Objectives:The study aimed to develop new national reference values for dynamic and static lung volumes, as well as diffusing capacity for carbon monoxide, measured in the same participants. These values were compared with existing reference values from GLI and ECCS. Additional aims included the development of lung function reference values based on arm span, the establishment of post-bronchodilator reference values for spirometry, the creation of reference values for bronchodilator response, and the identification of significant bronchodilator responses using z-scores. Furthermore, the study sought to observe and enhance the quality of Danish lung function laboratories. Methods:Spirometry, body plethysmography, single-breath diffusion capacity, and bronchodilator testing were performed on 908 healthy non-smokers aged 18-97 years, selected from municipalities served by 13 participating Danish centres. Strict quality control was maintained in accordance with ATS/ERS standards. Sex, age, age squared, weight, and height (or arm span) were used as independent variables in the multiple regression equations. The resulting lung function data were compared with predicted values from GLI and ECCS. Results:Sex-specific reference equations were established for 29 lung function parameters. Additionally, reference values based on arm span and post-bronchodilator spirometry were calculated, and bronchodilator response was established using four different endpoints, including z-scores. A substantial proportion of the new reference values differed clinically significantly from those predicted by GLI and ECCS equations. These discrepancies were more frequent in females than males, more pronounced for ECCS than GLI, and more common for flow and volume parameters than for diffusion capacity and ratios. Conclusion:Given that many of the new reference values differ clinically significantly from those provided from GLI and ECCS, we recommend the nationwide adoption of the new DALFUMAT reference values.

Background The efficacy of endobronchial valve (EBV) treatment has been demonstrated in randomized controlled trials. However, real-life nationwide data from more heterogeneous patient populations remains limited. Therefore, this study aims to evaluate the one-year outcome of EBV treatment in a nationwide cohort study. Method In this nationwide cohort study, Danish patients treated with endobronchial valves from 2017-2024 were included. Outcomes, such as lung function, exercise capacity, and dyspnea, were assessed at 3 and 12 months, together with data on complications and mortality. Data was obtained from electronic medical records. Results A total of 232 patients were included in the study. Follow-up visits at 3 (1-5) and 12 (9-18) months were available for 189 and 165 patients, respectively. Nine patients died within the first year, and 37 patients underwent valve removal. Significant improvements from baseline were observed at both follow-up points in lung function (forced expiratory volume in 1 second +4.75%points & +3.43 %points, residual volume -30.5%points & -27.7 %points, total lung capacity -7.0%points & -5.7%points), physical ability (6-minute walk distance +30.6 m & +20.8 m), and dyspnea (Medical Research Council dyspnea scale -0.73 & -0.47). Responder rates declined over time, but 40-50% of patients maintained a clinically meaningful benefit at the 12-month visit. Revision bronchoscopies were performed in 44% of the patients. Conclusions Endobronchial valve treatment is associated with statistically significant improvements in lung function, exercise capacity, and dyspnea at both 3 and 12 months, with considerable inter-individual variability.

As regulators of innate and adaptive immunity, microRNAs (miRNAs) could aid in the discrimination between tuberculosis disease (TB) and (latent) TB infection (TBI). We analysed 754 circulating miRNAs in participants diagnosed with TB and TBI using TaqMan™ Advanced miRNA Human A and B cards. MiRNAs were normalized exogenously and endogenously via geometric means of selected reference miRNAs. Expression analysis was used to identify miRNAs that were significantly differentially expressed between individuals with TB and those with TBI. We utilised recursive feature elimination with a Random Forest model to identify the miRNAs most effective at discriminating TB from TBI and subsequently validated the miRNA in another group. 95 persons diagnosed with TB or TBI was divided into a discovery group (n = 36) and a validation group (n = 59). In the discovery group, we identified 495 distinct miRNAs in 36 persons with TB or TBI and by recursive feature elimination identified hsa-miR-148a-3p, hsa-miR-204-5p and hsa-miR-584-5p and created a three-miRNA-diagnostic model. In the validation group, the three-miRNA-diagnostic model had poorer performance. Expression analysis revealed 13 significantly differentially expressed miRNAs, including hsa-miR-148a-3p and hsa-miR-204-5p. Subsequent analysis in a validation group consisting of 59 persons revealed that six of the 14 miRNAs, including hsa-miR-148a-3p, exhibited the same pattern, albeit without statistical significance. Three circulating miRNAs showed potential for differentiating TB from TBI in the discovery cohort, but these differences were less pronounced in the validation cohort.

BACKGROUND AND OBJECTIVES:Pneumothorax (PTX) is the most prevalent and serious adverse event associated with endobronchial valve (EBV) treatment in chronic obstructive pulmonary disease (COPD) with emphysema. This study aimed to compare preoperative characteristics and 30-day outcomes in patients with COPD with and without PTX. METHOD:This retrospective nationwide cohort study included patients treated with EBV between 2017 and 2023 at all EBV centres in Denmark. Data were retrieved from medical records. RESULTS:A total of 228 patients were included, of whom 46 (20.2%) had PTX. The median time to PTX was 7 h (IQR 2-22) and the median drain treatment duration was 13 days (IQR 8.5-22). The risk of PTX was significantly higher when EBV treatment was performed in the upper lobes than in the lower lobes (adjusted RR 6.32, 95% CI 2.56-15.60). High target lobe volume (adjusted OR pr 100 mL increase 1.12, 95% CI 1.02-1.22) and high residual volume (adjusted OR pr 10%pt. increase 1.11, 95% CI 1.01-1.23) were independent risk factors for PTX. More PTX patients had atelectasis after 2 h compared to patients without PTX. The risk of pneumonia (RR 4.5, 95% CI 1.7-11.8), empyema (p = 0.0047) and ICU admission (RR 9.89, 95% CI 1.98-49.4) were significantly higher in the PTX patients than in the patients without PTX. CONCLUSIONS:PTX was more prevalent when EBV treatment was performed in the upper lobes and with high residual volume and target lobe volume, leading to prolonged hospital admission and risk of hospital-acquired pneumonia.

IntroductionThe diagnosis of tuberculosis (TB) disease and TB infection (TBI) remains a challenge, and there is a need for non-invasive and blood-based methods to differentiate TB from conditions mimicking TB (CMTB), TBI, and healthy controls (HC). We aimed to determine whether combination of cytokines and established biomarkers could discriminate between 1) TB and CMTB 2) TB and TBI 3) TBI and HC. MethodsWe used hemoglobin, total white blood cell count, neutrophils, monocytes, C-reactive protein, and ten Meso Scale Discovery analyzed cytokines (interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon (IFN)-ɣ, and tumor necrosis factor (TNF)-α) in TruCulture whole blood tubes stimulated by lipopolysaccharides (LPS), zymosan (ZYM), anti-CD3/28 (CD3), and unstimulated (Null) to develop three index tests able to differentiate TB from CMTB and TBI, and TBI from HC. ResultsIn 52 persons with CMTB (n=9), TB (n=23), TBI (n=10), and HC (n=10), a combination of cytokines (LPS-IFN-ɣ, ZYM-IFN-ɣ, ZYM-TNF-α, ZYM-IL-1β, LPS-IL-4, and ZYM-IL-6) and neutrophil count could differentiate TB from CMTB with a sensitivity of 52.2% (95% CI: 30.9%–73.4%) and a specificity of 100 % (66.4%-100%). Null- IFN-ɣ, Null-IL-8, CD3-IL-6, CD3-IL-8, CD3-IL-13, and ZYM IL-1b discriminated TB from TBI with a sensitivity of 73.9% (56.5% - 91.3%) and a specificity of 100% (69.2-100). Cytokines and established biomarkers failed to differentiate TBI from HC with ≥ 98% specificity.DiscussionSelected cytokines may serve as blood-based add-on tests to detect TB in a low-endemic setting, although these results need to be validated.

Background: Patients with non-malignant respiratory diseases and severe symptom burden are rarely provided with specialized palliative care. This study explored and evaluated if an outpatient clinic for non-malignant respiratory palliation as an interdisciplinary collaboration between the departments of Respiratory Medicine and Specialized Palliative Care Unit, could identify and meet the needs for palliative care from patients. Aim: Evaluation of the effects of collaboration in palliation to patients with non-malignant respiratory diseases, based on patients' perspectives. Methods: A qualitative research design comprising eight in-depth semi-structured interviews with patients and field observations was conducted. Data were analyzed using theme analysis inspired by Brown and Clark and based on the concepts of Critical Psychology conduct of everyday life. Results: Semi-structured interviews revealed that acknowledgment of complex diseases and illness trajectories was considered important by the patients. The patients expressed a lack of knowledge on what they could expect from the consultation prior to attendance e.g. lack of knowledge about palliation. Though, the patients expected to be provided with management strategies in the conduct of everyday life having a severe respiratory disease. Patients considered the consultations important and rewarding. Conclusions: For all patients, the consultations led to management strategies for their conduct of everyday life. Despite different expectations prior to the consultation, all the patients found it to be important and rewarding. The patients concluded there was a need for end-of-life consultations.

Background Pseudomonas aeruginosa infection is seen in chronic pulmonary disease and is associated with exacerbations and poor long-term prognosis. However, evidence-based guidelines for the management and treatment of P. aeruginosa infection in chronic, non-cystic fibrosis (CF) pulmonary disease are lacking. The aim of this study is to investigate whether targeted antibiotic treatment against P. aeruginosa can reduce exacerbations and mortality in patients with chronic obstructive pulmonary disease (COPD), non-CF bronchiectasis, and asthma. Methods This study is an ongoing multicenter, randomized, controlled, open-label trial. A total of 150 patients with COPD, non-CF bronchiectasis or asthma, and P. aeruginosa -positive lower respiratory tract samples will be randomly assigned with a 1:1 ratio to either no antibiotic treatment or anti-pseudomonal antibiotic treatment with intravenous beta-lactam and oral ciprofloxacin for 14 days. The primary outcome, analyzed with two co-primary endpoints, is (i) time to prednisolone and/or antibiotic requiring exacerbation or death, in the primary or secondary health sector, within days 20–365 from study allocation and (ii) days alive and without exacerbation within days 20–365 from the study allocation. Discussion This trial will determine whether targeted antibiotics can benefit future patients with chronic, non-CF pulmonary disease and P. aeruginosa infection in terms of reduced morbidity and mortality, thus optimizing therapeutic approaches in this large group of chronic patients. Trial registration ClinicalTrials.gov NCT03262142 . Registered on August 25, 2017.

BACKGROUND:In Denmark emergency medical technicians transport patients with acute COPD exacerbations to the nearest emergency department. From a clinical and economic perspective, this transport and assessment at the hospital may be inconvenient if the patient is immediately discharged from the emergency department. We established an emergency technical technicians point-of-care diagnostics and treatment program of patients with COPD with use of ultrasound and blood analysis. Patients' perspectives on treatment at home and sense of security are important to qualify clinical practice at home with patients with acute exacerbation. AIM AND OBJECTIVES:To explore patient's and relatives' experience of treatment at home during emergency calls due to COPD in exacerbation and to investigate their attitude to avoid hospitalization as well as experience of stress during point-of-care diagnostics in their own home. METHOD:A qualitative study comprising semi-structured interviews with 16 patients carried out from April 1st, 2019 to March 31st, 2020 in Denmark. Data was analysed inspired by Malteruds' text condensation and informed by Critical Psychology with first person perspective focusing on the patient's views on point-of-care diagnostics and treatment of their COPD in acute exacerbation. RESULTS:The interviews revealed that in order to ensure an experience of quality in the assessment and treatment of patients in their own homes, it was important that the ambulance staff showed great safety and experience in the use of the technical equipment and treatment of dyspnea. It was also of importance that the patients felt confident that their general practitioner followed up on the home treatment initiated. CONCLUSION:Patients' perspectives showed that point-of-care diagnostics and treatment of acute COPD in exacerbation was considered a qualitative offer by the patients and their relatives. At the same time, it was crucial that the emergency medical technicians showed experience and safety in handling shortness of breath as well as the technical equipment. TRIAL REGISTRATION:Approved by the Danish Data Protection Agency Project-ID: 20/24845.

Chronic pulmonary aspergillosis (CPA) is a severe and underdiagnosed pulmonary fungal infection with a significant overlap in symptoms and imaging findings of mycobacterium tuberculosis (TB) and non-tuberculous mycobacterium (NTM). Infection with TB or NTM is a predisposing underlying condition for CPA in approximately one-third of patients. A previously published study from Uganda showed increased incidence and complication rate of CPA with respect to pre-existing radiographic cavitation in a post-treatment TB population. The aim of this study was to investigate the incidence of CPA in a low-endemic population of confirmed or suspected TB and NTM patients. We manually reviewed 172 patients referred on suspicion or for treatment of TB or NTM at the Department of Respiratory Medicine, Odense University Hospital during the period of 1 January 2018 to 31 December 2020. We found no CPA amongst TB patients as opposed to an incidence of 8.2% (n = 4) in NTM-infected patients. We identified possible investigatory differences in Aspergillus blood sample screening protocols depending on NTM or TB, initiated at the Department of Respiratory Medicine at Odense University Hospital. A focused screening and investigatory protocol in NTM patients with persisting or developing symptoms is warranted in relation to suspected CPA.

Background: Inhibition of phosphoinositide 3-kinase delta (PI3K delta) exerts corrective effects on the dysregulated migration characteristics of neutrophils isolated from patients with chronic obstructive pulmonary disease (COPD). Objective: To develop novel, induced sputum endpoints to demonstrate changes in neutrophil phenotype in the lung by administering nemiralisib, a potent and selective inhaled PI3K delta inhibitor, to patients with stable COPD or patients with acute exacerbation (AE) of COPD. Methods: In two randomized, double-blind, placebo-controlled clinical trials patients with A) stable COPD (N=28, randomized 3:1) or B) AECOPD (N=44, randomized 1:1) received treatment with inhaled nemiralisib (1mg). Endpoints included induced sputum at various time points before and during treatment for the measurement of transcriptomics (primary endpoint), inflammatory mediators, functional respiratory imaging (FRI), and spirometry. Results: In stable COPD patients, the use of nemiralisib was associated with alterations in sputum neutrophil transcriptomics suggestive of an improvement in migration phenotype; however, the same nemiralisib-evoked effects were not observed in AECOPD. Inhibition of sputum inflammatory mediators was also observed in stable but not AECOPD patients. In contrast, a placebo-corrected improvement in forced expiratory volume in 1 sec of 136 mL (95% Credible Intervals -46, 315mL) with a probability that the true treatment ratio was >0% (Pr(theta>0)) of 93% was observed in AECOPD. However, FRI endpoints remained unchanged. Conclusion: We provide evidence for nemiralisib-evoked changes in neutrophil migration phenotype in stable COPD but not AECOPD, despite improving lung function in the latter group. We conclude that induced sputum can be used for measuring evidence of alteration of neutrophil phenotype in stable patients, and our study provides a data set of the sputum transcriptomic changes during recovery from AECOPD.

1Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK; 2Biostatistics, GlaxoSmithKline R&D, Stevenage, UK; 3Computational Biology, Medicinal Science and Technology, GlaxoSmithKline, Stevenage, UK; 4Study Management, Clinical Development, GlaxoSmithKline, Mississauga, ON, Canada; 5Adaptive Immunity Research Unit, GlaxoSmithKline, Stevenage, UK; 6Nonclinical and Translational Statistics, GlaxoSmithKline, Stevenage, UK; 7Data Management & Strategy, Clinical Development, GlaxoSmithKline, Tokyo, Japan; 8Pharma Safety, Clinical Development, GlaxoSmithKline, Brentford, Middlesex, UK; 9FLUIDDA nv, Kontich, 2550, Belgium; 10Department of Respiratory Medicine, Odense University Hospital and University of Southern Denmark, Odense, Denmark; 11Centre for Heart and Lung Health, University of British Columbia, Vancouver, BC, Canada; 12Cardiorespiratory Research Laboratory, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada; 13Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada; 14Department of Medicine, Respiratory Medicine Division, University of Montreal, Montreal, QC, Canada; 15Institut Universitaire de Cardiologie et de Pneumologie de Québe, Université Laval, Quebec City, QC, Canada Background: Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) exerts corrective effects on the dysregulated migration characteristics of neutrophils isolated from patients with chronic obstructive pulmonary disease (COPD). Objective: To develop novel, induced sputum endpoints to demonstrate changes in neutrophil phenotype in the lung by administering nemiralisib, a potent and selective inhaled PI3Kδ inhibitor, to patients with stable COPD or patients with acute exacerbation (AE) of COPD. Methods: In two randomized, double-blind, placebo-controlled clinical trials patients with A) stable COPD (N=28, randomized 3:1) or B) AECOPD (N=44, randomized 1:1) received treatment with inhaled nemiralisib (1mg). Endpoints included induced sputum at various time points before and during treatment for the measurement of transcriptomics (primary endpoint), inflammatory mediators, functional respiratory imaging (FRI), and spirometry. Results: In stable COPD patients, the use of nemiralisib was associated with alterations in sputum neutrophil transcriptomics suggestive of an improvement in migration phenotype; however, the same nemiralisib-evoked effects were not observed in AECOPD. Inhibition of sputum inflammatory mediators was also observed in stable but not AECOPD patients. In contrast, a placebo-corrected improvement in forced expiratory volume in 1 sec of 136 mL (95% Credible Intervals −46, 315mL) with a probability that the true treatment ratio was >0% (Pr(θ>0)) of 93% was observed in AECOPD. However, FRI endpoints remained unchanged. Conclusion: We provide evidence for nemiralisib-evoked changes in neutrophil migration phenotype in stable COPD but not AECOPD, despite improving lung function in the latter group. We conclude that induced sputum can be used for measuring evidence of alteration of neutrophil phenotype in stable patients, and our study provides a data set of the sputum transcriptomic changes during recovery from AECOPD.

Pulmonary surfactant protein D (SP-D) is an important component of the pulmonary innate immune system with the ability to dampen cigarette smoke-induced lung inflammation. However, cigarette smoking mediates translocation of SP-D from the lung to the blood, and serum SP-D (sSP-D) has therefore previously been suggested as marker for smoke-induced lung injury. In support of this notion, associations between high sSP-D and low lung function measurements have previously been demonstrated in smokers and in chronic obstructive lung disease (COPD). The present investigations employ a 12-yr longitudinal Danish twin study to test the hypothesis that baseline sSP-D variation has the capacity to identify smokers with normal baseline lung function who are at high risk of significant future smoke-induced lung function decline. We find that sSP-D is significantly increased in those with normal lung function at baseline who develop lung function decline during follow-up compared with those who stay lung healthy. Moreover, we demonstrate that it is the smoke-induced baseline sSP-D level, and not the constitutional level, which has capacity as biomarker, and which is linearly increased with the decline in lung function during follow-up. In conclusion, we here present first observation of increased sSP-D for identification of high-risk smokers.

Background: The aim of this study was to investigate 30-day mortality for COPD patients treated by ambulances in the period before and after implementation of a pre-hospital oxygen protocol. Methods: Prehospital High-flow oxygen was used from April to September 2012 and titrated oxygen from April to September 2013. Primary outcome was 30-day mortality. Results: 707 patients were included; 209 in the high-flow group and 498 in the titration group. Of these, 56 and 132 arrived with acute exacerbation (AE). Overall 30-day mortality was 11.5% vs. 9.4% (p=0.41), respectively. For patients with AE, it was 19.6% vs. 4.6% (p=0.001). Conclusion: Change of treatment protocol is associated with a lower 30-day mortality for patients registered with acute exacerbation, but not for all COPD patients.

Objectives The incidence of primary spontaneous pneumothorax is partly unknown. Commonly quoted estimates were published decades ago and recent large-scale epidemiological publications lack validation. We validated the pneumothorax diagnosis in a national registry and estimated the incidence of primary spontaneous pneumothorax in young patients. Methods Complete data on patients with an assigned pneumothorax diagnosis was retrieved from the National Danish Patient Registry. Initially, we validated the diagnosis in a selected population: all patient charts with an assigned pneumothorax diagnosis from one cardiothoracic department over a 25-year period (1984–2008) were reviewed. Subsequently, the national incidence of primary spontaneous pneumothorax in young, healthy individuals was estimated by restricting our population to patients ≤40 years of age admitted during a 5-year period (2009–2014). We performed a systematic read-though of patient charts in 50% of the complete national cohort to ensure that we only included patients with their first episode of primary spontaneous pneumothorax. Results Validation revealed a poor inter-rater agreement (κ=0.08). Therefore, we abstained from further analysis on directly retrieved data from the national database. Subsequently, a systematic re-evaluation of 7022 patients revealed an incidence rate of 12.3 cases per 100 000 (95% CI 11.5–13.1) in males and 2.2 cases per 100 000 (95% CI 1.9–2.6) in females (male/female ratio 5.9). Compared with the general Danish population, pneumothorax patients had a lower body mass index (p<0.001) and smoked more than the Danish population in general (p<0.001). Conclusions The incidence of primary spontaneous pneumothorax in a validated national study was lower than previously reported.

Circulating MFAP4 is a relevant biomarker to identify COPD patients at risk of death and cardiovascular comorbidity after smoking cessation http://ow.ly/6vnL30o8t1g.

The decision to limit or discontinue treatment is a difficult issue, which all physicians will face. Timely communication with information on treatment possibilities and limitations, respectful listening to patients' and informal caregivers' wishes and early palliation is recommended in a stable phase. In some situations, it is better to stop life-prolonging treatment and optimise quality of life in patients with benign pulmonary diseases. Decision on treatment limitations or discontinuation is best taken at a conference and should be based on the patient's wishes, the disease stage and progression and potential reversible components.