Publications by authors named "Thomas Geiser"

123 Publications

Human-Based Advanced Approaches to Investigate Lung Fibrosis and Pulmonary Effects of COVID-19.

Front Med (Lausanne) 2021 7;8:644678. Epub 2021 May 7.

Department for BioMedical Research DBMR, Urology Research Laboratory, University of Bern, Bern, Switzerland.

The coronavirus disease 2019 (COVID-19) pandemic has caused considerable socio-economic burden, which fueled the development of treatment strategies and vaccines at an unprecedented speed. However, our knowledge on disease recovery is sparse and concerns about long-term pulmonary impairments are increasing. Causing a broad spectrum of symptoms, COVID-19 can manifest as acute respiratory distress syndrome (ARDS) in the most severely affected patients. Notably, pulmonary infection with Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the causing agent of COVID-19, induces diffuse alveolar damage (DAD) followed by fibrotic remodeling and persistent reduced oxygenation in some patients. It is currently not known whether tissue scaring fully resolves or progresses to interstitial pulmonary fibrosis. The most aggressive form of pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). IPF is a fatal disease that progressively destroys alveolar architecture by uncontrolled fibroblast proliferation and the deposition of collagen and extracellular matrix (ECM) proteins. It is assumed that micro-injuries to the alveolar epithelium may be induced by inhalation of micro-particles, pathophysiological mechanical stress or viral infections, which can result in abnormal wound healing response. However, the exact underlying causes and molecular mechanisms of lung fibrosis are poorly understood due to the limited availability of clinically relevant models. Recently, the emergence of SARS-CoV-2 with the urgent need to investigate its pathogenesis and address drug options, has led to the broad application of and models to study lung diseases. In particular, advanced models including precision-cut lung slices (PCLS), lung organoids, 3D tissues and lung-on-chip (LOC) models have been successfully employed for drug screens. In order to gain a deeper understanding of SARS-CoV-2 infection and ultimately alveolar tissue regeneration, it will be crucial to optimize the available models for SARS-CoV-2 infection in multicellular systems that recapitulate tissue regeneration and fibrotic remodeling. Current evidence for SARS-CoV-2 mediated pulmonary fibrosis and a selection of classical and novel lung models will be discussed in this review.
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http://dx.doi.org/10.3389/fmed.2021.644678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139419PMC
May 2021

[The Long-COVID Syndrome - a New Clinical Picture after COVID-19 Infection].

Praxis (Bern 1994) 2021 ;110(7):377-382

Universitätsklinik für Pneumologie und Allergologie, Inselspital, Universität Bern, Bern.

The Long-COVID Syndrome - a New Clinical Picture after COVID-19 Infection Long-term consequences are increasingly reported in the current literature after COVID-19 infections. Some patients suffer from persistent pulmonary and extrapulmonary symptoms even months after the acute infection. Pulmonary impairment, but also dysregulation and effects on immune system, cardiovascular system, neurological system, skin and kidney are described or anticipated. This mini review gives a short update to the practitioner about the current knowledge about Long COVID.
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http://dx.doi.org/10.1024/1661-8157/a003678DOI Listing
May 2021

Azithromycin for the Treatment of Chronic Cough in Idiopathic Pulmonary Fibrosis: A Randomized Controlled Cross-over Trial.

Ann Am Thorac Soc 2021 May 20. Epub 2021 May 20.

Inselspital, Bern University Hospital, University of Bern, Department of Pulmonary Medicine, Bern, Switzerland;

Rationale: Patients with idiopathic pulmonary fibrosis (IPF) frequently suffer from difficult to treat chronic cough, which substantially affects their quality of life. Azithromycin has been demonstrated to relieve chronic cough in some populations, however this has not been investigated in IPF.

Objectives: To determine the safety and efficacy of azithromycin for the treatment of chronic cough in patients with IPF.

Methods: In a double-blind randomized controlled cross-over trial, patients with IPF underwent two 12-week intervention periods (azithromycin 500mg or placebo 3 times per week). The primary outcome was change in cough-related quality of life measured by the Leicester cough questionnaire (LCQ). Secondary outcomes included cough severity measured using Visual Analog Scale (VAS), health-related quality of life assessed by the St. George's Respiratory Questionnaire (SGRQ), and objective cough frequency using audiovisual readings from 24h respiratory polygraphy.

Results: 25 patients were randomized (23 men, 2 women), 20 patients completed the study. Mean (standard deviation, SD) age was 67 (8) years, mean (SD) forced vital capacity (FVC) was 65 (16) %-predicted, and diffusion capacity (DLCO) 43 (16) %-predicted. Mean (SD) baseline LCQ was 11.7 (3.7) and 11.3 (3.3) for the azithromycin and the placebo period, respectively, and the corresponding mean (SD) cough VAS 5.6 (2.3) and 5.8 (2.1). There was no significant change in LCQ and VAS with azithromycin or placebo. Similarly, there was no significant difference in change in polygraphy measured cough frequency between the azithromycin and placebo periods. Gastrointestinal adverse effects were more frequent with azithromycin than with placebo (diarrhea 43% vs 5%, p=0.03).

Conclusions: This randomized controlled trial does not support the use of low dose azithromycin for chronic cough in patients with IPF. Clinical trial registered with ClinicalTrials.gov (NCT02173145).
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http://dx.doi.org/10.1513/AnnalsATS.202103-266OCDOI Listing
May 2021

Electrospray Mediated Localized and Targeted Chemotherapy in a Mouse Model of Lung Cancer.

Front Pharmacol 2021 20;12:643492. Epub 2021 Apr 20.

Department of Pulmonary Medicine, University Hospital Bern, Bern, Switzerland.

An advanced stage, centrally localized invasive tumor is a major cause of sudden death in lung cancer patients. Currently, chemotherapy, radiotherapy, laser ablation, or surgical resection if possible are the available state-of-the-art treatments but none of these guarantee remedy or long-term relief and are often associated with fatal complications. Allowing localized chemotherapy, by direct and confined drug delivery only at the tumor site, could be a promising option for preoperative down staging or palliative therapy. Here we report the localized and targeted application of intra tumor delivery of chemotherapeutics using a novel device based on the principle of electrospray. C57BL/6J mice were injected with Lewis lung carcinoma cells subcutaneously. After 15 days, the animals were anesthetized and the tumors were exposed by skin incision. Tumors were electrosprayed with 100 µg cisplatin on days 0 and 2, and tumor volumes were measured daily. Animals were sacrificed on day 7 after the first electrospray and tumors were analyzed by immunohistochemistry. In this proof-of-concept study, we report that the tumor volume was reduced by 81.2% (22.46 ± 12.14 mm) after two electrospray mediated Cisplatin deliveries, while the control tumor growth, at the same time point, increased by 200% (514.30 ± 104.50 mm). Moreover, tunnel and Caspase-3 positive cells were increased after Cisplatin electrospray compared to other experimental groups of animals. Targeted drug delivery by electrospray is efficient in the subcutaneous mouse model of lung cancer and offers a promising opportunity for further development toward its clinical application.
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http://dx.doi.org/10.3389/fphar.2021.643492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093875PMC
April 2021

Incidence and Prognostic Significance of Hypoxemia in Fibrotic Interstitial Lung Disease: An International Cohort Study.

Chest 2021 Apr 24. Epub 2021 Apr 24.

Centre for Heart Lung Innovation, Providence Health Care, Vancouver, BC, Canada; Department of Medicine, University of British Columbia, Vancouver, BC, Canada.

Background: Hypoxemia is a cardinal feature of fibrotic interstitial lung disease (ILD). The incidence, progression, and prognostic significance of hypoxemia in patients with fibrotic ILD currently is unknown.

Research Question: What are the epidemiologic features of hypoxemia and its additive prognostic value in a current risk prediction model of fibrotic ILD?

Methods: We identified 848 patients with fibrotic ILD (258 with idiopathic pulmonary fibrosis [IPF]) in five prospective ILD registries from Australia, Canada, and Switzerland. Cumulative incidence of exertional and resting hypoxemia from the time of diagnosis was estimated at 1-year intervals in patients with baseline 6-min walk tests, adjusted for competing risks of death and lung transplantation. Likelihood ratio tests were used to determine the prognostic significance of exertional and resting hypoxemia for 1-year mortality or transplantation when added to the ILD GAP model. The cohort was divided into derivation and validation subsets to evaluate performance characteristics of the extended model (the ILD GAP O model), which included oxygenation status as a predictor.

Results: The 1-, 2-, and 5-year overall cumulative incidence was 6.1%, 17.3%, and 40.1%, respectively, for exertional hypoxemia and 2.4%, 5.6%, and 16.5%, respectively, for resting hypoxemia, which were significantly higher in patients with IPF compared with patients without IPF (P < .001 for both). Addition of exertional or resting hypoxemia to the ILD GAP model improved 1-year mortality and transplantation prediction (P < .001 for both). The ILD GAP O model showed improved discrimination (C-index, 0.80 vs 0.75) and model fit (Akaike information criteria, 400 vs 422) in the validation cohort, with comparable calibration.

Interpretation: Patients with IPF have higher cumulative incidence of exertional and resting hypoxemia than patients without IPF. The extended ILD GAP O model provides additional risk stratification for 1-year prognosis in fibrotic ILD.
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http://dx.doi.org/10.1016/j.chest.2021.04.037DOI Listing
April 2021

Performance of a diagnostic algorithm for fibrotic hypersensitivity pneumonitis. A case-control study.

Respir Res 2021 Apr 23;22(1):120. Epub 2021 Apr 23.

Department of Pulmonary Medicine, Inselspital, Bern University Hospital, University of Bern, 3010, Bern, Switzerland.

Background: The differential diagnosis fibrotic hypersensitivity pneumonitis (HP) versus idiopathic pulmonary fibrosis (IPF) is important but challenging. Recent diagnostic guidelines for HP emphasize including multidisciplinary discussion (MDD) in the diagnostic process, however MDD is not comprehensively available. We aimed to establish the diagnostic accuracy and prognostic validity of a previously proposed HP diagnostic algorithm that foregoes MDD.

Methods: We tested the algorithm in patients with an MDD diagnosis of fibrotic HP or IPF (case control study) and determined diagnostic test performances for diagnostic confidences of ≥ 90% and ≥ 70%. Prognostic validity was established using Cox proportional hazards models.

Results: Thirty-one patients with fibrotic HP and 50 IPF patients were included. The algorithm-derived ≥ 90% confidence level for HP had high specificity (0.94, 95% confidence interval [CI] 0.83-0.99), but low sensitivity (0.35 [95%CI 0.19-0.55], J-index 0.29). Test performance was improved for the ≥ 70% confidence level (J-index 0.64) with a specificity of 0.90 (95%CI 0.78-0.97), and a sensitivity of 0.74 (95%CI 0.55-0.88). MDD fibrotic HP diagnosis was strongly associated with lower risk of death (adjusted hazard ratio [HR] 0.10 [0.01-0.92], p = 0.04), whereas the algorithm-derived ≥ 70% and ≥ 90% confidence diagnoses were not significantly associated with survival (adjusted HR 0.37 [0.07-1.80], p = 0.22, and adjusted HR 0.41 [0.05-3.25], p = 0.39, respectively).

Conclusion: The algorithm-derived ≥ 70% diagnostic confidence had satisfactory test performance for MDD-HP diagnosis, with insufficient sensitivity for ≥ 90% confidence. The lowest risk of death in the MDD-derived HP diagnosis validates the reference standard and suggests that a diagnostic algorithm not including MDD, might not replace the latter.
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http://dx.doi.org/10.1186/s12931-021-01727-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063331PMC
April 2021

Remodeling of an microvessel exposed to cyclic mechanical stretch.

APL Bioeng 2021 Jun 2;5(2):026102. Epub 2021 Apr 2.

Integrative Vascular Biology Laboratory, Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC),13092 Berlin, Germany.

In the lungs, vascular endothelial cells experience cyclic mechanical strain resulting from rhythmic breathing motions and intraluminal blood pressure. Mechanical stress creates evident physiological, morphological, biochemical, and gene expression changes in vascular endothelial cells. However, the exact mechanisms of the mechanical signal transduction into biological responses remain to be clarified. Besides, the level of mechanical stress is difficult to determine due to the complexity of the local distension patterns in the lungs and thus assumed to be the same as the one acting on the alveolar epithelium. Existing models used to investigate the effect of mechanical stretch on endothelial cells are usually limited to two-dimensional (2D) cell culture platforms, which poorly mimic the typical three-dimensional structure of the vessels. Therefore, the development of an advanced vasculature model that closely mimics the dynamic of the human lung vasculatures is highly needed. Here, we present the first study that investigates the interplay of the three-dimensional (3D) mechanical cyclic stretch and its magnitude with vascular endothelial growth factor (VEGF) stimulation on a 3D perfusable vasculature . We studied the effects of the cyclic strain on a perfusable 3D vasculature, made of either human lung microvascular endothelial cells or human umbilical vein endothelial cells embedded in a gel layer. The 3D vessels underwent both -like longitudinal and circumferential deformations, simultaneously. Our results showed that the responses of the human lung microvascular endothelial cells and human umbilical vein endothelial cells to cyclic stretch were in good agreement. Although our 3D model was in agreement with the 2D model in predicting a cytoskeletal remodeling in response to different magnitudes of cyclic stretch, however, we observed several phenomena in the 3D model that the 2D model was unable to predict. Angiogenic sprouting induced by VEGF decreased significantly in the presence of cyclic stretch. Similarly, while treatment with VEGF increased vascular permeability, the cyclic stretch restored vascular barrier tightness and significantly decreased vascular permeability. One of the major findings of this study was that a 3D microvasculature can be exposed to a much higher mechanical cyclic stress level than reported in the literature without any dysfunction of its barrier. For higher magnitudes of the cyclic stretch, the applied longitudinal strain level was 14% and the associated circumferential strain reached the equivalent of 63%. In sharp contrast to our findings, such strain typically leads to the disruption of the endothelial barrier in a 2D stretching assay and is considered pathological. This highlights the importance of 3D modeling to investigate mechanobiology effects rather than using a simple endothelial monolayer, which truly recapitulates the situation.
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http://dx.doi.org/10.1063/5.0010159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019357PMC
June 2021

Efficacy of Combined Electroporation-Mediated Gene Transfer of VEGF, HGF, and IL-10 on Skin Flap Survival, Monitored by Label-Free Optical Imaging: A Feasibility Study.

Front Surg 2021 23;8:639661. Epub 2021 Mar 23.

Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.

Preventing surgical flaps necrosis remains challenging. Laser Doppler imaging and ultrasound can monitor blood flow in flap regions, but they do not directly measure the cellular response to ischemia. The study aimed to investigate the efficacy of synergistic electroporation-mediated gene transfer of interleukin 10 (IL-10) with either hepatocyte growth factor (HGF) or vascular endothelial growth factor (VEGF) on the survival of a modified McFarlane flap, and to evaluate the effect of the treatment on cell metabolism, using label-free fluorescence lifetime imaging. Fifteen male Wistar rats (290-320 g) were randomly divided in three groups: group-A (control group) underwent surgery and received no gene transfer. Group-B received electroporation mediated hIL-10 gene delivery 24 h before and VEGF gene delivery 24 h after surgery. Group-C received electroporation mediated hIL-10 gene delivery 24 h before and hHGF gene delivery 24 h after surgery. The animals were assessed clinically and histologically. In addition, label-free fluorescence lifetime imaging was performed on the flap. Synergistic electroporation mediated gene delivery significantly decreased flap necrosis ( = 0.0079) and increased mean vessel density ( = 0.0079) in treatment groups B and C compared to control group-A. NADH fluorescence lifetime analysis indicated an increase in oxidative phosphorylation in the epidermis of the group-B ( = 0.039) relative to controls. These findings suggested synergistic electroporation-mediated gene transfer as a promising therapeutic approach to enhance viability and vascularity of skin flap. Furthermore, the study showed that combinational gene therapy promoted an increase in tissue perfusion and a relative increase in oxidative metabolism within the epithelium.
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http://dx.doi.org/10.3389/fsurg.2021.639661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021947PMC
March 2021

Man or machine? Impact of tutor-guided versus simulator-guided short-time bronchoscopy training on students learning outcomes.

BMC Med Educ 2021 Feb 22;21(1):123. Epub 2021 Feb 22.

Department of Emergency Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Background: Simulation based medical education is efficient for the acquisition of flexible bronchoscopy navigational skills and the knowledge of the tracheobronchial anatomy. However, bronchoscopy simulator training is not routinely integrated into pneumologic fellowship programs or undergraduate medical education for time and/or cost reasons. Our study compares the effect of self-guided bronchoscopy simulator training versus tutor guided training on the acquisition of navigational skills and knowledge of the bronchial anatomy.

Methods: Third-year undergraduate medical students were randomized to either a tutor- or simulator guided bronchoscopy simulator training focusing on the acquisition of navigational skills and the knowledge of the tracheobronchial anatomy. Every student performed a baseline bronchoscopy followed by a structured bronchoscopy simulator training and finally an assessment bronchoscopy at the end of the training program. Groups were compared by means of a repeated measurement ANOVA and effect sizes calculated as Cohens' d.

Results: Fifty-four eligible students participated in the study. Knowledge of the tracheobronchial anatomy significantly increased from pre- to post training (all p < 0.001; all d > 2), navigational skills significantly decreased (all p < 0.005; all d < 1). There were no significant differences between groups. Instruction by the simulator as well as by the tutor was rated as helpful by the students. Twenty-two (84.6%) of the participants of the simulator guided group would have appreciated an additional instruction by a tutor.

Conclusion: Short-time simulator guided bronchoscopy training improves knowledge of the tracheobronchial anatomy in novice bronchoscopists as much as tutor guided training, but navigational skills seem to worsen in both groups. Further studies assessing transfer to clinical practice are needed to find the optimal teaching method for basic flexible bronchoscopy.
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http://dx.doi.org/10.1186/s12909-021-02526-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898762PMC
February 2021

Second-generation lung-on-a-chip with an array of stretchable alveoli made with a biological membrane.

Commun Biol 2021 Feb 5;4(1):168. Epub 2021 Feb 5.

Organs-on-Chip Technologies Laboratory, ARTORG Center, University of Bern, Bern, Switzerland.

The air-blood barrier with its complex architecture and dynamic environment is difficult to mimic in vitro. Lung-on-a-chips enable mimicking the breathing movements using a thin, stretchable PDMS membrane. However, they fail to reproduce the characteristic alveoli network as well as the biochemical and physical properties of the alveolar basal membrane. Here, we present a lung-on-a-chip, based on a biological, stretchable and biodegradable membrane made of collagen and elastin, that emulates an array of tiny alveoli with in vivo-like dimensions. This membrane outperforms PDMS in many ways: it does not absorb rhodamine-B, is biodegradable, is created by a simple method, and can easily be tuned to modify its thickness, composition and stiffness. The air-blood barrier is reconstituted using primary lung alveolar epithelial cells from patients and primary lung endothelial cells. Typical alveolar epithelial cell markers are expressed, while the barrier properties are preserved for up to 3 weeks.
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http://dx.doi.org/10.1038/s42003-021-01695-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864995PMC
February 2021

S2K Guideline for Diagnosis of Idiopathic Pulmonary Fibrosis.

Respiration 2021 22;100(3):238-271. Epub 2021 Jan 22.

Center for Interstitial and Rare Lung Diseases, Pneumology Department, Ruhrlandklinik - University Hospital, University Duisburg-Essen, Essen, Germany.

Idiopathic pulmonary fibrosis (IPF) is a severe and often fatal disease. Diagnosis of IPF requires considerable expertise and experience. Since the publication of the international IPF guideline in the year 2011 and the update 2018 several studies and technical advances have occurred, which made a new assessment of the diagnostic process mandatory. The goal of this guideline is to foster early, confident, and effective diagnosis of IPF. The guideline focusses on the typical clinical context of an IPF patient and provides tools to exclude known causes of interstitial lung disease including standardized questionnaires, serologic testing, and cellular analysis of bronchoalveolar lavage. High-resolution computed tomography remains crucial in the diagnostic workup. If it is necessary to obtain specimens for histology, transbronchial lung cryobiopsy is the primary approach, while surgical lung biopsy is reserved for patients who are fit for it and in whom a bronchoscopic diagnosis did not provide the information needed. After all, IPF is a diagnosis of exclusion and multidisciplinary discussion remains the golden standard of diagnosis.
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http://dx.doi.org/10.1159/000512315DOI Listing
January 2021

Interactome Analysis of iPSC Secretome and Its Effect on Macrophages In Vitro.

Int J Mol Sci 2021 Jan 19;22(2). Epub 2021 Jan 19.

Department of Pulmonary Medicine, University Hospital Bern, 3008 Bern, Switzerland.

Induced pluripotent stem cell secretome (iPSC-CM) mitigate organ injury and help in repair. Macrophages play a critical role in tissue repair and regeneration and can be directed to promote tissue repair by iPSC-CM, although the exact mechanisms are not known. In the current investigative study, we evaluated the possible mechanism by which iPSC-CM regulates the phenotype and secretory pattern of macrophages in vitro. Macrophages were obtained from human peripheral blood mononuclear cells and differentiated to various subpopulations and treated with either iPSC-CM or control media in vitro. Macrophage phenotype was assessed by flow cytometry, gene expression changes by qRT PCR and secretory pattern by multiplex protein analysis. The protein and gene interaction network revealed the involvement of Amyloid precursor protein (APP) and ELAV-like protein 1 (ELAVL-1) both present in the iPSC-CM to play an important role in regulating the macrophage phenotype and their secretory pattern. This exploratory study reveals, in part, the possible mechanism and identifies two potential targets by which iPSC-CM regulate macrophages and help in repair and regeneration.
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http://dx.doi.org/10.3390/ijms22020958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835982PMC
January 2021

Serum calprotectin as new biomarker for disease severity in idiopathic pulmonary fibrosis: a cross-sectional study in two independent cohorts.

BMJ Open Respir Res 2021 Jan;8(1)

Department for Pulmonary Medicine, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland

Background: Non-invasive biomarkers for the assessment of disease severity in idiopathic pulmonary fibrosis (IPF) are urgently needed. Calprotectin belongs to the S-100 proteins produced by neutrophils, which likely contribute to IPF pathogenesis. Calprotectin is a well-established biomarker in inflammatory bowel diseases. In this cross-sectional study, we aimed to establish the potential role of calprotectin as a biomarker in IPF. Specifically, we hypothesised that patients with IPF have higher serum calprotectin levels compared with healthy controls, and that calprotectin levels are associated with disease severity.

Methods: Blood samples were obtained from healthy volunteers (n=26) and from two independent IPF cohorts (derivation cohort n=26, validation cohort n=66). Serum calprotectin levels were measured with a commercial kit adapted for that purpose and compared between healthy controls and patients with IPF. Clinical parameters, including forced vital capacity, diffusing capacity for carbon monoxide (DLCO) and the Composite Physiologic Index (CPI), were correlated with calprotectin serum levels.

Results: The IPF derivation cohort showed increased serum calprotectin levels compared with healthy controls (2.47±1.67 vs 0.97±0.53 µg/mL, p<0.001). In addition, serum calprotectin levels correlated with DLCO% predicted (r=-0.53, p=0.007) and with CPI (r=0.66, p=0.007). These findings were confirmed in an independent IPF validation cohort.

Conclusion: Serum calprotectin levels are significantly increased in patients with IPF compared with healthy controls and correlate with DLCO and CPI. Calprotectin might be a potential new biomarker for disease severity in IPF.
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http://dx.doi.org/10.1136/bmjresp-2020-000827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813379PMC
January 2021

Pulmonary function and radiological features 4 months after COVID-19: first results from the national prospective observational Swiss COVID-19 lung study.

Eur Respir J 2021 04 29;57(4). Epub 2021 Apr 29.

Dept of Pulmonary Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Background: The infectious coronavirus disease 2019 (COVID-19) pandemic is an ongoing global healthcare challenge. Up to one-third of hospitalised patients develop severe pulmonary complications and acute respiratory distress syndrome. Pulmonary outcomes following COVID-19 are unknown.

Methods: The Swiss COVID-19 lung study is a multicentre prospective cohort investigating pulmonary sequelae of COVID-19. We report on initial follow-up 4 months after mild/moderate or severe/critical COVID-19 according to the World Health Organization severity classification.

Results: 113 COVID-19 survivors were included (mild/moderate n=47, severe/critical n=66). We confirmed several comorbidities as risk factors for severe/critical disease. Severe/critical disease was associated with impaired pulmonary function, diffusing capacity of the lung for carbon monoxide () % predicted, reduced 6-min walk distance (6MWD) and exercise-induced oxygen desaturation. After adjustment for potential confounding by age, sex and body mass index (BMI), patients after severe/critical COVID-19 had a 20.9% pred (95% CI 12.4-29.4% pred, p=0.01) lower at follow-up. % pred was the strongest independent factor associated with previous severe/critical disease when age, sex, BMI, 6MWD and minimal peripheral oxygen saturation at exercise were included in the multivariable model (adjusted odds ratio per 10% predicted 0.59, 95% CI 0. 37-0.87; p=0.01). Mosaic hypoattenuation on chest computed tomography at follow-up was significantly associated with previous severe/critical COVID-19 including adjustment for age and sex (adjusted OR 11.7, 95% CI 1.7-239; p=0.03).

Conclusions: 4 months after severe acute respiratory syndrome coronavirus 2 infection, severe/critical COVID-19 was associated with significant functional and radiological abnormalities, potentially due to small-airway and lung parenchymal disease. A systematic follow-up for survivors needs to be evaluated to optimise care for patients recovering from COVID-19.
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http://dx.doi.org/10.1183/13993003.03690-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082329PMC
April 2021

Inhalational delivery of induced pluripotent stem cell secretome improves postpneumonectomy lung structure and function.

J Appl Physiol (1985) 2020 11 10;129(5):1051-1061. Epub 2020 Sep 10.

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.

Cell-free secretory products (secretome) of human induced pluripotent stem cells (iPSCs) have been shown to attenuate tissue injury and facilitate repair and recovery. To examine whether iPSC secretome facilitates mechanically induced compensatory responses following unilateral pneumonectomy (PNX), litter-matched young adult female hounds underwent right PNX (removing 55%-58% of lung units), followed by inhalational delivery of either the nebulized-conditioned media containing induced pluripotent stem cell secretome (iPSC CM) or control cell-free media (CFM); inhalation was repeated every 5 days for 10 treatments. Lung function was measured under anesthesia pre-PNX and 10 days after the last treatment (8 wk post-PNX); detailed quantitative analysis of lung ultrastructure was performed postmortem. Pre-PNX lung function was similar between groups. Compared with CFM control, treatment with iPSC CM attenuated the post-PNX decline in lung diffusing capacity for carbon monoxide and membrane diffusing capacity, accompanied by a 24% larger postmortem lobar volume and distal air spaces. Alveolar double-capillary profiles were 39% more prevalent consistent with enhanced intussusceptive angiogenesis. Frequency distribution of the harmonic mean thickness of alveolar blood-gas barrier shifted toward the lowest values, whereas alveolar septal tissue volume and arithmetic septal thickness were similar, indicating septal remodeling and reduced diffusive resistance of the blood-gas barrier. Thus, repetitive inhalational delivery of iPSC secretome enhanced post-PNX alveolar angiogenesis and septal remodeling that are associated with improved gas exchange compensation. Results highlight the plasticity of the remaining lung units following major loss of lung mass that are responsive to broad-based modulation provided by the iPSC secretome. To examine whether the secreted products of human induced pluripotent stem cells (iPSCs) facilitate innate adaptive responses following loss of lung tissue, adult dogs underwent surgical removal of one lung, then received repeated administration of iPSC secretory products via inhalational delivery compared with control treatment. Inhalation of iPSC secretory products enhanced capillary formation and beneficial structural remodeling in the remaining lung, leading to improved lung function.
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http://dx.doi.org/10.1152/japplphysiol.00205.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790128PMC
November 2020

In Vivo Electroporation-Mediated, Intrahepatic Alpha1 Antitrypsin Gene Transfer Reduces Pulmonary Emphysema in Pallid Mice.

Pharmaceutics 2020 Aug 21;12(9). Epub 2020 Aug 21.

Department of Pulmonary Medicine, University Hospital Bern, 3010 Bern, Switzerland.

Rationale: Mutation in the alpha1 antitrypsin (AAT) gene leads to low circulating levels of AAT, which is associated with several disease processes including pulmonary emphysema. The standard of care relies on substitution with plasma-purified AAT. We studied a novel approach to obtain sustained therapeutic levels of circulating AAT using nonviral in vivo electroporation-mediated gene transfer to the liver.

Methods: In vivo intrahepatic electroporation-mediated human AAT gene transfer was performed in C57 Bl/6J mice carrying a genetic deficiency of murine AAT (pallid mice) and suffering from pulmonary emphysema. The animals were evaluated for lung function using flexiVent and detailed stereological assessments. Lung neutrophilic burden was assessed.

Results: Pallid mice showed morphologically detectable pulmonary emphysema. Thirty days after in vivo electroporation-mediated gene transfer directly aimed at the liver, circulating human AAT was elevated and lung function was significantly improved compared to non-treated pallid mice. Stereological analysis revealed a reduction in pulmonary emphysema.

Conclusion: Our data indicate that in vivo intrahepatic electroporation-mediated gene transfer of AAT is a safe and efficient procedure resulting in reduction of pulmonary emphysema in pallid mice.
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http://dx.doi.org/10.3390/pharmaceutics12090793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559762PMC
August 2020

Urinary Leukotriene E and Prostaglandin D Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation. A Clinical Observational Study.

Am J Respir Crit Care Med 2021 01;203(1):37-53

The Center for Allergy Research.

New approaches are needed to guide personalized treatment of asthma. To test if urinary eicosanoid metabolites can direct asthma phenotyping. Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma. Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE and the PGD metabolite 2,3-dinor-11β-PGF. High concentrations of LTE and PGD metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers. Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.Clinical trial registered with www.clinicaltrials.gov (NCT01976767).
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http://dx.doi.org/10.1164/rccm.201909-1869OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781128PMC
January 2021

Transcriptomic profiling reveals disease-specific characteristics of epithelial cells in idiopathic pulmonary fibrosis.

Respir Res 2020 Jun 30;21(1):165. Epub 2020 Jun 30.

Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, CH-4031, Basel, Switzerland.

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.
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http://dx.doi.org/10.1186/s12931-020-01414-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329456PMC
June 2020

Evaluation of a Novel Ear Pulse Oximeter: Towards Automated Oxygen Titration in Eyeglass Frames.

Sensors (Basel) 2020 Jun 10;20(11). Epub 2020 Jun 10.

Department of Pulmonary Medicine, Inselspital, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland.

Current oxygen delivery modes lack monitoring and can be cumbersome for patients with chronic respiratory diseases. Integrating a pulse oximeter and nasal oxygen cannulas into eyeglasses would reduce the burden of current solutions. An ear pulse oximeter (OxyFrame) was evaluated on 16 healthy volunteers and 20 hypoxemic patients with chronic respiratory diseases undergoing a prespecified protocol simulating daily activities. Correlation, error, and accuracy root mean square error (A) were calculated to compare SO measured by OxyFrame, a standard pulse oximeter (MASIMO), and arterial blood gas analysis (aBGA). SO measured by OxyFrame and MASIMO correlated strongly in volunteers, with low error and high accuracy (r = 0.85, error = 0.2 ± 2.9%, A = 2.88%). Performances were similar in patients (r = 0.87, error 0 ± 2.5%, A = 2.49% compared with MASIMO; and r = 0.93, error = 0.4 ± 1.9%, A = 1.94% compared with aBGA). However, the percentage of rejected measurements was high (volunteers 77.2%, patients 46.9%). The OxyFrame cavum conchae pulse oximeter was successfully evaluated, and demonstrated accurate SO measurements, compliant with ISO 80601-2-61:2017. Several reasons for the high rejection rate were identified, and potential solutions were proposed, which might be valuable for optimization of the sensor hardware.
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http://dx.doi.org/10.3390/s20113301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308892PMC
June 2020

Correction to: Azithromycin has enhanced effects on lung fibroblasts from idiopathic pulmonary fibrosis (IPF) patients compared to controls.

Respir Res 2020 01 28;21(1):29. Epub 2020 Jan 28.

Department of Pulmonary Medicine, Inselspital, Bern University Hospital, University of Bern, CH-3010, Bern, Switzerland.

After publication of our article [1], we have been notified that an extra alpha symbol (α) was mistakenly added at the beginning of the title.
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http://dx.doi.org/10.1186/s12931-020-1304-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986083PMC
January 2020

Clinically Relevant Tissue Scale Responses as New Readouts from Organs-on-a-Chip for Precision Medicine.

Annu Rev Anal Chem (Palo Alto Calif) 2020 06 21;13(1):111-133. Epub 2020 Jan 21.

Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey 08854, USA.

Organs-on-chips (OOC) are widely seen as being the next generation in vitro models able to accurately recreate the biochemical-physical cues of the cellular microenvironment found in vivo. In addition, they make it possible to examine tissue-scale functional properties of multicellular systems dynamically and in a highly controlled manner. Here we summarize some of the most remarkable examples of OOC technology's ability to extract clinically relevant tissue-level information. The review is organized around the types of OOC outputs that can be measured from the cultured tissues and transferred to clinically meaningful information. First, the creation of functional tissues-on-chip is discussed, followed by the presentation of tissue-level readouts specific to OOC, such as morphological changes, vessel formation and function, tissue properties, and metabolic functions. In each case, the clinical relevance of the extracted information is highlighted.
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http://dx.doi.org/10.1146/annurev-anchem-061318-114919DOI Listing
June 2020

Azithromycin has enhanced effects on lung fibroblasts from idiopathic pulmonary fibrosis (IPF) patients compared to controls [corrected].

Respir Res 2020 01 15;21(1):25. Epub 2020 Jan 15.

Department of Pulmonary Medicine, Inselspital, Bern University Hospital, University of Bern, CH-3010, Bern, Switzerland.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease without a cure and new drug strategies are urgently needed. Differences in behavior between diseased and healthy cells are well known and drug response can be different between cells isolated from IPF patients and controls. The macrolide Azithromycin (AZT) has anti-inflammatory and immunomodulatory properties. Recently anti-fibrotic effects have been described. However, the anti-fibrotic effects on primary IPF-fibroblasts (FB) directly compared to control-FB are unknown. We hypothesized that IPF-FB react differently to AZT in terms of anti-fibrotic effects.

Methods: Primary normal human lung and IPF-FB were exposed to TGF-β (5 ng/ml), Azithromycin (50 μM) alone or in combination prior to gene expression analysis. Pro-collagen Iα1 secretion was assessed by ELISA and protein expression by western blot (αSMA, Fibronectin, ATP6V1B2, LC3 AB (II/I), p62, Bcl-xL). Microarray analysis was performed to screen involved genes and pathways after Azithromycin treatment in control-FB. Apoptosis and intraluminal lysosomal pH were analyzed by flow cytometry.

Results: AZT significantly reduced collagen secretion in TGF-β treated IPF-FB compared to TGF-β treatment alone, but not in control-FB. Pro-fibrotic gene expression was similarly reduced after AZT treatment in IPF and control-FB. P62 and LC3II/I western blot revealed impaired autophagic flux after AZT in both control and IPF-FB with significant increase of LC3II/I after AZT in control and IPF-FB, indicating enhanced autophagy inhibition. Early apoptosis was significantly higher in TGF-β treated IPF-FB compared to controls after AZT. Microarray analysis of control-FB treated with AZT revealed impaired lysosomal pathways. The ATPase and lysosomal pH regulator ATP6V0D2 was significantly less increased after additional AZT in IPF-FB compared to controls. Lysosomal function was impaired in both IPF and control FB, but pH was significantly more increased in TGF-β treated IPF-FB.

Conclusion: We report different treatment responses after AZT with enhanced anti-fibrotic and pro-apoptotic effects in IPF compared to control-FB. Possibly impaired lysosomal function contributes towards these effects. In summary, different baseline cell phenotype and behavior of IPF and control cells contribute to enhanced anti-fibrotic and pro-apoptotic effects in IPF-FB after AZT treatment and strengthen its role as a new potential anti-fibrotic compound, that should further be evaluated in clinical studies.
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http://dx.doi.org/10.1186/s12931-020-1275-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964061PMC
January 2020

Meta-analysis of the radiological and clinical features of Usual Interstitial Pneumonia (UIP) and Nonspecific Interstitial Pneumonia (NSIP).

PLoS One 2020 13;15(1):e0226084. Epub 2020 Jan 13.

Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital, Bern University Hospital, University of Bern, Switzerland.

Purpose: To conduct a meta-analysis to determine specific computed tomography (CT) patterns and clinical features that discriminate between nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP).

Materials And Methods: The PubMed/Medline and Embase databases were searched for studies describing the radiological patterns of UIP and NSIP in chest CT images. Only studies involving histologically confirmed diagnoses and a consensus diagnosis by an interstitial lung disease (ILD) board were included in this analysis. The radiological patterns and patient demographics were extracted from suitable articles. We used random-effects meta-analysis by DerSimonian & Laird and calculated pooled odds ratios for binary data and pooled mean differences for continuous data.

Results: Of the 794 search results, 33 articles describing 2,318 patients met the inclusion criteria. Twelve of these studies included both NSIP (338 patients) and UIP (447 patients). NSIP-patients were significantly younger (NSIP: median age 54.8 years, UIP: 59.7 years; mean difference (MD) -4.4; p = 0.001; 95% CI: -6.97 to -1.77), less often male (NSIP: median 52.8%, UIP: 73.6%; pooled odds ratio (OR) 0.32; p<0.001; 95% CI: 0.17 to 0.60), and less often smokers (NSIP: median 55.1%, UIP: 73.9%; OR 0.42; p = 0.005; 95% CI: 0.23 to 0.77) than patients with UIP. The CT findings from patients with NSIP revealed significantly lower levels of the honeycombing pattern (NSIP: median 28.9%, UIP: 73.4%; OR 0.07; p<0.001; 95% CI: 0.02 to 0.30) with less peripheral predominance (NSIP: median 41.8%, UIP: 83.3%; OR 0.21; p<0.001; 95% CI: 0.11 to 0.38) and more subpleural sparing (NSIP: median 40.7%, UIP: 4.3%; OR 16.3; p = 0.005; 95% CI: 2.28 to 117).

Conclusion: Honeycombing with a peripheral predominance was significantly associated with a diagnosis of UIP. The NSIP pattern showed more subpleural sparing. The UIP pattern was predominantly observed in elderly males with a history of smoking, whereas NSIP occurred in a younger patient population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226084PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957301PMC
April 2020

Computer-Aided Diagnosis of Pulmonary Fibrosis Using Deep Learning and CT Images.

Invest Radiol 2019 10;54(10):627-632

From the Departments of Diagnostic, Interventional, and Pediatric Radiology.

Objectives: The objective of this study is to assess the performance of a computer-aided diagnosis (CAD) system (INTACT system) for the automatic classification of high-resolution computed tomography images into 4 radiological diagnostic categories and to compare this with the performance of radiologists on the same task.

Materials And Methods: For the comparison, a total of 105 cases of pulmonary fibrosis were studied (54 cases of nonspecific interstitial pneumonia and 51 cases of usual interstitial pneumonia). All diagnoses were interstitial lung disease board consensus diagnoses (radiologically or histologically proven cases) and were retrospectively selected from our database. Two subspecialized chest radiologists made a consensual ground truth radiological diagnosis, according to the Fleischner Society recommendations. A comparison analysis was performed between the INTACT system and 2 other radiologists with different years of experience (readers 1 and 2). The INTACT system consists of a sequential pipeline in which first the anatomical structures of the lung are segmented, then the various types of pathological lung tissue are identified and characterized, and this information is then fed to a random forest classifier able to recommend a radiological diagnosis.

Results: Reader 1, reader 2, and INTACT achieved similar accuracy for classifying pulmonary fibrosis into the original 4 categories: 0.6, 0.54, and 0.56, respectively, with P > 0.45. The INTACT system achieved an F-score (harmonic mean for precision and recall) of 0.56, whereas the 2 readers, on average, achieved 0.57 (P = 0.991). For the pooled classification (2 groups, with and without the need for biopsy), reader 1, reader 2, and CAD had similar accuracies of 0.81, 0.70, and 0.81, respectively. The F-score was again similar for the CAD system and the radiologists. The CAD system and the average reader reached F-scores of 0.80 and 0.79 (P = 0.898).

Conclusions: We found that a computer-aided detection algorithm based on machine learning was able to classify idiopathic pulmonary fibrosis with similar accuracy to a human reader.
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http://dx.doi.org/10.1097/RLI.0000000000000574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738634PMC
October 2019

Nutritional assessment in adults with cystic fibrosis.

Nutrition 2019 Nov - Dec;67-68:110518. Epub 2019 Jun 12.

Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, University Hospital of Bern and University of Bern, Bern, Switzerland.

Objectives: Clinical experience with patients with cystic fibrosis (CF) suggests a nutritional risk in this population. In addition to the lung pathology, a main pathophysiologic concern is the viscous mucus blocking pancreatic ducts, leading to reduced production of pancreatic enzymes. Therefore, maldigestion and consequently malabsorption (particularly fat and fat-soluble vitamins) occur, resulting in steatorrhea, vitamin deficiencies, and subsequently manifest malnutrition. The aim of this study was to investigate the nutritional status and determine the prevalence of malnutrition in an adult Swiss CF cohort.

Methods: This was an observational cohort study in which the nutritional status and dietary habits of patients with CF and healthy controls were compared. Assessment was based on the nutritional risk screening (NRS-2002), dietary habits (7-d dietary record), body composition (bioelectrical impedance analysis), anthropometrics, resting energy expenditure (REE; indirect calorimetry), and physical or mental function (hand-grip strength, Short Form-36 v2).

Results: Nineteen patients (15 men, mean age 32 y) and 15 controls (8 men, mean age 49 y) were included. Eight patients (42%) were at nutritional risk (NRS-2002 ≥3). Patients had higher energy intake/body weight (P = 0.021) with lower body fat percentage (P < .001), body mass index (P = 0.030), and physical/mental health scores (P < 0.001) than controls. Energy intake was higher than REE in patients (P = 0.003), but not in controls (P = 0.373).

Conclusions: Prevalence of malnutrition was high in this CF cohort, coinciding with low body fat percentage and low body mass index despite high energy and protein intake. Energy requirements of patients with CF should be estimated as approximately twice the Harris-Benedict REE and 1.7 times indirect calorimetry REE, while ensuring adequate intake of pancreatic enzymes.
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http://dx.doi.org/10.1016/j.nut.2019.05.010DOI Listing
October 2020

New radiological diagnostic criteria: impact on idiopathic pulmonary fibrosis diagnosis.

Eur Respir J 2019 11 7;54(5). Epub 2019 Nov 7.

Dept of Diagnostic, Interventional and Pediatric Radiology, Inselspital, Bern University Hospital, University of Bern, Switzerland.

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http://dx.doi.org/10.1183/13993003.00905-2019DOI Listing
November 2019

Mitochondrial DNA mutations and respiratory chain dysfunction in idiopathic and connective tissue disease-related lung fibrosis.

Sci Rep 2019 04 2;9(1):5500. Epub 2019 Apr 2.

Department of Rheumatology, University Hospital Basel, Basel, Switzerland.

Reactive oxygen species (ROS) are implicated in the aetiology of interstitial lung disease (ILD). We investigated the role of large-scale somatically acquired mutations in mitochondrial DNA (mtDNA) and consecutive respiratory chain dysfunction as a trigger of ROS-formation and lung fibrosis. Mitochondria were analysed in lung biopsies from 30 patients with idiopathic or connective tissue disease (CTD)-related ILD and 13 controls. In 17 patients we had paired biopsies from upper and lower lobes. Control samples were taken from lung cancer resections without interstitial fibrosis. Malondialdehyde, a marker of ROS-formation, was elevated in ILD-biopsies (p = 0.044). The activity of the mitochondrial respiratory chain (cytochrome c-oxidase/succinate dehydrogenase [COX/SDH]-ratio) was depressed in ILD (median = 0.10,) compared with controls (0.12, p < 0.001), as was the expression of mtDNA-encoded COX-subunit-2 protein normalized for the nucleus-encoded COX-subunit-4 (COX2/COX4-ratio; ILD-median = 0.6; controls = 2.2; p < 0.001). Wild-type mtDNA copies were slightly elevated in ILD (p = 0.088). The common mtDNA deletion was only present at low levels in controls (median = 0%) and at high levels in ILD (median = 17%; p < 0.001). In ILD-lungs with paired biopsies, lower lobes contained more malondialdehyde and mtDNA deletions than upper lobes and had lower COX2/COX4-ratios and COX/SDH-ratios (all p < 0.001). Acquired mtDNA-mutations and consecutive respiratory chain dysfunction may both trigger and perpetuate ROS-formation in ILD.
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http://dx.doi.org/10.1038/s41598-019-41933-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445113PMC
April 2019

Predictive factors for exacerbation and re-exacerbation in chronic obstructive pulmonary disease: an extension of the Cox model to analyze data from the Swiss COPD cohort.

Multidiscip Respir Med 2019 5;14. Epub 2019 Feb 5.

1University Clinic of Medicine, Cantonal Hospital Baselland, University of Basel, Rheinstrasse 26, 4410 Liestal, Switzerland.

Background: The Swiss COPD cohort was established in 2006 to collect data in a primary care setting. The objective of this study was to evaluate possible predictive factors for exacerbation and re-exacerbation.

Methods: In order to predict exacerbation until the next visit based on the knowledge of exacerbation since the last visit, a multistate model described by Therneau and Grambsch was performed.

Results: Data of 1,247 patients (60.4% males, 46.6% current smokers) were analyzed, 268 (21.5%) did not fulfill spirometric diagnostic criteria for COPD. Data of 748 patients (63% males, 44.1% current smokers) were available for model analysis. In order to predict exacerbation an extended Cox Model was performed. Mean FEV/FVC-ratio was 53.1% (±11.5), with a majority of patients in COPD GOLD classes 2 or 3. Hospitalization for any reason (HR1.7;  = 0.04) and pronounced dyspnea (HR for mMRC grade four 3.0;  < 0.001) at most recent visit as well as prescription of short-acting bronchodilators (HR1.7;  < 0.001), inhaled (HR1.2;  = 0.005) or systemic corticosteroids (HR1.8;  = 0.015) were significantly associated with exacerbation when having had no exacerbation at most recent visit. Higher FEV/FVC (HR0.9;  = 0.008) and higher FEV values (HR0.9;  = 0.001) were protective. When already having had an exacerbation at the most recent visit, pronounced dyspnea (HR for mMRC grade 4 1.9;  = 0.026) and cerebrovascular insult (HR2.1;  = 0.003) were significantly associated with re-exacerbation. Physical activity (HR0.6;  = 0.031) and treatment with long-acting anticholinergics (HR0.7;  = 0.044) seemed to play a significant protective role. In a best subset model for exacerbation, higher FEV significantly reduced and occurrence of sputum increased the probability of exacerbation. In the same model for re-exacerbation, coronary heart disease increased and hospitalization at most recent visit seemed to reduce the risk for re-exacerbation.

Conclusion: Our data confirmed well-established risk factors for exacerbations whilst analyzing their predictive association with exacerbation and re-exacerbation. This study confirmed the importance of spirometry in primary care, not only for diagnosis but also as a risk evaluation for possible future exacerbations.

Trial Registration: Our study got approval by local ethical committee in 2006 (EK Nr. 170/06) and was registered retrospectively on ClinicalTrials.gov (NCT02065921, 19 of February 2014).
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http://dx.doi.org/10.1186/s40248-019-0168-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364405PMC
February 2019

Impaired Wound Healing of Alveolar Lung Epithelial Cells in a Breathing Lung-On-A-Chip.

Front Bioeng Biotechnol 2019 22;7. Epub 2019 Jan 22.

ARTORG Center, Medical Faculty, University of Bern, Bern, Switzerland.

The lung alveolar region experiences remodeling during several acute and chronic lung diseases, as for instance idiopathic pulmonary fibrosis (IPF), a fatal disease, whose onset is correlated with repetitive microinjuries to the lung alveolar epithelium and abnormal alveolar wound repair. Although a high degree of mechanical stress (>20% linear strain) is thought to potentially induce IPF, the effect of lower, physiological levels of strain (5-12% linear strain) on IPF pathophysiology remains unknown. In this study, we examined the influence of mechanical strain on alveolar epithelial wound healing. For this purpose, we adopted the "organ-on-a-chip" approach, which provides the possibility of reproducing unique aspects of the cellular microenvironment, in particular its dynamic nature. Our results provide the first demonstration that a wound healing assay can be performed on a breathing lung-on-a-chip equipped with an ultra-thin elastic membrane. We cultured lung alveolar epithelial cells to confluence, the cells were starved for 24 h, and then wounded by scratching with a standard micropipette tip. Wound healing was assessed after 24 h under different concentrations of recombinant human hepatic growth factor (rhHGF) and the application of cyclic mechanical stretch. Physiological cyclic mechanical stretch (10% linear strain, 0.2 Hz) significantly impaired the alveolar epithelial wound healing process relative to culture in static conditions. This impairment could be partially ameliorated by administration of rhHGF. This proof-of-concept study provides a way to study of more complex interactions, such as a co-culture with fibroblasts, endothelial cells, or immune cells, as well as the study of wound healing at an air-liquid interface.
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http://dx.doi.org/10.3389/fbioe.2019.00003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360510PMC
January 2019