Peripheral blood biomarkers associated with combination of immune checkpoint blockade plus chemotherapy in NSCLC.

BACKGROUND: Biomarkers predicting clinical outcomes of treating non-small cell lung cancer (NSCLC) with combination of immune checkpoint inhibitors (ICIs) and chemotherapy would be valuable. OBJECTIVE: This study aims to seek predictors of combination of ICI/chemotherapy response in NSCLC patients using peripheral blood samples. METHODS: Patients diagnosed with advanced NSCLC between July 2019 and May 2021 receiving combination of ICI/chemotherapy were included and assessed for partial responses (PR), stable disease (SD) or progressive disease (PD). We measured circulating immune cells, plasma cytokines and chemokines. RESULTS: Nineteen patients were enrolled. The proportions of circulating natural killer (NK) cells within CD45 + cells, programmed death 1 (PD-1) + Tim-3 + T cells within CD4 + cells, and the amount of chemokine C-X-C ligand (CXCL10) in the plasma were significantly elevated in PR relative to SD/PD patients (median 8.1%-vs-2.1%, P= 0.0032; median 1.2%-vs-0.3%, P= 0.0050; and median 122.6 pg/ml-vs-76.0 pg/ml, P= 0.0125, respectively). Patients with 2 or 3 elevated factors had longer progression-free survival than patients with 0 or only one (not reached-vs-5.6 months, P= 0.0002). CONCLUSIONS: We conclude that NK cells, CD4 + PD-1 + Tim-3 + T cells, and CXCL10 levels in pre-treatment peripheral blood may predict the efficacy of combination of ICI/chemotherapy in NSCLC.

Treatment with systemic corticosteroid versus placebo for exacerbations of COPD: A systematic review and meta-analysis.

BACKGROUND: For the treatment of COPD exacerbations, systemic corticosteroids are recommended in addition to short-acting bronchodilators. Although there have been several systemic reviews, many of the included studies were conducted before 2007 and a re-evaluation has not been performed since 2014. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety profile of systemic corticosteroids in patients with COPD during exacerbations. METHODS: We searched relevant randomized control trials (RCTs) and analyzed the treatment failure, relapse, lung function, improvement in PaO2 and PaCO2, dyspnea, quality of life (QOL), length of stay in hospital and adverse events including hyperglycemia and mortality as the outcomes of interest. RESULTS: We identified a total of 12 RCTs (N = 1336). Systemic corticosteroids significantly reduced the treatment failure (odds ratios; OR 0.41, 95% confidence intervals; CI 0.25 to 0.67) and hospital length of stay (mean difference; MD -1.57 days, 95% CI -2.36 to -0.78) and improved FEV1 (MD 0.18 L, 95% CI 0.08 to 0.28) and dyspnea (transitional dyspnea index; MD 1.90, 95% CI 0.26 to 3.54) in COPD exacerbations compared to placebo. However, systemic corticosteroids were associated with a significantly higher incidence of adverse events (OR 1.83, 95% CI 1.25 to 2.69) and hyperglycemia (OR 2.94, 95% CI 1.68 to 5.14). CONCLUSIONS: In patients with moderate and severe COPD and severe obstructive impairment during exacerbations, systemic corticosteroids cause more adverse events, including hyperglycemia, than placebo but significantly reduce the treatment failure and hospital length of stay and improve FEV1 and dyspnea.

Identification of Siglec-1-negative alveolar macrophages with pro-inflammatory phenotypes in chronic obstructive pulmonary disease.

Alveolar macrophages (AMs) in patients with chronic obstructive pulmonary disease (COPD) orchestrate persistent inflammation in the airway. However, sub-populations of AMs participating in the chronic inflammation have been poorly characterized. We previously reported that Siglec-1 expression on AMs, which is important for bacteria engulfment, was decreased in COPD. Here, we show that Siglec-1-negative AMs isolated from COPD lung tissues exhibit a pro-inflammatory phenotype and is associated with poor clinical outcomes in patients with COPD. Using flow-cytometry, we segregated three subsets of AMs based on the expression of Siglec-1 and their side scattergram (SSC) and forward scattergram (FSC) properties: Siglec-1+SSChiFSChi, Siglec-1-SSChiFSChi and Siglec-1-SSCloFSClo subsets. The Siglec-1-SSCloFSClo subset number was increased in COPD. RNA-sequencing revealed upregulation of multiple pro-inflammatory signaling pathways and emphysema-associated matrix metalloproteases in the Siglec-1-SSCloFSClo subset. Gene set enrichment analysis indicated that the Siglec-1-SSCloFSClo subset adopted intermediate phenotypes between monocytes and mature alveolar macrophages. Functionally, these cells produced TNF-α, IL-6 and IL-8 at baseline, and these cytokines were significantly increased in response to viral RNA. The increase in Siglec-1-negative AMs in induced sputum is associated with future exacerbation risk and lung function decline in patients with COPD. Collectively, the novel Siglec-1-SSCloFSClo subset of AMs display pro-inflammatory properties, and their emergence in COPD airways may be associated with poor clinical outcomes.

Combined Fat Mass and Fat-free Mass Indices and Lung Function Among Japanese Population: The Tohoku Medical Megabank Community-based Cohort Study.

BACKGROUND: Although fat mass index (FMI) and fat-free mass index (FFMI) affect lung function, FMI and FFMI are not independent of each other, since FMI and FFMI were calculated as fat mass and fat-free mass divided by height squared, respectively. We aimed to examine the association of combined FMI and FFMI with lung function. METHODS: In this cross-sectional study, lung function was evaluated using forced expiratory volume at 1 s (FEV1) and forced vital capacity (FVC) measured using spirometry. Both FMI and FFMI were classified into sex-specific quartiles (16 groups). Analysis of covariance was used to assess the associations of combined FMI and FFMI with lung function. The trend test was conducted by stratifying the FMI and FFMI, scoring the categories from 1-4 (lowest-highest), and entering the number as a continuous term in the regression model. RESULTS: This study included 3,736 men and 8,821 women aged ≥20 years living in Miyagi Prefecture, Japan. The mean FEV1 was 3.0 (standard deviation [SD], 0.7) L for men and 2.3 (SD, 0.5) L for women. The mean FVC was 3.8 (SD, 0.7) L for men and 2.8 (SD, 0.5) L for women. FMI was inversely associated with lung function among all FFMI subgroups in both sexes. Conversely, FFMI was positively associated with lung function in all FMI subgroups in both sexes. CONCLUSION: Higher FMI was associated with lower lung function independent of FFMI; higher FFMI was associated with higher lung function independent of FMI. Reducing FMI and maintaining FFMI might be important for respiratory health.

CYP27A1-27-hydroxycholesterol axis in the respiratory system contributes to house dust mite-induced allergic airway inflammation.

BACKGROUND: 27-Hydroxycholesterol (27-HC) derived from sterol 27-hydroxylase (CYP27A1) has pro-inflammatory biological activity and is associated with oxidative stress and chronic inflammation in COPD. However, the role of regulation of CYP27A1- 27-HC axis in asthma is unclear. This study aimed to elucidate the contribution of the axis to the pathophysiology of asthma. METHODS: House dust mite (HDM) extract was intranasally administered to C57BL/6 mice and the expression of CYP27A1 in the airways was analyzed by immunostaining. The effect of pre-treatment with PBS or CYP27A1 inhibitors on the cell fraction in the bronchoalveolar lavage fluid (BALF) was analyzed in the murine model. In vitro, BEAS-2B cells were treated with HDM and the levels of CYP27A1 expression were examined. Furthermore, the effect of 27-HC on the expressions of E-cadherin and ZO-1 in the cells was analyzed. The amounts of RANTES and eotaxin from the 27-HC-treated cells were analyzed by ELISA. RESULTS: The administration of HDM increased the expression of CYP27A1 in the airways of mice as well as the number of eosinophils in the BALF. CYP27A1 inhibitors ameliorated the HDM-induced increase in the number of eosinophils in the BALF. Treatment with HDM increased the expression of CYP27A1 in BEAS-2B cells. The administration of 27-HC to BEAS-2B cells suppressed the expression of E-cadherin and ZO-1, and augmented the production of RANTES and eotaxin. CONCLUSIONS: The results of this study suggest that aeroallergen could enhance the induction of CYP27A1, leading to allergic airway inflammation and disruption of the airway epithelial tight junction through 27-HC production.

Supersulphides provide airway protection in viral and chronic lung diseases.

Supersulphides are inorganic and organic sulphides with sulphur catenation with diverse physiological functions. Their synthesis is mainly mediated by mitochondrial cysteinyl-tRNA synthetase (CARS2) that functions as a principal cysteine persulphide synthase (CPERS). Here, we identify protective functions of supersulphides in viral airway infections (influenza and COVID-19), in aged lungs and in chronic lung diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF). We develop a method for breath supersulphur-omics and demonstrate that levels of exhaled supersulphides increase in people with COVID-19 infection and in a hamster model of SARS-CoV-2 infection. Lung damage and subsequent lethality that result from oxidative stress and inflammation in mouse models of COPD, IPF, and ageing were mitigated by endogenous supersulphides production by CARS2/CPERS or exogenous administration of the supersulphide donor glutathione trisulphide. We revealed a protective role of supersulphides in airways with various viral or chronic insults and demonstrated the potential of targeting supersulphides in lung disease.

Associations between birth weight and lung function in a Japanese adult population: The tohoku medical megabank community-based cohort study.

BACKGROUND: Birth weight, as a measure of intrauterine growth, is commonly used in epidemiological studies and is reported to be associated with adult lung function. However, findings regarding this association in previous studies have been inconsistent. Furthermore, no studies have reported associations stratified by age or smoking status, or adjusted for eosinophil count or other parameters related to type 2 airway inflammation. METHODS: This cross-sectional study included 2632 men and 7237 women aged ≥20 years living in Miyagi Prefecture, Japan. Lung function was assessed based on spirometry. Birth weight data were obtained through a questionnaire survey. Analysis of covariance was used to evaluate the associations between birth weight and lung function, adjusting for potential confounders. Stratified analyses by age and smoking status were also conducted, together with a sub-analysis for low birth-weight participants. RESULTS: Birth weight was positively associated with forced expiratory volume in 1 s (FEV1) for both sexes and with vital capacity in women, after adjusting for height, age, smoking status, and parameters related to type 2 airway inflammation. The stratified analysis for smoking status revealed associations in never-smokers and ex-smokers. When stratified by age, the associations were confirmed in middle-aged participants. The effect of smoking status on the FEV1 of low birth-weight participants was not significant. CONCLUSIONS: Our analysis of a large, Japanese adult population showed that birth weight was independently and positively associated with adult lung function, even after adjustment for age, height, smoking status, and parameters related to type 2 airway inflammation.

Circulating Extracellular Vesicle Levels in Patients with Coronavirus Disease 2019 Coagulopathy: A Prospective Cohort Study.

Coronavirus disease 2019 (COVID-19) is associated with coagulopathy. However, the underlying mechanisms are not completely understood. We evaluated the association between COVID-19 coagulopathy and extracellular vesicle (EV) levels. We hypothesized that several EV levels would be higher in COVID-19 coagulopathy patients than in non-coagulopathy patients. This prospective observational study was conducted in four tertiary care faculties in Japan. We enrolled 99 COVID-19 patients (48 with coagulopathy and 51 without coagulopathy) aged ≥20 years who required hospitalization, and 10 healthy volunteers; we divided the patients into coagulopathy and non-coagulopathy groups according to the D-dimer levels (≥1 µg/mL and <1 µg/mL, respectively). We used flow cytometry to measure the tissue-factor-bearing, endothelium-derived, platelet-derived, monocyte-derived, and neutrophil-derived EV levels in platelet-free plasma. The EV levels were compared between the two COVID-19 groups as well as among the coagulopathy patients, non-coagulopathy patients, and healthy volunteers. No significant difference was found in EV levels between the two groups. Meanwhile, the cluster of differentiation (CD) 41 + EV levels were significantly higher in COVID-19 coagulopathy patients than in healthy volunteers (549.90 [255.05-984.65] vs. 184.3 [150.1-254.1] counts/µL, p = 0.011). Therefore, CD41+ EVs might play an essential role in COVID-19 coagulopathy development.

Real-world efficacy of anti-IL-5 treatment in patients with allergic bronchopulmonary aspergillosis.

Despite standard treatment with systemic corticosteroids and/or antifungal triazoles, a substantial proportion of patients with allergic bronchopulmonary aspergillosis (ABPA) experience frequent relapses and require long-term treatment despite unfavorable adverse effects. We investigated the efficacy and safety of anti-interleukin (IL)-5/IL-5 receptor α chain (Rα) monoclonal antibodies (mAbs) in patients with ABPA complicated by asthma. ABPA cases treated with anti-IL-5/IL-5Rα mAbs were collected from 132 medical institutes in 2018 and published case reports in Japan. Clinical outcomes, laboratory and physiological data, and radiographic findings during 32 weeks before and after treatment were retrospectively evaluated. We analyzed 29 cases of ABPA: 20 treated with mepolizumab and nine with benralizumab. Treatment with anti-IL-5/IL-5Rα mAbs reduced the frequency of exacerbations (p = 0.03), decreased the dose of oral corticosteroids (p < 0.01), and improved pulmonary function (p = 0.01). Mucus plugs in the bronchi shrank or diminished in 18 patients (82%). Despite the clinical/radiographical improvement, serum levels of total IgE, the key biomarker for the pharmacological response in ABPA, were unchanged. Anti-IL-5/IL-5Rα mAbs that directly target eosinophils are promising candidates for the treatment of patients with ABPA, especially those with mucus plugs in the bronchi.

Association between lung function and hypertension and home hypertension in a Japanese population: the Tohoku Medical Megabank Community-Based Cohort Study.

BACKGROUND: Although several studies have shown an inverse association between lung function and hypertension, few studies have examined the association between lung function and hypertension among never-smokers, and no study has investigated the association between lung function and home hypertension. We investigated the associations between lung function and hypertension in a Japanese population. INDIVIDUALS AND METHODS: We conducted a cross-sectional study of 3728 men and 8795 women aged 20 years or older living in Miyagi Prefecture, Japan. Lung function was assessed using forced expiratory volume at 1 s (FEV 1 ) and forced vital capacity (FVC), measured by spirometry. Hypertension was defined as a casual blood pressure at least 140/90 mmHg and/or self-reported treatment for hypertension. Home hypertension was defined as morning home blood pressure at least 135/85 mmHg and/or self-reported treatment for hypertension. Multivariate logistic regression models adjusted for potential confounders were used to assess the association between lung function and hypertension. RESULTS: The mean ages (±SD) of men and women were 60.1 (±14.0) years and 56.2 (±13.4) years, respectively, and 1994 (53.5%) men and 2992 (34.0%) women had hypertension. In the multivariable models, FEV 1 and FVC were inversely associated with hypertension. Inverse associations between lung function and hypertension were observed even among never-smokers. Furthermore, reduced lung function was associated with higher prevalence of home hypertension in men and women. CONCLUSION: Reduced lung function was associated with higher prevalence of hypertension, independent of smoking status. Assessment of the lung function or blood pressure may be required in individuals with reduced lung function or hypertension.

The Association of Lung Function and Carotid Intima-Media Thickness in a Japanese Population: The Tohoku Medical Megabank Community-Based Cohort Study.

AIM: Impaired lung function is associated with atherosclerotic vascular events. Carotid intima-media thickness (cIMT) is a marker for subclinical atherosclerosis. However, few studies have examined the association between lung function and cIMT among never smokers or individuals stratified by age. We investigated the association between lung function and cIMT in the Japanese population. METHODS: We conducted a cross-sectional study of 3,716 men and 8,765 women aged 20 years or older living in Miyagi Prefecture, Japan. Lung function was evaluated using forced expiratory volume at 1 s (FEV1) and forced vital capacity (FVC) was measured using spirometry. The maximum common carotid artery was measured using high-resolution B-mode ultrasound. An analysis of covariance was used to assess associations between lung function and cIMT and adjusted for potential confounders. A linear trend test was conducted by scoring the categories from 1 (lowest) to 4 (highest) and entering the score as a continuous term in the regression model. RESULTS: After adjusting for potential confounders including passive smoking, lower FEV1 and FVC were associated with higher cIMT in both men and women (P＜0.001 for linear trend). This association was confirmed even when we restricted our study to never smokers. Furthermore, even when we stratified by age, an inverse association between lung function and cIMT was confirmed in middle-aged (40-64 years) and elderly participants (65-74 years). CONCLUSIONS: Lower lung function was associated with higher cIMT in the Japanese population independent of age and smoking. Assessment of atherosclerosis or lung function may be required for individuals with lower lung function or atherosclerosis.

Clinical manifestations of hospitalized influenza patients without risk factors: A prospective multicenter cohort study in Japan via internet surveillance.

INTRODUCTION: Influenza remains a clinically heavy burden worldwide. It is well known that some populations are at high risk of complications from influenza, whereas, even previously healthy people might suffer from severe influenza. The objective of this study was to clarify clinical manifestations of hospitalized patients without risk factors infected with influenza. METHODS: The clinical data for patients who were severely ill with influenza, and required hospitalization were gathered and analyzed between November 2014 and August 2020 (6 influenza seasons) using an internet-surveillance system. Among them, the patients who had no risk factors of complications from influenza were extracted. RESULTS: Finally, a total of 91 patients (9.0% of all influenza-related hospitalizations) without risk factors were analyzed. The no risk group was younger than the risk group, though other significant differences of clinical characteristics were not recognized between the groups. Pneumonia was the most common cause of hospitalization in the no risk group, and primary influenza viral pneumonia was the most common pneumonia. Antiviral drugs were administered in 96.7% of the no-risk group, and artificial ventilation was performed in 18.7%. In-hospital death was recorded for 3 patients without risk factors. CONCLUSIONS: Severe complications of influenza which required hospitalization may occur in a certain degree of patients with no risk factors. Efforts are needed to diagnose and treat influenza appropriately even in previously healthy younger patients. Continuous nationwide surveillance will be required to clarify risk factors for severe influenza even in previously healthy younger patients. (UMIN000015989).

Decreased expression of airway epithelial Axl is associated with eosinophilic inflammation in severe asthma.

BACKGROUND: Airway epithelium-derived cytokines are critical to provoke and perpetuate type 2 inflammation in asthma. Yet it is poorly understood how this epithelial cell-driven inflammatory response is negatively regulated. We previously reported that Axl receptor tyrosine kinase was expressed by basal cells in the airway epithelium and had a role in defining their stem cell identity. However, whether and how Axl regulates airway type 2 inflammation remains unknown. METHODS: We performed immunofluorescence staining to compare Axl expression in airway epithelium between non-asthmatic subjects, mild-moderate asthma and severe asthma. We confirmed this result by interrogating public databases of global gene expression in endobronchial biopsies. We then quantified eosinophil numbers infiltrating into the trachea of wild-type or Axl-knockout mice that were intranasally treated with house dust mite extracts (HDM). Cell-based assays using siRNA targeting Axl were further performed to identify molecules involved in Axl-mediated regulation of inflammation. RESULTS: Histological assessments and transcriptome analyses revealed decreases in protein and mRNA of Axl in airway basal cells of severe asthmatics. This reduction of Axl expression was correlated with infiltration of eosinophils and mast cells in severe asthmatics. Eosinophil infiltration was more evident in the trachea of Axl-knockout mice in response to repetitive HDM administration. siRNA-mediated knockdown of Axl increased mRNA and protein expression of granulocyte macrophage-colony stimulating factor (GM-CSF) in human bronchial epithelial cells. CONCLUSIONS: Axl kinase expressed by basal cells may suppress excessive eosinophilic inflammation via inhibition of GM-CSF in the airway. Axl reduction has clinical implications for the pathogenesis of severe asthma.

Sinobronchial Syndrome Patients with Suspected Non-Tuberculous Mycobacterium Infection Exacerbated by Exophiala dermatitidis Infection.

Background: Exophiala dermatitidis is an environmental black fungus that rarely causes respiratory infections, yet its pathophysiological features and treatment regimens have not been established. Case Series: Two cases of exacerbations of chronic bronchitis and sinusitis due to E. dermatitidis infection in Japan are presented. Both patients were women, and non-tuberculous Mycobacterium (NTM) infection was suspected based on chest radiological findings, but E. dermatitidis was detected from bronchial lavage fluid and nasal mucus, respectively. Both cases were successfully treated by antifungal agents such as liposomal amphotericin B, voriconazole, and itraconazole, but clarithromycin, rifampicin, ethambutol, and sitafloxacin for NTM were not effective. Conclusion: E. dermatitidis can become a respiratory pathogen, especially in patients with chronic sinobronchial syndrome.

Increased LHX9 expression in alveolar epithelial type 2 cells of patients with chronic obstructive pulmonary disease.

BACKGROUND: Alveolar epithelial type 2 (AT2) cells serve as stem cells in alveolar epithelium and are assumed to lose their stem cell function in the lungs of chronic obstructive pulmonary disease (COPD). Although we previously reported that LHX9 mRNA expression was up-regulated in AT2 cells of COPD lung tissues, it is yet to be elucidated how LHX9 is associated with the vulnerability of AT2 cells in COPD. METHODS: AT2 cells were isolated from lung tissues of 10 non-COPD subjects and 11 COPD patients. LHX9 mRNA expression was determined by quantitative RT-PCR. To identify up-stream molecules, an alveolar epithelial cell line A549 was exposed to pro-inflammatory cytokines in vitro. siRNA-mediated Lhx9 knockdown was performed to determine how Lhx9 affected the cellular viability and the cell-division cycle. RESULTS: LHX9 mRNA expression was increased in AT2 cells from COPD lung tissues, compared to those from non-COPD tissues. The airflow obstruction was independently correlated with the increase in LHX9 expression. Among several pro-inflammatory cytokines, interferon-γ was a strong inducer of LHX9 expression in A549 cells. Lhx9 was involved in the increased susceptibility to serum starvation-induced death of A549 cells. CONCLUSIONS: Our data suggest that IFN-γ predominantly increases the LHX9 expression which enhances the susceptibility to cell death. Considering the independent association of the increased LHX9 expression in AT2 cells with airflow obstruction, the IFN-γ-Lhx9 axis might contribute to the vulnerability of AT2 cells in the lungs of COPD patients.

Triple versus LAMA/LABA combination therapy for Japanese patients with COPD: A systematic review and meta-analysis.

BACKGROUND: In symptomatic COPD patients with a history of exacerbations, additional treatment with inhaled corticosteroid (ICS) to long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist (LABA) combination therapy is recommended based on the evidence of low incidence of exacerbations but with a caution for pneumonia. However, ethnic differences may affect the response to drugs. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of this treatment in the Japanese population (PROSPERO: CRD42020191978). METHODS: We searched relevant randomized control trials and analyzed the exacerbations, quality of life, lung function, and adverse events including pneumonia and mortality as the outcomes of interest. RESULTS: We identified a total of three RCTs (N = 632). Treatment with ICS/LAMA/LABA triple therapy significantly decreased the exacerbations (rate ratio, 0.56; 95% CI, 0.38 to 0.85) and improved the trough FEV1 (mean difference, 0.04; 95% CI, 0.01 to 0.07) compared to LAMA/LABA therapy. However, triple therapy showed a significantly higher incidence of pneumonia compared to LAMA/LABA (odds ratio, 3.38; 95% CI, 1.58 to 7.22). Concerning other adverse events including mortality, there were no significant difference between these therapies. CONCLUSIONS: In the current meta-analysis of the Japanese population, we confirmed that triple therapy causes a higher incidence of pneumonia than LAMA/LABA treatment but is a more preferable treatment since it showed a lower incidence of exacerbations and higher trough FEV1 in patients with symptomatic moderate to severe COPD. However, since the sample sizes were not statistically large enough, further trials involving Japanese patients are needed.

Genetic loci for lung function in Japanese adults with adjustment for exhaled nitric oxide levels as airway inflammation indicator.

Lung function reflects the ability of the respiratory system and is utilized for the assessment of respiratory diseases. Because type 2 airway inflammation influences lung function, genome wide association studies (GWAS) for lung function would be improved by adjustment with an indicator of the inflammation. Here, we performed a GWAS for lung function with adjustment for exhaled nitric oxide (FeNO) levels in two independent Japanese populations. Our GWAS with genotype imputations revealed that the RNF5/AGER locus including AGER rs2070600 SNP, which introduces a G82S substitution of AGER, was the most significantly associated with FEV1/FVC. Three other rare missense variants of AGER were further identified. We also found genetic loci with three candidate genes (NOS2, SPSB2 and RIPOR2) associated with FeNO levels. Analyses with the BioBank-Japan GWAS resource revealed genetic links of FeNO and asthma-related traits, and existence of common genetic background for allergic diseases and their biomarkers. Our study identified the genetic locus most strongly associated with airway obstruction in the Japanese population and three genetic loci associated with FeNO, an indicator of type 2 airway inflammation in adults.

Upregulation of leukocyte immunoglobulin-like receptor B4 on interstitial macrophages in COPD; their possible protective role against emphysema formation.

BACKGROUND: Leukocyte immunoglobulin-like receptor B4 (LILRB4) is one of the inhibitory receptors in various types of immune cells including macrophages. Previous reports suggested that LILRB4 could be involved in a negative feedback system to prevent excessive inflammatory responses. However, its role has been unclear in chronic obstructive pulmonary disease (COPD), in which macrophages play a crucial role in the pathogenesis. In this study, we aimed to examine the changes of LILRB4 on macrophages both in the lung specimens of COPD patients and the lungs of a mouse emphysema model. We then tried to compare the differences in both inflammation and emphysematous changes of the model between wild-type and LILRB4-deficient mice in order to elucidate the role of LILRB4 in the pathogenesis of COPD. METHODS: We prepared single-cell suspensions of resected lung specimens of never-smokers (n = 21), non-COPD smokers (n = 16), and COPD patients (n = 14). The identification of LILRB4-expressing cells and the level of LILRB4 expression were evaluated by flow cytometry. We analyzed the relationships between the LILRB4 expression and clinical characteristics including respiratory function. In the experiments using an elastase-induced mouse model of emphysema, we also analyzed the LILRB4 expression on lung macrophages. We compared inflammatory cell accumulation and emphysematous changes induced by elastase instillation between wild-type and LILRB4-deficient mice. RESULTS: The levels of surface expression of LILRB4 are relatively high on monocyte linage cells including macrophages in the human lungs. The percentage of LILRB4+ cells in lung interstitial macrophages was increased in COPD patients compared to non-COPD smokers (p = 0.018) and correlated with the severity of emphysematous lesions detected by CT scan (rs = 0.559, p < 0.001), whereas the amount of smoking showed no correlation with LILRB4 expression. Increased LILRB4 on interstitial macrophages was also observed in elastase-treated mice (p = 0.008). LILRB4-deficient mice showed severer emphysematous lesions with increased MMP-12 expression in the model. CONCLUSIONS: LILRB4 on interstitial macrophages was upregulated both in human COPD lungs and in a mouse model of emphysema. This upregulated LILRB4 may have a protective effect against emphysema formation, possibly through decreasing MMP-12 expression in the lungs.

Triple versus LAMA/LABA combination therapy for patients with COPD: a systematic review and meta-analysis.

BACKGROUND: Recently, the addition of inhaled corticosteroid (ICS) to long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist (LABA) combination therapy has been recommended for patients with COPD who have severe symptoms and a history of exacerbations because it reduces the exacerbations. In addition, a reducing effect on mortality has been shown by this treatment. However, the evidence is mainly based on one large randomized controlled trial IMPACT study, and it remains unclear whether the ICS add-on treatment is beneficial or not. Recently, a large new ETHOS trial has been performed to clarify the ICS add-on effects. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety including ETHOS trial. METHODS: We searched relevant randomized control trials (RCTs) and analyzed the exacerbations, quality of life (QOL), dyspnea symptom, lung function and adverse events including pneumonia and mortality, as the outcomes of interest. RESULTS: We identified a total of 6 RCTs in ICS add-on protocol (N = 13,579). ICS/LAMA/LABA treatment (triple therapy) significantly decreased the incidence of exacerbations (rate ratio 0.73, 95% CI 0.64-0.83) and improved the QOL score and trough FEV1 compared to LAMA/LABA. In addition, triple therapy significantly improved the dyspnea score (mean difference 0.33, 95% CI 0.18-0.48) and mortality (odds ratio 0.66, 95% CI 0.50-0.87). However, triple therapy showed a significantly higher incidence of pneumonia (odds ratio 1.52, 95% CI 1.16-2.00). In the ICS-withdrawal protocol including 2 RCTs, triple therapy also showed a significantly better QOL score and higher trough FEV1 than LAMA/LABA. Concerning the trough FEV1, QOL score and dyspnea score in both protocols, the differences were less than the minimal clinically important difference. CONCLUSION: Triple therapy causes a higher incidence of pneumonia but is a more preferable treatment than LAMA/LABA due to the lower incidence of exacerbations, higher trough FEV1 and better QOL score. In addition, triple therapy is also superior to LABA/LAMA due to the lower mortality and better dyspnea score. However, these results should be only applied to patients with symptomatic moderate to severe COPD and a history of exacerbations. CLINICAL TRIAL REGISTRATION: PROSPERO; CRD42020191978.