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.

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.

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.

Perspectives on End-of-Life Treatment among Patients with COPD: A Multicenter, Cross-sectional Study in Japan.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality. Since patients with severe COPD may experience exacerbations and eventually face mortality, advanced care planning (ACP) has been increasingly emphasized in the recent COPD guidelines. We conducted a multicenter, cross-sectional study to survey the current perspectives of Japanese COPD patients toward ACP. "High-risk" COPD patients and their attending physicians were consecutively recruited. The patients' family configurations, understanding of COPD pathophysiology, current end-of-life care communication with physicians and family members, and preferences for invasive life-sustaining treatments including mechanical ventilation (MV) and cardiopulmonary resuscitation (CPR) were evaluated using a custom-made, structured, self-administered questionnaire. Attending physicians were also interviewed, and we evaluated the patient-physician agreement. Among the 224 eligible "high-risk" patients, 162 participated. Half of the physicians (54.4%) thought they had communicated detailed information; however, only 19.4% of the COPD patients thought the physicians did so (κ score = 0.16). Less than 10% of patients wanted to receive invasive treatment (MV, 6.3% and CPR, 9.4%); interestingly, more than half marked their decision as "refer to the physician" (MV 42.5% and CPR 44.4%) or "refer to family" (MV, 13.8% and CPR, 14.4%). Patients with less knowledge of COPD were less likely to indicate that they had already made a decision. Although ACP is necessary to cope with severe COPD, Japanese "high-risk" COPD patients were unable to make a decision on their preferences for invasive treatments. Lack of disease knowledge and communication gaps between patients and physicians should be addressed as part of these patients' care.

Fraction of MHCII and EpCAM expression characterizes distal lung epithelial cells for alveolar type 2 cell isolation.

BACKGOUND: Alveolar type 2 (AT2) cells play important roles in maintaining adult lung homeostasis. AT2 cells isolated from the lung have revealed the cell-specific functions of AT2 cells. Comprehensive molecular and transcriptional profiling of purified AT2 cells would be helpful for elucidating the underlying mechanisms of their cell-specific functions. To enable the further purification of AT2 cells, we aimed to discriminate AT2 cells from non-AT2 lung epithelial cells based on surface antigen expression via fluorescence activated cell sorting (FACS). METHODS: Single-cell suspensions obtained from enzymatically digested murine lungs were labeled for surface antigens (CD45/CD31/epithelial cell adhesion molecule (EpCAM)/ major histocompatibility complex class II (MHCII)) and for pro-surfactant protein C (proSP-C), followed by FACS analysis for surface antigen expression on AT2 cells. AT2 cells were sorted, and purity was evaluated by immunofluorescence and FACS. This newly developed strategy for AT2 cell isolation was validated in different strains and ages of mice, as well as in a lung injury model. RESULTS: FACS analysis revealed that EpCAM+ epithelial cells existed in 3 subpopulations based on EpCAM and MHCII expression: EpCAMmedMHCII+ cells (Population1:P1), EpCAMhiMHCII- cells (P2), and EpCAMlowMHCII- cells (P3). proSP-C+ cells were enriched in P1 cells, and the purity values of the sorted AT2 cells in P1 were 99.0% by immunofluorescence analysis and 98.0% by FACS analysis. P2 cells were mainly composed of ciliated cells and P3 cells were composed of AT1 cells, respectively, based on the gene expression analysis and immunofluorescence. EpCAM and MHCII expression levels were not significantly altered in different strains or ages of mice or following lipopolysaccharide (LPS)-induced lung injury. CONCLUSIONS: We successfully classified murine distal lung epithelial cells based on EpCAM and MHCII expression. The discrimination of AT2 cells from non-AT2 epithelial cells resulted in the isolation of pure AT2 cells. Highly pure AT2 cells will provide accurate and deeper insights into the cell-specific mechanisms of alveolar homeostasis.

Preliminary study of assessing cognitive impairment in older patients with chronic obstructive pulmonary disease by using a cognitive functional assessment tool via a touchscreen personal computer.

Background: Unique cognitive impairments related to chronic obstructive pulmonary diseases (COPD) have been increasingly reported. Considering the dementia risk and medication management, older patients with COPD should be evaluated for cognitive impairment. This study aimed to examine whether specific cognitive impairments related to COPD could be detected by an assessment tool using a touchscreen personal computer (PC) in older patients with COPD. Methods: This study included 28 older male patients with COPD and 30 healthy older male individuals. A touchscreen PC-based cognitive assessment application called CogEvo was used to assess and compare the cognitive function according to five domains: spatial cognition, orientation, working memory, executive function, and attention. Results: Analysis of variance showed an interaction effect on the indices of cognitive function based on five domains between the two groups, indicating differences in the characteristics of cognitive function in such groups. Betweengroup comparisons as a subtest showed that attention, executive function, and working memory were significantly lower in the COPD group than in the healthy group. Conclusions: CogEvo can detect specific cognitive impairments associated with COPD, suggesting that it can be potentially used as a screening tool for cognitive impairment in older patients with COPD.

Chronic obstructive pulmonary disease features in patients visiting primary respiratory clinic and tertiary hospital in Japan.

Pulmonologists in primary care clinics are positioned between those in tertiary hospitals and general practitioners in clinics and are anticipated to promote hospital-clinic collaboration for patients with chronic obstructive pulmonary disease (COPD). However, the clinical features of patients in primary respiratory clinics are unclear. This multicenter study cross-sectionally compared the characteristics of patients with COPD in a respiratory clinic (n = 69) with those in a university hospital (n = 124). More patients visited the clinic for symptom relief without a referral, whereas more visited the hospital for consultation of abnormal spirometry/computed tomography (CT). The patients in the clinic showed female predilection, higher prevalence of current smokers, severe dyspnea, and concomitant heart failure, and higher CT-measured cross-sectional area ratio of pectoralis muscle to adjacent subcutaneous adipose tissue compared to those in the hospital (all p < 0.05). The observed differences between the two groups suggest the need to establish the role of primary pulmonologists in hospital-clinic collaboration for better COPD management.

Non-respiratory symptom dominance is associated with depression in patients with chronic obstructive pulmonary disease.

INTRODUCTION: Depression is a common and important comorbidity in patients with chronic obstructive pulmonary disease (COPD). Depressive status is associated with a high COPD assessment test (CAT) total score, but it is difficult to distinguish patients with depression from those with severe symptomatic COPD. We hypothesized that a non-respiratory symptom-dominant elevation in CAT score is associated with depression in patients with COPD. METHODS: A total of 226 patients in the KYOTO cohort in Japan and 924 patients in the Korea COPD Subgroup Study (KOCOSS) cohort in the Republic of Korea were analyzed. Depression was diagnosed based on a PHQ-9 (patient health questionnaire-9) ≥5 in the KYOTO cohort and a BDI-II (Beck Depression Inventory-II) ≥17 in the KOCOSS cohort. Sums of respiratory symptoms (Q1-Q4; Q1234) and non-respiratory symptoms (Q5-Q8; Q5678) from CAT items were analyzed. RESULTS: Fifty-three (23.5%) patients in the KYOTO cohort and 111 (11.2%) patients in the KOCOSS cohort were identified as having depression. Fifty-five patients (24.3%) in the KYOTO cohort and 249 patients (26.9%) in the KOCOSS cohort showed non-respiratory symptom dominance (Q1234 ≤ Q5678), and they had a significantly higher prevalence of depression than did patients with respiratory symptom dominance (Q1234 > Q5678). Multivariable logistic regression analysis showed that both the CAT total score and Q1234 ≤ Q5678 were significantly associated with depression in both cohorts. Moreover, even in symptomatic patients (CAT total score ≥10), these significant associations were preserved. CONCLUSION: Non-respiratory symptom dominance in CAT is a suspicious feature for depression in patients with COPD.

Associations of pulmonary and extrapulmonary computed tomographic manifestations with impaired physical activity in symptomatic patients with chronic obstructive pulmonary disease.

In patients with chronic obstructive pulmonary disease (COPD), emphysema, airway disease, and extrapulmonary comorbidities may cause various symptoms and impair physical activity. To investigate the relative associations of pulmonary and extrapulmonary manifestations with physical activity in symptomatic patients, this study enrolled 193 patients with COPD who underwent chest inspiratory/expiratory CT and completed COPD assessment test (CAT) and the Life-Space Assessment (LSA) questionnaires to evaluate symptom and physical activity. In symptomatic patients (CAT ≥ 10, n = 100), emphysema on inspiratory CT and air-trapping on expiratory CT were more severe and height-adjusted cross-sectional areas of pectoralis muscles (PM index) and adjacent subcutaneous adipose tissue (SAT index) on inspiratory CT were smaller in those with impaired physical activity (LSA < 60) than those without. In contrast, these findings were not observed in less symptomatic patients (CAT < 10). In multivariable analyses of the symptomatic patients, severe air-trapping and lower PM index and SAT index, but not CT-measured thoracic vertebrae bone density and coronary artery calcification, were associated with impaired physical activity. These suggest that increased air-trapping and decreased skeletal muscle and subcutaneous adipose tissue quantity are independently associated with impaired physical activity in symptomatic patients with COPD.

Exertional multidimensional dyspnoea predicts exacerbation in stable outpatients with COPD.

This study assessed the sensory and emotional aspects of breathlessness under the same exercise load in patients with COPD. Breathing discomfort with constant exercise predicted exacerbations within 1 year. https://bit.ly/3l2oA4A.

Effects of Sarcopenia on Ventilatory Behavior and the Multidimensional Nature of Dyspnea in Patients With Chronic Obstructive Pulmonary Disease.

OBJECTIVES: This study tested the hypothesis that sarcopenia, a common extrapulmonary feature of chronic obstructive pulmonary disease (COPD), can affect ventilatory behavior, and worsen the multidimensional nature of dyspnea in patients with COPD. DESIGN: Cross-sectional survey study. SETTING: and Participants: Stable outpatients with COPD encountered in general practice and respiratory clinic. METHOD: Sarcopenia was diagnosed according to an appendicular skeletal muscle mass index based on measurements of electrical impedance and handgrip strength. Exertional dyspnea was tested using a 3-minute Step Test and a 6-minute Walk Test. The dimensions of dyspnea were assessed by a multidimensional dyspnea profile. RESULTS: Of 60 stable patients with COPD, 16 met the criteria for sarcopenia. During the 3-minute Step Test, minute ventilation as a proportion of exercise time, tidal volume as a proportion of inspiratory capacity, the change in inspiratory capacity, and ventilation as a proportion of maximal voluntary ventilation did not differ between patients with and without sarcopenia. Patients with sarcopenia exhibited lower evolution of tidal volume, higher evolution of respiratory frequency versus ventilation and breathing discomfort on the 3-minute Step Test, as well as increased physical breathing effort on the 6-minute Walk Test, compared with those without sarcopenia. In a multivariable model adjusted using inverse probability weighting, sarcopenia was independently associated with breathing discomfort during the 3-minute Step Test and physical breathing effort during the 6-minute Walk Test. CONCLUSIONS AND IMPLICATIONS: Sarcopenia may be associated with shallow breathing and diverse sensory and affective components of exertional dyspnea in patients with COPD. The study indicates that improvement of the rapid breathing pattern may offer unique ways to alleviate dyspnea in older patients with COPD and sarcopenia.

Expiratory central airway collapse and symptoms in smokers.

BACKGROUND: The prevalence and clinical impacts of expiratory central airway collapse (ECAC) in smokers remain controversial. Although studies have shown associations of ECAC with airflow limitation and symptoms, others have shown that higher tracheal collapsibility is associated with lower expiratory-to-inspiratory ratio of lung volume (E/I-LV), but not airflow limitation. This study tested whether ECAC of the trachea and main bronchi could occur exclusively in smokers with lower E/I-LV and affect their symptoms independent of emphysema and intrapulmonary airway disease. METHODS: ECAC was defined as the expiratory-to-inspiratory ratio of cross-sectional lumen area <0.5 for at least one of the three locations, including the trachea, right and left main bronchi on static full-inspiratory, and end-tidal expiratory CT. Symptoms were assessed using the chronic obstructive pulmonary disease (COPD) assessment test (CAT) and modified MRC scale (mMRC). RESULTS: Out of 241 smokers with and without COPD (n = 189 and 52, respectively), ECAC was found in 21 (9%) smokers. No ECAC was found in smokers with E/I-LV ≥0.75. CAT and mMRC in smokers with ECAC were higher than in non-ECAC smokers with E/I-LV <0.75, but comparable to those in non-ECAC smokers with E/I-LV ≥0.75. In the multivariable analysis of smokers with E/I-LV <0.75, ECAC was associated with increased mMRC and CAT independent of CT-emphysema severity, wall area percent of segmental airways, and forced expiratory volume in 1 s CONCLUSIONS: ECAC is associated with worsening of symptoms independent of emphysema and segmental airway disease in smokers with a lower expiratory-to-inspiratory lung volume ratio.

Low serum free light chain is associated with risk of COPD exacerbation.

BACKGROUND: Most exacerbations of chronic obstructive pulmonary disease (COPD) are triggered by respiratory tract infections. Adaptive immunity via antibody production is important in preventing infections. Impaired antibody production is reported to be associated with an increased risk of exacerbations of COPD. In the present study, we elucidated whether reduced free light chains (FLCs), which are excessive amounts of light chains produced during antibody synthesis and can be used to estimate systemic antibody production, may be a promising biomarker to predict the risk of exacerbations of COPD. METHODS: We enrolled stable male patients with COPD and prospectively observed them for 2 years. At baseline, serum combined FLC (cFLC; sum of kappa and lambda values) and pulmonary function were evaluated. Exacerbation was defined as a worsening of symptoms requiring treatments with antibiotics, corticosteroids or both. RESULTS: 63 patients with stable COPD were enrolled (72.8±8.1 years, GOLD A/B/C/D=24/28/6/5), and 51 patients completed the 2-year follow-up. Serum cFLC was 31.1 mg·L-1 on average and ranged widely (1.4 to 89.9 mg·L-1). The patients with low cFLC (below the mean-sd, n=6) experienced a significantly shorter time to the first exacerbation of COPD (p<0.0001 by the log-rank test). A multivariate Cox proportional hazard model, including the COPD assessment test score, % predicted forced expiratory volume in 1 s (FEV1 % pred), and number of previous exacerbations demonstrated that low cFLC and low FEV1 % pred were independently and significantly correlated with the risk for exacerbations of COPD. CONCLUSION: Low cFLC may be a B-cell-associated novel biomarker associated with risk of COPD exacerbation.

Gastroesophageal reflux symptoms and nasal symptoms affect the severity of bronchitis symptoms in patients with chronic obstructive pulmonary disease.

BACKGROUND: Cough and sputum production (symptoms of bronchitis) are common in chronic obstructive pulmonary disease (COPD). Extrapulmonary comorbidities, such as gastroesophageal reflux disease (GERD) and post-nasal drip, also cause bronchitis symptoms. The impact of extrapulmonary comorbidities on the severity of bronchitis symptoms in COPD is unknown. The aim of this study was to quantify bronchitis symptoms and assess the impact of GERD and nasal symptoms on the severity of bronchitis symptoms in COPD. METHODS: In this cross-sectional study, stable COPD patients were recruited and completed the COPD assessment test (CAT) and Cough and Sputum Assessment Questionnaire (CASA-Q) to quantify bronchitis symptoms. To evaluate extrapulmonary comorbidities, the Frequency Scale for Symptoms of GERD (FSSG) questionnaire and nasal symptom questionnaire were completed. The impact of these comorbidities on the severity of bronchitis symptoms was analyzed. RESULTS: Ninety-nine COPD patients were recruited. The presence of GERD symptoms (24.2% in the study population) was associated with more sputum symptoms. The presence of nasal discharge (43.4%) was associated with more cough and sputum symptoms, whereas post-nasal drip (13.1%) was associated with more sputum symptoms. On multivariate analyses, nasal discharge was associated with more cough symptoms. GERD and post-nasal drip were associated with more sputum symptoms. CONCLUSION: This study showed that the presence of GERD and/or nasal symptoms is associated with an increase in bronchitis symptoms. Careful assessment of extrapulmonary comorbidities is necessary in the evaluation of bronchitis symptoms in COPD patients.