Longitudinal assessment of interstitial lung abnormalities on CT in patients with COPD using artificial intelligence-based segmentation: a prospective observational study.

BACKGROUND: Interstitial lung abnormalities (ILAs) on CT may affect the clinical outcomes in patients with chronic obstructive pulmonary disease (COPD), but their quantification remains unestablished. This study examined whether artificial intelligence (AI)-based segmentation could be applied to identify ILAs using two COPD cohorts. METHODS: ILAs were diagnosed visually based on the Fleischner Society definition. Using an AI-based method, ground-glass opacities, reticulations, and honeycombing were segmented, and their volumes were summed to obtain the percentage ratio of interstitial lung disease-associated volume to total lung volume (ILDvol%). The optimal ILDvol% threshold for ILA detection was determined in cross-sectional data of the discovery and validation cohorts. The 5-year longitudinal changes in ILDvol% were calculated in discovery cohort patients who underwent baseline and follow-up CT scans. RESULTS: ILAs were found in 32 (14%) and 15 (10%) patients with COPD in the discovery (n = 234) and validation (n = 153) cohorts, respectively. ILDvol% was higher in patients with ILAs than in those without ILA in both cohorts. The optimal ILDvol% threshold in the discovery cohort was 1.203%, and good sensitivity and specificity (93.3% and 76.3%) were confirmed in the validation cohort. 124 patients took follow-up CT scan during 5 ± 1 years. 8 out of 124 patients (7%) developed ILAs. In a multivariable model, an increase in ILDvol% was associated with ILA development after adjusting for age, sex, BMI, and smoking exposure. CONCLUSION: AI-based CT quantification of ILDvol% may be a reproducible method for identifying and monitoring ILAs in patients with COPD.

Angiopoietin-like 4 Is a Critical Regulator of Fibroblasts during Pulmonary Fibrosis Development.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible interstitial pneumonia caused by the excessive production and deposition of extracellular matrix components, including type I collagen. Activated fibroblasts, called α-SMA (α-smooth muscle actin)-expressing myofibroblasts, are the major source of type I collagen in pulmonary fibrosis (PF), but the mechanisms underlying disease progression have not been fully elucidated. Here, we obtained lung fibroblasts from patients with IPF from both nonfibrotic and fibrotic areas as determined by a lung computed tomography scan and compared gene expression between these areas by DNA microarray. We found that ANGPTL4 (angiopoietin-like 4) was highly expressed only in fibroblasts from the fibrotic area. ANGPTL4 was selectively expressed in the fibroblastic area of IPF lungs, where the myofibroblast marker α-SMA was also expressed. ANGPTL4 also regulates the gene expression of fibrosis-related markers, cell migration, and proliferation. In addition, ANGPTL4 expression in a murine model of PF induced by treatment with bleomycin was significantly induced in the lungs from the acute to the chronic phase. Single-cell transcriptome analysis during the course of bleomycin-induced PF revealed that Angptl4 was predominantly expressed in the activated fibroblasts and myofibroblasts. Moreover, the administration of recombinant ANGPTL4 to the bleomycin-induced fibrosis model significantly increased collagen deposition and exacerbated the PF. In contrast, the pathogenesis of PF in Angptl4-deficient mice was improved. These results indicate that ANGPTL4 is critical for the progression of PF and might be an early diagnostic marker and therapeutic target for IPF.

Mini Nutritional Assessment Short-Form as screening tool for osteoporosis in patients with chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVES: Osteoporosis is a common complication of chronic obstructive pulmonary dis-ease (COPD). It is impractical to measure bone mineral density (BMD) in all patients with COPD. This study aimed to investigate the relationship between Mini Nutritional Assessment Short-Form (MNA-SF), a simple nutritional status questionnaire, and osteoporosis, and to determine whether it can be used as a reliable screening tool for osteoporosis in patients with COPD. METHODS AND STUDY DESIGN: Thirty-seven patients with stable COPD were enrolled in this prospective cohort study. Patients with MNA-SF scores >11 were defined as well-nourished, and those with scores of ≤11 being at risk for malnutrition. Body composition, BMD, and undercarboxylated osteocalcin (ucOC), a bone metabolism marker, were measured using bioelectrical impedance, dual energy X-ray, and electrochemiluminescence immunoassay, respectively. RESULTS: Seventeen (45.9%) were classified as at risk for malnutrition, and 13 (35.1%) had osteoporosis. Patients at risk for malnutrition had significantly more osteoporosis and higher ucOC values than well-nourished patients (p=0.007, p=0.030, respectively). Patients with osteoporosis also had significantly lower body mass index (BMI) and fat-free mass index than those without osteoporosis (p= 0.007 and p=0.005, respectively), although FEV1 % pred was not significantly different. MNA-SF (cutoff value; 11) had better sensitivity to identify the presence of osteoporosis than BMI (cutoff value; 18.5 kg/m2) (sensitivity, 0.769; specificity, 0.708; sensitivity, 0.462; specificity, 0.875, respectively). CONCLUSIONS: MNA-SF was associated with osteoporosis and bone metabolism markers in patients with COPD. MNA-SF may be a useful screening tool for osteoporo-sis in patients with COPD.

The efficacy and safety of additional treatment with short-acting muscarinic antagonist combined with long-acting beta-2 agonist in stable patients with chronic obstructive pulmonary disease: A systematic review and meta-analysis.

BACKGROUND: The rationale for additional treatment with short-acting bronchodilators combined with long-acting bronchodilators for patients with chronic obstructive pulmonary disease (COPD) is not adequately studied. METHODS: We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of a short-acting muscarinic antagonist (SAMA) therapy combined with a long-acting beta-2 agonist (LABA) in patients with stable COPD. Pulmonary function, dyspnea, health-related quality of life, exercise tolerance, physical activity, exacerbations of COPD, and adverse events during regular use were set as outcomes of interest. RESULTS: We included five controlled trials including two sets of publicly available online data without article publications for the meta-analysis. Additional use of SAMA plus LABA showed a significant improvement in the peak response in FEV1 (mean difference (MD) 98.70 mL, p < .00001), transitional dyspnea index score (MD .85, p = .02), and St George's Respiratory Questionnaire score (MD -2.00, p = .008) compared to LABA treatment. There was no significant difference in the risk of exacerbation of COPD (p = .20) and only a slight trend of increased severe adverse events (OR: 2.16, p = .08) and cardiovascular events (OR: 2.38, p = .06). CONCLUSION: Additional treatment with SAMA combined with LABA could be a feasible choice due to its efficacy and safety.

Prospective nationwide multicentre cohort study of the clinical significance of autoimmune features in idiopathic interstitial pneumonias.

BACKGROUND: Some patients with idiopathic interstitial pneumonia (IIP) show autoimmune features. Interstitial pneumonia with autoimmune features (IPAF) was recently proposed as a research concept in these patients. However, retrospective studies reported conflicting results of its prognosis. Therefore, this study was conducted to prospectively evaluate the clinical significance of autoimmune features in patients with IIP. METHODS: This nationwide multicentre study prospectively enrolled consecutive patients with IIP. At the diagnosis, we systematically evaluated 63 features suggestive of connective tissue diseases using a checklist including symptoms/signs and autoantibodies, which contained most items of the IPAF criteria and followed up with the patients. Clinical phenotypes were included in a cluster analysis. RESULTS: In 376 patients with IIP enrolled, 70 patients (18.6%) met the IPAF criteria. The proportion of patients with IPAF was significantly lower in idiopathic pulmonary fibrosis (IPF) than in non-IPF (6.0% vs 24.3%, respectively). During a median observation period of 35 months, patients with IPAF more frequently developed systemic autoimmune diseases and had less frequent acute exacerbation of IIPs than patients with non-IPAF. IPAF diagnosis was significantly associated with better survival and was an independent positive prognostic factor in total and patients with non-IPF. Cluster analysis by similarity of clinical phenotypes identified a cluster in which there was a higher number of women, and patients had more autoimmune features and a better prognosis than other clusters. INTERPRETATION: These observations suggest that some patients with IIP show autoimmune features with distinct characteristics and favourable prognosis. However, we were not able to determine the appropriate therapies for these patients.

Physiological Impairments on Respiratory Oscillometry and Future Exacerbations in Chronic Obstructive Pulmonary Disease Patients without a History of Frequent Exacerbations.

Respiratory oscillometry allows measuring respiratory resistance and reactance during tidal breathing and may predict exacerbations in patients with chronic obstructive pulmonary disease (COPD). While the Global Initiative for Chronic Obstructive Lung Disease (GOLD) advocates the ABCD classification tool to determine therapeutic approach based on symptom and exacerbation history, we hypothesized that in addition to spirometry, respiratory oscillometry complemented the ABCD tool to identify patients with a high risk of exacerbations. This study enrolled male outpatients with stable COPD who were prospectively followed-up over 5 years after completing mMRC scale and COPD assessment test (CAT) questionnaires, post-bronchodilator spirometry and respiratory oscillometry to measure resistance, reactance, and resonant frequency (Fres), and emphysema quantitation on computed tomography. Total 134 patients were classified into the GOLD A, B, C, and D groups (n = 48, 71, 5, and 9) based on symptoms on mMRC and CAT and a history of exacerbations in the previous year. In univariable analysis, higher Fres was associated with an increased risk of exacerbation more strongly than other respiratory oscillometry indices. Fres was closely associated with forced expiratory volume in 1 sec (FEV1). In multivariable Cox-proportional hazard models of the GOLD A and B groups, either lower FEV1 group or higher Fres group was associated with a shorter time to the first exacerbation independent of the GOLD group (A vs B) and emphysema severity. Adding respiratory oscillometry to the ABCD tool may be useful for risk estimation of future exacerbations in COPD patients without frequent exacerbation history.

Associations of CT evaluations of antigravity muscles, emphysema and airway disease with longitudinal outcomes in patients with COPD.

Multiple CT indices are associated with disease progression and mortality in patients with COPD, but which indices have the strongest association remain unestablished. This longitudinal 10-year observational study (n=247) showed that the emphysema severity on CT is more closely associated with the progression of airflow limitation and that a reduction in the cross-sectional area of erector spinae muscles (ESMCSA) on CT is more closely associated with mortality than the other CT indices, independent of patient demographics and pulmonary function. ESMCSA is a useful CT index that is more closely associated with long-term mortality than emphysema and airway disease in patients with COPD.

Efficacy of budesonide/glycopyrronium/formoterol metered dose inhaler in patients with COPD: post-hoc analysis from the KRONOS study excluding patients with airway reversibility and high eosinophil counts.

BACKGROUND: In the Phase III KRONOS study, triple therapy with budesonide/glycopyrronium/formoterol fumarate metered dose inhaler (BGF MDI) was shown to reduce exacerbations and improve lung function versus glycopyrronium/formoterol fumarate dihydrate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). However, whether the benefits related to the ICS component of BGF are driven by patients with high blood eosinophil counts (EOS) and/or airway reversibility has not been previously studied. METHODS: KRONOS was a Phase III, double-blind, parallel-group, multicenter, randomized, controlled study of patients with moderate-to-very-severe COPD. Patients were randomized 2:2:1:1 to receive BGF 320/14.4/10 µg, GFF 14.4/10 µg, budesonide/formoterol fumarate dihydrate (BFF) MDI 320/10 µg via a single Aerosphere inhaler, or open-label budesonide/formoterol fumarate dihydrate dry powder inhaler 400/12 µg (BUD/FORM DPI; Symbicort Turbuhaler) twice-daily for 24 weeks. Efficacy outcomes included in this post-hoc analysis were change from baseline in morning pre-dose trough FEV1 over weeks 12-24 and the rate of moderate-to-severe and severe COPD exacerbations. Adverse events in the non-reversible subgroup are also reported. RESULTS: Of 1896 patients analyzed, 948 (50%) were non-reversible and had EOS < 300 cells/mm3. In this group, BGF significantly improved morning pre-dose trough FEV1 versus BFF and BUD/FORM (least squares mean treatment difference, 95% confidence interval [CI] 69 mL [39, 99], unadjusted p < 0.0001 and 51 mL [20, 81], unadjusted p = 0.0011, respectively) and was comparable to GFF. BGF also significantly reduced annual moderate-to-severe exacerbation rates versus GFF (rate ratio [95% CI] 0.53 [0.37, 0.76], unadjusted p = 0.0005), with numerical reductions observed versus BFF and BUD/FORM. These results were similar for the overall study population. Safety findings were generally similar between non-reversible patients with EOS < 300 cells/mm3 and the overall population. CONCLUSIONS: In patients with moderate-to-very-severe COPD without airway reversibility and EOS < 300 cells/mm3, BGF significantly improved morning pre-dose trough FEV1 versus BFF and BUD/FORM and significantly reduced the rate of moderate-to-severe exacerbations versus GFF. These findings demonstrate that BGF can provide benefits for a broad range of patients with COPD, and that the overall findings of the KRONOS primary analysis were not driven by patients with reversible airflow obstruction or high eosinophil counts. Trial registration ClinicalTrials.gov, NCT02497001. Registered 14 July 2015, https://clinicaltrials.gov/ct2/show/NCT02497001.

Real-world effectiveness of early intervention with fixed-dose tiotropium/olodaterol vs tiotropium in Japanese patients with COPD: a high-dimensional propensity score-matched cohort analysis.

BACKGROUND: Escalation to triple therapy (long-acting muscarinic antagonist/ß2-agonist, inhaled corticosteroid [ICS]) in chronic obstructive pulmonary disorder (COPD) is recommended for patients on LAMA/LABA combinations with frequent exacerbations and severe symptoms. An extended time-to-escalation to triple therapy suggests patients are in a stable condition and is an indicator of treatment effectiveness. No studies in Japanese clinical practice have compared the effectiveness of LAMA/LABA fixed-dose combination therapies with LAMA monotherapy in terms of time-to-escalation to triple therapy. The primary objective of this real-world study in Japan was to compare time-to-escalation to triple therapy among new users of tiotropium/olodaterol or tiotropium monotherapy for COPD without asthma. METHODS: In this active-comparator cohort study, new users of tiotropium/olodaterol (n = 1436) and tiotropium monotherapy (n = 5352) were identified from a large Japanese hospital-based database (Medical Data Vision Co., Ltd., Tokyo; prespecified study period: 1 April 2015 to 31 March 2019); patients in each group were matched 1:1 using high-dimensional propensity scores (hdPS). The primary outcome was time-to-escalation to triple therapy. RESULTS: For the prespecified study period in the hdPS-matched cohort, escalation to triple therapy was infrequent among new users of tiotropium/olodaterol (n = 1302, 7 escalation events) and tiotropium monotherapy (n = 1302, 8 escalation events). The difference in time-to-escalation to triple therapy between groups was not statistically significant (median [interquartile range]: 28 days [15.0-139.2] for tiotropium monotherapy vs 193 days [94.5-302.0] for tiotropium/olodaterol; hazard ratio: 0.89; 95% CI: 0.32-2.46). Similar findings (hazard ratio: 0.71; 95% Cl: 0.36-1.40) were observed in a post hoc analysis, which extended the study period by 1 year to 31 March 2020. Risks of first moderate and/or severe COPD exacerbation were lower for tiotropium/olodaterol than tiotropium monotherapy (between-group differences not significant). There were no significant between-group differences for the risks of all-cause inpatient mortality, major adverse cardiovascular events, and first use of home oxygen therapy. CONCLUSIONS: ICS monotherapy or ICS/LABA added to tiotropium or tiotropium/olodaterol is limited in Japanese clinical settings. The number of escalations to triple therapy was very limited in the dataset and there was insufficient power to detect differences between the treatment groups in the primary hdPS-matched cohort.

Gastroesophageal reflux disease is a risk factor for sputum production in the general population: the Nagahama study.

BACKGROUND: Chronic sputum production in the general population is historically associated with clinical indices including male sex and smoking history. However, its relationship with gastroesophageal reflux disease (GERD), which may prove an underlying factor in sputum production, is unclear. We aimed to clarify factors associated with sputum production in the general population in cross-sectional and longitudinal manners. METHODS: In the Nagahama study, a community-based cohort study, 9804 subjects were recruited between 2008 and 2010 (baseline assessment), 8293 of whom were followed from 2013 to 2015 (follow-up assessment). This study contained a self-completed questionnaire which included medical history, assessment of sputum production, and a frequency scale for symptoms of GERD. A Frequency Scale for Symptoms of Gastroesophageal Reflux Disease score of ≥ 8 was defined as GERD. In addition to the frequency of sputum production at each assessment, frequency of persistent sputum production defined as sputum production at both assessments was examined. RESULTS: Frequency of sputum production was 32.0% at baseline and 34.5% at follow-up. Multivariable analysis demonstrated that sputum production at baseline was significantly associated with GERD [odds ratio (OR), 1.92; 95% confidence interval (CI) 1.73-2.13] and post-nasal drip (PND) (OR, 2.40; 95% CI 2.15-2.68), independent of other known factors such as older age, male sex and smoking history. These associations between sputum production and GERD or PND were also observed at follow-up. In longitudinal analysis, 19.4% had persistent sputum production and 12.3% had transient sputum production, i.e., at baseline only. Multivariable analysis for risk of persistence of sputum production revealed that persistent sputum production was associated with GERD and PND, in addition to the known risk factors listed above. The proportion of subjects with GERD at both assessments was highest among subjects with persistent sputum production. CONCLUSIONS: Cross-sectional and longitudinal analysis demonstrated an association in the general population between sputum production and GERD, as well as PND, independent of known risk factors. The presence of GERD should be assessed in patients complaining of sputum production.

Potential patient screening for late-onset Pompe disease in suspected sleep apnea: a rationale and study design for a Prospective Multicenter Observational Cohort Study in Japan (PSSAP-J Study).

BACKGROUND: Pompe disease is an autosomal recessive disorder caused by deficiency of the acid α-glucosidase (GAA) enzyme. GAA deficiency induces progressive glycogen accumulation which leads to weakness of the respiratory muscle including the diaphragm. Pompe disease is one of the few myopathies, for which an established therapy is available. Thus, earlier detection of potential late-onset Pompe disease (LOPD) and earlier intervention would have a significant clinical impact. PURPOSE: Our hypothesis is that sleep problems including sleep disordered breathing (SDB) and clinical symptoms may indicate an early stage of LOPD since decreased respiratory muscle activity generally first presents during sleep. Thus, the aims of this prospective, multicenter observational cohort study in Japan (PSSAP-J) are to demonstrate a higher prevalence of LOPD in a sleep lab-based population (primary outcome), and to identify predictive factors for LOPD from findings in diagnostic polysomnography (PSG) and clinical symptoms (secondary outcomes). METHODS: The study design is a prospective multicenter observational cohort study. Consecutive patients who present to sleep labs due to suspected SDB for an overnight PSG will be enrolled. All patients will be measured for creatine kinase, GAA activity, and if necessary, genetic analysis of GAA. Furthermore, chest X-ray, pulmonary function test, and arterial blood gas analysis will be collected. Then, prevalence and specific findings of LOPD will be assessed. RESULT: Congenital myopathy shows a shift from slow-deep to rapid-shallow breathing during transition from wakefulness to sleep accompanying a symptom of waking with gasping (actual further results are pending). DISCUSSION: The distribution in respiratory physiology between during wakefulness and sleep specific to LOPD may provide insights into early-stage detection. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000039191, UMIN Clinical Trials Registry ( http://www.umin.ac.jp/ctr ).

Serine Protease Imbalance in the Small Airways and Development of Centrilobular Emphysema in Chronic Obstructive Pulmonary Disease.

Epithelial dysfunction in the small airways may cause the development of emphysema in chronic obstructive pulmonary disease. C/EBPα (CCAAT/enhancer binding protein-α), a transcription factor, is required for lung maturation during development, and is also important for lung homeostasis after birth, including the maintenance of serine protease/antiprotease balance in the bronchiolar epithelium. This study aimed to show the roles of C/EBPα in the distal airway during chronic cigarette smoke exposure in mice and in the small airways in smokers. In a model of chronic smoke exposure using epithelial cell-specific C/EBPα-knockout mice, significant pathological phenotypes, such as higher protease activity, impaired ciliated cell regeneration, epithelial cell barrier dysfunction via reduced zonula occludens-1 (Zo-1), and decreased alveolar attachments, were found in C/EBPα-knockout mice compared with control mice. We found that Spink5 (serine protease inhibitor kazal-type 5) gene (encoding lymphoepithelial Kazal-type-related inhibitor [LEKTI], an anti-serine protease) expression in the small airways is a key regulator of protease activity in this model. Finally, we showed that daily antiprotease treatment counteracted the phenotypes of C/EBPα-knockout mice. In human studies, CEBPA (CCAAT/enhancer binding protein-α) gene expression in the lung was downregulated in patients with emphysema, and six smokers with centrilobular emphysema (CLE) showed a significant reduction in LEKTI in the small airways compared with 22 smokers without CLE. LEKTI downregulation in the small airways was associated with disease development during murine small airway injury and CLE in humans, suggesting that LEKTI might be a key factor linking small airway injury to the development of emphysema.

Per cent low attenuation volume and fractal dimension of low attenuation clusters on CT predict different long-term outcomes in COPD.

BACKGROUND: Fractal dimension (D) characterises the size distribution of low attenuation clusters on CT and assesses the spatial heterogeneity of emphysema that per cent low attenuation volume (%LAV) cannot detect. This study tested the hypothesis that %LAV and D have different roles in predicting decline in FEV1, exacerbation and mortality in patients with COPD. METHODS: Chest inspiratory CT scans in the baseline and longitudinal follow-up records for FEV1, exacerbation and mortality prospectively collected over 10 years in the Hokkaido COPD Cohort Study were examined (n=96). The associations between CT measures and long-term outcomes were replicated in the Kyoto University cohort (n=130). RESULTS: In the Hokkaido COPD cohort, higher %LAV, but not D, was associated with a greater decline in FEV1 and 10-year mortality, whereas lower D, but not %LAV, was associated with shorter time to first exacerbation. Multivariable analysis for the Kyoto University cohort confirmed that lower D at baseline was independently associated with shorter time to first exacerbation and that higher LAV% was independently associated with increased mortality after adjusting for age, height, weight, FEV1 and smoking status. CONCLUSION: These well-established cohorts clarify the different prognostic roles of %LAV and D, whereby lower D is associated with a higher risk of exacerbation and higher %LAV is associated with a rapid decline in lung function and long-term mortality. Combination of %LAV and fractal D may identify COPD subgroups at high risk of a poor clinical outcome more sensitively.

Long-term expansion of alveolar stem cells derived from human iPS cells in organoids.

The stable expansion of tissue-specific stem cells in vitro has contributed to research on several organs. Alveolar epithelial type II (AT2) cells function as tissue stem cells in the lung, but robust models for studying human AT2 cells are lacking. Here we report a method for the efficient generation and long-term expansion of alveolar organoids (AOs) harboring SFTPC+ alveolar stem cells derived from human induced pluripotent stem cells (hiPSCs). hiPSC-derived SFTPC+ cells self-renewed, with transcriptomes and morphology consistent with those of AT2 cells, and were able to differentiate into alveolar epithelial type I (AT1)-like cells. Single-cell RNA-seq of SFTPC+ cells and their progenitors demonstrated that their differentiation process and cellular heterogeneity resembled those of developing AT2 cells in vivo. AOs were applicable to drug toxicology studies recapitulating AT2-cell-specific phenotypes. Our methods can help scientists overcome the limitations of current approaches to the modeling of human alveoli and should be useful for disease modeling and regenerative medicine.

Indacaterol/glycopyrronium versus tiotropium or glycopyrronium in long-acting bronchodilator-naïve COPD patients: A pooled analysis.

BACKGROUND AND OBJECTIVE: Indacaterol/glycopyrronium (IND/GLY) 110/50 µg once daily (q.d.) has demonstrated greater improvements in lung function, patient-reported outcomes and lower exacerbation rates versus mono long-acting muscarinic antagonists (LAMA) in chronic obstructive pulmonary disease (COPD) patients. However, data are limited on initial treatment with IND/GLY 110/50 µg q.d. versus mono LAMA in COPD patients, not previously on maintenance treatment with long-acting bronchodilators (LABD). METHODS: A pooled analysis of ARISE, SHINE and SPARK trials was conducted to evaluate the efficacy of IND/GLY 110/50 µg q.d. versus open-label (OL) tiotropium (TIO) 18 µg q.d. and GLY 50 µg q.d. in COPD patients, not on maintenance treatment with LABD at study entry (LABD-naïve). Efficacy was assessed after 24/26 weeks of treatment. RESULTS: In total, 998 LABD-naïve patients were included (IND/GLY: 353; OL TIO: 328; GLY: 317). Patients treated with IND/GLY 110/50 µg q.d. experienced greater improvements in trough forced expiratory volume in 1 s (FEV1 ) versus OL TIO 18 µg q.d. (least squares mean treatment difference (Δ): 0.086 L) and GLY 50 µg q.d. (Δ: 0.080 L) after 24/26 weeks. Improvements in electronic diary (eDiary) symptom scores, transition dyspnoea index (TDI) focal score, St George's Respiratory Questionnaire (SGRQ) total score and rescue medication use were also greater with IND/GLY versus OL TIO and GLY. Greater proportion of patients achieved minimal clinically important difference in trough FEV1 , TDI and SGRQ with IND/GLY versus OL TIO and GLY. CONCLUSION: LABD-naïve patients treated with IND/GLY 110/50 µg q.d. achieved improvements in lung function, daily symptoms, dyspnoea, health-related quality of life and rescue medication use versus those who received single LAMA.

Accelerated Loss of Antigravity Muscles Is Associated with Mortality in Patients with COPD.

BACKGROUND: Low antigravity muscle mass is strongly associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). However, the significance of longitudinal changes in antigravity muscle mass remains unclear in patients with COPD. OBJECTIVES: The aims of this study were to investigate the factors associated with the longitudinal loss of antigravity muscles and whether the accelerated loss of these muscles has a negative impact on prognosis. METHODS: This study was part of a prospective observational study at Kyoto University. We enrolled stable male patients with COPD who underwent longitudinal quantitative CT analysis of the cross-sectional area of the erector spinae muscles (ESMCSA) at an interval of 3 years. The associations between the rate of change in ESMCSA (%ΔESM) and clinical parameters, such as anthropometry, symptoms, lung function, exacerbation frequency, and all-cause mortality, were investigated. RESULTS: In total, 102 stable male COPD patients were successfully evaluated in this study (71.3 ± 8.3 years, GOLD stage I/II/III/IV = 20/47/28/7 patients). ESMCSA significantly decreased from 30.53 to 28.98 cm2 (p < 0.0001) in 3 years, and the mean %ΔESM was 5.21 ± 7.24%. The rate of survival during the observation period was 85.3% (87/102). Patients with an accelerated decline in ESMCSA (n = 31; more than double the mean rate of decline) had a significantly higher frequency of moderate-to-severe exacerbations during the interval (p = 0.015). They also had significantly worse survival (p = 0.035 by log-rank test). A multivariate Cox proportional hazard model showed that lower ESMCSA and greater %ΔESM decline were independently and significantly associated with mortality. CONCLUSIONS: Frequent exacerbations were related to the loss of antigravity muscles in COPD patients. The accelerated loss of antigravity muscles was associated with a poor prognosis.

Disproportionally Impaired Diffusion Capacity Relative to Airflow Limitation in COPD.

Forced expiratory volume in 1 s (FEV1) is a standard physiological index of chronic obstructive pulmonary disease (COPD), but reflects emphysema and vascular abnormalities less sensitively than diffusion capacity for carbon monoxide (DLCO). This study tested whether a disproportionally impaired DLCO relative to FEV1 (FEV1z-score>-3 and DLCOz-score≤-3) is a common functional COPD phenotype associated with distinct clinical and structural features and the prognosis of two cohorts. The cross-sectional analyses of the Korea COPD Subgroup Study (KOCOSS) cohort (multicenter study in Korea) included 743 males with COPD whose DLCO was available. The cross-sectional and longitudinal analyses of the Kyoto University Cohort (single-center study in Japan) included 195 males with COPD who were prospectively followed for 10 years. A disproportionally impaired DLCO relative to FEV1 was observed in 29% and 31% of patients in the KOCOSS and Kyoto University cohorts, respectively. In the multivariable analysis, the disproportionally impaired DLCO was associated with worse symptoms, shorter 6-minute walking distance, paraseptal and centrilobular emphysema on computed tomography, and reduced arterial oxygen and carbon dioxide pressures compared to the reference (FEV1z-score>-3 and DLCOz-score>-3). In the multivariable Cox proportional hazard model, a higher long-term mortality was observed in the disproportionally impaired DLCO group than in the reference group (hazard ratio [95% confidence interval] = 3.09 [1.52-6.29]) and similar to the DLCOz-score≤-3 and FEV1z-score≤-3 group. The disproportionally impaired DLCO relative to FEV1 is common and associated with increased symptoms, emphysema, arterial blood gas abnormalities, and increased long-term mortality in patients with COPD.

Correlation between eosinophil count, its genetic background and body mass index: The Nagahama Study.

BACKGROUND: Obesity affects the pathogenesis of various chronic diseases, including asthma. Research on correlations between obesity/BMI and eosinophilic inflammation in asthma has yielded contradictory results, which could be partly ascribed to the absence of epidemiological data on the correlations. We aimed to elucidate the correlations between blood eosinophil count, its genetic backgrounds, and BMI in the general population. METHODS: This community-based Nagahama study in Japan enrolled 9789 inhabitants. We conducted self-reporting questionnaires, lung function tests, and blood tests in the baseline and 5-year follow-up studies. A genome-wide association study (GWAS) was performed in 4650 subjects at the baseline and in 4206 of these at the follow-up to determine single-nucleotide polymorphisms for elevated blood eosinophil counts. We assessed the correlations between BMI and eosinophil counts using a multifaceted approach, including the cluster analysis. RESULTS: Eosinophil counts positively correlated with BMI, observed upon the interchange of an explanatory variable, except for subjects with the highest quartile of eosinophils (≥200/µL), in whom BMI negatively correlated with eosinophil counts. GWAS and human leukocyte antigen (HLA) imputation identified rs4713354 variant (MDC1 on chromosome 6p21) for elevated eosinophil counts, independent of BMI and IgE. Rs4713354 was accumulated in a cluster characterized by elevated eosinophil counts (mean, 498 ± 178/µL) but normal BMI. CONCLUSIONS: Epidemiologically, there may be a positive association between blood eosinophil counts and BMI in general, but there was a negative correlation in the population with high eosinophil counts. Factors other than BMI, particularly genetic backgrounds, may contribute to elevated eosinophil counts in such populations.

Associations of airway tree to lung volume ratio on computed tomography with lung function and symptoms in chronic obstructive pulmonary disease.

BACKGROUND: Decreased airway lumen size and increased lung volume are major structural changes in chronic obstructive pulmonary disease (COPD). However, even though the outer wall of the airways is connected with lung parenchyma and the mechanical properties of the parenchyma affect the behaviour of the airways, little is known about the interactions between airway and lung sizes on lung function and symptoms. The present study examined these effects by establishing a novel computed tomography (CT) index, namely, airway volume percent (AWV%), which was defined as a percentage ratio of the airway tree to lung volume. METHODS: Inspiratory chest CT, pulmonary function, and COPD Assessment Tests (CAT) were analysed in 147 stable males with COPD. The whole airway tree was automatically segmented, and the percentage ratio of the airway tree volume in the right upper and middle-lower lobes to right lung volume was calculated as the AWV% for right lung. Low attenuation volume % (LAV%), total airway count (TAC), luminal area (Ai), and wall area percent (WA%) were also measured. RESULTS: AWV% decreased as the Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric grade increased (p < 0.0001). AWV% was lower in symptomatic (CAT score ≥ 10) subjects than in non-symptomatic subjects (p = 0.036). AWV% was more closely correlated with forced expiratory volume in 1 s (FEV1) and ratio of residual volume to total lung capacity (RV/TLC) than Ai, Ai to lung volume ratio, and volume of either the lung or the airway tree. Multivariate analyses showed that lower AWV% was associated with lower FEV1 and higher RV/TLC, independent of LAV%, WA%, and TAC. CONCLUSIONS: A disproportionally small airway tree with a relatively large lung could lead to airflow obstruction and gas trapping in COPD. AWV% is an easily measured CT biomarker that may elucidate the clinical impacts of the airway-lung interaction in COPD.

Annual decline in arterial blood oxygen predicts development of chronic respiratory failure in COPD with mild hypoxaemia: A 6-year follow-up study.

BACKGROUND AND OBJECTIVE: Chronic respiratory failure (CRF) with hypoxaemia is an important pathophysiology in patients with chronic obstructive pulmonary disease (COPD), and existing mild hypoxaemia may be a sign of future CRF development. However, little is known about the trajectory of partial arterial pressure of oxygen (PaO2 ) decline in patients with COPD. We assessed decline in PaO2 and the impact of short-term reductions in PaO2 to predict future decline in PaO2 . METHODS: A total of 172 outpatients with COPD from a prospective cohort study were enrolled. Pulmonary function tests and arterial blood gas (ABG) analyses were conducted at baseline and 1 year after enrolment and changes in PaO2 (ΔPaO2 ) and other parameters were calculated. Survival and incidence of CRF (as assessed by prescription of long-term home oxygen therapy) were monitored for 6 years. RESULTS: A total of 164 patients completed the observation period and 101 patients had mild hypoxaemia (PaO2 < 80 Torr) at baseline. No patients with normal PaO2 (≥80 Torr) developed CRF, and 10 patients with mild hypoxaemia developed CRF in 6 years. Baseline airflow limitation and diffusion capacity were significantly associated with development of CRF. Receiver-operating characteristic curve analysis showed that ΔPaO2 of -3.05 Torr/year is a useful cut-off value to predict development of CRF in 6 years (hazard ratio (HR): 12.6, 95% CI: 3.48-58.73, P < 0.0001). CONCLUSION: Patients with COPD and mild hypoxaemia may benefit from repeat ABG after 1 year. Although PaO2 trajectories widely varied, significant annual changes in PaO2 of at least -3.0 Torr/year were predictive of CRF development.