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ABSTRACTBackground Autoimmune rheumatologic disease associated interstitial lung diseases (ARD-ILD) are rare conditions and the association between ARDs and respiratory symptoms often goes unrecognised by ARD patients and general practitioners (GPs). The diagnostic trajectory from the first respiratory symptoms to an ARD-ILD diagnosis is often delayed and may increase the burden of symptoms and allow further disease progression.The aim of this study was to 1) characterise the diagnostic trajectories of ARD-ILD patients and to 2) identify barriers for obtaining a timely ILD diagnosis based on the experiences and perceptions of both patients and healthcare professionals.Method Semi-structured qualitative interviews were conducted with Danish ARD-ILD patients, rheumatologists, pulmonologists and ILD nurses.Results Sixteen patients, six rheumatologists, three ILD nurses and three pulmonologists participated. Five characteristics of diagnostic trajectories were identified in the patient interviews: 1) early referral to lung specialists; 2) early delay; 3) delay or shortcut depending on specific circumstances; 4) parallel diagnostic trajectories connected late in the process; 5) early identification of lung involvement without proper interpretation. With the exception of early referral to lung specialists, all of the diagnostic trajectory characteristics identified led to delayed diagnosis. Delayed diagnostic trajectories resulted in patients experiencing increased uncertainty. Inconsistent disease terminology, insufficient knowledge and lack of awareness of ARD-ILD among central healthcare professionals and delayed referral to ILD specialists were main contributors to the diagnostic delay identified by the informants.Conclusion Five characteristics of the diagnostic trajectories were identified, four of which led to diagnostic delay of ARD-ILD. Improved diagnostic trajectories can shorten the diagnostic trajectory and increase early access to appropriate specialist medical care. Improved awareness and expertise in ARD-ILD across different medical specialties, especially among GPs, may contribute to more efficient and timely diagnostic trajectories and improved patient experiences.

Fibrosis, driven by fibroblast activities, is an important contributor to morbidity and mortality in most chronic diseases. Endotrophin, a signaling molecule derived from processing of type VI collagen by highly activated fibroblasts, is involved in fibrotic tissue remodeling. Circulating levels of endotrophin have been associated with an increased risk of mortality in multiple chronic diseases. We conducted a systematic literature review collecting evidence from original papers published between 2012 and January 2023 that reported associations between circulating endotrophin (PROC6) and mortality. Cohorts with data available to the study authors were included in an Individual Patient Data (IPD) meta-analysis that evaluated the association of PROC6 with mortality (PROSPERO registration number: CRD42023340215) after adjustment for age, sex and BMI, where available. In the IPD meta-analysis including sixteen cohorts of patients with different non-communicable chronic diseases (NCCDs) (N = 15,205) the estimated summary hazard ratio for 3-years all-cause mortality was 2.10 (95 % CI 1.75-2.52) for a 2-fold increase in PROC6, with some heterogeneity observed between the studies (I 2 =70 %). This meta-analysis is the first study documenting that fibroblast activities, as quantified by circulating endotrophin, are independently associated with mortality across a broad range of NCCDs. This indicates that, irrespective of disease, interstitial tissue remodeling, and consequently fibroblast activities, has a central role in adverse clinical outcomes, and should be considered with urgency from drug developers as a target to treat., Competing Interests: Declaration of competing interest Federica Genovese, Cecilie Bager, Peder Frederiksen, Dario Vazquez, Jannie Marie Bülow Sand, Diana Julie Leeming, Daniel Guldager Kring Rasmussen, Alexander Lynge Reese-Petersen, Neel I Nissen and Morten Karsdal are or have been at the time of writing, full-time employees at Nordic Bioscience. Federica Genovese, Cecilie Bager, Jannie Maria Bülow Sand, Diana Julie Leeming, Daniel Guldager Kring Rasmussen, Alexander Lynge Reese-Petersen and Morten Karsdal hold Nordic Bioscience stocks. Nordic Bioscience holds the patent for the PROC6 assays and commercializes the assay. Peter Rossing has received research support from Astra Zeneca, Novo Nordisk and Bayer, and has received honoraria (to Steno Diabetes Center Copenhagen) from Astra Zeneca, Boehringer Ingelheim, Bayer, Novo Nordisk, Gilead, Sanofi, Abbott for consultancy or education. Louise V. Wain has received research funding or collaborative support from Orion Pharma, GSK, Genentech, AstraZeneca and Sysmex, outside of the submitted work and provided consultancy for GSK and Galapagos., (Copyright © 2024. Published by Elsevier B.V.)

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibrosis in the lungs. Activated fibroblasts play a central role in fibrogenesis and express fibroblast activation protein α. A truncated, soluble form (sFAP) can be measured in blood and is a potential novel biomarker of disease activity. The aim was to study the association between sFAP and clinical, radiological, and histopathological measures of disease severity, progression, and survival in a prospective, multicentre, real-world cohort of patients with IPF. Patients with IPF were recruited from the tertiary interstitial lung disease centres in Denmark and followed for up to 3 years. Baseline serum levels of sFAP were measured by ELISA in patients with IPF and compared to healthy controls. Pulmonary function tests, 6-minute walk test and quality of life measures were performed at baseline and during follow-up. The study included 149 patients with IPF. Median sFAP in IPF was 49.6 ng/mL (IQR: 43.1-61.6 ng/mL) and in healthy controls 73.8 ng/mL (IQR: 62.1-92.0 ng/mL). Continuous sFAP was not associated with disease severity, progression or survival (p > 0.05). After dichotomization of sFAP below or above mean sFAP + 2 SD for healthy controls, higher levels of sFAP were associated with lower FVC % predicted during follow-up (p < 0.01). Higher than normal serum levels of sFAP were associated with longitudinal changes in FVC % predicted, but sFAP did not show clear associations with other baseline or longitudinal parameters. As such, sFAP has limited use as a biomarker of disease progression or survival in patients with IPF., (© 2024 The Author(s). Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.)

Interstitial lung abnormalities (ILA) are incidentally observed specific CT findings in patients without clinical suspicion of interstitial lung disease (ILD). ILA with basal and peripheral predominance and features suggestive of fibrosis in more than 5% of any part of the lung should be referred for pulmonologist review. The strategy for monitoring as described in this review is based on clinical and radiological risk factors. ILA are associated with risk of progression to ILD and increased mortality. Early identification and assessment of risk factors for progression are essential to improve outcome., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) and other fibrotic interstitial lung diseases (AE-ILD) is defined by significant acute respiratory worsening and new widespread alveolar damage. This review summarises the current knowledge of diagnosis and treatment of these events. The diagnosis of AE-IPF and AE-ILD is based on typical HRCT findings of new and bilateral ground glass opacification and/or consolidation, and exclusion of fluid overload or cardiac failure. Treatment relies, despite low quality of evidence, on glucocorticoid in addition to supportive and palliative treatment. Despite treatment, the prognosis is poor, with a median survival of 2-4 months.

Background: Autoimmune rheumatologic disease associated interstitial lung diseases (ARD-ILD) are rare conditions and the association between ARDs and respiratory symptoms often goes unrecognised by ARD patients and general practitioners (GPs). The diagnostic trajectory from the first respiratory symptoms to an ARD-ILD diagnosis is often delayed and may increase the burden of symptoms and allow further disease progression.The aim of this study was to 1) characterise the diagnostic trajectories of ARD-ILD patients and to 2) identify barriers for obtaining a timely ILD diagnosis based on the experiences and perceptions of both patients and healthcare professionals., Method: Semi-structured qualitative interviews were conducted with Danish ARD-ILD patients, rheumatologists, pulmonologists and ILD nurses., Results: Sixteen patients, six rheumatologists, three ILD nurses and three pulmonologists participated. Five characteristics of diagnostic trajectories were identified in the patient interviews: 1) early referral to lung specialists; 2) early delay; 3) delay or shortcut depending on specific circumstances; 4) parallel diagnostic trajectories connected late in the process; 5) early identification of lung involvement without proper interpretation. With the exception of early referral to lung specialists, all of the diagnostic trajectory characteristics identified led to delayed diagnosis. Delayed diagnostic trajectories resulted in patients experiencing increased uncertainty. Inconsistent disease terminology, insufficient knowledge and lack of awareness of ARD-ILD among central healthcare professionals and delayed referral to ILD specialists were main contributors to the diagnostic delay identified by the informants., Conclusion: Five characteristics of the diagnostic trajectories were identified, four of which led to diagnostic delay of ARD-ILD. Improved diagnostic trajectories can shorten the diagnostic trajectory and increase early access to appropriate specialist medical care. Improved awareness and expertise in ARD-ILD across different medical specialties, especially among GPs, may contribute to more efficient and timely diagnostic trajectories and improved patient experiences., Competing Interests: EB reports unrestricted grants, a fee for educational activities and advisory board meetings from Boehringer Ingelheim and Hoffmann-la-Roche outside this work and a fee for educational activities from Chiesi and Astra Zeneca. SBS reports a fee for lectures and educational activities from Boehringer Ingelheim and Astra Zeneca. Boehringer Ingelheim was given the opportunity to review the manuscript for medical as well as scientific accuracy and intellectual property considerations, if applicable., (© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

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.

Rheumatoid arthritis (RA) affects more than 30,000 Danes. In this review, we discuss RA in connection with chronic obstructive pulmonary disease (COPD), bronchiectasis and interstitial lung disease (ILD) which are among the most common lung manifestations and are associated with increased mortality. Early suspicion based upon respiratory symptoms should prompt imaging and pulmonary function test. Smoking cessation, vaccination, and rehabilitation are important. COPD and bronchiectasis are treated according to guidelines. Multidisciplinary collaboration in RA-ILD is important and treatment decisions are based on clinical experience and imaging suggesting an inflammatory or fibrotic phenotype.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease for which two effective antifibrotics, nintedanib and pirfenidone, are available. However, many patients receive a reduced dosage or pause treatment due to side effects although the impact of antifibrotic treatment reduction is uncertain., Methods: We retrospectively investigated the impact of antifibrotic treatment reduction on death in a large real-life IPF cohort. The primary endpoint of the analyses was time until death by any cause. Five patient groups were defined based on treatment intensity (full, reduced or no treatment) and the antifibrotic drug type (pirfenidone or nintedanib). Between group survival was compared using Cox proportional hazards analysis adjusted for age, sex, smoking status, and lung function at baseline., Results: 375 patients from the Danish PFBIO-cohort were followed from April 2016 until November 2021 with a median follow-up time of 1.84 years. Of patients receiving nintedanib and pirfenidone, 80.19% and 67.42% had reduced treatment, respectively, when considering the entire follow-up period. Treatment with nintedanib and pirfenidone was associated with improved survival compared to no antifibrotic treatment independent of treatment intensity (nintedanib: HR: 0.31, 95%-CI: 0.19-0.53, p &lt; 0.001 & pirfenidone: HR: 0.26, 95%-CI: 0.16-0.42, p &lt; 0.001). Nintedanib and pirfenidone in lower intensities were not associated with worse survival outcomes., Conclusion: A substantial proportion of patients with IPF receive reduced antifibrotic treatment to ameliorate the side effects associated with a full dosage regime. Treatment with nintedanib and pirfenidone, independent of treatment intensity, was preferable over no antifibrotic treatment in improving survival and reduced dose appears to be a good alternative if full dose is not tolerated., Competing Interests: Declaration of competing interest SP reports unrestricted research grants from Aase og Ejnar Danielsens Fond, Roche and Skibsreder Per Henriksen, R. og Hustrus Fond. NH reports unrestricted research grants from Aase og Ejnar Danielsens Fond, Roche and Skibsreder Per Henriksen, R. og Hustrus Fond. SBS reports participation in advisory board meetings for Boehringer Ingelheim and Roche, receiving support for participation in scientific meetings from Boehringer Ingelheim and lecture fees from Boehringer Ingelheim and Astra Zeneca …, (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The diagnosis of idiopathic pulmonary fibrosis (IPF) is often delayed up to several years. The objective of this study was to assess the impact of the diagnostic delay on progression-free survival, quality of life and hospitalisation rates., Methods: A total of 264 incident patients with IPF were included immediately after their diagnosis and followed for up to 5 years, with regular collection of clinical data, quality-of-life questionnaires and assessment of disease progression. Hospitalisation data were extracted from electronic patient records. Analyses were performed on the entire cohort and strata according to forced vital capacity (FVC) at diagnosis., Results: A long diagnostic delay (>1 year) was associated with worse progression-free survival compared with a short diagnostic delay (<1 year) (HR: 1.70, 95% CI: 1.18 to 2.46, p=0.004) especially in patients with mild disease at the time of diagnosis (FVC>80% predicted). Mean total scores of the St. George's respiratory questionnaire (SGRQ), a derived IPF-specific version of the SGRQ and the chronic obstructive pulmonary disease assessment test (CAT) were consistently higher in patients with long diagnostic delays, indicating worse quality of life. Mean hospitalisation rates were higher during the first year after diagnosis (Incidence rate ratio [IRR]: 3.28, 95% CI: 1.35 to 8.55, p=0.01) and during the entire follow-up (IRR: 1.74, 95% CI: 1.01 to 3.02, p=0.04)., Conclusion: A diagnostic delay of more than 1 year negatively impacts progression-free survival, quality of life and hospitalisation rates in patients with IPF. These findings highlight the importance of an early diagnosis for proper management of IPF., Trial Registration Number: NCT02755441., Competing Interests: Competing interests: NH reports unrestricted research grants from Aase og Ejnar Danielsens Fond, Roche and Skibsreder Per Henriksen, R. og Hustrus Fond. TSP reports an unrestricted research grant from Boehringer Ingelheim, contact with Galapagos and consulting fees from Boehringer Ingelheim. EB reports payment for presentations from Boehringer Ingelheim, Hofmann la Roche, Galapagos and Astra Zeneca, support for attending meetings from Boehringer Ingelheim and Hofmann la Roche, and participation in advisory boards for Boehringer Ingelheim and Hofmann la Roche. SBS reports payment for presentations from Boehringer Ingelheim and Roche, support for attending meetings from Boehringer Ingelheim, and participation in advisory board for Boehringer Ingelheim., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate incidence and prevalence of Systemic Sclerosis (SSc) and association with interstitial lung disease (SSc-ILD) in a nationwide population-based study., Methods: Patients with an incident diagnosis of SSc in 2000-2016 were identified in the Danish National Patient Registry and categorised based on diagnosis of ILD. Incidence- and prevalence proportions were calculated based on the annual population estimates. A cox proportional hazards model was used to evaluate the association between age, sex, region and marital status and presence of ILD., Results: In total, 1869 patients with SSc were identified; 275 patients (14.7%) had SSc-ILD. The majority of patients were females (75.5%). The percentage of males was higher in SSc-ILD than in SSc alone (30.9% and 23.4%, p = 0.008). Median time from SSc to ILD diagnosis was 1.4 years (range 0-14.2). ILD was diagnosed from ≤4 years before to ≥7 years after SSc. Development of ILD was associated with male gender (HR 1.75, 95% CI 1.15-2.66), age 41-50 (HR 1.81, 95% CI 1.07-3.05) and residency in the North Denmark Region (HR 1.95, 9 5% CI 1.12-3.40). Mean annual incidence proportion of SSc was 2.9/100,000 and mean annual prevalence proportion was 16.8/100,000. The incidence remained stable, but prevalence proportion increased from 14.1 - 16.5/100,000 in 2000-2008 to 17.9-19.2/100,000 in 2009-2016., Conclusion: The prevalence of SSc increased during the study period, while the incidence remained stable. The prevalence of SSc-ILD was 14.7% and thus less frequent than expected. Male sex and age between 41 and 50 years were associated with ILD.

Background: Remodeling of the extracellular matrix (ECM) is a central mechanism in the progression of idiopathic pulmonary fibrosis (IPF), and remodeling of type VI collagen has been suggested to be associated with disease progression. Biomarkers that reflect and predict the progression of IPF would provide valuable information for clinicians when treating IPF patients., Methods: Two serological biomarkers reflecting formation (PRO-C6) and degradation (C6M) of type VI collagen were evaluated in a real-world cohort of 178 newly diagnoses IPF patients. All patients were treatment naïve at the baseline visit. Blood samples and clinical data were collected from baseline, six months, and 12 months visit. The biomarkers were measured by competitive ELISA using monoclonal antibodies., Results: Patients with progressive disease had higher (P = 0.0099) serum levels of PRO-C6 compared to those with stable disease over 12 months with an average difference across all timepoints of 12% (95% CI 3-22), whereas C6M levels tended (P = 0.061) to be higher in patients with progressive disease compared with stable patients over 12 months with an average difference across all timepoints of 12% (95% CI - 0.005-27). Patients who did not receive antifibrotic medicine had a greater increase of C6M (P = 0.043) compared to treated patients from baseline over 12 months with an average difference across all timepoints of 12% (95% CI - 0.07-47). There were no differences in biomarker levels between patients receiving pirfenidone or nintedanib., Conclusions: Type VI collagen formation was related to progressive disease in patients with IPF in a real-world cohort and antifibrotic therapy seemed to affect the degradation of type VI collagen. Type VI collagen formation and degradation products might be potential biomarkers for disease progression in IPF., (© 2021. The Author(s).)

Background: Health-related quality of life (HRQL) is impaired in patients with idiopathic pulmonary fibrosis (IPF). HRQL is often measured using the St. George's Respiratory Questionnaire (SGRQ) despite the development of an IPF-specific version (SGRQ-I). Using data from a real-world cohort of patients with IPF, we aimed to transform SGRQ into a derived version of SGRQ-I, SGRQ-I der , to examine the cross-sectional and longitudinal validity of SGRQ-I der and to compare SGRQ-I der to SGRQ-I., Methods: Based on results from SGRQ, SGRQ-I der was derived applying the algorithm used to develop SGRQ-I. Of the 50 items in SGRQ, 34 items were retained in SGRQ-I der . Response options for seven items were collapsed and minor adjustments were made to the weights of two items after correspondence with the developers of SGRQ-I. Cross-sectional validation, responsiveness and minimal clinically important difference (MCID) were assessed by comparison to other HRQL instruments, pulmonary function tests and 6-min walk test performed at baseline, 6 and 12 months. Furthermore, the association between SGRQ-I der scores and mortality was examined., Results: A total of 150 IPF patients participated and 124 completed follow-up at 12 months. SGRQ-I der performed comparably to SGRQ-I with a high concurrent validity, good test-retest reliability and high known-groups validity. SGRQ-I der was responsive to change in HRQL and physiological anchors. MCID of SGRQ-I der for improvement and deterioration was 3.5 and 5.7, respectively. SGRQ-I der scores were associated with mortality in both univariate (HR 1.82, 95% CI 1.42-2.34 per 20-point increase) and multivariate analyses (HR 1.57, 95% CI 1.20-2.05 per 20-point increase)., Conclusions: The SGRQ-I der is a valid, reliable and responsive HRQL instrument in patients with IPF and has psychometric properties comparable to SGRQ-I. Thus, SGRQ results can reliably be transformed into the SGRQ-I der . The MCID estimates were calculated for improvement and deterioration separately. Increasing SGRQ-I der score was associated with increased mortality., (© 2021. The Author(s).)

Introduction: Comorbidities are common in patients with idiopathic pulmonary fibrosis (IPF) and negatively impact health-related quality of life, health-care costs and mortality. Retrospective studies have focused on individual comorbidities, but clusters of multiple comorbidities have rarely been analysed. This study aimed to comprehensively and prospectively assess comorbidities in a multicentre, real-world cohort of patients with IPF, including prespecified conditions of special interest and to analyse clusters of comorbidities and examine characteristics, disease course and mortality of the clusters., Methods: Several measurements, questionnaires, medications and medical history were combined to assess comorbidities. Using self-organizing maps, clusters of comorbidities were identified and phenotypes characterized. Disease course was assessed using mixed effects models and mortality using Cox regression., Results: One-hundred and fifty IPF patients were included prospectively. All except one patient suffered from at least one comorbidity and multimorbidity was common. Arterial hypertension, gastro-oesophageal reflux disease, hypercholesterolemia, emphysema and obstructive sleep apnea were most prevalent. Four comorbidity clusters were identified. Each cluster had distinct comorbidity profiles, patient characteristics, symptom burden and disease severity. Patients with fewer comorbidities had better exercise capacity and less dyspnea at baseline, but a trend towards faster deterioration was observed. Mortality analyses showed no significant differences between clusters., Conclusions: Multimorbidity is prevalent in patients with IPF. Four specific clusters of comorbidities may represent phenotypes in IPF. A trend towards faster decline in exercise capacity and dyspnea was observed in patients with fewer comorbidities. Increased knowledge of comorbidities facilitates prevention and treatment of comorbidities in patients with IPF., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of fibrillar collagens in the alveolar space resulting in reduced pulmonary function and a high mortality rate. Biomarkers measuring the turnover of type I and III collagen could provide valuable information for prognosis and treatment decisions in IPF., Methods: Serological biomarkers reflecting the formation of type III collagen (PRO-C3) and degradation of type I (C1M) and III collagen (C3M) were evaluated in a real-world cohort of 178 newly diagnosed IPF patients. Blood samples and clinical data were collected at baseline, six, and 12 months. Baseline and longitudinal biomarker levels were related to disease progression of IPF (defined as ≥ 5% decline in forced vital capacity (FVC) and/or ≥ 10% decline in diffusing capacity for carbon monoxide (DLco) and/or all-cause mortality at 12 months). Furthermore, we analysed differences in percentage change of biomarker levels from baseline between patients receiving antifibrotic treatment or not., Results: Increased baseline levels of type I and III collagen turnover biomarkers were associated with a greater risk of disease progression within 12 months compared to patients with a low baseline type I and III collagen turnover. Patients with progressive disease had higher serum levels of C1M (P = 0.038) and PRO-C3 (P = 0.0022) compared to those with stable disease over one year. There were no differences in biomarker levels between patients receiving pirfenidone, nintedanib, or no antifibrotics., Conclusion: Baseline levels of type I and III collagen turnover were associated with disease progression within 12 months in a real-world cohort of IPF patients. Longitudinal biomarker levels of type I and III collagen turnover were related to progressive disease. Moreover, antifibrotic therapy did not affect type I and III collagen turnover biomarkers in these patients. PRO-C3 and C1M may be potential biomarkers for a progressive disease behavior in IPF., (© 2021. The Author(s).)

Background and Objective: Prediction of idiopathic pulmonary fibrosis (IPF) progression is vital for the choice and timing of treatment and patient follow-up. This could potentially be achieved by prognostic blood biomarkers of extracellular matrix (ECM) remodelling., Methods: Neoepitope biomarkers of types III and VI collagen turnover (C3M, C6M, PRO-C3 and PRO-C6) were measured in 185 patients with newly diagnosed IPF. Disease severity at baseline and progression over 6 months was assessed by lung function tests and 6-min walk tests. All-cause mortality was assessed over a 3-year follow-up period., Results: High baseline levels of C3M, C6M, PRO-C3 and PRO-C6 were associated with more advanced disease at the time of diagnosis. Baseline levels of C6M and PRO-C3 were also associated with mortality over 3 years of follow-up (hazard ratio [HR]: 2.3, 95% CI: 1.3-3.9, p = 0.002 and HR: 1.8, 95% CI: 1.1-3.0, p = 0.03). Patients with several increased biomarkers at baseline, representing a high ECM remodelling phenotype, had more advanced disease at baseline, higher risk of progression or death at 6 months (OR: 1.4, 95% CI: 1.1-1.8, p = 0.002) and higher mortality over 3 years of follow-up (HR: 2.4, 95% CI: 1.3-4.5, p = 0.007)., Conclusion: Blood biomarkers of types III and VI collagen turnover, assessed at the time of diagnosis, are associated with several indices of disease severity, short-term progression and long-term mortality. These biomarkers can help to identify patients with a high ECM remodelling phenotype at high risk of disease progression and death., (© 2021 Asian Pacific Society of Respirology.)

Objectives: MTX is the most commonly recommended DMARD for first-line treatment of RA, however, it has been hypothesized to cause lung disease as an adverse effect. We investigated the risk of interstitial lung disease (ILD) and acute and chronic respiratory failure in persons with RA treated with MTX and other medications., Methods: From the Danish National Patient Register (NPR) and the DANBIO register for rheumatic diseases, we retrieved data on 30 512 persons with RA registered in 1997-2015. Information on ILD and respiratory failure was obtained from the NPR. Information on age and sex for all Danish citizens was obtained from the Danish Civil Registration System. MTX and other medication purchases were retrieved from the Danish Prescription Registry. Associations between MTX and lung disease outcomes were analysed in Cox regression models with adjustment for age, calendar time, sex and other medications. Standardized incidence ratios (SIRs) of lung disease were calculated to compare the RA population with the general population., Results: There was no increased risk of lung disease with MTX treatment [one or more purchases compared with no purchases; HR 1.00 (95% CI 0.78, 1.27) for ILD and 0.54 (95% CI 0.43, 0.67) for respiratory failure] at the 5 year follow-up. The SIR was three to four times higher for ILD in MTX-treated persons with RA, but similar to the whole RA population compared with the background population., Conclusion: Persons with RA had an increased risk of ILD compared with the general population, but there was no further increased risk associated with MTX treatment., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: There is an urgent need for treatments that can shorten hospitalization and lower the risk of secondary infection and death in patients with corona disease. The ProPac-COVID trial evaluates whether combination therapy with macrolide azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy, and pre-emptive treatment of supra-infections can shorten hospitalization duration and reduce the risk of non-invasive ventilation, treatment in the intensive care unit, and death in patients with acute hospital admission and a positive test for 2019-nCoV and symptoms of COVID-19 disease., Methods: The ProPAC-COVID is a multi-center, randomized, placebo-controlled, double-blinded clinical trial. The primary outcome is number of days spent alive and out of hospital within 14 days from randomization. Randomization will be in blocks of unknown size, and the final allocation will be stratified for age, site of recruitment, and whether the patient has any chronic lung diseases. Data is analyzed using intention-to-treat (ITT) principles, and main analyses will also be subject to modified ITT analysis and per protocol analysis., Discussion: This paper describes the detailed statistical analysis plan for the evaluation of primary and secondary endpoints of the ProPAC-COVID study. Enrolment of patients to the ProPAC-COVID study is still ongoing. The purpose of this paper is to provide primary publication of study results to prevent selective reporting of outcomes, data-driven analysis, and to increase transparency., Trial Registration: ClinicalTrials.gov NCT04322396 . Registered on 26 March 2020.

Background: Idiopathic pulmonary fibrosis (IPF) specific version of St. George's Respiratory Questionnaire (SGRQ-I) and King's Brief Interstitial Lung Disease questionnaire (K-BILD) are validated health-related quality of life (HRQL) instruments, but no or limited data exist on their responsiveness and minimal clinically important difference (MCID). The objectives of this study were to assess responsiveness of SGRQ-I and K-BILD and determine MCID separately for deterioration and improvement in a large, prospective cohort of patients with IPF in a real-world setting., Methods: Consecutive patients with IPF were recruited. SGRQ-I, K-BILD, SGRQ, Shortness of Breath Questionnaire, pulmonary function tests and 6-min walk test measurements were obtained at baseline and at six and 12 months; at six and 12 months, patients also completed Global Rating of Change Scales. Responsiveness was assessed using correlation coefficients and linear regression. Cox regression was used for mortality analyses. MCID was estimated using receiver operating characteristic curves with separate analyses for improvement and deterioration., Results: A total of 150 IPF patients were included and 124 completed the 12-month follow-up. Based on all HRQL anchors and most physiological anchors, responsiveness analyses supported the evidence pointing towards SGRQ-I and K-BILD as responsive instruments. Multivariate analyses showed an association between SGRQ-I and mortality (HR: 1.18, 95% CI: 1.02 to 1.36, p = 0.03) and a trend was found for K-BILD (HR: 0.82, 95% CI: 0.64 to 1.05, p = 0.12). MCID was estimated for all domains of SGRQ-I and K-BILD. MCID for improvement differed from deterioration for both SGRQ-I Total (3.9 and 4.9) and K-BILD Total (4.7 and 2.7)., Conclusions: SGRQ-I and K-BILD were responsive to change concerning both HRQL and most physiological anchors. MCID was determined separately for improvement and deterioration, resulting in different estimates; especially a smaller estimate for deterioration compared to improvement in K-BILD., Trial Registration: Clinicaltrials.gov, no. NCT02818712. Registered 30 June 2016.

Background: Interstitial lung abnormalities (ILA) are common in participants of lung cancer screening trials and broad population-based cohorts. They are associated with increased mortality, but less is known about disease specific morbidity and healthcare utilisation in individuals with ILA., Methods: We included all participants from the screening arm of the Danish Lung Cancer Screening Trial with available baseline CT scan data (n = 1990) in this cohort study. The baseline scan was scored for the presence of ILA and patients were followed for up to 12 years. Data about all hospital admissions, primary healthcare visits and medicine prescriptions were collected from the Danish National Health Registries and used to determine the participants' disease specific morbidity and healthcare utilisation using Cox proportional hazards models., Results: The 332 (16.7%) participants with ILA were more likely to be diagnosed with one of several respiratory diseases, including interstitial lung disease (HR: 4.9, 95% CI: 1.8-13.3, p = 0.008), COPD (HR: 1.7, 95% CI: 1.2-2.3, p = 0.01), pneumonia (HR: 2.0, 95% CI: 1.4-2.7, p <  0.001), lung cancer (HR: 2.7, 95% CI: 1.8-4.0, p <  0.001) and respiratory failure (HR: 1.8, 95% CI: 1.1-3.0, p = 0.03) compared with participants without ILA. These findings were confirmed by increased hospital admission rates with these diagnoses and more frequent prescriptions for inhalation medicine and antibiotics in participants with ILA., Conclusions: Individuals with ILA are more likely to receive a diagnosis and treatment for several respiratory diseases, including interstitial lung disease, COPD, pneumonia, lung cancer and respiratory failure during long-term follow-up.

Background: Health-related quality of life (HRQL) is impaired in patients with idiopathic pulmonary fibrosis (IPF). The King's Brief Interstitial Lung Disease questionnaire (K-BILD) is a validated measure of HRQL, but no previous studies have focused on the validity of K-BILD in IPF. Moreover, the relationship between K-BILD and dyspnoea or the 6-min walk test (6MWT) has not been assessed. The aim of this study was to validate K-BILD in the largest cohort of patients with IPF to date and assess how K-BILD correlates to dyspnoea and 6MWT., Methods: Firstly, K-BILD was translated into Danish using validated translation procedures. Consecutive patients with IPF were recruited. At baseline, patients completed K-BILD, the IPF-specific version of St. Georges Respiratory Questionnaire, University of California, San Diego Shortness of Breath Questionnaire (SOBQ) Short Form-36, and pulmonary function tests and 6MWT were performed. After 14 days, K-BILD and Global Rating of Change Scales were completed. Internal consistency, concurrent validity, test-retest reliability and known groups validity were assessed. Analyses were also performed in subgroups of patients with different time since diagnosis., Results: At baseline, 150 patients with IPF completed the questionnaires, and 139 patients completed the questionnaires after 14 days. K-BILD had a high internal consistency (Cronbach's α = 0.92). The concurrent validity was strong compared to SOBQ (r = - 0.66) and moderate compared to 6MWT (r = 0.43). Intraclass correlation coefficients (ICC = 0.91) and a Bland Altman plot demonstrated a good reliability. K-BILD was also able to discriminate between patients with different stages of disease (p < 0.002, Δscore > 7.4) and most results were comparable in patients with different time since diagnosis., Conclusion: K-BILD is a valid and reliable instrument in patients with IPF and in patients with different time since diagnosis. To a major extent, K-BILD scores reflected the impact of dyspnoea on HRQL and the impact of physical functional capacity measured by the 6MWT to a moderate degree. Compared to PFTs alone, K-BILD provides additional information on the burden of living with IPF, and importantly, K-BILD is simple to implement in both research and clinical contexts., Trial Registration: Clinicaltrials.org (NCT02818712) on 30 June 2016.

Background: Patients with idiopathic pulmonary fibrosis (IPF) have impaired health-related quality of life (HRQL). To measure HRQL, an IPF-specific version of the St. George's Respiratory Questionnaire (SGRQ-I) was developed, but not sufficiently validated. This study aimed to assess the validity (i.a. known-groups validity and concurrent validity) and test-retest reliability of SGRQ-I in IPF patients with different disease durations., Methods: Patients with IPF were consecutively recruited and completed SGRQ, SGRQ-I, King's Brief Interstitial Lung Disease questionnaire (K-BILD), University of California, San Diego Shortness of Breath Questionnaire (SOBQ) and Short Form-36 (SF-36) along with pulmonary function tests and a 6-min walk test (6MWT) at baseline. After two weeks, SGRQ-I and Global Rating of Change Scales (GRCS) were completed., Results: At baseline and after two weeks, 150 and 134 patients completed the questionnaires, respectively. The internal consistency of SGRQ-I was high (Cronbach's α = 0.92). Good concurrent validity was demonstrated by high intraclass correlation coefficients (ICC = 0.97), Bland-Altman plots and moderate to strong correlations to K-BILD, SOBQ and SF-36 (r = - 0.46 to 0.80). High ICC (0.92) and a Bland-Altman plot indicated good test-retest reliability. SGRQ-I was good at discriminating between patients with different stages of disease (Δscore > 18.1, effect sizes > 0.10). Validity was similar across groups of different disease duration., Conclusions: SGRQ-I proved to be valid at distinguishing between different disease severities, valid compared to other HRQL instruments, applicable across different disease durations and reliable upon repetition. SGRQ-I is a valid option for measuring HRQL in patients with IPF., Trial Registration: The study was registered at clinicaltrials.org ( NCT02818712 ) on 15 June 2016.

Background: Surveys and retrospective studies of patients with idiopathic pulmonary fibrosis (IPF) have shown a significant diagnostic delay. However, the causes and risk factors for this delay are not known., Methods: Dates at six time points before the IPF diagnosis (onset of symptoms, first contact to a general practitioner, first hospital contact, referral to an interstitial lung disease (ILD) centre, first visit at an ILD centre, and final diagnosis) were recorded in a multicentre cohort of 204 incident IPF patients. Based on these dates, the delay was divided into specific patient-related and healthcare-related delays. Demographic and clinical data were used to determine risk factors for a prolonged delay, using multivariate negative binomial regression analysis., Results: The median diagnostic delay was 2.1 years (IQR: 0.9-5.0), mainly attributable to the patients, general practitioners and community hospitals. Male sex was a risk factor for patient delay (IRR: 3.84, 95% CI: 1.17-11.36, p = 0.006) and old age was a risk factor for healthcare delay (IRR: 1.03, 95% CI: 1.01-1.06, p = 0.004). The total delay was prolonged in previous users of inhalation therapy (IRR: 1.99, 95% CI: 1.40-2.88, p <  0.0001) but not in patients with airway obstruction. Misdiagnosis of respiratory symptoms was reported by 41% of all patients., Conclusion: Despite increased awareness of IPF, the diagnostic delay is still 2.1 years. Male sex, older age and treatment attempts for alternative diagnoses are risk factors for a delayed diagnosis of IPF. Efforts to reduce the diagnostic delay should focus on these risk factors., Trial Registration: This study was registered at http://clinicaltrials.gov (NCT02772549) on May 10, 2016.

Background: Chest x-ray is central in screening and diagnosis of tuberculosis. However, sputum culture remains gold standard for diagnosis., Aim: To establish the rate of normal chest x-rays in tuberculosis patients found by spot sputum culture screening, and compare them to a group identified through passive case finding., Method: Chest x-rays from 39 culture-positive patients, identified by spot sputum culture screening in Copenhagen from 2012 to 2014, were included in the study (spot sputum culture group(SSC)). 39 normal chest x-rays from persons screened by mobile x-ray, and 39 chest x-rays from tuberculosis-patients identified through passive case finding(PCF) were anonymised and randomised. Two respiratory physicians and two radiologists assessed the chest x-rays., Results: The normal chest x-ray rate was higher in the non-tuberculosis control group (median = 32 (82.1%), range = 74.4% - 100%), compared to the SSC group (median = 7 (17.9%), range = 10.3% - 33.3%), and the PCF controls (median = 3(7.7%), range = 2.6% - 15.4%). In the SSC group 14 (35.9%) were categorized as normal by at least one study participant., Conclusion: A substantial minority of patients diagnosed with tuberculosis by spot sputum culture screening, and through passive case finding would not have been identified with chest x-ray alone, highlighting that a normal chest x-ray does not exclude pulmonary tuberculosis., (© 2019 The Authors. Published by Elsevier Ltd.)

Introduction: Fibrotic interstitial lung disease (f-ILD) comprises a group of diseases with lung scarring and reduced life expectancy. The short time from diagnosis to death affects the patients' bereaved spouses, who risk developing prolonged grief. In Denmark palliative care is most often offered to cancer patients., Aim: We aimed to investigate the experience of spouses of f-ILD patients during the final stages of illness and up to the first year after the patient's death to investigate if palliative care could ease the transition and prevent PGD., Methods: Our study had a qualitative design triangulating in-depth interviews, field notes, participant diaries and the prolonged grief questionnaire PG-13. We included 20 spouses and applied thematic analysis. Initial coding was performed deductively according to the chronological stages of before, during and after the death of the patient. We subsequently coded inductively within the stages., Results: During the final days the spouses experienced emotional ambivalence shifting between hope, acceptance and despair. Factors affecting the spouses during the final hours were the timing, location, and process of death. After the patient's death the spouses experienced feelings of grief and optimism as they moved toward a new life on their own., Conclusions: Some of the factors affecting the spouses and potentially causing prolonged grief might be alleviated by offering palliative/supportive care and advance care planning to f-ILD patients and their family., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic disease with high morbidity and mortality. A reliable and manageable questionnaire that assesses patients' quality of life is needed to help to improve the content of clinical consultations. The chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) is used in clinical practice; therefore, the aim of this study was to investigate correlations among the CAT, St. George's Respiratory Questionnaire (SGRQ) and clinical parameters among patients diagnosed with IPF. Methods: A retrospective cohort design was employed in which 87 patients diagnosed with IPF who were receiving treatment at an outpatient clinic were included. Results: The CAT was found to be significantly correlated with SGRQ ( p < 0.001). Furthermore, the CAT was significantly correlated with all of the included physiological variables. Conclusions: This add to support the validity of the COPD Assessment test (CAT) as a measure of symptoms in patients with IPF which in clinical practice in combination with dialogue between healthcare professionals and the patient, can help to improve the content of a clinical consultation.

Background:  Chronic non-malignant lung diseases such as chronic obstructive pulmonary disease (COPD) and interstitial lung diseases (ILD) result in reduced quality of life (QoL), a high symptom burden and reduced survival. Patients with chronic non-malignant lung disease often have limited access to palliative care. The symptom burden and the QoL of these patients resembles patients with cancer and the general palliative approach is similar. However, the disease trajectory is often slow and unpredictable, and the palliative effort must be built on accessibility, continuity and professional competences. The Danish Health Authority as well as the WHO recommends that there is access to palliative care for all patients with life-threatening diseases regardless of diagnosis. In 2011, the Danish Health Authority requested that the national medical societies would to formulate guidelines for palliation. Methods: In 2015, a group of members of the Danish Respiratory Society (DRS) was appointed for this purpose. It was composed of experienced ILD and COPD researchers as well as clinicians from different parts of Denmark. A literature review was made, a draft was prepared, and all recommendations were agreed upon unanimously. Results: The Danish version of the position paper was finally submitted for review and accepted by all members of DRS. Conclusion: In this position paper we provide recommendations on the terminology of chronic and terminal lung failure, rehabilitation and palliative care, advanced care planning, informal caregivers and bereavement, symptom management, the imminently dying patient, and organization of palliative care for patients with chronic non-malignant lung diseases.

Asbestos was used in numerous products until its total ban in Denmark in 1988. The prevalence of asbestosis and pleural plaques does not yet appear to be falling. Unfortunately the statistics are unreliable due to errors in the Danish translation of the ICD-10 codes of the disease. In this review, clinical and radiologic diagnostic criteria of asbestosis and pleural plaques and recommendations for follow-up of patients are described. Typical changes on a high-resolution CT scan combined with relevant asbestos exposure is essential for the diagnosis. Asbestosis and pleural plaques are both notifiable in Denmark.

Objective: The aim of this study was to investigate whether smokers with incidental findings of interstitial lung abnormalities have an increased mortality during long-term follow-up, and review the contributing causes of death., Methods: Baseline CT scans of 1990 participants from the Danish Lung Cancer Screening Trial were qualitatively assessed for predefined interstitial lung abnormalities of any severity. Inclusion criteria for this lung cancer screening trial included current or former smoking, > 20 pack-years, and age 50-70 years. Patients were followed up for up to 12 years., Results: We found interstitial lung abnormalities in 332 participants (16.7%). Interstitial lung abnormalities were associated with increased all-cause mortality in the full cohort (HR: 2.0, 95% CI: 1.4-2.7, P < 0.001) and in lung cancer-free participants (HR: 1.6, 95% CI: 1.1-2.4, P = 0.007). The findings were associated with death from lung cancer (HR: 3.2, 95% CI: 1.7-6.2, P < 0.001) and non-pulmonary malignancies (HR: 2.1, 95% CI: 1.1-4.0, P = 0.02). Participants with fibrotic and non-fibrotic interstitial lung abnormalities had similar survival., Conclusion: Interstitial lung abnormalities were common in this lung cancer screening population of relatively healthy smokers and were associated with mortality regardless of the interstitial morphological phenotype. The increased mortality was partly due to an association with lung cancer and non-pulmonary malignancies., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Pirfenidone was approved by the European Medicines Agency and introduced in most European countries in 2011 for treatment of idiopathic pulmonary fibrosis (IPF)., Objective: To describe the national Danish experiences of pirfenidone treatment for IPF during 30 months with respect to target population, safety, adherence to the treatment and effect analysis in a well-characterised IPF population in a real-life setting., Methods: Retrospective data collection from medical records of all patients in Denmark with IPF from 2011 to 2014. Data included baseline demographics, high-resolution computed tomography (HRCT), histopathology, forced vital capacity (FVC) and 6-min walk test (6MWT). Longitudinal data on FVC, walk test, adherence to the treatment and vital status were also collected., Results: Pirfenidone treatment was initiated in 113 patients. Mean age was 69.6±8.1 years (±SD), and 71% were male. Definite IPF diagnosis required thoracoscopic lung biopsy in 45 patients (39.8%). The remaining 68 cases had a definite (64 patients) or possible usual interstitial pneumonia (four patients) pattern on HRCT. Patients were followed for 0.1-33.8 months (median 9.4 months). Fifty-one patients (45.2%) needed dose adjustment, 18 (16%) patients discontinued therapy and 13 patients (11.5%) died. The annual mean decline in FVC was 164 ml (SE 33.2). The decline in 6MWT was 18.2 m (SE 11.2). Nausea (44.2%), fatigue (38.9%) and skin reactions (32.7%) were frequent adverse events., Conclusion: Patients with IPF treated with pirfenidone experienced tolerable adverse events. Patients were maintained on treatment due to a careful follow-up and dose adjustment programme. The annual decline in physiological parameters and mortality rate was comparable to previous randomised controlled trials.

The disease course in idiopathic pulmonary fibrosis (IPF) is variable, but patients experience a progressive decline in lung function and increased symptom burden leading to death. Little is known about the patients' experience and their needs during the disease course or about the burden on family caregivers. Both patients and family caregivers face an altered life as the disease progresses. The aim of our study was to increase knowledge of life with IPF for patients and family caregivers.This study had a qualitative descriptive design using in-depth dyadic interviews with IPF patients (n=25) and family caregivers (n=24). We used the five-step analysis from the framework method and analysed the data on three levels: the patient, the family caregivers and couple level.The following six themes emerged as the main results: information and disclosure, reactional dyssynchrony, perpetual vigilance, emotional ambivalence, gradual and tacit role shift, and adapted coping strategies.Our findings suggest that IPF patients need information at the time of diagnosis, but some issues should be paced as the disease progresses. A palliation plan was demanded by patients and their caregivers. Further efforts are required to provide palliative care to IPF patients starting at the time of diagnosis., (Copyright ©ERS 2016.)

Objectives: Screening for lung cancer should be limited to a high-risk-population, and abnormalities in low-dose computed tomography (CT) screening images may be relevant for predicting the risk of lung cancer. Our aims were to compare the occurrence of visually detected emphysema and interstitial abnormalities in subjects with and without lung cancer in a screening population of smokers., Methods: Low-dose chest CT examinations (baseline and latest possible) of 1990 participants from The Danish Lung Cancer Screening Trial were independently evaluated by two observers who scored emphysema and interstitial abnormalities. Emphysema (lung density) was also measured quantitatively., Results: Emphysema was seen more frequently and its extent was greater among participants with lung cancer on baseline (odds ratio (OR), 1.8, p = 0.017 and p = 0.002) and late examinations (OR 2.6, p < 0.001 and p < 0.001). No significant difference was found using quantitative measurements. Interstitial abnormalities were more common findings among participants with lung cancer (OR 5.1, p < 0.001 and OR 4.5, p < 0.001).There was no association between presence of emphysema and presence of interstitial abnormalities (OR 0.75, p = 0.499)., Conclusions: Even early signs of emphysema and interstitial abnormalities are associated with lung cancer. Quantitative measurements of emphysema-regardless of type-do not show the same association., Key Points: • Visually detected emphysema on CT is more frequent in individuals who develop lung cancer. • Emphysema grading is higher in those who develop lung cancer. • Interstitial abnormalities, including discrete changes, are associated with lung cancer. • Quantitative lung density measurements are not useful in lung cancer risk prediction. • Early CT signs of emphysema and interstitial abnormalities can predict future risk.

Background: Emphysema is an important component of COPD; however, in previous studies of the correlation between airflow limitation (AFL) and computed tomography (CT) lung density as a surrogate for emphysema has varied. We hypothesised a good correlation between lung function (forced expiratory volume in first second [FEV 1 ]) and emphysema (15 th percentile density [PD15]) and that this correlation also exists between loss of lung tissue and decline in lung function even within the time frame of longitudinal studies of relatively short duration. Methods: We combined 2 large longitudinal studies (the Danish Lung Cancer Screening Trial [DLCST] and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints [ECLIPSE]) of smokers or former smokers, with a wide range of AFL and CT lung density, and analysed data from 2148 participants who did not change smoking habits and who had at least 2 CT scans and 2 FEV 1 measurements at least 3 years apart. Results: Baseline correlation between FEV 1 and PD15 was high (r=0.716, 95% confidence interval [CI]: 0.694-0.736, p <0.001) indicating that at least half of the variation in FEV 1 can be explained by variation in CT lung density. Correlation between the decline in FEV 1 and progression of PD15 was considerably weaker (r= 0.081, 95% CI: 0.038-0.122, p <0.001). Conclusions: Correlation is very high between lung density and lung function in a broad spectrum of smokers and ex-smokers. In contrast, the temporal associations ( slopes ) are weakly correlated, probably due to uncertainty in the estimation of slopes within a time frame of 3-4 years., Competing Interests: LHT received an unrestricted grant from the Danish Lung Association. RTS is an employee of GlaxoSmithKline. No other authors have conflicts of interest to declare.

Objectives: To evaluate interobserver agreement and time-trend in chest CT assessment of emphysema, airways, and interstitial abnormalities in a lung cancer screening cohort., Methods: Visual assessment of baseline and fifth-year examination of 1990 participants was performed independently by two observers. Results were standardised by means of an electronic score sheet; kappa and time-trend analyses were performed., Results: Interobserver agreement was substantial in early emphysema diagnosis; highly significant (p < 0.001) time-trends in both emphysema presence and grading were found (higher prevalence and grade of emphysema in late CT examinations). Significant progression in emphysema was seen in continuous smokers, but not in former smokers. Agreement on centrilobular emphysema subtype was substantial; agreement on paraseptal subtype, moderate. Agreement on panlobular and mixed subtypes was only fair. Agreement was fair regarding airway analysis. Interstitial abnormalities were infrequent in the cohort, and agreement on these was fair to moderate. A highly significant time-trend was found regarding interstitial abnormalities, which were more frequent in late examinations., Conclusions: Visual scoring of chest CT is able to characterise the presence, pattern, and progression of early emphysema. Continuous smokers progress; former smokers do not., Key Points: • Substantial interobserver consistency in determining early-stage emphysema in low-dose CT. • Longitudinal analyses show clear time-trends for emphysema presence and grading. • For continuous smokers, progression of emphysema was seen in all lung zones. • For former smokers, progression of emphysema was undetectable by visual assessment. • Onset and progression of interstitial abnormalities are visually detectable.

Progressive decline in lung function has been widely accepted as the hallmark of chronic obstructive pulmonary disease (COPD); however, recent evidence indicates that the rate of decline measured as decline in forced expiratory volume in one second (FEV1) is higher in mild to moderate COPD than in severe COPD. Usually changes in FEV1 are measured in ml that is "absolute"; however, changes can also be measured "relative" as a percentage of the actual FEV1. We hypothesize that relative measurements could be more appropriate than absolute measurements for describing changes in lung function. We analyzed data from 3,218 relatively healthy heavy smokers who participated in the Danish Lung Cancer Screening Trial. The influences of age, sex, height, body mass index, smoking, and severity of airflow limitation on FEV1 were analyzed in mixed effects models. In absolute terms those with the best lung function consistently showed the steepest decline, whereas in relative terms most fast decliners are found among those with low lung function. Measuring changes in relative terms implied statistically significant acceleration of decline with advancing age, smoking (pack-years) and severity of airflow limitation. Relative measurements may lead to a better understanding of changes in lung function. Smoking and severity of airflow limitation speed up the loss of lung function, and this emphasizes the importance of abstaining from smoking the sooner the better. Measuring changes in relative terms could have important implications for the interpretation of results from clinical trials where FEV1 is the primary outcome. DLCST; www.ClinicalTrials.org , registration number: NCT00496977.

Lung cancer screening trials provide an opportunity to study the natural history of emphysema by using computed tomography (CT) lung density as a surrogate parameter. In the Danish Lung Cancer Screening Trial, 2,052 participants were included. At screening rounds, smoking habits were recorded and spirometry was performed. CT lung density was measured as the volume-adjusted 15th percentile density (PD15). A mixed effects model was used with former smoking males with <30 pack-yrs and without airflow obstruction (AFO) at entry as a reference group. At study entry, 893 (44%) participants had AFO. For the reference group, PD15 was 72.6 g·L(-1) with an annual decline of -0.33 g·L(-1). Female sex and current smoking increased PD15 at baseline, 17.3 g·L(-1) (p<0.001) and 10 g·L(-1) (p<0.001), respectively; and both increased the annual decline in PD15 (female: -0.3 g·L(-1); current smoking: -0.4 g·L(-1)). The presence and severity of AFO was a strong predictor of low PD15 at baseline (Global Initiative for Chronic Obstructive Lung Disease (GOLD) I: -1.4 g·L(-1); GOLD II: -6.3 g·L(-1); GOLD III: -17 g·L(-1)) and of increased annual decline in PD15 (GOLD I: -0.2 g·L(-1); GOLD II: -0.5 g·L(-1); GOLD III: -0.5 g·L(-1)). Female sex, active smoking and the presence of AFO are associated with accelerated decline in lung density.

Introduction: Whether smoking-induced lung inflammation subsides after smoking cessation is currently a matter of debate. We used computed tomography (CT) to evaluate the effect of smoking cessation on lung density in patients with COPD., Material and Methods: Thirty-six patients quit smoking out of 254 current smokers with COPD who were followed with annual CT and lung function tests (LFT) for 2?4 years as part of a randomised placebo-controlled trial of the effect of inhaled budesonide on CT-lung density. Lung density was expressed as the 15th percentile density (PD15) and relative area of emphysema below -910 HU (RA-910). From the time-trends in the budesonide and placebo groups the expected CT-lung densities at the first visit after smoking cessation were calculated by linear regression and compared to the observed densities., Results: Following smoking cessation RA-910 increased by 2.6% (p = 0.003) and PD15 decreased by -4.9 HU (p = 0.0002). Furthermore, changes were larger in the budesonide group than the placebo group (PD15: -7.1 vs -2.8 HU. RA-910 3.7% vs 1.7%). These differences were, however, not statistically significant. The LFT parameters (FEV(1) and diffusion capacity) were not significantly influenced by smoking cessation., Conclusion: Inflammation partly masks the presence of emphysema on CT and smoking cessation results in a paradoxical fall in lung density, which resembles rapid progression of emphysema. This fall in density is probably due to an anti-inflammatory effect of smoking cessation.

Background: The effect of smoking cessation and smoking relapse on lung density was studied using low-dose CT., Methods: Spiral, multidetector, low-dose CT was performed on 726 current and former smokers (>20 pack-years) recruited from a cancer screening trial. Lung density was quantified by calculating the 15th percentile density (PD15), which was adjusted to predicted total lung capacity. Data were analysed by linear regression models., Results: At baseline mean PD15 was 45 g/l in former smokers (n=178) and 55 g/l in current smokers (n=548), representing a difference of 10 g/l (p<0.001). After smoking cessation (n=77) PD15 decreased by 6.2 g/l (p<0.001) in the first year, and by a further 3.6 g/l (p<0.001) in the second year, after which no further change could be detected. Moreover, the first year after relapse to smoking (n=18) PD15 increased by 3.7 g/l (p=0.02)., Conclusions: Current smoking status has a major influence on lung density assessed by CT, and the difference in lung density between current and former smokers observed in cross-sectional studies corresponds closely to the change in lung density seen in the years after smoking cessation. Current smoking status, and time since cessation or relapse, should be taken into account when assessing the severity of diseases such as emphysema by CT lung density.

Objective: We examined the reproducibility of lung nodule volumetry software that offers three different volumetry algorithms., Methods: In a lung cancer screening trial, 188 baseline nodules >5 mm were identified. Including follow-ups, these nodules formed a study-set of 545 nodules. Nodules were independently double read by two readers using commercially available volumetry software. The software offers readers three different analysing algorithms. We compared the inter-observer variability of nodule volumetry when the readers used the same and different algorithms., Results: Both readers were able to correctly segment and measure 72% of nodules. In 80% of these cases, the readers chose the same algorithm. When readers used the same algorithm, exactly the same volume was measured in 50% of readings and a difference of >25% was observed in 4%. When the readers used different algorithms, 83% of measurements showed a difference of >25%., Conclusion: Modern volumetric software failed to correctly segment a high number of screen detected nodules. While choosing a different algorithm can yield better segmentation of a lung nodule, reproducibility of volumetric measurements deteriorates substantially when different algorithms were used. It is crucial even in the same software package to choose identical parameters for follow-up.

A 71-year-old man was referred to the lung department with pain in the right side of the chest through three months, especially when physically active. The patient presented with a tendency to shortness of breath, fatigue, low energy level and night sweats. The tentative diagnosis of pleural tumour/metastases was made. Chest x-ray showed pleural thickening and poorly defined ribs on the right side, consistent with bone destruction. Computed tomography showed a big mass in the 5th rib and universal bone lesions. Biopsy from the rib revealed the diagnosis of myelomatosis.

We aim at improving quantitative measures of emphysema in computed tomography (CT) images of the lungs. Current standard measures, such as the relative area of emphysema (RA), rely on a single intensity threshold on individual pixels, thus ignoring any interrelations between pixels. Texture analysis allows for a much richer representation that also takes the local structure around pixels into account. This paper presents a texture classification-based system for emphysema quantification in CT images. Measures of emphysema severity are obtained by fusing pixel posterior probabilities output by a classifier. Local binary patterns (LBP) are used as texture features, and joint LBP and intensity histograms are used for characterizing regions of interest (ROIs). Classification is then performed using a k nearest neighbor classifier with a histogram dissimilarity measure as distance. A 95.2% classification accuracy was achieved on a set of 168 manually annotated ROIs, comprising the three classes: normal tissue, centrilobular emphysema, and paraseptal emphysema. The measured emphysema severity was in good agreement with a pulmonary function test (PFT) achieving correlation coefficients of up to |r| = 0.79 in 39 subjects. The results were compared to RA and to a Gaussian filter bank, and the texture-based measures correlated significantly better with PFT than did RA.

In this paper, a texton-based classification system based on raw pixel representation along with a support vector machine with radial basis function kernel is proposed for the classification of emphysema in computed tomography images of the lung. The proposed approach is tested on 168 annotated regions of interest consisting of normal tissue, centrilobular emphysema, and paraseptal emphysema. The results show the superiority of the proposed approach to common techniques in the literature including moments of the histogram of filter responses based on Gaussian derivatives. The performance of the proposed system, with an accuracy of 96.43%, also slightly improves over a recently proposed approach based on local binary patterns.

Assessment of emphysema-modifying therapy is difficult, but newer outcome measures offer advantages over traditional methods. The EXAcerbations and Computed Tomography scan as Lung End-points (EXACTLE) trial explored the use of computed tomography (CT) densitometry and exacerbations for the assessment of the therapeutic effect of augmentation therapy in subjects with alpha(1)-antitrypsin (alpha(1)-AT) deficiency. In total, 77 subjects (protease inhibitor type Z) were randomised to weekly infusions of 60 mg x kg(-1) human alpha(1)-AT (Prolastin) or placebo for 2-2.5 yrs. The primary end-point was change in CT lung density, and an exploratory approach was adopted to identify optimal methodology, including two methods of adjustment for lung volume variability and two statistical approaches. Other end-points were exacerbations, health status and physiological indices. CT was more sensitive than other measures of emphysema progression, and the changes in CT and forced expiratory volume in 1 s were correlated. All methods of densitometric analysis concordantly showed a trend suggestive of treatment benefit (p-values for Prolastin versus placebo ranged 0.049-0.084). Exacerbation frequency was unaltered by treatment, but a reduction in exacerbation severity was observed. In patients with alpha(1)-AT deficiency, CT is a more sensitive outcome measure of emphysema-modifying therapy than physiology and health status, and demonstrates a trend of treatment benefit from alpha(1)-AT augmentation.