that may affect any organ of the body. The most frequent loci of manifestation are the lungs. However, there are individual cases where bones are affected. The literature describes cases in which swelling or fistula were the first findings of a bone lesion. This is the first case reporting an osteolysis in both angles of the mandibles which led to the diagnosis of sarcoidosis with multi-organ involvement., Case Presentation: The authors present a 74 years old European female patient without previous diagnosis of sarcoidosis who presented with pain in the area of the jaw angles. There were no further clinical symptoms. Bone biopsy following radiological investigation demonstrated non-caseating granulomas consistent with sarcoidosis of the bone. Further evaluation confirmed multi-organ disease with involvement of lungs, intrathoracic lymph nodes, and the central nervous system., Conclusion: This case report shows that diagnosis of a severe disease can be missed if systematic clinical signs are not given. Furthermore, an accurate anamnesis and examination is required to receive an early diagnosis which often needs an interdisciplinary approach.

Background: Thoracic surgery mandates usually a one-lung ventilation (OLV) strategy with the collapse of the operated lung and ventilation of the non-operated lung. These procedures trigger a substantial inflammatory response. The aim of this study was to analyze the cytokine and chemokine reaction in both lungs, pleural space and blood in patients undergoing lung resection with OLV with special interest in the chemokine growth-regulated peptide alpha (GROα) which is the human equivalent to the rat cytokine-induced neutrophil chemoattractant-1 (CINC-1)., Methods: Broncho-alveolar lavage (BAL) fluid of both the collapsed, operated and the ventilated, non-operated lung, respectively, pleural space drainage fluid and blood was collected and the concentrations of interleukin (IL)-6, IL-1RA and GROα were determined with enzyme-linked immunosorbent assays in 15 patients., Results: Substantial inter-individual differences in the BAL fluid between patients in cytokine and chemokine levels occurred. In the pleural fluid and the blood these inter-individual differences were less pronounced. Both sides of the lung were affected and showed a significant increase in IL-6 and IL-1RA concentrations over time but not in GROα concentrations. Except for IL-6, which increased more in the collapsed, operated lung, no difference between the collapsed, operated and the ventilated, non-operated lung occurred. In the blood, IL-6 and IL-1RA increased early, already at the end of surgery. GROα was not detectable. In the pleural fluid, both cytokine and chemokine concentrations increased by day one. The increase was significantly higher in the pleural fluid compared to the blood., Conclusion: The inflammatory response of cytokines affects both the collapsed, operated and the ventilated, non-operated lungs. The difference in extent of response underlines the complexity of the inflammatory processes during OLV. In contrast to the cytokines, the chemokine GROα concentrations did not react in the BAL fluid or in the blood. This indicates that GROα might not be useful as marker for the inflammatory reaction in complex surgical procedures.