The challenges of recruiting never-smokers with chronic obstructive pulmonary disease from the large population-based Swedish CArdiopulmonary bioImage study (SCAPIS) cohort.

Background: A substantial proportion of individuals with COPD have never smoked, and it is implied to be more common than previously anticipated but poorly studied. Aim: To describe the process of recruitment of never-smokers with COPD from a population-based cohort (n = 30 154). Methods: We recruited never-smokers with COPD, aged 50-75 years, from six University Hospitals, based on: 1) post broncho-dilator forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 0.70 and 2) FEV1 50-100% of predicted value and 3) being never-smokers (self-reported). In total 862 SCAPIS participants were identified, of which 652 were reachable and agreed to a first screening by telephone. Altogether 128 (20%) were excluded due to previous smoking or declined participation. We also applied a lower limit of normal (LLN) of FEV1/FVC (z-score<-1.64) according to the Global Lung Initiative to ensure a stricter definition of airflow obstruction. Results: Data on respiratory symptoms, health status, and medical history were collected from 492 individuals, since 32 were excluded at a second data review (declined or previous smoking), prior to the first visit. Due to not matching the required lung function criteria at a second spirometry, an additional 334 (68%) were excluded. These exclusions were by reason of: FEV1/FVC ≥0.7 (49%), FEV1 > 100% of predicted (26%) or z-score ≥ -1,64 (24%). Finally, 154 never-smokers with COPD were included: 56 (36%) women, (mean) age 60 years, FEV1 84% of predicted, FEV1/FVC: 0.6, z-score: -2.2, Oxygen saturation: 97% and BMI: 26.8 kg/m2. Conclusions: The challenges of a recruitment process of never-smokers with COPD were shown, including the importance of correct spirometry testing and strict inclusion criteria. Our findings highlight the importance of repeated spirometry assessments for improved accuracy in diagnosing COPD.

Clinical validation of the Swedish version of Dyspnoea-12 instrument in outpatients with cardiorespiratory disease.

Introduction: Breathlessness is the cardinal symptom in both cardiac and respiratory diseases, and includes multiple dimensions. The multidimensional instrument Dyspnoea-12 has been developed to assess both physical and affective components of breathlessness. This study aimed to perform a clinical validation of the Swedish version of Dyspnoea-12 in outpatients with cardiorespiratory disease. Methods: Stable outpatients with cardiorespiratory disease and self-reported breathlessness in daily life were recruited from five Swedish centres. Assessments of Dyspnoea-12 were performed at baseline, after 30-90 min and after 2 weeks. Factor structure was tested using confirmatory factor analysis and internal consistency using Cronbach's alpha. Test-retest reliability was analysed using intraclass correlation coefficients (ICCs). Concurrent validity at baseline was evaluated by examining correlations with lung function and several instruments for the assessment of symptoms and health status. Results: In total, 182 patients were included: with the mean age of 69 years and 53% women. The main causes of breathlessness were chronic obstructive pulmonary disease (COPD; 25%), asthma (21%), heart failure (19%) and idiopathic pulmonary fibrosis (19%). Factor analysis confirmed the expected underlying two-component structure with two subdomains. The Dyspnoea-12 total score, physical subdomain score and affective subdomain scores showed high internal consistency (Cronbach's alpha 0.94, 0.84 and 0.80, respectively) and acceptable reliability after 2 weeks (ICC total scores 0.81, 0.79 and 0.73). Dyspnoea-12 showed concurrent validity with the instruments modified Medical Research Council scale, COPD Assessment Test, European Quality of Life-Five Dimensions-Five levels, the Functional Assessment of Chronic Illness Therapy-Fatigue, the Hospital Anxiety and Depression Scale, and with forced expiratory volume in 1 s in percentage of predicted value. The results were consistent across different cardiorespiratory conditions. Conclusion: The Dyspnoea-12 is a valid instrument for multidimensional assessment of breathlessness in Swedish patients with cardiorespiratory diseases.

Delay and inequalities in the treatment of idiopathic pulmonary fibrosis: the case of two Nordic countries.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive loss of lung function with high mortality within the first 5 years from diagnosis. In 2011-2014, two drugs, pirfenidone and nintedanib, have been approved worldwide for prevention of IPF progression. National IPF-registries have been established in both Finland and Sweden. Our study explored potential differences in the care of IPF in these two countries. METHODS: Patients included consecutively in the Finnish and Swedish IPF-registries from January 1, 2014 through December 31, 2016 were included in the study. Data on demographics and lung function at the time of inclusion were collected. Access to antifibrotic drugs and data on disease outcomes, mortality and the proportion of patients who underwent lung transplantation, was collected during a 3-year follow up. RESULTS: One-hundred and fifty-two patients from the Finnish and 160 patients from the Swedish IPF-cohorts were included in the study. At inclusion, Finnish patients were significantly older than the Swedish patients (74.6 years vs 72.5 years, p = 0.017). The proportion of non-smokers was significantly higher in the Finnish cohort (41.7% vs 26.9%, p = 0.007). Forced vital capacity (FVC), % of predicted (78.2 vs 71.7 for Finnish and Swedish patients, respectively, p = 0.01) and diffusion capacity for carbon monoxide (DLCO), % of predicted (53.3 vs 48.2 for Finnish and Swedish patients, respectively, p = 0.002) were significantly higher in the Finnish cohort compared to the Swedish cohort at the time of inclusion. During the 3-year follow up period, 45 (29.6%) Finnish and 111 (69.4%) Swedish patients, respectively, were initiated on treatment with an antifibrotic drug (pirfenidone or nintedanib) (p <  0.001). When comparing possible determinants of treatment, patients with higher FVC % were less likely to start antifibrotic drugs (OR 0.96, 95%CI 0.93-1.00, p <  0.024). To be resident in Sweden was the main determinant for receiving antifibrotic drugs (OR 5.48, 95%CI 2.65-11.33, p < 0.0001). No significant difference in number of deaths and lung transplantation during the follow up period was found. CONCLUSIONS: This study highlights differences concerning how IPF patients are treated in Finland and Sweden. How these differences will influence the long-term outcome of these patients is unknown.

A retrospective chart review of pirfenidone-treated patients in Sweden: the REPRIS study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease that usually results in respiratory failure and death. Pirfenidone was approved as the first licensed therapy for IPF in Europe based on phase III trials where patients with a forced vital capacity (FVC) >50% of predicted were included. The aim of this study was to characterise patients treated with pirfenidone in Swedish clinical practice and to describe the adherence to the reimbursement restriction since reimbursement was only applied for patients with FVC below 80% of predicted. METHODS: This was a retrospective, observational chart review of IPF patients treated with pirfenidone from three Swedish university clinics. Patients initiated on treatment during the period 28 June 2012 to 20 November 2014 were included. Data on patient characteristics, basis of diagnosis, treatment duration, quality of life, and adverse drug reactions (ADRs) were collected from medical charts. RESULTS: Forty-four patients were screened and 33 were included in the study. The mean treatment duration from start of pirfenidone until discontinuation or end of study was 38 weeks. At the initiation of pirfenidone treatment, FVC was 62.7% (12.1) [mean (SD)], diffusion capacity (DLco) was 45.1% (13.8) of predicted, and the ratio of forced expiratory volume on 1 sec (FEV1) to FVC was 0.78 (0.1). The percentage of patients with an FVC between 50 and 80% was 87%. Ten of the patients had ADRs including gastrointestinal and skin-related events, cough and signs of impaired hepatic function, but this led to treatment discontinuation in only two patients. CONCLUSION: Data from this chart review showed that adherence to the Swedish reimbursement restriction was followed in the majority of patients during the study period. At the start of pirfenidone treatment, lung function, measured as FVC, was lower in the present cohort of Swedish IPF patients compared with other registry and real-life data. About a third of the patients had ADRs, but discontinuation of the treatment because of ADRs was relatively uncommon.

Lung density on high resolution computer tomography (HRCT) reflects degree of inflammation in smokers.

BACKGROUND: Smokers have increased cell concentration in the lower respiratory tract indicating a chronic inflammatory state, which in some individuals may lead to development of chronic obstructive pulmonary disease (COPD). Computer tomography (CT) imaging provides means of quantifying pulmonary structure and early signs of disease. We investigated whether lung density on high resolution CT differs between smokers and never-smokers and if this were associated to intensity of inflammation. METHODS: Forty smoking volunteers with normal pulmonary function, 40 healthy never-smokers and 40 patients with COPD of GOLD stage I-II, were included. Mean lung attenuation and percentage of pixels in the lung with attenuation between -750 and -900 HU (percentage higher density spectrum (%HDS)) were calculated on inspiratory CT-scans. Markers of systemic inflammation in blood and cell counts in bronchoalveolar lavage (BAL) fluid were recorded. RESULTS: Lung density expressed as %HDS was increased in smokers (44.0 ± 5.8%) compared to both never-smokers (38.3 ± 5.8%) and patients with COPD (39.1 ± 5.8%), (p < 0.001, for both). Females had denser lungs than males, which was dependent on body height. Cell concentration in BAL were correlated to lung density in smokers (r = 0.50, p < 0.001). CONCLUSIONS: Lung density on CT is associated with cell concentration in BAL in smokers and may mirror an inflammatory response in the lung. Gender difference in lung density is dependent on height. In COPD with emphysema, loss of lung tissue may counterbalance the expected increase in density due to inflammation. The findings may help to interpret high resolution CT in the context of smoking and gender and highlight the heterogeneity of structural changes in COPD.

Structural changes and antibody enrichment in the lungs are early features of anti-citrullinated protein antibody-positive rheumatoid arthritis.

OBJECTIVE: It has been suggested that immunologic events in the lungs may be involved in triggering immunity, in particular production of anti-citrullinated protein antibodies (ACPAs) during early phases of rheumatoid arthritis (RA). The aim of this study was to investigate the structural and immunologic features of the lungs in incident cases of early RA in relation to ACPA presence and smoking status. METHODS: High-resolution computed tomography (HRCT) was used to examine the lungs of 105 patients with early, untreated RA (70 with ACPA-positive RA and 35 with ACPA-negative RA) and 43 healthy individuals. Bronchoscopy with collection of bronchoalveolar lavage (BAL) fluid and mucosal bronchial biopsy specimens was performed in 23 RA patients. The presence of citrullinated proteins in the bronchial tissue was detected by immunohistochemical staining. ACPAs (detected with an anti-cyclic citrullinated peptide 2 test) and total Ig levels were determined in the sera and BAL fluid of RA patients. RESULTS: HRCT imaging revealed that 63% of ACPA-positive RA patients had parenchymal lung abnormalities, compared with only 37% of ACPA-negative RA patients and 30% of healthy controls (each P < 0.05). These significant differences remained after adjustment for smoking status. Airway changes detected by HRCT were more frequent in RA patients than in healthy controls (66% versus 42%; P < 0.05), but there was no difference between ACPA-positive and ACPA-negative RA patients. Immunohistochemical studies of the bronchial tissue showed increased staining for citrullinated proteins in ACPA-positive RA patients compared with ACPA-negative RA patients (P < 0.05). ACPA levels were relatively higher in the BAL fluid as compared with the sera of ACPA-positive RA patients, suggesting that there is local production of ACPAs in the lungs of these patients. CONCLUSION: The presence of ACPAs is associated with parenchymal lung abnormalities, site-specific citrullination, and antibody enrichment in the lungs early in the development of ACPA-positive RA.

Agonist-specific patterns of beta 2-adrenoceptor responses in human airway cells during prolonged exposure.

BACKGROUND AND PURPOSE: Beta(2)-adrenoceptor agonists (beta(2)-agonists) are important bronchodilators used in the treatment of asthma and chronic obstructive pulmonary disease. At the molecular level, beta(2)-adrenergic agonist stimulation induces desensitization of the beta(2)-adrenoceptor. In this study, we have examined the relationships between initial effect and subsequent reduction of responsiveness to restimulation for a panel of beta(2)-agonists in cellular and in vitro tissue models. EXPERIMENTAL APPROACH: Beta(2)-adrenoceptor-induced responses and subsequent loss of receptor responsiveness were studied in primary human airway smooth muscle cells and bronchial epithelial cells by measuring cAMP production. Receptor responsiveness was compared at equi-effective concentrations, either after continuous incubation for 24 h or after a 1 h pulse exposure followed by a 23 h washout. Key findings were confirmed in guinea pig tracheal preparations in vitro. KEY RESULTS: There were differences in the reduction of receptor responsiveness in human airway cells and in vitro guinea pig trachea by a panel of beta(2)-agonists. When restimulation occurred immediately after continuous incubation, loss of responsiveness correlated with initial effect for all agonists. After the 1 h pulse exposure, differences between agonists emerged, for example isoprenaline and formoterol induced the least reduction of responsiveness. High lipophilicity was, to some extent, predictive of loss of responsiveness, but other factors appeared to be involved in determining the relationships between effect and subsequent loss of responsiveness for individual agonists. CONCLUSIONS AND IMPLICATIONS: There were clear differences in the ability of different beta(2) agonists to induce loss of receptor responsiveness at equi-effective concentrations.

Creatine supplementation and physical training in patients with COPD: a double blind, placebo-controlled study.

STUDY OBJECTIVES: Patients with chronic obstructive pulmonary disease (COPD) have low exercise capacity and low content of high energetic phosphates in their skeletal muscles. The aim of the present study was to investigate whether creatine supplementation together with exercise training may increase physical performance compared with exercise training in patients with COPD. DESIGN: In a randomized, double-blind, placebo-controlled study, 23 patients with COPD (forced expiratory volume in one second [FEV1] < 70% of predicted) were randomized to oral creatine (n = 13) or placebo (n = 10) supplementation during an 8-week rehabilitation programme including exercise training. Physical performance was assessed by Endurance Shuttle Walking Test (ESWT), dyspnea and leg fatigue with Borg CR- 10, quality of life with St George's Respiratory Questionnaire (SGRQ). In addition, lung function test, artery blood gases, grip strength test, muscle strength and fatigue in knee extensors were measured. RESULTS: COPD patients receiving creatine supplementation increased their average walking time by 61% (ESWT) (p < 0.05) after the training period compared with 48% (p = 0.07) in the placebo group. Rated dyspnea directly after the ESWT decreased significantly from 7 to 5 (p < 0.05) in the creatine group. However, the difference between the groups was not statistically significant neither in walking time nor in rated dyspnea. Creatine supplementation did not increase the health related quality of life, lung function, artery blood gases, grip strength and knee extensor strength/fatigue. CONCLUSIONS: Oral creatine supplementation in combination with exercise training showed no significant improvement in physical performance, measured as ESWT, in patients with COPD compared with exercise training alone.