Titration of anti-IL-5 biologics in severe asthma: an open-label randomised controlled trial (the OPTIMAL study).

BACKGROUND: Anti-interleukin (IL)-5 biologics effectively reduce exacerbations and the need for maintenance oral corticosteroids (mOCS) in severe eosinophilic asthma. However, it is unknown how long anti-IL-5 treatment should be continued. Data from clinical trials indicate a gradual but variable loss of control after treatment cessation. In this pilot study of titration, we evaluated a dose-titration algorithm in patients who had achieved clinical control on an anti-IL-5 biologic. METHODS: In this open-label randomised controlled trial conducted over 52 weeks, patients with clinical control (no exacerbations or mOCS) on anti-IL-5 treatment were randomised to continue with unchanged intervals or have dosing intervals adjusted according to a titration algorithm that gradually extended dosing intervals and reduced them again at signs of loss of disease control. The OPTIMAL algorithm was designed to down-titrate dosing until signs of loss of control, to enable assessment of the longest dosing interval possible. RESULTS: Among 73 patients enrolled, 37 patients were randomised to the OPTIMAL titration arm; 78% of patients tolerated down-titration of treatment. Compared to the control arm, the OPTIMAL arm tended to have more exacerbations during the study (32% versus 17%; p=0.13). There were no severe adverse events related to titration, and lung function and symptoms scores remained stable and comparable in both study arms throughout. CONCLUSION: This study serves as a proof of concept for titration of anti-IL-5 biologics in patients with severe asthma with clinical control on treatment, and the OPTIMAL algorithm provides a potential framework for individualising dosing intervals in the future.

Identification of patients' smoking status using an explainable AI approach: a Danish electronic health records case study.

BACKGROUND: Smoking is a critical risk factor responsible for over eight million annual deaths worldwide. It is essential to obtain information on smoking habits to advance research and implement preventive measures such as screening of high-risk individuals. In most countries, including Denmark, smoking habits are not systematically recorded and at best documented within unstructured free-text segments of electronic health records (EHRs). This would require researchers and clinicians to manually navigate through extensive amounts of unstructured data, which is one of the main reasons that smoking habits are rarely integrated into larger studies. Our aim is to develop machine learning models to classify patients' smoking status from their EHRs. METHODS: This study proposes an efficient natural language processing (NLP) pipeline capable of classifying patients' smoking status and providing explanations for the decisions. The proposed NLP pipeline comprises four distinct components, which are; (1) considering preprocessing techniques to address abbreviations, punctuation, and other textual irregularities, (2) four cutting-edge feature extraction techniques, i.e. Embedding, BERT, Word2Vec, and Count Vectorizer, employed to extract the optimal features, (3) utilization of a Stacking-based Ensemble (SE) model and a Convolutional Long Short-Term Memory Neural Network (CNN-LSTM) for the identification of smoking status, and (4) application of a local interpretable model-agnostic explanation to explain the decisions rendered by the detection models. The EHRs of 23,132 patients with suspected lung cancer were collected from the Region of Southern Denmark during the period 1/1/2009-31/12/2018. A medical professional annotated the data into 'Smoker' and 'Non-Smoker' with further classifications as 'Active-Smoker', 'Former-Smoker', and 'Never-Smoker'. Subsequently, the annotated dataset was used for the development of binary and multiclass classification models. An extensive comparison was conducted of the detection performance across various model architectures. RESULTS: The results of experimental validation confirm the consistency among the models. However, for binary classification, BERT method with CNN-LSTM architecture outperformed other models by achieving precision, recall, and F1-scores between 97% and 99% for both Never-Smokers and Active-Smokers. In multiclass classification, the Embedding technique with CNN-LSTM architecture yielded the most favorable results in class-specific evaluations, with equal performance measures of 97% for Never-Smoker and measures in the range of 86 to 89% for Active-Smoker and 91-92% for Never-Smoker. CONCLUSION: Our proposed NLP pipeline achieved a high level of classification performance. In addition, we presented the explanation of the decision made by the best performing detection model. Future work will expand the model's capabilities to analyze longer notes and a broader range of categories to maximize its utility in further research and screening applications.

Lung cancer: a nationwide analysis of sex and age incidence trends from 1980 to 2022.

BACKGROUND: Lung cancer, once rare, has evolved into the global leading cause of cancer-related mortality, primarily driven by widespread cigarette smoking in the 20th century. This study explores the historical trends of lung cancer incidence in Denmark over four decades, emphasizing the impact of smoking prevalence, age, and gender on the observed patterns. MATERIALS AND METHODS: Drawing upon data from the Danish National Patient Register and information on smoking habits provided by the Danish Health Authority, this study investigates lung cancer incidence rates, demographic shifts, and smoking prevalence from 1980 to 2022. RESULTS: Smoking prevalence exhibited a consistent decline in males from 1950 to 2022, whereas female smoking prevalence maintained a stable level from 1950 to 1987, followed by a subsequent decline from 1987 to 2022. A peak in lung cancer crude incidence rates was identified during 2014-2017, with no significant difference observed before and after this period. Over the period, the gender distribution transitioned from a male majority to an equal male-female ratio, and age-specific disparities indicated declines in patients aged 50-59 and increases in those above 80 years. INTERPRETATION: The certainty of a decline in lung cancer incidence in the coming years remains unclear. Based on smoking prevalence, it might still be a decade away. To ensure a sustained decline in lung cancer incidence, targeted interventions are imperative, including customized smoking cessation programs that could be designed favorably for females. Given the modest decline in smoking prevalence over the last decade, legislation aimed at discouraging young individuals from smoking is pivotal. As of now, these efforts have not been implemented in Denmark.

Consequences of Losing Incidental Pulmonary Nodules to Follow-Up: Unmonitored Nodules Progressing to Stage IV Lung Cancer.

INTRODUCTION: Lung cancer is the leading cause of cancer-related death globally. Incidental pulmonary nodules represent a golden opportunity for early diagnosis, which is critical for improving survival rates. This study explores the impact of missed pulmonary nodules on the progression of lung cancer. METHODS: A total of 4,066 stage IV lung cancer cases from 2019 to 2021 in Danish hospitals were investigated to determine whether a chest computed tomography (CT) had been performed within 2 years before diagnosis. CT reports and images were reviewed to identify nodules that had been missed by radiologists or were not appropriately monitored, despite being mentioned by the radiologist, and to assess whether these nodules had progressed to stage IV lung cancer. RESULTS: Among stage IV lung cancer patients, 13.6% had undergone a chest CT scan before their diagnosis; of these, 44.4% had nodules mentioned. Radiologists missed a nodule in 7.6% of cases. In total, 45.3% of nodules were not appropriately monitored. An estimated 2.5% of stage IV cases could have been detected earlier with proper surveillance. CONCLUSION: This study underlines the significance of monitoring pulmonary nodules and proposes strategies for enhancing detection and surveillance. These strategies include centralized monitoring and the implementation of automated registries to prevent gaps in follow-up.

Telephone follow-up as a substitute for standard out-clinic follow-up in CPAP therapy for obstructive sleep apnea patients: a randomized controlled trial.

PURPOSE: This study assessed the feasibility of telephone follow-up consultations (TC) using an online data sharing and editing function (Airview™), as alternative to standard out-clinic follow-up consultations (SC) on adherence to continuous positive airway pressure (CPAP) in obstructive sleep apnea (OSA) patients. Furthermore, we investigated compliance to follow-up consultations and examined potential influencing factors, including baseline AHI (apnea-hypopnea-index), age, and distance from home to the hospital on consultation compliance. METHODS: Two hundred OSA patients, with AHI ≥ 5 were randomly assigned (1:1) to receive TC or SC with follow-up after one month and 12 month of CPAP initiation. Adherence goal was defined as achieving ≥ 4 h of CPAP use daily in 70% of the days in a 365-days period. RESULTS: The proportion of participants achieving CPAP adherence was non-significantly lower in the TC group compared to the SC group (TC: 30% versus SC: 36%, adjusted OR 0.84, p = 0.59). Of participants who completed the study, the TC group had a significant average of 107 min less use of CPAP compared to the SC group (p = 0.048). However, a higher proportion of participants was compliant to consultations in the TC group. The only influencing factor found was increasing baseline AHI, which might be a predictor for compliance to consultations and adherence to CPAP therapy. CONCLUSION: TC might serve as substitute for SC in some part of the OSA population. If TC becomes a part of CPAP therapy management, it is important to consider patient characteristics and treatment-related issues to prevent decline in adherence.

Prevalence estimates of tuberculosis infection in adults in Denmark: a retrospective nationwide register-based cross-sectional study, 2010 to 2018.

BackgroundTuberculosis (TB) elimination requires identifying and treating persons with TB infection (TBI).AimWe estimate the prevalence of positive interferon gamma release assay (IGRA) tests (including TB) and TBI (excluding TB) in Denmark based on TBI screening data from patients with inflammatory bowel disease (IBD) or inflammatory rheumatic disease (IRD).MethodsUsing nationwide Danish registries, we included all patients with IBD or IRD with an IGRA test performed between 2010 and 2018. We estimated the prevalence of TBI and positive IGRA with 95% confidence intervals (CI) in adolescents and adults aged 15-64 years after sample weighting adjusting for distortions in the sample from the background population of Denmark for sex, age group and TB incidence rates (IR) in country of birth.ResultsIn 13,574 patients with IBD or IRD, 12,892 IGRA tests (95.0%) were negative, 461 (3.4%) were positive and 221 (1.6%) were indeterminate, resulting in a weighted TBI prevalence of 3.2% (95% CI: 2.9-3.5) and weighted positive IGRA prevalence of 3.8% (95% CI: 3.5-4.2) among adults aged 15-64 years in the background population of Denmark. Unweighted TBI prevalence increased with age and birthplace in countries with a TB IR higher than 10/100,000 population.ConclusionEstimated TBI prevalence is low in Denmark. We estimate that 200,000 persons have TBI and thus are at risk of developing TB. Screening for TBI and preventive treatment, especially in persons born in high TB incidence countries or immunosuppressed, are crucial to reduce the risk of and eliminate TB.

Experiences of receiving a medical consultation - an interview study among hospitalized psychiatric patients.

PURPOSE: People with mental illness often experience more physical health problems, compared to the general population. Therefore, we conducted medical consultations to hospitalized psychiatric patients. The purpose of our study was to investigate experiences of medical consultations from a patient perspective. MATERIALS AND METHODS: We conducted 17 qualitative, semi-structured interviews with hospitalized psychiatric patients who received a medical consultation in the period of February to May 2023. The interviews were analyzed using Braun and Clarke's thematic analysis. RESULTS: Patients perceived the medical consultation as important in bridging the gap between psychiatric and somatic treatment. The consultation created a sense of security, with patients emphasizing the importance of acknowledgment by the medical doctor. However, some patients were affected by their state of mind and their psychiatric treatment, resulting in memory impairment, which prevented fully utilization of the medical consultation. The support from psychiatric staff proved crucial for patients in initiating somatic interventions.The results are presented in the two overarching themes: (1) Experiences of a medical consultation in a psychiatric setting and (2) communication and support as influential factors for benefits of the medical consultation. CONCLUSION: Our interview study reveals that hospitalized psychiatric patients experience a medical consultation as an important initiative. The relationship between the patient and the medical doctor, the patient's state of mind, and the support of the psychiatric staff play significant roles. Incorporating these factors in the medical consultation enables a beneficial outcome that can improve the health of people with mental illness.

NK cell activity and methylated HOXA9 ctDNA as prognostic biomarkers in patients with non-small cell lung cancer treated with PD-1/PD-L1 inhibitors.

BACKGROUND: PD-1/PD-L1 inhibitors have improved survival for patients with non-small cell lung cancer (NSCLC). We evaluated natural killer cell activity (NKA) and methylated HOXA9 circulating tumor DNA (ctDNA) as prognostic biomarkers in NSCLC patients treated with PD-1/PD-L1 inhibitors. METHODS: Plasma was prospectively collected from 71 NSCLC patients before treatment with PD-1/PD-L1 inhibitors and before cycles 2-4. We used the NK Vue® assay to measure the level of interferon gamma (IFNγ) as a surrogate for NKA. Methylated HOXA9 was measured by droplet digital PCR. RESULTS: A score combining NKA and ctDNA status measured after one treatment cycle had a strong prognostic impact. Group 1 had IFNγ < 250 pg/ml and detectable ctDNA (n = 27), group 2 consisted of patients with either low levels of IFNγ and undetectable ctDNA or high levels of IFNγ and detectable ctDNA (n = 29), group 3 had IFNγ ≥250 pg/ml and undetectable ctDNA (n = 15). Median OS was 221 days (95% CI 121-539 days), 419 days (95% CI 235-650 days), and 1158 days (95% CI 250 days-not reached), respectively (P = 0.002). Group 1 had a poor prognosis with a hazard ratio of 5.560 (95% CI 2.359-13.101, n = 71, P < 0.001) adjusting for PD-L1 status, histology, and performance status. CONCLUSIONS: Combining NKA and ctDNA status after one cycle of treatment was prognostic in patients with NSCLC treated with PD-1/PD-L1 inhibitors.

Severe asthma trajectories in adults: findings from the NORDSTAR cohort.

BACKGROUND: There is limited evidence on the pathways leading to severe asthma and we are presently unable to effectively predict the progression of the disease. We aimed to describe the longitudinal trajectories leading to severe asthma and to describe clinical events preceding disease progression in a nationwide population of patients with severe asthma. METHODS: We conducted an observational study based on Swedish data from the NORdic Dataset for aSThmA Research (NORDSTAR) research collaboration platform. We identified adult patients with severe asthma in 2018 according to the European Respiratory Society/American Thoracic Society definition and used latent class analysis to identify trajectories of asthma severity over a 10-year retrospective period from 2018. RESULTS: Among 169 128 asthma patients, we identified 4543 severe asthma patients. We identified four trajectories of severe asthma that were labelled as: trajectory 1 "consistently severe asthma" (n=389 (8.6%)), trajectory 2 "gradual onset severe asthma" (n=942 (20.7%)), trajectory 3 "intermittent severe asthma" (n=1685 (37.1%)) and trajectory 4 "sudden onset severe asthma" (n=1527 (33.6%)). "Consistently severe asthma" had a higher daily inhaled corticosteroid dose and more prevalent osteoporosis compared with the other trajectories. Patients with "gradual onset severe asthma" and "sudden onset severe asthma" developed type 2-related comorbidities concomitantly with development of severe asthma. In the latter group, this primarily occurred within 1-3 years preceding onset of severe asthma. CONCLUSIONS: Four distinct trajectories of severe asthma were identified illustrating different patterns of progression of asthma severity. This may eventually enable the development of better preventive management strategies in severe asthma.

Adherence and persistence in allergen immunotherapy (APAIT): A reporting checklist for retrospective studies.

BACKGROUND: Adherence is essential for the long-term efficacy of allergen immunotherapy (AIT) and has been evaluated in numerous retrospective studies. However, there are no published guidelines for best practice in measuring and reporting adherence or persistence to AIT, which has resulted in substantial heterogeneity among existing studies. The 'adherence and persistence in AIT (APAIT)' checklist has been developed to guide the reporting, design and interpretation of retrospective studies that evaluate adherence or persistence to AIT in clinical practice. METHODS: Five existing checklists, focussing on study protocol design, the use of retrospective databases/patient registries, and the appraisal and reporting of observational studies, were identified and merged. Relevant items were selected and tailored to be specific to AIT. The content of the checklist was discussed by 11 experts from Europe, the United States and Canada, representing allergy, healthcare and life sciences, and health technology appraisal. RESULTS: The APAIT checklist presents a set of items that should either be included or at least considered, when reporting retrospective studies that assess adherence or persistence to AIT. Items are organized into four categories comprising study objective, design and methods, data analysis, and results and discussion. The checklist highlights the need for clarity and transparency in reporting and emphasizes the importance of considering potential sources of bias in retrospective studies evaluating adherence or persistence to AIT. CONCLUSIONS: The APAIT checklist provides a pragmatic guide for reporting retrospective adherence and persistence studies in AIT. Importantly, it identifies potential sources of bias and discusses how these influence outcomes.

Comparative effectiveness of anti-IL5 and anti-IgE biologic classes in patients with severe asthma eligible for both.

BACKGROUND: Patients with severe asthma may present with characteristics representing overlapping phenotypes, making them eligible for more than one class of biologic. Our aim was to describe the profile of adult patients with severe asthma eligible for both anti-IgE and anti-IL5/5R and to compare the effectiveness of both classes of treatment in real life. METHODS: This was a prospective cohort study that included adult patients with severe asthma from 22 countries enrolled into the International Severe Asthma registry (ISAR) who were eligible for both anti-IgE and anti-IL5/5R. The effectiveness of anti-IgE and anti-IL5/5R was compared in a 1:1 matched cohort. Exacerbation rate was the primary effectiveness endpoint. Secondary endpoints included long-term-oral corticosteroid (LTOCS) use, asthma-related emergency room (ER) attendance, and hospital admissions. RESULTS: In the matched analysis (n = 350/group), the mean annualized exacerbation rate decreased by 47.1% in the anti-IL5/5R group and 38.7% in the anti-IgE group. Patients treated with anti-IL5/5R were less likely to experience a future exacerbation (adjusted IRR 0.76; 95% CI 0.64, 0.89; p < 0.001) and experienced a greater reduction in mean LTOCS dose than those treated with anti-IgE (37.44% vs. 20.55% reduction; p = 0.023). There was some evidence to suggest that patients treated with anti-IL5/5R experienced fewer asthma-related hospitalizations (IRR 0.64; 95% CI 0.38, 1.08), but not ER visits (IRR 0.94, 95% CI 0.61, 1.43). CONCLUSIONS: In real life, both anti-IgE and anti-IL5/5R improve asthma outcomes in patients eligible for both biologic classes; however, anti-IL5/5R was superior in terms of reducing asthma exacerbations and LTOCS use.

Impaired phosphate transport in SLC34A2 variants in patients with pulmonary alveolar microlithiasis.

BACKGROUND: Variants in SLC34A2 encoding the sodium-dependent phosphate transport protein 2b (NaPi-IIb) cause the rare lung disease pulmonary alveolar microlithiasis (PAM). PAM is characterised by the deposition of calcium-phosphate concretions in the alveoli usually progressing over time. No effective treatment is available. So far, 30 allelic variants in patients have been reported but only a few have been functionally characterised. This study aimed to determine the impact of selected SLC34A2 variants on transporter expression and phosphate uptake in cellular studies. METHODS: Two nonsense variants (c.910A > T and c.1456C > T), one frameshift (c.1328delT), and one in-frame deletion (c.1402_1404delACC) previously reported in patients with PAM were selected for investigation. Wild-type and mutant c-Myc-tagged human NaPi-IIb constructs were expressed in Xenopus laevis oocytes. The transport function was investigated with a 32Pi uptake assay. NaPi-IIb protein expression and localisation were determined with immunoblotting and immunohistochemistry, respectively. RESULTS: Oocytes injected with the wild-type human NaPi-IIb construct had significant 32Pi transport compared to water-injected oocytes. In addition, the protein had a molecular weight as expected for the glycosylated form, and it was readily detectable in the oocyte membrane. Although the protein from the Thr468del construct was synthesised and expressed in the oocyte membrane, phosphate transport was similar to non-injected control oocytes. All other mutants were non-functional and not expressed in the membrane, consistent with the expected impact of the truncations caused by premature stop codons. CONCLUSIONS: Of four analysed SLC34A2 variants, only the Thr468del showed similar protein expression as the wild-type cotransporter in the oocyte membrane. All mutant transporters were non-functional, supporting that dysfunction of NaPi-IIb underlies the pathology of PAM.

Who are the vulnerable lung cancer patients at risk for not receiving first-line curative or palliative treatment?

BACKGROUND: To identify non-small-cell lung cancer (NSCLC) patients in need of comprehensive support, we examined the association between patient and disease-related factors of vulnerability related to not receiving guideline-recommended treatment. MATERIAL AND METHODS: We identified 14,597 non-small-cell lung cancer (NSCLC) patients with performance status <3 during 2013-2018 in the Danish Lung Cancer Registry. Multivariate logistic regression models were used to estimate Odds Ratios (ORs) and 95% confidence intervals (CIs) for receiving guideline-recommended treatment according to stage, comorbidities, age, performance status, long distance to hospital, cohabitation status, education and alcohol abuse. RESULTS: 21% of stage I-IIIA NSCLC patients did not receive curative treatment while 10% with stage IIIB-IV did not receive any oncological therapy. Factors associated with reduced likelihood of receiving curative treatment included: advanced stage (OR = 0.45; 95% CI = 0.42-0.49), somatic comorbidity (OR = 0.72; 95% CI = 0.63-0.83), age ≥ 80 years (OR = 0.59; 95% CI = 0.55-0.64), performance status = 2 (OR = 0.33; 95% CI = 0.28-0.39) and living alone (OR = 0.79; 95% CI = 0.69-0.90). Results were similar for stage IIIB-IV NSCLC patients, although a statistically significant association was also seen for long distances to the hospital (OR = 0.71; 95% CI = 0.58-0.86). CONCLUSIONS: Several factors are associated with not receiving guideline-recommended NSCLC treatment with age, performance status, comorbidity and stage being most predictive of no treatment receipt. Efforts should be made to develop support for vulnerable lung cancer patients to improve adherence to optimal first-line therapy.

Fatigue in Patients with Sarcoidosis in Denmark.

INTRODUCTION: Sarcoidosis is a systemic granulomatous disease of unknown etiology, primarily affecting the lungs and thoracic lymph nodes. Fatigue is a frequent and disabling symptom in sarcoidosis with a significant impact on quality of life. In Denmark, the incidence of sarcoidosis has increased; however, the extent and risk factors of fatigue have not been investigated and no recent reports of the characteristics of patients with sarcoidosis in Denmark exist. AIM: To assess the frequency of fatigue in patients with sarcoidosis in Denmark at diagnosis and to investigate if fatigue correlated with relevant disease parameters. Moreover, to characterize patients with sarcoidosis in Denmark at time of diagnosis. METHODS: Data were collected in 150 patients with recently diagnosed sarcoidosis. Fatigue was measured using the Fatigue Assessment Scale (FAS). Patients with fatigue were compared to non-fatigue patients regarding clinical parameters. RESULTS: FAS was completed by 145 of 150 patients. Fifty-one percent reported significant fatigue. Mean FAS score was 23.6 and 51% had a FAS score ≥ 22. Fatigue in 89 incident patients did not correlate significantly with demographics, physiological, or clinical parameters. Fifty-nine percent were males. Mean age was 47 years; mean values (% predicted) for pulmonary function tests were normal and 71% at Scadding stage 0-I. CONCLUSION: In Denmark, fatigue was frequent in patients with sarcoidosis. The majority of patients had mild disease at diagnosis and were older but lower at Scadding stage at diagnosis compared to previous cohorts.

Comorbidity and mortality in systemic sclerosis and matched controls: Impact of interstitial lung disease. A population based cohort study based on health registry data.

OBJECTIVE: This population-based, matched cohort study evaluates the impact of comorbidities on mortality among systemic sclerosis (SSc) patients with and without interstitial lung disease (ILD). METHOD: Patients with a first-time SSc diagnosis between 2002 and 2015 were identified in the Danish National Patient Registry, separated into two cohorts - with ILD (SSc-ILD) and without ILD (non-ILD SSc), and matched 1:4 with controls from the general population on age, sex, residency and marital status. Comorbidity and mortality data were obtained from national registries. The Deyo-Charlson comorbidity score (DCcs) was used for assessment of the burden of comorbidities. RESULTS: 1732 patients with SSc and 6919 controls were included; 258 (14.9%) patients had SSc-ILD. The hazard ratio (HR) for death was 2.8 (95% CI 2.4-3.3) in SSc, and especially increased in SSc-ILD (HR 4.2 (95% CI 3.2-5.4)), males (HR 3.1 95% CI 2.4-4.1) and younger adults (aged 18-40 (HR 6.9, 95% CI 3.4-14.2) and 41-50 (HR 7.7, 95% CI 3.8-15.6)). In non-ILD SSc, mortality increased with increasing DCcs. Cancer was the most frequent cause of death in SSc (24.9% of deaths) and in controls (33.5%), in SSc followed by musculoskeletal and connective tissue diseases (22.7%); the cause of only 0.8% of deaths among controls. CONCLUSION: The high prevalence of comorbidities in SSc had extensive impact on mortality. Mortality was increased in males, in young adults and in SSc-ILD, underlining the excess mortality associated with ILD. These findings emphasise the importance of timely diagnosis and optimal management of organ involvement and comorbidities in SSc.

Use of Singing for Lung Health as an alternative training modality within pulmonary rehabilitation for COPD: a randomised controlled trial.

BACKGROUND: Pulmonary rehabilitation (PR) is a cornerstone in chronic obstructive pulmonary disease (COPD) management. However, PR adherence is generally low, and barriers include availability, economic issues, motivation and an inability to attend or perform physical training. Therefore, alternative, evidence-based PR activities are required. Singing may have benefits for quality of life (QoL), respiratory control and well-being in COPD, but the impact on the PR key outcome, physical exercise capacity, is uncertain. METHODS: In this randomised controlled trial (NCT03280355), we investigated the effectiveness of 10 weeks of PR, including either "Singing for Lung Health" (SLH) training or standard physical exercise training (PExT). The primary outcome was a change in exercise capacity (6-min walk distance (6MWD)) from baseline to post-PR. Secondary outcomes were changes in QoL (St George's Respiratory Questionnaire (SGRQ)), Hospital Anxiety and Depression Score (HADS), lung function, dyspnoea and adherence. RESULTS: We included 270 COPD patients, and 195 completed the study. Demographics across groups were comparable, and both groups improved significantly in 6MWD and SGRQ score. SLH was non-inferior to PExT in improving 6MWD (mean±sd 13.1±36.3 m versus 14.1±32.3 m, p=0.81; difference 1.0 m, 95% CI -7.3-9.3 m) with 21.8% and 25.0%, respectively (p=0.57), reaching the 6MWD minimal important difference of 30 m. We found no significant between-group differences concerning SGRQ, HADS, lung function, dyspnoea or adherence. CONCLUSION: Our study suggests that SLH is non-inferior to PExT in improving 6MWD during a 10-week PR programme. Future studies addressing reproducibility, long-term effects and health economics are needed.

Sarcoidosis-related mortality and the impact of corticosteroid treatment: A population-based cohort study.

BACKGROUND AND OBJECTIVE: The aims of this national cohort study were: (1) to evaluate mortality in patients with sarcoidosis, stratified by gender, age and systemic corticosteroid (SC) treatment and (2) to characterize comorbidities in this cohort. METHODS: Patients diagnosed with sarcoidosis from 2001 to 2015 were identified in the Danish National Patient Registry. Subgroup analyses were performed on cases treated/not treated with SCs within 3 years of the initial sarcoidosis diagnosis (as a proxy for disease severity). The Deyo-Charlson Comorbidity Index was used to evaluate pre-diagnostic comorbidity. Cases were matched (1:4) with controls from the general population. RESULTS: We identified 9795 cases with sarcoidosis. Mean age was 46.5 ± 15.9 years and 55% were male. The adjusted hazard ratio (HR) for death was 1.48 (95% CI 1.31-1.68). Mortality was higher than for controls in all age groups and in both genders. HR for death for cases treated with SCs was 1.78 (95% CI 1.49-2.13) and, for cases receiving no treatment, 1.24 (95% CI 1.04-1.48). Sarcoidosis was the most commonly registered cause of death (13.3%). CONCLUSION: Patients with sarcoidosis have an increased mortality compared with matched controls. Mortality is particularly high in patients treated with SCs.

Direct and indirect costs of systemic sclerosis and associated interstitial lung disease: A nationwide population-based cohort study.

BACKGROUND AND OBJECTIVE: The study aimed to evaluate the direct and indirect costs of systemic sclerosis (SSc) in cases with and without interstitial lung disease (ILD). METHODS: Cases diagnosed with SSc (2002-2015) were identified in the Danish National Patient Registry. Cases were matched 1:4 with non-SSc controls from the general population. Data on costs were obtained from national databases. Excess cost was estimated as the annual cost per case subtracting the costs of the control. RESULTS: We identified 1869 cases and 7463 controls. Total excess cost (direct healthcare, elderly care and indirect costs) in the SSc-ILD cohort was €29,725, and €17,905 in the non-ILD SSc cohort. In- and out-patient contacts and forgone earnings were the key drivers of costs in both cohorts. Healthcare costs were higher before and after the diagnosis compared with the controls. Men incurred higher excess healthcare costs than women. Hospitalization and outpatient services were the key drivers of the gender-associated differences. Income from employment decreased more rapidly after diagnosis in the SSc-ILD cohort than in the non-ILD SSc cohort. Public transfer income increased after diagnosis, with the most pronounced difference in the SSc-ILD cohort. Disability pension was the key driver of public transfer income. CONCLUSION: SSc is associated with a significant individual and societal burden that is evident several years before and after the diagnosis. Total excess costs are higher in SSc-ILD than in the non-ILD SSc underlining the severity of pulmonary involvement. Initiatives to maintain work ability and to reduce hospital admissions may reduce the economic burden of SSc.

Senicapoc treatment in COVID-19 patients with severe respiratory insufficiency-A randomized, open-label, phase II trial.

BACKGROUND: The aim of the current study was to determine if treatment with senicapoc, improves the PaO2 /FiO2 ratio in patients with COVID-19 and severe respiratory insufficiency. METHODS: Investigator-initiated, randomized, open-label, phase II trial in four intensive care units (ICU) in Denmark. We included patients aged ≥18 years and admitted to an ICU with severe respiratory insufficiency due to COVID-19. The intervention consisted of 50 mg enteral senicapoc administered as soon as possible after randomization and again after 24 h. Patients in the control group received standard care only. The primary outcome was the PaO2 /FiO2 ratio at 72 h. RESULTS: Twenty patients were randomized to senicapoc and 26 patients to standard care. Important differences existed in patient characteristics at baseline, including more patients being on non-invasive/invasive ventilation in the control group (54% vs. 35%). The median senicapoc concentration at 72 h was 62.1 ng/ml (IQR 46.7-71.2). The primary outcome, PaO2 /FiO2 ratio at 72 h, was significantly lower in the senicapoc group (mean 19.5 kPa, SD 6.6) than in the control group (mean 24.4 kPa, SD 9.2) (mean difference -5.1 kPa [95% CI -10.2, -0.04] p = .05). The 28-day mortality in the senicapoc group was 2/20 (10%) compared with 6/26 (23%) in the control group (OR 0.36 95% CI 0.06-2.07, p = .26). CONCLUSIONS: Treatment with senicapoc resulted in a significantly lower PaO2 /FiO2 ratio at 72 h with no differences for other outcomes.

Does the Addition of Radial Endobronchial Ultrasound Improve the Diagnostic Yield of Electromagnetic Navigation Bronchoscopy? A Systematic Review.

BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. Early diagnosis is crucial to increased survival rates. Radial endobronchial ultrasound (rEBUS) and electromagnetic navigation bronchoscopy (ENB) have been developed for the diagnosis of small lung lesions. The aim of this systematic review was to evaluate whether the combination of rEBUS and ENB is superior to ENB alone. METHOD: A systematic search was performed using MEDLINE, Embase, and Cochrane Library databases on "ENB," and conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The project was registered with PROSPERO, number CRD42020214682. RESULTS: In total, 2,092 studies were identified through a literature search. Five studies were included in the final review. One study found that the addition of rEBUS increased diagnostic yield, while another concluded the converse. Three studies did not have significant results. Meta-analysis was not feasible due to heterogeneity and the small number of studies. CONCLUSION: As the current evidence on the topic is sparse and heterogeneous, it is not possible to conclude whether the addition of rEBUS to ENB has a significant impact on diagnostic yield. Further studies are needed to illuminate this question in order to ensure optimal choice of endoscopic technique as well as used time and resources. The project received funding from the Region of Southern Denmark's PhD fund.