Long-Term Mechanical Ventilation: Recommendations of the Swiss Society of Pulmonology.

Long-term mechanical ventilation is a well-established treatment for chronic hypercapnic respiratory failure (CHRF). It is aimed at improving CHRF-related symptoms, health-related quality of life, survival, and decreasing hospital admissions. In Switzerland, long-term mechanical ventilation has been increasingly used since the 1980s in hospital and home care settings. Over the years, its application has considerably expanded with accumulating evidence of beneficial effects in a broad range of conditions associated with CHRF. Most frequent indications for long-term mechanical ventilation are chronic obstructive pulmonary disease, obesity hypoventilation syndrome, neuromuscular and chest wall diseases. In the current consensus document, the Special Interest Group of the Swiss Society of Pulmonology reviews the most recent scientific literature on long-term mechanical ventilation and provides recommendations adapted to the particular setting of the Swiss healthcare system with a focus on the practice of non-invasive and invasive home ventilation in adults.

Treatment of COPD Exacerbation in Switzerland: Results and Recommendations of the European COPD Audit.

BACKGROUND: The European COPD Audit initiated by the European Respiratory Society (ERS) evaluated the management of hospital admissions due to exacerbation of chronic obstructive pulmonary disease (COPD) in several European countries. Data on the treatment of severe acute exacerbations of COPD (AECOPDs) in Switzerland are scarce. OBJECTIVES: In light of the GOLD 2010 guidelines, this work aims to examine the quality of care for AECOPD and to provide specific recommendations for the management of severe AECOPD in Switzerland. METHODS: A total of 295 patients requiring hospital admission to 19 Swiss hospitals due to exacerbation of COPD during a predefined 60 days in 2011 were included in the study. We compared the Swiss data to the official GOLD 2010 recommendations and to the results of the other European countries. RESULTS: Approximately 43% of the Swiss patients with severe AECOPD were current smokers at hospital admission, compared to 33% of the patients in other European countries (p < 0.001). In Switzerland and in Europe, spirometry data were not available for most patients at hospital admission (65 and 60%, respectively; p = 0.08). In comparison to other European countries, antibiotics were prescribed 14% less often in Switzerland (p < 0.001). Only 79% of the patients in the Swiss cohort received treatment with a short-acting bronchodilator at admission. CONCLUSIONS: Considering the overall high standard of health care in Switzerland, in light of the GOLD 2010 guidelines we are able to make 7 recommendations to improve and standardize the management of severe AECOPD for patients treated in Switzerland.

Baseline predictors of adherence to positive airway pressure therapy for sleep apnea: a 10-year single-center observational cohort study.

BACKGROUND: Positive airway pressure (PAP) therapy is the standard treatment for obstructive sleep apnea syndrome (OSAS). OBJECTIVES: The aim of the current study was to determine operational long-term adherence to PAP and its predictors. METHODS: In a retrospective single-center observational cohort study, we analyzed all patients referred to our center with suspected OSAS between November 2001 and November 2011. Baseline results and last follow-up data of each patient were analyzed. Kaplan-Meier estimates of adherence and Cox proportional hazard regression for age, gender, Epworth sleepiness scale (ESS) scores, body mass index, apnea-hypopnea index (AHI) and oxygen desaturation index (ODI) were performed. Evolution of adherence was analyzed in yearly cohorts comparing the proportion of patients discontinuing PAP within 6 and 12 months. RESULTS: Of 4,638 referrals, 2,187 confirmed OSAS patients started PAP, 297 (14%) were referred out to other centers to follow-up, 42 (2%) died, and 92 (5%) no longer needed PAP. Of 1,756 patients, the median follow-up was 36 months [95% confidence interval (CI) 33.6-37.8], and adherence at 1, 5 and 10 years was 74 (CI 71-75; n = 1,028), 55 (CI 53-58; n = 281) and 51% (CI 48-55; n = 10), respectively. Adherence is associated with ESS score [hazard ratio (HR) 0.60; CI 0.47-0.78], ODI (HR 0.50; CI 0.32-0.77) and AHI (HR 0.56; CI 0.37-0.85). In yearly cohorts according to inclusion date, the absconder rate at 6 and 12 months was 20 (CI 18-22) and 27% (CI 25-30) for the first 8 years and improved to 10 (CI 7-15) and 14% (CI 10-19) for the last 2 years, respectively. CONCLUSIONS: Long-term adherence to PAP in OSAS is associated with baseline measures of disease severity. After 2009, an improvement in the adherence rate was observed.

Exploring the transcription factor activity in high-throughput gene expression data using RLQ analysis.

BACKGROUND: Interpretation of gene expression microarray data in the light of external information on both columns and rows (experimental variables and gene annotations) facilitates the extraction of pertinent information hidden in these complex data. Biologists classically interpret genes of interest after retrieving functional information from a subset of genes of interest. Transcription factors play an important role in orchestrating the regulation of gene expression. Their activity can be deduced by examining the presence of putative transcription factors binding sites in the gene promoter regions. RESULTS: In this paper we present the multivariate statistical method RLQ which aims to analyze microarray data where additional information is available on both genes and samples. As an illustrative example, we applied RLQ methodology to analyze transcription factor activity associated with the time-course effect of steroids on the growth of primary human lung fibroblasts. RLQ could successfully predict transcription factor activity, and could integrate various other sources of external information in the main frame of the analysis. The approach was validated by means of alternative statistical methods and biological validation. CONCLUSIONS: RLQ provides an efficient way of extracting and visualizing structures present in a gene expression dataset by directly modeling the link between experimental variables and gene annotations.

Fast beneficial systemic anti-inflammatory effects of inhaled budesonide and formoterol on circulating lymphocytes in asthma.

BACKGROUND AND OBJECTIVE: Inhaled glucocorticoids and long acting ß2 -agonists reduce airway inflammation. It is unclear if this effect is based on the local action of the drugs or is due to a systemic effect on circulating peripheral blood lymphocytes. We assessed whether inhaled budesonide and/or formoterol modify the activity of circulating peripheral blood lymphocytes. METHODS: Placebo controlled crossover design, including healthy (n = 10) or mild asthmatic males (n = 8). Blood was collected in the morning at 08:00 before drug inhalation, and drugs (placebo, budesonide 400 µg, formoterol 12 µg) were inhaled alone or in combination at 08:30. Four more blood samples were collected after inhalation at 09:00, 09:30, 12:30 and at 09:30 am on the following day. The activity of the glucocorticoid receptor, NFκB and IκB was determined in isolated lymphocytes. Lymphocytes were stimulated with lipopolysaccharide (LPS 10 µg/mL) for 24 h and interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor (TNF)-α, eotaxin level were determined. Lymphocyte proliferation was induced by phytohaemagglutinin (PHA 10 µg/mL) over 24 h. RESULTS: When combined, the drugs synergistically activated the glucocorticoid receptor within 30 min but did not modify NFκB or IκB activity. Inhaled budesonide significantly reduced LPS-induced IL-1ß, IL-6, IL-8 and TNF-α secretion, while inhaled formoterol had no such effect; however when combined, the inhibitory effect of budesonide was significantly increased by formoterol. PHA-induced proliferation was reduced by both drugs alone and in combination. CONCLUSIONS: Combined budesonide and formoterol may reduce airway inflammation and immune reactivity of circulating lymphocytes through its local and systemic effects.

The effect of the COVID-19 pandemic on severe asthma care in Europe: will care change for good?

Background: The coronavirus disease 2019 (COVID-19) pandemic has put pressure on healthcare services, forcing the reorganisation of traditional care pathways. We investigated how physicians taking care of severe asthma patients in Europe reorganised care, and how these changes affected patient satisfaction, asthma control and future care. Methods: In this European-wide cross-sectional study, patient surveys were sent to patients with a physician-diagnosis of severe asthma, and physician surveys to severe asthma specialists between November 2020 and May 2021. Results: 1101 patients and 268 physicians from 16 European countries contributed to the study. Common physician-reported changes in severe asthma care included use of video/phone consultations (46%), reduced availability of physicians (43%) and change to home-administered biologics (38%). Change to phone/video consultations was reported in 45% of patients, of whom 79% were satisfied or very satisfied with this change. Of 709 patients on biologics, 24% experienced changes in biologic care, of whom 92% were changed to home-administered biologics and of these 62% were satisfied or very satisfied with this change. Only 2% reported worsening asthma symptoms associated with changes in biologic care. Many physicians expect continued implementation of video/phone consultations (41%) and home administration of biologics (52%). Conclusions: Change to video/phone consultations and home administration of biologics was common in severe asthma care during the COVID-19 pandemic and was associated with high satisfaction levels in most but not all cases. Many physicians expect these changes to continue in future severe asthma care, though satisfaction levels may change after the pandemic.

Cell density and serum exposure modify the function of the glucocorticoid receptor C/EBP complex.

The glucocorticoid receptor (GR) is a major control factor for proliferation, differentiation, and inflammation. Our knowledge about the GR is focused on its function as a transcription regulator. However, cells do not always respond to steroids in the same way or develop resistance. The mechanism underlying such a modified steroid response is not well understood, and may depend on the microenvironment of the cells or on the stage of their differentiation. Therefore, we studied the effect of cell density and inflammatory conditions on the expression, compartmentalization, activation, and the anti-proliferative function of the GR in primary human lung fibroblast cultures. In subconfluent cells the GR was located perinuclear, while in confluent cells it was ubiquitously expressed. Serum stimulation up-regulated the level of GR mRNA and protein under all conditions. In subconfluent cells dexamethasone activated the nuclear accumulation and DNA binding of the GR persistently, while in confluent cells its activity declined after 6 hours. In subconfluent cells, but not in confluent cells, the GR interacted with a 42-kD, but not the 30-kD C/EBP-alpha isoprotein, which resulted in an up-regulation of p21((Waf1/Cip1)) expression and suppression of proliferation. In confluent cells, glucocorticoids induced p27((Kip1)) expression via p38 mitogen-activated protein kinase and a 52-kD C/EBP-beta isoprotein. However, p27((Kip1)) did not mediate the antiproliferative effect of glucocorticoids, but simultaneous inhibition of p21((Waf1/Cip1)) and p27((Kip1)) unlocked contact inhibition in confluent cells. Our results indicate that cell density and serum exposure alter the localization and function of the GR.

Dysfunctional interaction of C/EBPalpha and the glucocorticoid receptor in asthmatic bronchial smooth-muscle cells.

BACKGROUND: Increased proliferation of bronchial smooth-muscle cells may lead to increased muscle mass in the airways of patients with asthma. The antiproliferative effect of glucocorticoids in bronchial smooth-muscle cells in subjects without asthma is mediated by a complex of the glucocorticoid receptor and the CCAAT/enhancer binding protein alpha (C/EBPalpha). We examined the signaling pathway controlling the inhibitory effect of glucocorticoids on cell proliferation and interleukin-6 synthesis in bronchial smooth-muscle cells of subjects with asthma and those without asthma. METHODS: Lines of bronchial smooth-muscle cells were established from cells from 20 subjects with asthma, 8 subjects with emphysema, and 26 control subjects. Cell proliferation was determined by means of cell counts and [3H]thymidine incorporation. Signal transduction was studied by means of an electrophoretic DNA mobility-shift assay, a supershift electrophoretic-mobility assay, immunoblotting, use of C/EBPalpha antisense oligonucleotides, and use of a human C/EBPalpha expression vector. Interleukin-6 release was determined by means of an enzyme-linked immunosorbent assay. RESULTS: Glucocorticoids activated the glucocorticoid receptor and inhibited serum-induced secretion of interleukin-6 in bronchial smooth-muscle cells from both subjects with asthma and those without asthma; however, glucocorticoids inhibited proliferation only in bronchial smooth-muscle cells from subjects without asthma. C/EBPalpha protein was detected by immunoblotting in all bronchial smooth-muscle cells from subjects without asthma but not in those with asthma, whereas the protein was expressed in lymphocytes from both groups of subjects. C/EBPalpha antisense oligonucleotides or the glucocorticoid-receptor inhibitor mifepristone reversed the antiproliferative effect of glucocorticoids in bronchial smooth-muscle cells from subjects without asthma. When bronchial smooth-muscle cells from subjects with asthma were transiently transfected with an expression vector for human C/EBPalpha, two forms of the protein were expressed, and subsequent administration of glucocorticoids inhibited cell proliferation. CONCLUSIONS: We hypothesize that a cell-type-specific absence of C/EBPalpha is responsible for the enhanced proliferation of bronchial smooth-muscle cells derived from subjects with asthma and that it explains the failure of glucocorticoids to inhibit proliferation in vitro.

NIV by an interdisciplinary respiratory care team in severe respiratory failure in the emergency department limited to day time hours.

Non-invasive ventilatory support is frequently used in patients with severe respiratory failure (SRF), but is often limited to intensive care units (ICU). We hypothesized that an instantaneous short course of NIV (up to 2 h), limited to regular working hours as an additional therapy on the emergency department (ED) would be feasible and could improve patient´s dyspnoea measured by respiratory rate and Borg visual dyspnea scale. NIV was set up by an interdisciplinary respiratory care team. Outside these predefined hours NIV was performed in the ICU. This is an observational cohort study over 1 year in the ED in a non-university hospital. Fifty-one % of medical emergencies arrived during regular working hours (5475 of 10,718 patients). In total, 63 patients were treated with instantaneous NIV. Door to NIV in the ED was 56 (31-97) min, door to ICU outside regular working hours was 84 (57-166) min. Within 1 h of NIV, the respiratory rate decreased from 30/min (25-35) to 19/min (14-24, p < 0.001), the Borg dyspnoea scale improved from 7 (5-8) to 2 (0-3, p < 0.001). In hypercapnic patients, the blood-pH increased from 7.29 (7.24-7.33) to 7.35 (7.29-7.40) and the pCO2 dropped from 8.82 (8.13-10.15) to 7.45 (6.60-8.75) kPa. In patients with SRF of varying origin, instantaneous NIV in the ED during regular working hours was feasible in a non-university hospital setting, and rapidly and significantly alleviated dyspnoea and reduced respiratory rate. This approach proved to be useful as a bridge to the ICU as well as an efficient palliative dyspnoea treatment.

Transcutaneous versus blood carbon dioxide monitoring during acute noninvasive ventilation in the emergency department - a retrospective analysis.

QUESTIONS UNDER STUDY: Transcutaneous measurement of carbon dioxide (PtCO2) has been suggested as an alternative to invasively obtained PaCO2 for the monitoring of patients with hypercapnic respiratory failure during noninvasive ventilation (NIV). Current data on monitoring in hypoxaemic respiratory failure are scarce and show conflicting results in hypercapnic patients in the emergency department. METHODS AND SETTING: We performed a retrospective comparison of real-time PtCO2 (SenTec Digital Monitor) and arterial/venous carbon dioxide tension (PaCO2/PvCO2) measurements in patients with severe hypoxaemic and/or hypercapnic respiratory failure during NIV. Agreement between PtCO2 and PaCO2/PvCO2 was the primary endpoint. Bland-Altman analysis and linear regression were used. RESULTS: 102 patients had at least one matched measurement of PtCO2 and PaCO2/PvCO2. For patients with arterial blood gas analysis, the mean difference was 0.46 kPa at baseline (95% confidence interval [CI] 0.23 to 0.60, limits of agreement 95% CI -0.54 to 1.45) and 0.12 kPa after NIV (95% CI -0.04 to 0.29, limits of agreement 95% CI: -0.61 to 0.86). The linear regression analysis found a correlation R2 of 0.88 (p <0.001) at baseline and an R2 of 0.99 (p <0.001) after initiating NIV. For patients with venous blood gas analysis, the mean difference was 0.64 kPa at baseline (95% CI 0.04 to 1.24, limits of agreement 95% CI -0.72 to 2) and 0.80 kPa after NIV (95% CI 0.51 to 1.10, limits of agreement 95% CI 0.29 to 1.32), R2 0.78 (p <0.001) at baseline and R2 0.91 (p <0.001) after initiating NIV. A PaCO2/PvCO2 >8 kPa was associated with a lesser degree of agreement between the levels of PtCO2 and PaCO2/PvCO2 (p <0.001). CONCLUSION: Transcutaneous PCO2 monitoring shows a good concordance with PaCO2 and is a reliable, feasible, patient-friendly and safe alternative to repeated blood gas analysis for patients with severe hypoxaemic and/or hypercapnic respiratory failure receiving emergency NIV in the emergency department. An initial blood gas analysis to evaluate the respiratory and metabolic state and to rule out a significant discrepancy compared with the transcutaneous measurement is recommended.

Interaction of C/EBPalpha and the glucocorticoid receptor in vivo and in nontransformed human cells.

Belonging to the family of steroid hormones, glucocorticoids are essential for development and survival of vertebrates. The cellular response to glucocorticoids is attributed to the glucocorticoid receptor, which functions as a transcription factor. However, the majority of glucocorticoid-modulated genes lack a DNA binding site for the glucocorticoid receptor, raising the question of which mechanism mediates the responses to glucocorticoids. It has been suggested that besides direct DNA binding of the glucocorticoid receptor, interaction with members of other transcription factor families modulates the effect of the glucocorticoid receptor. However, the significance of such transcription factor interaction is not clear. In cultured human mesenchymal cells and peripheral blood leukocytes of human volunteers treated with glucocorticoids, we detected the formation of a complex between the GR and the CCAAT/enhancer binding protein alpha. In in vitro experiments, this interaction turned out to be responsible for the inhibitory action of glucocorticoids on lymphocytic and mesenchymal cell proliferation. Our results suggest that complex formation of the GR with C/EBPalpha accounts for a novel pathway of glucocorticoid action.

Accuracy of the Hospital Anxiety and Depression Scale for identifying depression in chronic obstructive pulmonary disease patients.

Psychological morbidity is common in chronic respiratory diseases. The diagnostic accuracy of the Hospital Anxiety and Depression Scale (HADS) and risk factors for comorbid depression in chronic obstructive pulmonary disease (COPD) are addressed. Consecutive COPD patients (GOLD stage I-IV, 40-75 years old) were enrolled in a multicentre, cross-sectional cohort study. Diagnosis of depression was ascertained through clinical records. Lung function, HADS score, 6-minute walking test (6-MWT), MRC dyspnoea score, and COPD Assessment Test (CAT) were evaluated. Two hundred fifty-nine COPD patients (mean age 62.5 years; 32% female; mean FEV1 48% predicted) were included. Patients diagnosed with depression (29/259; 11.2%) had significantly higher HADS-D and HADS-Total scores than nondepressed patients (median (quartiles) HADS-D 6 [4; 9] versus 4 [2; 7], median HADS-Total 14 [10; 20] versus 8 [5; 14]). Receiver-operating characteristic plots showed moderate accuracy for HADS-D, AUC 0.662 (95%CI 0.601-0.719), and HADS-Total, AUC 0.681 (95%CI 0.620-0.737), with optimal cut-off scores of >5 and >9, respectively. Sensitivity and specificity were 62.1% and 62.6% for HADS-D compared to 75.9% and 55.2% for HADS-Total. Age, comorbidities, sex, and lower airflow limitation predicted depression. The HADS exhibits low diagnostic accuracy for depression in COPD patients. Younger men with comorbidities are at increased risk for depression.

Identification of a novel IL-6 isoform binding to the endogenous IL-6 receptor.

Interleukin (IL)-6 is a multifunctional cytokine showing a wide variety of biologic functions on various tissues. Extracellular IL-6 signals through heterohexameric complex formation with IL-6 receptor-alpha (IL-6Ralpha) and IL-6 receptor-beta (IL-6Rbeta). In analogy to cytokines IL-2 and IL-4, we investigated the expression of IL-6 splice variants in lung tissue and cultivated fibroblasts. In human lung specimens, four different IL-6 transcripts were characterized as follows: native IL-6; IL-6 missing either exon 2 (IL-6Delta2), exon 4 (IL-6Delta4), or missing both; and exons 2 and 4 (IL-6Delta2,4). Only native IL-6 and IL-6Delta4 encoded for proteins of ~ 26 and 17 kD, respectively. Although the overall structure and most functional sites of the IL-6Delta4 protein were predicted to be maintained, IL-6Delta4 was found to lack two amino acids necessary for IL-6/IL-6 homodimerization as well as two of the six amino acids required for interaction with IL-6Rbeta. Receptor mobility shift assays confirmed that the new isoform formed a stable complex with IL-6Ralpha; however, no interaction with IL-6Rbeta was observed. Thus, IL-6Delta4 is likely to compete with native IL-6 for IL-6Ralpha binding but fails to transmit IL-6Rbeta-mediated signaling.

Interaction between glucocorticoids and beta2 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling.

BACKGROUND: Increased airway smooth muscle bulk is a pathological feature of asthma. Asthma is well controlled by the combined inhalation of glucocorticoids and beta2-adrenoceptor agonists. The basic molecular mechanism of the interaction of the two drugs on proliferation of airway smooth muscle cells is yet to be identified. Our aim was to elucidate how glucocorticoids and beta2 agonists affect the growth of human bronchial airway smooth muscle cells. METHODS: We assessed the effect of formoterol and budesonide on the activation and function of transcription factors by immunohistochemistry, western blotting, DNA mobility shift assay, and a luciferase reporter gene assay. The effect of the drugs and the involvement of specific transcription factors on cell proliferation was ascertained by direct cell count and confirmed by thymidine incorporation. FINDINGS: Both classes of drugs (10(-8) mol/L) activated C/EBP-alpha and the glucocorticoid receptor with different kinetic profiles, and inhibited proliferation. The combination of lower doses of drugs (10(-12) to 10(-9) mol/L) resulted in a synchronised activation of the transcription factors and an enhanced antiproliferative effect. The action of the drugs alone or in combination on transcription-factor activity and proliferation was suppressed by either depletion of C/EBP-alpha or in the presence of a glucocorticoid-receptor blocker. INTERPRETATION: Our findings could provide one explanation for the interaction of beta2 agonists and glucocorticoids at a molecular level, and indicate that the concentration of inhaled glucocorticoids can be reduced when combined with beta2 agonists, minimising the side-effects of the drugs.