Baseline Blood CD8+ T Cell Activation Potency Discriminates Responders from Non-Responders to Immune Checkpoint Inhibition Combined with Stereotactic Radiotherapy in Non-Small-Cell Lung Cancer.

BACKGROUND: Tumor-infiltrating immune cells have been correlated with prognosis for patients treated with immune checkpoint inhibitor (ICI) treatment of various cancers. However, no robust biomarker has been described to predict treatment response yet. We hypothesized that the activation potency of circulating T cells may predict response to ICI treatment. METHODS: An exploratory analysis was conducted to investigate the association between the response to immune checkpoint inhibition (ICI) combined with stereotactic radiotherapy (SBRT) and the potency of circulating T cells to be activated. Blood-derived lymphocytes from 14 patients were stimulated ex vivo with, among others, Staphylococcal enterotoxin B (SEB) and compared to healthy controls (HCs). Patients were grouped into responders (>median progression free survival (PFS)) and non-responders (

Non-tuberculous mycobacteria disease pre-lung transplantation: A systematic review of the treatment regimens and duration pre- and post-transplant.

BACKGROUND: There is lack of consensus on non-tuberculous mycobacteria pulmonary disease (NTM-PD) treatment regimen and duration in patient listed for lung transplantation (LTx). We conducted a systematic review on treatment regimen and duration pre- and directly post-LTx, for patients with known NTM-PD pre-LTx. Additionally, we searched for risk factors for NTM disease development post-LTx and for mortality. METHODS: Literature was reviewed on PubMed, Embase and the Cochrane Library, for articles published from inception to January 2022. Individual patient data were sought. RESULTS: Sixteen studies were included reporting 92 patients. Most frequent used agents were aminoglycosides and macrolides for Mycobacterium abscessus (M. abscessus) and macrolides and tuberculostatic agents for Mycobacterium avium complex (M. avium complex). The median treatment duration pre-LTx was 10 months (IQR 6-17) and 2 months (IQR 2-8) directly post-LTx. Longer treatment duration pre-LTx was observed in children and in patients with M. abscessus. 46% of the patients with NTM-PD pre-LTx developed NTM disease post-LTx, related mortality rate was 10%. Longer treatment duration pre-LTx (p < 0.001) and sputum non-conversion pre-LTx (p = 0.003) were significantly associated with development of NTM-disease post-LTx. Longer treatment duration pre-LTx (p = 0.004), younger age (p < 0.001) and sputum non-conversion (p = 0.044) were risk factors for NTM related death. CONCLUSIONS: The median treatment duration pre-LTx was 10 months (IQR 6-17) and 2 months (IQR 2-8) directly post-LTx. Patients with longer treatment duration for NTM-PD pre-LTx and with sputum non-conversion are at risk for NTM disease post-LTx and for NTM-related death. Children were particularly at risk for NTM related death.

IL-33 Expression Is Lower in Current Smokers at both Transcriptomic and Protein Levels.

Rationale: IL-33 is a proinflammatory cytokine thought to play a role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). A recent clinical trial using an anti-IL-33 antibody showed a reduction in exacerbation and improved lung function in ex-smokers but not current smokers with COPD. Objectives: This study aimed to understand the effects of smoking status on IL-33. Methods: We investigated the association of smoking status with the level of gene expression of IL-33 in the airways in eight independent transcriptomic studies of lung airways. Additionally, we performed Western blot analysis and immunohistochemistry for IL-33 in lung tissue to assess protein levels. Measurements and Main Results: Across the bulk RNA-sequencing datasets, IL-33 gene expression and its signaling pathway were significantly lower in current versus former or never-smokers and increased upon smoking cessation (P < 0.05). Single-cell sequencing showed that IL-33 is predominantly expressed in resting basal epithelial cells and decreases during the differentiation process triggered by smoke exposure. We also found a higher transitioning of this cellular subpopulation into a more differentiated cell type during chronic smoking, potentially driving the reduction of IL-33. Protein analysis demonstrated lower IL-33 levels in lung tissue from current versus former smokers with COPD and a lower proportion of IL-33-positive basal cells in current versus ex-smoking controls. Conclusions: We provide strong evidence that cigarette smoke leads to an overall reduction in IL-33 expression in transcriptomic and protein level, and this may be due to the decrease in resting basal cells. Together, these findings may explain the clinical observation that a recent antibody-based anti-IL-33 treatment is more effective in former than current smokers with COPD.

Triple Therapy with Mometasone/Indacaterol/Glycopyrronium or Doubling the ICS/LABA Dose in GINA Step 4: IRIDIUM Analyses.

INTRODUCTION: GINA guidelines recommend increasing the dose of inhaled corticosteroids (ICS) as a step-up option for patients with inadequately controlled asthma at GINA step 4 [inadequately controlled asthma on medium-dose ICS/long-acting beta-2 agonist (LABA)]. The aim of this study was to compare the efficacy and safety of long-acting muscarinic antagonists (LAMA) add-on to medium-dose ICS/LABA in patients at GINA 2022 step 4. METHODS: This post hoc analysis of the IRIDIUM study evaluated the change from baseline in trough forced expiratory volume (FEV1 ) in patients receiving medium-dose MF/IND/GLY versus high-dose MF/IND and high-dose FLU/SAL at Week 26. Other outcomes included improvement in lung functions [peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow between 25% and 75% of the FVC (FEF)25-75%)], asthma control [Asthma Control Questionnaire (ACQ-7)], responder analysis (≥ 0.5 unit improvement in ACQ-7), and reduction in asthma exacerbations at Weeks 26 and 52. RESULTS: A total of 1930 patients were included in this analysis. Medium-dose MF/IND/GLY improved trough FEV1 versus high-dose MF/IND (Δ 41 mL; 95% CI - 7-90) and high-dose FLU/SAL (Δ 88 mL; 95% CI 39-137) at Week 26 which were sustained until Week 52. Exacerbation rates were 16% lower with medium-dose MF/IND/GLY versus high-dose MF/IND for all (mild, moderate, and severe) exacerbations and 21-30% lower versus high-dose FLU/SAL for all (mild, moderate, and severe), moderate or severe, and severe exacerbations over 52 weeks. Further improvements in other lung functions were observed with medium-dose MF/IND/GLY. No new safety signals were identified. CONCLUSION: Medium-dose MF/IND/GLY improved lung function and reduced asthma exacerbations compared to high-dose ICS/LABA and may be an undervalued option in patients at GINA 2022 step 4. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02571777.

"This is What Lies Ahead". Perspectives of Oxygen-Naïve COPD Patients on Long-Term Oxygen Use. A Qualitative Study.

Purpose: Oxygen is commonly prescribed to patients with severe COPD. However, little is known about the perspectives COPD patients, who do not yet use oxygen, have on this treatment. Patients and Methods: A total of 14 oxygen-naïve patients with COPD Gold stages 3-4 and a high symptom burden participated in semi-structured interviews, in which their beliefs and expectations regarding oxygen therapy were explored. We used conventional content analysis to process our qualitative data. Results: Four main themes were identified: seeking information, expected impact on quality of life, expected social impact and stigma, and last phase of life. Conclusion: The message that home oxygen should be started, was regarded as bad news by most participants. The rationale behind the therapy and the way it is delivered were unknown to most participants. Some participants anticipated smoking-related stigma and social isolation. Misconceptions such as tank explosions, becoming housebound, full dependency on oxygen and an imminent death were common amongst interviewees. Clinicians should be aware of these fears and assumptions when communicating with patients on this subject.

Smoking induces shifts in cellular composition and transcriptome within the bronchial mucus barrier.

BACKGROUND AND OBJECTIVE: Smoking disturbs the bronchial-mucus-barrier. This study assesses the cellular composition and gene expression shifts of the bronchial-mucus-barrier with smoking to understand the mechanism of mucosal damage by cigarette smoke exposure. We explore whether single-cell-RNA-sequencing (scRNA-seq) based cellular deconvolution (CD) can predict cell-type composition in RNA-seq data. METHODS: RNA-seq data of bronchial biopsies from three cohorts were analysed using CD. The cohorts included 56 participants with chronic obstructive pulmonary disease [COPD] (38 smokers; 18 ex-smokers), 77 participants without COPD (40 never-smokers; 37 smokers) and 16 participants who stopped smoking for 1 year (11 COPD and 5 non-COPD-smokers). Differential gene expression was used to investigate gene expression shifts. The CD-derived goblet cell ratios were validated by correlating with staining-derived goblet cell ratios from the COPD cohort. Statistics were done in the R software (false discovery rate p-value < 0.05). RESULTS: Both CD methods indicate a shift in bronchial-mucus-barrier cell composition towards goblet cells in COPD and non-COPD-smokers compared to ex- and never-smokers. It shows that the effect was reversible within a year of smoking cessation. A reduction of ciliated and basal cells was observed with current smoking, which resolved following smoking cessation. The expression of mucin and sodium channel (ENaC) genes, but not chloride channel genes, were altered in COPD and current smokers compared to never smokers or ex-smokers. The goblet cell-derived staining scores correlate with CD-derived goblet cell ratios. CONCLUSION: Smoking alters bronchial-mucus-barrier cell composition, transcriptome and increases mucus production. This effect is partly reversible within a year of smoking cessation. CD methodology can predict goblet-cell percentages from RNA-seq.

External Validation and User Experiences of the ProPal-COPD Tool to Identify the Palliative Phase in COPD.

Background: Difficulty predicting prognosis is a major barrier to timely palliative care provision for patients with COPD. The ProPal-COPD tool, combining six clinical indicators and the Surprise Question (SQ), aims to predict 1-year mortality as a proxy for palliative care needs. It appeared to be a promising tool for healthcare providers to identify patients with COPD who could benefit from palliative care. Objective: To externally validate the ProPal-COPD tool and to assess user experiences. Methods: Patients admitted with an acute exacerbation COPD were recruited across 10 hospitals. Demographics, clinical characteristics and survival status were collected. Sensitivity, specificity, positive and negative predictive values of the tool using two cut-off values were calculated. Also, predictive properties of the SQ were calculated. In monitoring meetings and interviews, healthcare providers shared their experiences with the tool. Transcripts were deductively coded using six user experience domains: Acceptability, Satisfaction, Credibility, Usability, User-reported adherence and Perceived impact. Results: A total of 523 patients with COPD were included between May 2019 and August 2020, of whom 100 (19.1%) died within 12 months. The ProPal-COPD tool had an AUC of 0.68 and a low sensitivity (55%) and moderate specificity (74%) for predicting 1-year all-cause mortality. Using a lower cut-off value, sensitivity was higher (74%), but specificity lower (46%). Sensitivity and specificity of the SQ were 56% and 73%, respectively (AUC 0.65). However, healthcare providers generally appreciated using the tool because it increased awareness of the palliative phase and provided a shared understanding of prognosis, although they considered its outcome not always correct. Conclusion: The accuracy of the ProPal-COPD tool to predict 1-year mortality is limited, although screening patients with its indicators increases healthcare providers' awareness of palliative care needs and encourages them to timely initiate appropriate care.

Implementation of a palliative care intervention for patients with COPD - a mixed methods process evaluation of the COMPASSION study.

OBJECTIVES: Little direction exists on how to effectively implement palliative care for patients with COPD. In the COMPASSION study, we developed, executed, and evaluated a multifaceted implementation strategy to improve the uptake of region-tailored palliative care intervention components into routine COPD care. We evaluated the implementation strategy and assessed the implementation process, barriers, and facilitators. METHODS: A mixed methods process evaluation was performed. Primary and secondary healthcare providers in four hospital regions in the Netherlands were trained. Patients identified during hospitalisation for an acute exacerbation received palliative care and were followed for a year. Various sources were used: process data, questionnaires including the End-of-life Professional Caregiver Survey (EPCS), medical records, monitoring meetings, and interviews. The Consolidated Framework of Implementation Research (CFIR) was used to categorize implementation determinants. RESULTS: The training sessions with roleplay were positively evaluated and increased professionals' self-efficacy in providing palliative care statistically significantly. Of 98 patients identified, 44 (44.9%) received one or more palliative care conversations at the outpatient clinic. Having those conversations was highly valued by healthcare providers because it led to clarity and peace of mind for the patient and higher job satisfaction. Coordination and continuity remained suboptimal. Most important barriers to implementation were time constraints, the COVID-19 pandemic, and barriers related to transmural and interdisciplinary collaboration. Facilitators were the systematic screening of patients for palliative care needs, adapting to the patient's readiness, conducting palliative care conversations with a pulmonologist and a COPD nurse together, and meeting regularly with a small team led by a dedicated implementation leader. CONCLUSIONS: Providing integrated palliative care for patients with COPD is highly valued by healthcare providers but remains challenging. Our findings will guide future implementation efforts. Future research should focus on how to optimize transmural and interdisciplinary collaboration. Trial registration The COMPASSION study is registered in the Netherlands Trial Register (NTR): NL7644. Registration date: 07/04/2019.

Chronic kidney disease after lung transplantation in a changing era.

Lung transplant (LTx) physicians are responsible for highly complex post-LTx care, including monitoring of kidney function and responding to kidney function loss. Better survival of the LTx population and changing patient characteristics, including older age and increased comorbidity, result in growing numbers of LTx patients with chronic kidney disease (CKD). CKD after LTx is correlated with worse survival, decreased quality of life and high costs. Challenges lie in different aspects of post-LTx renal care. First, serum creatinine form the basis for estimating renal function, under the assumption that patients have stable muscle mass. Low or changes in muscle mass is frequent in the LTx population and may lead to misclassification of CKD. Second, standardizing post-LTx monitoring of kidney function and renal care might contribute to slow down CKD progression. Third, new treatment options for CKD risk factors, such as diabetes mellitus, proteinuria and heart failure, have entered clinical practice. These new treatments have not been studied in LTx yet but are of interest for future use. In this review we will address the difficult aspects of post-LTx renal care and evaluate new and promising future approaches to slow down CKD progression.

Function-specific IL-17A and dexamethasone interactions in primary human airway epithelial cells.

Asthmatics have elevated levels of IL-17A compared to healthy controls. IL-17A is likely to contribute to reduced corticosteroid sensitivity of human airway epithelium. Here, we aimed to investigate the mechanistic underpinnings of this reduced sensitivity in more detail. Differentiated primary human airway epithelial cells (hAECs) were exposed to IL-17A in the absence or presence of dexamethasone. Cells were then collected for RNA sequencing analysis or used for barrier function experiments. Mucus was collected for volume measurement and basal medium for cytokine analysis. 2861 genes were differentially expressed by IL-17A (Padj < 0.05), of which the majority was not sensitive to dexamethasone (< 50% inhibition). IL-17A did inhibit canonical corticosteroid genes, such as HSD11B2 and FKBP5 (p < 0.05). Inflammatory and goblet cell metaplasia markers, cytokine secretion and mucus production were all induced by IL-17A, and these effects were not prevented by dexamethasone. Dexamethasone did reverse IL-17A-stimulated epithelial barrier disruption, and this was associated with gene expression changes related to cilia function and development. We conclude that IL-17A induces function-specific corticosteroid-insensitivity. Whereas inflammatory response genes and mucus production in primary hAECs in response to IL-17A were corticosteroid-insensitive, corticosteroids were able to reverse IL-17A-induced epithelial barrier disruption.

Reduction of Lung Hyperinflation Improves Cardiac Preload, Contractility, and Output in Emphysema: A Clinical Trial in Patients Who Received Endobronchial Valves.

Rationale: Pulmonary hyperinflation in patients with chronic obstructive pulmonary disease has been related to smaller cardiac chamber sizes and impaired cardiac function. Currently, bronchoscopic lung volume reduction (BLVR) with endobronchial valves is a treatment option to reduce pulmonary hyperinflation in patients with severe emphysema. Objectives: We hypothesized that reduction of hyperinflation would improve cardiac preload in this patient group. In addition, we investigated whether the treatment would result in elevated pulmonary artery pressures because of pulmonary vascular bed reduction. Methods: We included patients with emphysema and severe hyperinflation (defined by a baseline residual volume >175% of predicted) who were eligible for BLVR with endobronchial valves. Cardiac magnetic resonance imaging was obtained one day before treatment and at 8-week follow-up. Primary endpoint was cardiac preload, as measured by the right ventricle end-diastolic volume index. As secondary endpoints, we measured indexed end-diastolic and end-systolic volumes of the right ventricle, left atrium, and left ventricle; pulmonary artery pressures; cardiac output; ejection fraction; and strain. Measurements and Main Results: Twenty-four patients were included. At 8-week follow-up, right ventricle end-diastolic volume index was significantly improved (+7.9 ml/m2; SD, 10.0; P = 0.001). In addition to increased stroke volumes, we found significantly higher ejection fractions and strain measurements. Although cardiac output was significantly increased (+0.9 L/min; SD, 1.5; P = 0.007), there were no changes in pulmonary artery pressures. Conclusions: We found that reduction of hyperinflation using BLVR with endobronchial valves significantly improved cardiac preload, myocardial contractility, and cardiac output, without changes in pulmonary artery pressures. Clinical trial registered with www.clinicaltrials.gov (NCT03474471).

Bronchial wall parameters on CT in healthy never-smoking, smoking, COPD, and asthma populations: a systematic review and meta-analysis.

OBJECTIVE: Research on computed tomography (CT) bronchial parameter measurements shows that there are conflicting results on the values for bronchial parameters in the never-smoking, smoking, asthma, and chronic obstructive pulmonary disease (COPD) populations. This review assesses the current CT methods for obtaining bronchial wall parameters and their comparison between populations. METHODS: A systematic review of MEDLINE and Embase was conducted following PRISMA guidelines (last search date 25th October 2021). Methodology data was collected and summarised. Values of percentage wall area (WA%), wall thickness (WT), summary airway measure (Pi10), and luminal area (Ai) were pooled and compared between populations. RESULTS: A total of 169 articles were included for methodologic review; 66 of these were included for meta-analysis. Most measurements were obtained from multiplanar reconstructions of segmented airways (93 of 169 articles), using various tools and algorithms; third generation airways in the upper and lower lobes were most frequently studied. COPD (12,746) and smoking (15,092) populations were largest across studies and mostly consisted of men (median 64.4%, IQR 61.5 - 66.1%). There were significant differences between populations; the largest WA% was found in COPD (mean SD 62.93 ± 7.41%, n = 6,045), and the asthma population had the largest Pi10 (4.03 ± 0.27 mm, n = 442). Ai normalised to body surface area (Ai/BSA) (12.46 ± 4 mm2, n = 134) was largest in the never-smoking population. CONCLUSIONS: Studies on CT-derived bronchial parameter measurements are heterogenous in methodology and population, resulting in challenges to compare outcomes between studies. Significant differences between populations exist for several parameters, most notably in the wall area percentage; however, there is a large overlap in their ranges. KEY POINTS: • Diverse methodology in measuring airways contributes to overlap in ranges of bronchial parameters among the never-smoking, smoking, COPD, and asthma populations. • The combined number of never-smoking participants in studies is low, limiting insight into this population and the impact of participant characteristics on bronchial parameters. • Wall area percent of the right upper lobe apical segment is the most studied (87 articles) and differentiates all except smoking vs asthma populations.

Bronchoscopic Targeted Lung Denervation in Patients with Severe Asthma: Preliminary Findings.

Treatment options for severe asthma are limited, particularly in those patients who do not meet criteria for biologicals. Targeted lung denervation (TLD) is the bronchoscopic ablation of the peribronchial vagal nerve trunks to reduce cholinergic stimulation of airway smooth muscle and submucosal glands. This report describes the experience of the first 2 asthma patients treated with TLD worldwide. The participants were 54 and 51 years of age, and both had severe asthma (GINA 5) (FEV1: 53% and 113% of predicted; AQLQ scores: 5.3 and 4.4). Both participants were treated with TLD in a single day-case procedure under general anaesthesia. Lung function, health status, and adverse event data were collected at baseline and 12 months after TLD. No treatment-related serious adverse events were reported up to 12 months. Cough symptoms improved in both participants, and 1 participant reported a marked reduction in rescue medication use at 6 months. There were no significant changes in spirometry, lung volumes, or health status. In conclusion, TLD was performed safely in both participants, but more evidence is needed to clarify safety and efficacy of TLD in severe asthma. Therefore, further investigation of the treatment in severe asthma patients would be useful.

Determinants of Lung Fissure Completeness.

Rationale: New advanced bronchoscopic treatment options for patients with severe chronic obstructive pulmonary disease (COPD) have led to increased interest for COPD phenotyping, including fissure completeness. Objectives: We investigated clinical, environmental, and genetic factors contributing to fissure completeness in patients with and without COPD. Methods: We used data from 9,926 participants of the COPDGene study who underwent chest computed tomographic (CT) scans. Fissure completeness was calculated from CT scans after quantitative CT analysis at baseline and 5-year follow-up. Clinical and environmental factors, including sex, race, smoking, COPD, emphysema, maternal smoking during pregnancy and maternal COPD, were tested for impact on fissure completeness. Genome-wide association analyses were performed separately in non-Hispanic White subjects and African American subjects. Measurements and Main Results: African American subjects had significantly higher fissure completeness than non-Hispanic White subjects for all three fissures (P < 0.001). There was no change in fissure completeness between baseline and 5-year follow-up. For all fissures, no clinically relevant differences in fissure completeness were found for other clinical or environmental factors, including COPD severity. Rs2173623, rs264866, rs2407284, rs7310342, rs4904145, rs6504172, and rs7209556 showed genome-wide significant associations with fissure completeness in non-Hispanic White subjects. In African American subjects, rs264866, rs4904145 and rs6504172 were identified as significant associations. Rs2173623, rs6504172, and rs7209556 lead to WNT5A and HOXB antisense RNA expression, which play an important role during embryogenesis. Conclusions: Fissure completeness is genetically determined and not dependent on age, sex, smoking status, the presence and severity of COPD (including exacerbation frequency), maternal smoking during pregnancy, or maternal COPD.

Provision of Palliative Care in Patients with COPD: A Survey Among Pulmonologists and General Practitioners.

INTRODUCTION: Patients with advanced chronic obstructive pulmonary disease (COPD) experience significant symptom burden, leading to poor quality of life. Although guidelines recommend palliative care for these patients, this is not widely implemented and prevents them from receiving optimal care. OBJECTIVE: A national survey was performed to map the current content and organization of palliative care provision for patients with COPD by pulmonologists and general practitioners (GPs) in the Netherlands. METHODS: We developed a survey based on previous studies, guidelines and expert opinion. Dutch pulmonologists and GPs were invited to complete the survey between April and August 2019. RESULTS: 130 pulmonologists (15.3%; covering 76% of pulmonology departments) and 305 GPs (28.6%) responded. Median numbers of patients with COPD in the palliative phase treated were respectively 20 and 1.5 per year. 43% of pulmonologists and 9% of GPs reported some formalized agreements regarding palliative care provision. Physicians most often determined the start of palliative care based on clinical expertise or the Surprise Question. 31% of pulmonologists stated that they often or always referred palliative patients with COPD to a specialist palliative care team; a quarter rarely referred. 79% of the respondents mentioned to often or always administer opioids to treat dyspnea. The topics least discussed were non-invasive ventilation and the patient's spiritual needs. The most critical barrier to starting a palliative care discussion was difficulty in predicting the disease course. CONCLUSION: Although pulmonologists and GPs indicated to regularly address palliative care aspects, palliative care for patients with COPD remains unstructured and little formalized. However, our data revealed a high willingness to improve this care. Clear guidance and standardization of practice are needed to help providers decide when and how to initiate discussions, when to involve specialist palliative care and how to optimize information exchange between care settings.

CT-Derived Pulmonary Artery Diameters to Preselect for Echocardiography in COPD Patients Eligible for Bronchoscopic Treatments.

BACKGROUND: Currently, patients with COPD who are evaluated for bronchoscopic treatments are routinely screened for pulmonary hypertension (PH) and systolic left ventricle dysfunction by echocardiography. OBJECTIVES: We evaluated the prevalence of PH and systolic left ventricle dysfunction in this patient group and investigated if the previously proposed CT-derived pulmonary artery to aorta (PA:A) ratio >1 and PA diameter measurements can be used as alternative screening tools for PH. METHODS: Two hundred fifty-five patients were included in this retrospective analysis (FEV1 25%pred, RV 237%pred). All patients received transthoracic echocardiography and chest CT scans on which diameters of the aorta and pulmonary artery were measured at the bifurcation and proximal to the bifurcation. RESULTS: Following echocardiography, 3 patients (1.2%) had PH and 1 (0.4%) had systolic left ventricle dysfunction. Using a PA:A ratio >1, only 10.3% of the patients with a right ventricular systolic pressure (RVSP) ≥35 mm Hg were detected and none of the patients with an RVSP >50 mm Hg were detected. Patients with an RVSP ≥35 mm Hg had significantly higher PA diameters (29.5 vs. 27.5 mm; p = 0.02) but no significantly different PA:A ratios. All patients with an RVSP >50 mm Hg had PA diameters >30 mm. CONCLUSIONS: The prevalence of PH and systolic left ventricle dysfunction is low in this preselected cohort of patients with severe COPD. In this population, a PA:A ratio >1 is not a useful cardiac screening tool for PH. A PA diameter >30 mm could substitute for routinely performed echocardiography in the screening for PH in this patient group.

Reducing the Number of Hospitalization Days for COPD: Setting up a Transmural-Care Pathway.

Background: Many patients with chronic obstructive pulmonary disease (COPD) experience exacerbations of symptoms, leading to a large burden on patients and the health system and costs to society. To address this burden, a 25% reduction in number of hospitalization days for COPD exacerbations was recently declared a national goal in the Netherlands, to be achieved in 5 years. Methods: A national care pathway was designed following an established managed clinical pathway setup, which involved prior national surveys and the identification of ten key elements. The concept was discussed, made locally applicable, and finally tested in eight regions containing eleven hospitals and surrounding primary-care groups in a prospective cohort study. All patients were followed for 1 year, starting at hospitalization. Results: In total, 752 patients gave informed consent and participated (mean age 70 years, 58% female). Of these, 120 (16%) died within a year. The median length of index hospitalization was 5 days, and 43% had at least one rehospitalization within 1 year (range 0-8). There was a 19.4% reduction in number of total hospitalization days, without a decrease in health-related quality of life or perceived quality of care. Elements that contributed significantly to the reduction were contact in the first week after hospitalization, and during the year of follow-up pharmacological and nonpharmacological smoking-cessation guidance, checks on inhalation technique, and discussion of lung-attack plan. Discussion: With concerted action between patients and health workers in the hospital and in the community, a large reduction in number of hospitalization days can be achieved. The program was quite demanding for both patients and health workers. In our subsequent national implementation plan after this pilot study, we have named the major contributors to success and advocate the stepwise introduction of the elements in light of feasibility.

A cluster randomized controlled trial on a multifaceted implementation strategy to promote integrated palliative care in COPD: study protocol of the COMPASSION study.

BACKGROUND: Despite the urgent need for palliative care for patients with advanced chronic obstructive pulmonary disease (COPD), it is not yet daily practice. Important factors influencing the provision of palliative care are adequate communication skills, knowing when to start palliative care and continuity of care. In the COMPASSION study, we address these factors by implementing an integrated palliative care approach for patients with COPD and their informal caregivers. METHODS: An integrated palliative care intervention was developed based on existing guidelines, a literature review, and input from patient and professional organizations. To facilitate uptake of the intervention, a multifaceted implementation strategy was developed, comprising a toolbox, (communication) training, collaboration support, action planning and monitoring. Using a hybrid effectiveness-implementation type 2 design, this study aims to simultaneously evaluate the implementation process and effects on patient, informal caregiver and professional outcomes. In a cluster randomized controlled trial, eight hospital regions will be randomized to receive the integrated palliative care approach or to provide care as usual. Eligible patients are identified during hospitalization for an exacerbation using the Propal-COPD tool. The primary outcome is quality of life (FACIT-Pal) at 6 months. Secondary outcome measures include spiritual well-being, anxiety and depression, unplanned healthcare use, informal caregiver burden and healthcare professional's self-efficacy to provide palliative care. The implementation process will be investigated by a comprehensive mixed-methods evaluation assessing the following implementation constructs: context, reach, dose delivered, dose received, fidelity, implementation level, recruitment, maintenance and acceptability. Furthermore, determinants to implementation will be investigated using the Consolidated Framework for Implementation Research. DISCUSSION: The COMPASSION study will broaden knowledge on the effectiveness and process of palliative care integration into COPD-care. Furthermore, it will improve our understanding of which strategies may optimize the implementation of integrated palliative care. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NL7644 . Registration date: April 7, 2019.

The effects of lung volume reduction treatment on diffusing capacity and gas exchange.

Lung volume reduction (LVR) treatment in patients with severe emphysema has been shown to have a positive effect on hyperinflation, expiratory flow, exercise capacity and quality of life. However, the effects on diffusing capacity of the lungs and gas exchange are less clear. In this review, the possible mechanisms by which LVR treatment can affect diffusing capacity of the lung for carbon monoxide (D LCO) and arterial gas parameters are discussed, the use of D LCO in LVR treatment is evaluated and other diagnostic techniques reflecting diffusing capacity and regional ventilation (V')/perfusion (Q') mismatch are considered.A systematic review of the literature was performed for studies reporting on D LCO and arterial blood gas parameters before and after LVR surgery or endoscopic LVR with endobronchial valves (EBV). D LCO after these LVR treatments improved (40 studies, n=1855) and the mean absolute change from baseline in % predicted D LCO was +5.7% (range -4.6% to +29%), with no real change in blood gas parameters. Improvement in V' inhomogeneity and V'/Q' mismatch are plausible explanations for the improvement in D LCO after LVR treatment.

Long-acting dual bronchodilator therapy (indacaterol/glycopyrronium) versus nebulized short-acting dual bronchodilator (salbutamol/ipratropium) in chronic obstructive pulmonary disease: A double-blind, randomized, placebo-controlled trial.

INTRODUCTION: Most guidelines recommend long-acting bronchodilators over short-acting bronchodilators for patients with chronic obstructive pulmonary disease (COPD). The available evidence for the guidelines was based on dry powder or pressurized metered dose inhalers, but not nebulizations. Nevertheless, there is considerable, poorly evidenced based, use of short acting nebulized bronchodilators. METHODS: This was an investigator initiated, randomized, active controlled, cross-over, double-blind and double-dummy single centre study in patients with stable COPD. The active comparators were indacaterol/glycopyrronium 110/50 µg as Ultibro® via Breezhaler® (IND/GLY) and salbutamol/ipratropium 2,5/0,5 mg via air driven nebulization (SAL/IPR), both given as a single dose on separate days. The primary end point was the area under the FEV1 curve from baseline till 6 h. Secondary end points included change in Borg dyspnoea score, adverse events and change in hyperinflation measured by the inspiratory capacity. RESULTS: A total of 33 COPD patients completed the trial and were evaluable, most of them were ex-smokers. The difference between the tested regimens for the primary endpoint, FEV1 AUC 0-6 h, 2965 ± 1544 mL (mean ± SD) for IND/GLY versus 3513 ± 1762 mL for SAL/IPR, was not significant (P = 0.08). The peak in FEV1 was higher and was reached faster with SAL/IPR compared to IND/GLY. No other significant differences were detected for the secondary endpoints including the Borg score, or adverse events. CONCLUSION: Among patients with stable COPD, dry powder long-acting single inhalation of a LABA and a LAMA (IND/GLY) was not superior compared to nebulized short-acting salbutamol plus ipratropium (SAL/IPR) in its bronchodilating effects over 6 h.The effects of the nebulization kicked in faster and peaked higher. The observed differences may be caused by the difference in dosing between the two regimens. The improvement in Borg dyspnoea score did not favour the nebulization. Long-term outcomes were not assessed in this study.