Applicable predictive factors extracted from peak flow trajectory for the prediction of asthma exacerbation.

BACKGROUND: Real-time asthma exacerbation prediction and acute asthma attack detection are essential for patients with severe asthma. Peak expiratory flow (PEF) exhibits a potential for use in long-term asthma self-monitoring. However, the method for processing PEF calculations remains to be clarified. OBJECTIVE: To develop clinically applicable novel exacerbation predictors calculated using PEF records. METHODS: Previously proposed exacerbation predictors, including the slope of PEF, percentage predicted PEF, percentage best PEF, the highest PEF over the lowest PEF within specific periods, and PEF coefficient of variation, in addition to a novel indicator delta PEF moving average (ΔMA), defined as the difference between 14-day and 3-day average PEF values, along with moving average (MA) adjusted for PEF reference (%ΔMA), were verified using the Hokkaido-based Investigative Cohort Analysis for Refractory Asthma data of 127 patients with severe asthma from whom 73,503 PEF observations were obtained. Receiver operating characteristic curves for all predictors were drawn, and the corresponding areas under the curve (AUCs) were computed. Regression analysis for MA and percentage MA were conducted. RESULTS: The most outstanding performance was shown by ΔMA and %ΔMA, with AUC values of 0.659 and 0.665 in the univariate model, respectively. When multivariate models were incorporated with random intercepts for individual participants, the AUC for ΔMA and %ΔMA increased to 0.907 and 0.919, respectively. CONCLUSION: The MA and percentage MA are valuable indicators that should be considered when deriving predictors from the PEF trajectory for monitoring exacerbations in patients with severe asthma. TRIAL REGISTRATION: The Hokkaido-based Investigative Cohort Analysis for Refractory Asthma was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN ID: 000003254). https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000003917.

Apoptosis inhibitor of macrophage (AIM)/CD5L is involved in the pathogenesis of COPD.

BACKGROUND: Alveolar macrophages (AMs) and AM-produced matrix metalloprotease (MMP)-12 are known to play critical roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). The apoptosis inhibitor of the macrophages (AIM)/CD5 molecule-like (CD5L) is a multifunctional protein secreted by the macrophages that mainly exists in the blood in a combined form with the immunoglobulin (Ig)M pentamer. Although AIM has both facilitative and suppressive roles in various diseases, its role in COPD remains unclear. METHODS: We investigated the role of AIM in COPD pathogenesis using porcine pancreas elastase (PPE)-induced and cigarette smoke-induced emphysema mouse models and an in vitro model using AMs. We also analyzed the differences in the blood AIM/IgM ratio among nonsmokers, healthy smokers, and patients with COPD and investigated the association between the blood AIM/IgM ratio and COPD exacerbations and mortality in patients with COPD. RESULTS: Emphysema formation, inflammation, and cell death in the lungs were attenuated in AIM-/- mice compared with wild-type (WT) mice in both PPE- and cigarette smoke-induced emphysema models. The PPE-induced increase in MMP-12 was attenuated in AIM-/- mice at both the mRNA and protein levels. According to in vitro experiments using AMs stimulated with cigarette smoke extract, the MMP-12 level was decreased in AIM-/- mice compared with WT mice. This decrease was reversed by the addition of recombinant AIM. Furthermore, an analysis of clinical samples showed that patients with COPD had a higher blood AIM/IgM ratio than healthy smokers. Additionally, the blood AIM/IgM ratio was positively associated with disease severity in patients with COPD. A higher AIM/IgM ratio was also associated with a shorter time to the first COPD exacerbation and higher all-cause and respiratory mortality. CONCLUSIONS: AIM facilitates the development of COPD by upregulating MMP-12. Additionally, a higher blood AIM/IgM ratio was associated with poor prognosis in patients with COPD. TRIAL REGISTRATION: This clinical study, which included nonsmokers, healthy smokers, and smokers with COPD, was approved by the Ethics Committee of the Hokkaido University Hospital (012-0075, date of registration: September 5, 2012). The Hokkaido COPD cohort study was approved by the Ethics Committee of the Hokkaido University School of Medicine (med02-001, date of registration: December 25, 2002).

Clinical characteristics and natural course of chronic obstructive pulmonary disease and/or asthma in Japanese patients: a summary report of two Hokkaido-based cohort studies.

Chronic obstructive pulmonary disease (COPD) and asthma are the most common chronic airway diseases and are characterized by chronic airway inflammation and airflow limitation. Japanese patients with COPD or asthma have characteristics different from those of Westerners. Therefore, understanding the characteristics and clinical course of Japanese patients with COPD and those with asthma, particularly severe asthma, is critical for their management and appropriate treatment. The Hokkaido COPD cohort and Hokkaido-based Investigative Cohort Analysis for Refractory Asthma (Hi-CARAT) are high-quality cohort studies of COPD and asthma in the Japanese population and provide valuable data. This report summarizes the clinical findings from the two cohort studies and provides data for more appropriate management of Japanese patients with COPD and/or asthma. Overall, 279 patients with COPD were followed up for up to 10 years in the Hokkaido COPD cohort study, and 127 with severe asthma were followed up for up to 6 years in the Hi-CARAT study. Seventy-nine patients with mild-to-moderate asthma provided baseline data for the Hi-CARAT study. In each disease, several distinct factors, including systemic status and non-pulmonary factors, were associated with important clinical outcomes, such as lung function decline, exacerbations, impaired quality of life, and mortality. Therefore, multifaceted evaluation based on the characteristics of the Japanese population is necessary for the management of COPD and asthma.

Relationships of computed tomography-based small vessel indices of the lungs with ventilation heterogeneity and high transfer coefficients in non-smokers with asthma.

Background: The mechanism of high transfer coefficients of the lungs for carbon monoxide (Kco) in non-smokers with asthma is explained by the redistribution of blood flow to the area with preserved ventilation, to match the ventilation perfusion. Objectives: To examine whether ventilation heterogeneity, assessed by pulmonary function tests, is associated with computed tomography (CT)-based vascular indices and Kco in patients with asthma. Methods: Participants were enrolled from the Hokkaido-based Investigative Cohort Analysis for Refractory Asthma (Hi-CARAT) study that included a prospective asthmatic cohort. Pulmonary function tests including Kco, using single breath methods; total lung capacity (TLC), using multiple breath methods; and CT, were performed on the same day. The ratio of the lung volume assessed using single breath methods (alveolar volume; VA) to that using multiple breath methods (TLC) was calculated as an index of ventilation heterogeneity. The volume of the pulmonary small vessels <5 mm2 in the whole lung (BV5 volume), and number of BV5 at a theoretical surface area of the lungs from the plural surface (BV5 number) were evaluated using chest CT images. Results: The low VA/TLC group (the lowest quartile) had significantly lower BV5 number, BV5 volume, higher BV5 volume/BV5 number, and higher Kco compared to the high VA/TLC group (the highest quartile) in 117 non-smokers, but not in 67 smokers. Multivariable analysis showed that low VA/TLC was associated with low BV5 number, after adjusting for age, sex, weight, lung volume on CT, and CT emphysema index in non-smokers (not in smokers). Conclusion: Ventilation heterogeneity may be associated with low BV5 number and high Kco in non-smokers (not in smokers). Future studies need to determine the dynamic regional system in ventilation, perfusion, and diffusion in asthma.

Stronger Associations of Centrilobular Than Paraseptal Emphysema With Longitudinal Changes in Diffusing Capacity and Mortality in COPD.

BACKGROUND: The factors associated with longitudinal changes in diffusing capacity remain unclear among patients with COPD. Centrilobular emphysema (CLE) and paraseptal emphysema (PSE) are major emphysema subtypes that may have distinct clinical-physiological impacts in these patients. RESEARCH QUESTION: Are CLE and PSE differently associated with longitudinal changes in diffusing capacity and mortality in patients with COPD? STUDY DESIGN AND METHODS: This pooled analysis included 399 patients with COPD from two prospective observational COPD cohorts. CLE and PSE were visually assessed on CT scan according to the Fleischner Society statement. The diffusing capacity and transfer coefficient of the lung for carbon monoxide (Dlco and KCO) and FEV1 were evaluated at least annually over a 5-year period. Mortality was recorded over 10 years. Longitudinal changes in FEV1, Dlco, and KCO and mortality were compared between mild or less severe and moderate or more severe CLE and between present and absent PSE in each Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage. RESULTS: The Dlco and KCO decline was weakly associated with FEV1 and greater in GOLD stage 3 or higher than in GOLD stages 1 and 2. Furthermore, moderate or more severe CLE, but not present PSE, was associated with steeper declines in Dlco for GOLD stages 1 and 3 or higher and KCO for all GOLD stages independent of age, sex, height, and smoking history. The moderate or more severe CLE, but not present PSE, was associated with additional FEV1 decline and higher 10-year mortality among patients with GOLD stage 3 or higher. INTERPRETATION: A CT scan finding of moderate or more severe CLE, but not PSE, was associated with a subsequent accelerated impairment in diffusing capacity and higher long-term mortality in severe GOLD stage among patients with COPD.

Association of serum CC16 levels with eosinophilic inflammation and respiratory dysfunction in severe asthma.

BACKGROUND: There are knowledge gaps in the potential role of Club cell 16-kDa secretory protein (CC16) in severe asthma phenotypes and type 2 inflammation, as well as the longitudinal effect of CC16 on pulmonary function tests and exacerbation risk in epidemiological studies. OBJECTIVE AND METHODS: To assess whether serum CC16 is associated with eosinophilic inflammation in patients with severe asthma. We also examined the effect of this protein on the annual decline in forced expiratory volume in the first second (FEV1) and the risk of exacerbation using a longitudinal approach. We recruited 127 patients with severe asthma from 30 hospitals/pulmonary clinics in Hokkaido, Japan. The least square means and standard error were calculated for T-helper 2 (Th2) biomarkers and pulmonary function test across CC16 tertiles at baseline. We did the same for asthma exacerbation and annual decline in FEV1 with 3 and 5 years' follow-up, respectively. RESULTS: We found that serum CC16 was inversely associated with sputum eosinophils and blood periostin in a dose-response manner. Baseline CC16 and FEV1/forced vital capacity ratio were positively associated in adjusted models (p for trend = 0.008). Patients with the lowest tertile of serum CC16 levels at baseline had a -14.3 mL decline in FEV1 than those with the highest tertile over 5 years of follow-up (p for trend = 0.031, fully adjusted model). We did not find any association of CC16 with exacerbation risk. CONCLUSION: Patients with severe asthma with lower circulatory CC16 had enhanced eosinophilic inflammation with rapid FEV1 decline over time.

Differential role of mucus plugs in asthma: Effects of smoking and association with airway inflammation.

BACKGROUND: The physiological importance of mucus plugs in computed tomography (CT) imaging is being increasingly recognized. However, whether airway inflammation and smoking affect the association between mucus plugs and clinical-physiological outcomes in asthma remains to be elucidated. The objective of this study is to examine how airway inflammation and/or smoking affect the correlation of CT-based mucus plug scores with exacerbation frequency and airflow limitation indices in asthma. METHODS: A total of 168 patients with asthma who underwent chest CT and sputum evaluation were enrolled and classified in eosinophilic asthma (EA; n = 103) and non-eosinophilic asthma (NEA; n = 65) groups based on sputum eosinophil percentage (cut-off: 3%). The mucus plug score was defined as the number of lung segments with mucus plugs seen on CT. RESULTS: More mucus plugs were detected on CT scans in the EA group than in the NEA group, regardless of smoking status. Mucus plug score and exacerbation frequency during one year after enrollment were significantly associated in the EA group but not in the NEA group after adjusting for demographics, blood eosinophil count, and fractional exhaled nitric oxide. Mucus plug score was associated with percentage of predicted forced expiratory volume in 1 s in non-smoking individuals in the EA and NEA group and in smoking individuals in the EA group but not in the NEA group after adjusting for demographics. CONCLUSIONS: The association of mucus plug score with exacerbation frequency and reduced lung function may vary due to airway inflammatory profile and smoking status in asthma.

Blood eosinophil count variability in chronic obstructive pulmonary disease and severe asthma.

BACKGROUND: Blood eosinophils are essential biomarkers that vary substantially over time in patients with COPD and asthma. However, no study has identified the changes and effects in the changes of the blood eosinophil counts over time in both diseases. This study aimed to demonstrate blood eosinophil variability in patients with COPD and severe asthma based on these backgrounds. METHODS: A total of 172 patients with COPD from the Hokkaido COPD cohort study and 96 patients with severe asthma from the Hokkaido Severe Asthma Cohort Study, whose blood eosinophil counts were measured annually over a 3-year period, were analyzed. The factors contributing to consistently high or low blood eosinophil counts were examined in each cohort. The stability of the eosinophil classification (<150, 150-299, ≥300 cells/µL) was compared based on the number of asthma-like features in patients with COPD and the smoking status in patients with severe asthma. RESULTS: Among all the patients, the most stable range of baseline blood eosinophil counts differed between the two diseases, with <150 cells/µL in COPD and ≥300 cells/µL in severe asthma. In COPD, the number of asthma-like features (bronchodilator reversibility, blood eosinophilia, and atopy) affects the blood eosinophil count variation patterns. In severe asthma, smoking status did not affect the blood eosinophil count variation patterns. CONCLUSIONS: We identified variations in the blood eosinophil counts and their contributing factors in patients with COPD and severe asthma.

Subtyping emphysematous COPD by respiratory volume change distributions on CT.

BACKGROUND: There is considerable heterogeneity among patients with emphysematous chronic obstructive pulmonary disease (COPD). We hypothesised that in addition to emphysema severity, ventilation distribution in emphysematous regions would be associated with clinical-physiological impairments in these patients. OBJECTIVE: To evaluate whether the discordance between respiratory volume change distributions (from expiration to inspiration) in emphysematous and non-emphysematous regions affects COPD outcomes using two cohorts. METHODS: Emphysema was quantified using a low attenuation volume percentage on inspiratory CT (iLAV%). Local respiratory volume changes were calculated using non-rigidly registered expiratory/inspiratory CT. The Ventilation Discordance Index (VDI) represented the log-transformed Wasserstein distance quantifying discordance between respiratory volume change distributions in emphysematous and non-emphysematous regions. RESULTS: Patients with COPD in the first cohort (n=221) were classified into minimal emphysema (iLAV% <10%; n=113) and established emphysema with high VDI and low VDI groups (n=46 and 62, respectively). Forced expiratory volume in 1 s (FEV1) was lower in the low VDI group than in the other groups, with no difference between the high VDI and minimal emphysema groups. Higher iLAV%, more severe airway disease and hyperventilated emphysematous regions in the upper-middle lobes were independently associated with lower VDI. The second cohort analyses (n=93) confirmed these findings and showed greater annual FEV1 decline and higher mortality in the low VDI group than in the high VDI group independent of iLAV% and airway disease on CT. CONCLUSION: Lower VDI is associated with severe airflow limitation and higher mortality independent of emphysema severity and airway morphological changes in patients with emphysematous COPD.

Association of longitudinal changes in quality of life with comorbidities and exacerbations in patients with severe asthma.

BACKGROUND: Quality of life (QoL) assessment is important in the management of severe asthma, and comorbidities and/or exacerbations may affect longitudinal QoL. However, there are few reports on the longitudinal assessment of QoL in patients with asthma over multiple years and its related factors. This study aimed to clarify the relationship of longitudinal changes in QoL with comorbidities and/or exacerbations during a prolonged observation period in patients with severe asthma. METHODS: A total of 105 subjects who participated in the Hokkaido-based Investigative Cohort Analysis for Refractory Asthma (Hi-CARAT) with a six-year follow-up were analyzed. QoL was assessed annually, using the Standardized Asthma Quality of Life Questionnaire, and the subjects were divided into three groups: (1) persistently good QoL, (2) persistently poor QoL, and (3) fluctuating QoL. Assessed comorbidities comprised depression, gastroesophageal reflux disease, and excessive daytime sleepiness (EDS), a key symptom of obstructive sleep apnea. RESULTS: Of 105 subjects with severe asthma, 53 (50%) were classified in the persistently good QoL group, 10 (10%) in the persistently poor QoL group, and 42 (40%) in the fluctuating QoL group. The persistently poor QoL group was associated with shorter time to hospitalization due to exacerbation and the presence of multiple comorbidities. In addition, the presence of EDS was an independent contributor to the fluctuating QoL group compared to the persistently good QoL group. CONCLUSIONS: The presence of multiple comorbidities and hospitalization due to exacerbation contribute to longitudinal changes in QoL in patients with severe asthma.

Effects of obesity on CC16 and their potential role in overweight/obese asthma.

INTRODUCTION: Club cell secretory protein-16 (CC16) is a major anti-inflammatory protein expressed in the airway; however, the potential role of CC16 on overweight/obese asthma has not been assessed. In this study, we examined whether obesity reduces airway/circulatory CC16 levels using experimental and epidemiological studies. Then, we explored the mediatory role of CC16 in the relationship of overweight/obesity with clinical asthma measures. METHODS: Circulating CC16 levels were assessed by ELISA in three independent human populations, including two groups of healthy and general populations and asthma patients. The percentage of cells expressing club markers in obese vs. non-obese mice and human airways was determined by immunohistochemistry. A causal mediation analysis was conducted to determine whether circulatory CC16 acted as a mediator between overweight/obesity and clinical asthma measures. RESULTS: BMI was significantly and monotonously associated with reduced circulating CC16 levels in all populations. The percentage of CC16-expressing cells was reduced in the small airways of both mice and humans with obesity. Finally, mediation analysis revealed significant contributions of circulatory CC16 in the association between BMI and clinical asthma measures; 21.8% of its total effect in BMI's association with airway hyperresponsiveness of healthy subjects (p = 0.09), 26.4% with asthma severity (p = 0.030), and 23% with the required dose of inhaled corticosteroid (p = 0.042). In logistic regression analysis, 1-SD decrease in serum CC16 levels of asthma patients was associated with 87% increased odds for high dose ICS requirement (p < 0.001). CONCLUSIONS: We demonstrate that airway/circulating CC16, which is inversely associated with BMI, may mediate development and severity in overweight/obese asthma.

Further evidence for association of YKL-40 with severe asthma airway remodeling.

BACKGROUND: The chitinase-like protein YKL-40 is associated with airflow limitation on spirometry and airway remodeling in patients with asthma. It remains unclear whether YKL-40 is associated with morphologic changes in the airways and parenchyma or with future progression of airflow limitation in severe asthma. OBJECTIVE: To evaluate the association of circulating YKL-40 levels with morphologic changes in the airways and parenchyma and with longitudinal progression of airflow limitation. METHODS: The patients were participants in the Hokkaido Severe Asthma Cohort Study (n = 127), including smokers. This study consisted of 2 parts. In analysis 1, we analyzed associations between circulating YKL-40 levels and several asthma-related indices, including computed tomography-derived indices of proximal wall area percentage, the complexity of the airways (airway fractal dimension), and the parenchyma (exponent D) cross-sectionally (n = 97). In analysis 2, we evaluated the impact of circulating YKL-40 levels on forced expiratory volume in 1 second (FEV1) decline longitudinally for a 5-year follow-up (n = 103). RESULTS: Circulating YKL-40 levels were significantly associated with proximal wall area percentage and airway fractal dimension (r = 0.25, P = .01; r = -0.22, P = .04, respectively), but not with exponent D. The mean annual change in FEV1 was -33.7 (± 23.3) mL/y, and the circulating YKL-40 level was a significant independent factor associated with annual FEV1 decline (ß = -0.24, P = .02), even after controlling for exponent D (ß = -0.26, P = .01). CONCLUSION: These results provide further evidence for the association of YKL-40 with the pathogenesis of airway remodeling in severe asthma.

Unique clinical phenotypes of patients with obstructive sleep apnea in a Japanese population: a cluster analysis.

STUDY OBJECTIVES: In an attempt to better understand the heterogeneity of individuals with obstructive sleep apnea (OSA), unbiased analytic approaches such as cluster analysis have been used worldwide; however, only a few such studies have been conducted for Asian populations alone, despite the potential racial/ethnic differences. We thus applied this approach to a Japanese population with OSA. METHODS: In this single-center, retrospective, observational study, our nocturnal polysomnography dataset included the findings for 1,020 patients between May 2016 and December 2020. Of these, 712 patients met the study criteria: aged > 20 years, fully completed questionnaire, no missing data on all-night full polysomnography, and confirmed OSA diagnosis with an apnea-hypopnea index (AHI) > 15 events/h. We employed hierarchical cluster analysis using demographic data, self-reported symptoms, and polysomnographic data. RESULTS: We identified 5 distinct clinical clusters within the OSA patient population, which were labeled as "classic OSA" (20--67 years, obese, high AHI, high Epworth Sleepiness Scale [ESS]), "milder classic OSA" (22--77 years, obese, high AHI, low ESS), "nonobese and minimally symptomatic" (20--88 years, moderate AHI, low ESS), "excessive sleepiness without severe OSA" (26--79 years, moderate AHI, high ESS), and "older adult and severe OSA" 55--92 years, (high AHI, low ESS). Of these, the last 3 clusters were characterized as nonobese. Notably, we identified the cluster with excessive sleepiness despite less severe OSA. We did not identify any clusters with predominant upper-airway obstruction symptoms because the symptoms were prevalent and equally distributed in all clusters. CONCLUSIONS: We found some unique clinical phenotypes in nonobese patients with OSA in a Japanese population. CITATION: Ida H, Suga T, Nishimura M, Aoki Y. Unique clinical phenotypes of patients with obstructive sleep apnea in a Japanese population: a cluster analysis. J Clin Sleep Med. 2022;18(3):895-902.

Exposure to PM2.5 and Lung Function Growth in Pre- and Early-Adolescent Schoolchildren: A Longitudinal Study Involving Repeated Lung Function Measurements in Japan.

Rationale: Epidemiological evidence indicates that ambient exposure to particulate matter ⩽2.5 µm in aerodynamic diameter (PM2.5) has adverse effects on lung function growth in children, but it is not actually clear whether exposure to low-level PM2.5 results in long-term decrements in lung function growth in pre- to early-adolescent schoolchildren. Objectives: To examine long-term effects of PM2.5 within the 4-year average concentration range of 10-19 µg/m3 on lung function growth with repeated measurements of lung function tests. Methods: Longitudinal analysis of 6,233 lung function measurements in 1,466 participants aged 8-12 years from 16 school communities in 10 cities around Japan, covering a broad area of the country to represent concentration ranges of PM2.5, was done with a multilevel linear regression model. Forced expiratory volume in 1 second, forced vital capacity (FVC), and maximal expiratory flow at 50% of FVC were used as lung function indicators to examine the effects of 10-µg/m3 increases in the PM2.5 concentration on relative growth per each 10-cm increase in height. Results: The overall annual mean PM2.5 level was 13.5 µg/m3 (range, 10.4-19.0 µg/m3). We found no association between any of the lung function growth indicators and increases in PM2.5 levels in children of either sex, even after controlling for potential confounders. Analysis with two-pollutant models with O3 or NO2 did not change the null results. Conclusions: This nationwide longitudinal study suggests that concurrent, long-term exposure to PM2.5 at concentrations ranging from 10.4 to 19.0 µg/m3 has little effect on lung function growth in preadolescent boys or pre- to early-adolescent girls.

Parenchymal destruction in asthma: Fixed airflow obstruction and lung function trajectory.

BACKGROUND: Fixed airflow obstruction (FAO) in asthma, particularly in nonsmokers, is generally believed to be caused by airway remodeling. However, parenchymal destruction may also contribute to FAO and longitudinal decline in forced expiratory volume in 1 second (FEV1). OBJECTIVES: To evaluate parenchymal destruction, we used emphysema indices, exponent D, and low-attenuation area percentage (LAA%) on computed tomography (CT), and test whether the parenchymal destruction and airway disease are independently associated with FAO and FEV1 decline in both smoking and nonsmoking asthma. METHODS: Exponent D, LAA%, wall area percentage at segmental airways, and airway fractal dimension (AFD) in those with asthma were measured on inspiratory CT and compared to those in patients with chronic obstructive pulmonary disease (COPD). RESULTS: Exponent D was lower and LAA% was higher in COPD (n = 42) and asthma with FAO (n = 101) than in asthma without FAO (n = 88). The decreased exponent D and increased LAA% were associated with FAO regardless of smoking status or asthma severity. In multivariable analysis, decreased exponent D and increased LAA% were associated with an increased odds ratio of FAO and decreased FEV1, irrespective of wall area percentage and airway fractal dimension. Moreover, decreased exponent D affected the longitudinal decline in FEV1 in those with severe asthma, independent of smoking status. CONCLUSIONS: Patients with asthma with FAO showed parenchymal destruction regardless of smoking status and asthma severity. Parenchymal destruction was associated with an accelerated FEV1 decline, suggesting the involvements of both airway and parenchyma in the pathophysiology of a subgroup of asthma.

Large-scale plasma proteomics can reveal distinct endotypes in chronic obstructive pulmonary disease and severe asthma.

BACKGROUND: Chronic airway diseases including chronic obstructive pulmonary disease (COPD) and asthma are heterogenous in nature and endotypes within are underpinned by complex biology. This study aimed to investigate the utility of proteomic profiling of plasma combined with bioinformatic mining, and to define molecular endotypes and expand our knowledge of the underlying biology in chronic respiratory diseases. METHODS: The plasma proteome was evaluated using an aptamer-based affinity proteomics platform (SOMAscan®), representing 1238 proteins in 34 subjects with stable COPD and 51 subjects with stable but severe asthma. For each disease, we evaluated a range of clinical/demographic characteristics including bronchodilator reversibility, blood eosinophilia levels, and smoking history. We applied modified bioinformatic approaches used in the evaluation of RNA transcriptomics. RESULTS: Subjects with COPD and severe asthma were distinguished from each other by 365 different protein abundancies, with differential pathway networks and upstream modulators. Furthermore, molecular endotypes within each disease could be defined. The protein groups that defined these endotypes had both known and novel biology including groups significantly enriched in exosomal markers derived from immune/inflammatory cells. Finally, we observed associations to clinical characteristics that previously have been under-explored. CONCLUSION: This investigational study evaluating the plasma proteome in clinically-phenotyped subjects with chronic airway diseases provides support that such a method can be used to define molecular endotypes and pathobiological mechanisms that underpins these endotypes. It provided new concepts about the complexity of molecular pathways that define these diseases. In the longer term, such information will help to refine treatment options for defined groups.

Annual Body Weight Change and Prognosis in Chronic Obstructive Pulmonary Disease.

PURPOSE: Low body mass index (BMI) has been reported to be associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). In contrast, a detailed analysis of the association between body weight change over time and prognosis is not sufficient, particularly in Japanese patients with COPD who have been reported to be much thinner compared to Westerners. This study aimed to investigate the relationship between annual body weight change and long-term prognosis in Japanese patients with COPD in two independent cohorts. PATIENTS AND METHODS: We analyzed 279 patients with COPD who participated in the Hokkaido COPD cohort study as a discovery cohort. We divided participants into three groups according to quartiles of annual body weight change calculated by the data from the first 5 years: weight loss group (<-0.17 kg/year), no change group (-0.17 to ≤0.20 kg/year), and weight gain group (>0.20 kg/year). The association between annual body weight change and prognosis was replicated in the Kyoto University cohort (n = 247). RESULTS: In the Hokkaido COPD cohort study, the weight loss group had significantly worse mortality than the other groups, whereas there was no difference in BMI at baseline. In the multivariate analysis, annual body weight change was an independent risk factor for all-cause mortality, which was confirmed in the Kyoto University cohort. CONCLUSION: Annual body weight loss is associated with poor prognosis in Japanese patients with COPD, independent of baseline BMI. Longitudinal assessment of body weight is important for the management of COPD.

Prognostic significance of OX40+ lymphocytes in tumor stroma of surgically resected small-cell lung cancer.

OX40 (CD134) is a co-stimulatory molecule mostly expressed on activated T lymphocytes. Previous reports have shown that OX40 can be an immuno-oncology target and a clinical biomarker for cancers of various organs. In this study, we collected formalin-fixed paraffin-embedded tumor samples from 124 patients with small-cell lung cancer (SCLC) who had undergone surgery. We analyzed the expression profiles of OX40 and other relevant molecules, such as CD4, CD8, and Foxp3, in tumor stroma and cancer nest using immunohistochemistry and investigated their association with survival. High infiltration of OX40+ lymphocytes (OX40high) in tumor stroma was positively associated with relapse-free survival (RFS) and overall survival (OS) compared with low infiltration of OX40+ lymphocytes (OX40low) (RFS, median, 26.0 months [95% confidence interval (CI), not reached (NR)-NR] vs 13.2 months [9.1-17.2], p = .024; OS, NR [95% CI, NR-NR] vs 29.8 months [21.3-38.2], p = .049). Multivariate analysis revealed that OX40high in tumor stroma was an independent indicator of prolonged RFS. Moreover, RFS of patients with OX40high/CD4high in tumor stroma was significantly longer than that of patients with OX40low/CD4low. The RFS of patients with tumor stroma with OX40high/CD8high was significantly longer than that of patients with tumor stroma with OX40low/CD8high, OX40high/CD8low, or OX40low/CD8low. These findings suggest that OX40+ lymphocytes in tumor stroma play a complementary role in regulating the relapse of early-stage SCLC. Reinforcing immunity by coordinating the recruitment of OX40+ lymphocytes with CD4+ and CD8+ T cells in tumor stroma may constitute a potential immunotherapeutic strategy for patients with SCLC.

Combined assessment of pulmonary arterial enlargement and coronary calcification predicts the prognosis of patients with chronic obstructive pulmonary disease.

INTRODUCTION: In chronic obstructive pulmonary disease (COPD), chest computed tomography (CT) provides clinically important cardiovascular findings, which include diameter of pulmonary artery (PA), its ratio to the diameter of the aorta (PA:A ratio), and coronary artery calcium score (CACS). The clinical importance of these cardiovascular findings has not been fully assessed in Japan, where cardiovascular morbidity and/or mortality is reported to be much less compared with Western counterparts. METHODS: PA diameter and PA:A ratio were measured in 172 and 130 patients with COPD who enrolled in the Hokkaido COPD cohort study and the Kyoto University cohort, respectively. CACS was measured in 131 and 128 patients in each cohort. RESULTS: While the highest quartile group in PA diameter was associated with higher all-cause mortality compared to the lowest quartile group in both cohorts, individual assessments of PA:A ratio and CACS were not associated with the long-term clinical outcomes. When PA diameter and CACS were combined, patients with PA enlargement (diameter >29.5 mm) and/or coronary calcification (score >440.8) were associated with higher all-cause mortality in both cohorts. CONCLUSION: Combined assessment of PA enlargement and CACS was associated with poor prognosis, which provides a clinical advantage in management of patients with COPD even in geographical regions with lower risk of cardiovascular diseases.