Search

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

Background and objective The efficacy of combination therapy with corticosteroids and CNI, TAC and CsA, for PM/DM-ILD has been described retrospectively. However, it remains unknown which CNI treatment regimens, TAC or CsA regimens, are more effective as initial treatments for patients with PM/DM-ILD. Methods We conducted a prospective multicentre, open-label, randomized, 52-week phase 2 trial. Patients with PM/DM-ILD were randomly allocated to receive PSL plus TAC (TAC group) or PSL plus CsA (CsA group). The primary endpoint was PFS rate in the intention-to-treat population at 52 weeks. The secondary endpoints were OS rate at 52 weeks, changes in pulmonary function tests from baseline to 52 weeks and AE. Results Fifty-eight patients were randomly assigned to the TAC group (n = 30) and the CsA group (n = 28). The PFS rates at 52 weeks were 87% in the TAC group and 71% in the CsA group (P = 0.16). The OS rates at 52 weeks were 97% in the TAC group and 93% in the CsA group (P = 0.50). The %FVC at 52 weeks in the per-protocol populations significantly increased in both groups. None of the patients discontinued the treatment due to AE. Conclusion PSL plus TAC treatment may achieve a better short-term PFS rate compared with PSL plus CsA treatment. Further studies must be conducted to evaluate the long-term efficacy and safety of such treatment.

Objective: Dual bronchodilation with long-acting muscarinic antagonist and long-acting β2-agonist combinations are available worldwide in COPD patients. However, the choice of agents remains under debate. We hypothesized that switching devices between dry powder and soft mist inhalers without a wash-out period to mimic clinical practice would improve clinical symptoms and lung function. The aim of this study was to examine the effects of switching between once-daily glycopyrronium/indacaterol (GLY/IND) or umeclidinium/vilanterol (UMEC/VI), dry powder inhalers, and tiotropium/olodaterol (TIO/OLO), a soft mist inhaler, in COPD patients. Methods: This was a prospective, open-label, 8-week, observational study with follow-up. Subjects included 57 COPD patients, who attended outpatient clinics at Shizuoka General Hospital for routine check-ups between February and December 2015, receiving GLY/IND (50/110 μg) or UMEC/VI (62.5/25 μg). After an 8-week run-in period, medications were switched to TIO/OLO (5/5 μg). Study outcomes included patient’s global rating (PGR), modified MRC (mMRC), COPD assessment test (CAT), and spirometric and forced oscillatory parameters after 8 weeks. PGR used in this study was a 7-point scale ranging from 1 to 7, with 4 in the middle. Patients who consented to switch from TIO/OLO to GLY/IND or UMEC/VI were followed-up thereafter. Results: In total, 53 patients completed the study (mean age, 75 years; 48 males and 5 females; GOLD 1/2/3/4 = 19/27/6/1; mMRC 0/1/2/3/4 = 14/22/12/4/1; UMEC/VI 26, GLY/IND 27). PGR, mMRC, and CAT improved in 20 (38%), 9 (17%), and 15 patients (28%), respectively. Respiratory system resistance at 5 Hz (R5), 20 Hz (R20), and the difference between R5 and R20 (R5 - R20) significantly improved. In a follow-up of 16 patients after switching from TIO/OLO to UMEC/VI (9) or GLY/IND (7), PGR, mMRC, and CAT improved in 5 (31%), 3 (12%), and 4 patients (25%), respectively, and R20 significantly improved (p = 0.011). Conclusions: Switching dual bronchodilators between dry powder and soft mist inhalers improves symptoms and airway narrowing in some COPD patients.

Background Lung fibrosis is a serious life-threatening condition whose manifestation varies according to the localization and characteristics of fibroblasts, which are considered heterogeneous. Therefore, to better understand the pathology and improve diagnosis and treatment of this disease, it is necessary to elucidate the nature of this heterogeneity and identify markers for the accurate classification of human lung fibroblast subtypes. Methods We characterized distinct mouse lung fibroblast subpopulations isolated by fluorescence-activated cell sorting (FACS) and performed microarray analysis to identify molecular markers that could be useful for human lung fibroblast classification. Based on the expression of these markers, we evaluated the fibroblast-like cell subtype localization in normal human lung samples and lung samples from patients with idiopathic pulmonary fibrosis (IPF). Results Mouse lung fibroblasts were classified into Sca-1high fibroblasts and Sca-1low fibroblasts by in vitro biological analyses. Through microarray analysis, we demonstrated CD248 and integrin alpha-8 (ITGA8) as cell surface markers for Sca-1high fibroblasts and Sca-1low fibroblasts, respectively. In mouse lungs, Sca-1high fibroblasts and Sca-1low fibroblasts were localized in the collagen fiber-rich connective tissue and elastic fiber-rich connective tissue, respectively. In normal human lungs and IPF lungs, two corresponding major fibroblast-like cell subtypes were identified: CD248highITGA8low fibroblast-like cells and CD248lowITGA8high fibroblast-like cells, localized in the collagen fiber-rich connective tissue and in the elastic fiber-rich connective tissue, respectively. Conclusion CD248highITGA8low fibroblast-like cells and CD248lowITGA8high fibroblast-like cells were localized in an almost exclusive manner in human lung specimens. This human lung fibroblast classification using two cell surface markers may be helpful for further detailed investigations of the functions of lung fibroblast subtypes, which can provide new insights into lung development and the pathological processes underlying fibrotic lung diseases.

Background Few studies have examined whether baseline spirometry and the forced oscillation technique (FOT) would predict The COPD Assessment Test (CAT) score improvement after treatment of untreated COPD patients. Methods The study subjects included 65 untreated COPD patients. They underwent the CAT, spirometry, and FOT (MostGraph) before and after treatment for more than 2 months. In addition, recursive partitioning analysis was performed using spirometry and the FOT parameters to identify the predictors of CAT improvement (CAT score ≥2). Results CAT scores and lung function significantly improved after treatment. Recursive partitioning analysis identified 3 improved classes, defined by Rrs at 20 Hz (R20), Xrs at 5 Hz (X5), and ΔX5, but not by spirometry. The accuracy of predicting CAT improvement was as follows: odds ratio, 25.3; 95 % confidence interval, 6.1 to 104.1; sensitivity, 91.2 %; specificity, 71.0 %; positive likelihood ratio, 3.14; and negative likelihood ratio, 0.12. Conclusions FOT helps predict improved health status in untreated COPD patients.

There are reports concerning mucus plugs detected on high-resolution computed tomography images and airflow obstruction in asthma and chronic obstructive pulmonary disease (COPD). However, little is known about the associations between mucus plugs and small airway dysfunction (SAD). We evaluated the relationship between mucus plugs and pulmonary function in patients with asthma, COPD, and asthma-COPD overlap (ACO), and investigated the relevance to SAD and type 2 inflammation in a retrospective study.Subjects included 49 asthmatic, 40 ACO, and 41 COPD patients. ACO was diagnosed based on the Japanese Respiratory Society ACO guidelines. Clinical and laboratory parameters, including blood eosinophil count, serum total IgE levels, fractional exhaled nitric oxide (FeNO), spirometry, and forced oscillation technique (FOT), were compared between patients with and without mucus plugs.Mucus plugs were found in 29 (59%) asthmatic, 25 (65%) ACO, 17 (41%) COPD patients. Patients with mucus plugs had reduced spirometry and larger FOT parameters, especially in COPD patients. Mucus scores correlated positively with IgE in ACO and FeNO in asthmatic patients, but not in COPD patients. Multivariate logistic regression analysis revealed that SAD parameters, including forced vital capacity and resonant frequency, a respiratory reactance parameter, were significantly associated with the presence of mucus plugs in the whole studied population.SAD, rather than large airway dysfunction, was associated with mucus plugs in asthma, ACO, and COPD patients.

Objective Benralizumab is a promising drug for severe uncontrolled asthma. This study aimed to clarify the effectiveness of benralizumab in a real-life setting. Methods Subjects included 24 patients with severe type 2 asthma who received benralizumab between April 2018 and July 2019. Changes in parameters, exacerbation frequency, and oral corticosteroid (OCS) use after 4 and 24 weeks of administration were examined. The parameters included the Global Evaluation of Treatment Effectiveness (GETE) scale, Asthma Control Questionnaire (ACQ), Asthma Control Test (ACT), blood eosinophils, fractional exhaled nitric oxide (FeNO), and spirometry. The response to treatment was defined as follows: for patients with exacerbations or OCS use before treatment initiation, a reduction of ≥50% in exacerbation frequency or OCS use; and for patients without exacerbations or OCS use, an improvement of ≥0.5 in ACQ scores and ≥3 in ACT scores, or of ≥10.38% in FEV1. Results Twenty-one patients completed the treatment for 24 weeks. Excellent and good GETE scales and ACQ and ACT improvement were found in 67% of the patients at 4 weeks, and the effect continued until 24 weeks. The patients' rate with exacerbations was significantly reduced compared to the previous 24 weeks before administration. In 17 patients receiving OCS, the use could be reduced or quit in 14 patients. Overall, 16 patients (76.2%) met the responder definition and could be predicted by the baseline eosinophil count and FeNO levels with the best cutoff values of 100/μL and 40 ppb, respectively. Conclusions Blood eosinophil and FeNO could predict benralizumab effectiveness.

Background Cough is one of the most common distressing symptoms of lung cancer. However, there is no specific measure of cough in lung cancer in Japanese. The present study aimed to determine the validity of the Japanese version of the Manchester Cough in Lung Cancer Scale (MCLCS). Methods The MCLCS is a cough-specific quality of life (QOL) questionnaire for lung cancer that consists of 10 items on cough frequency, distress, impact, and severity. Items are evaluated on a scale of 1–5 (1: never, 2: some of the time, 3: often, 4: most of the time, and 5: all of the time). Total scores can range from 1 to 50, with higher scores indicating worse cough-related QOL. The Japanese version of the MCLCS was created through forward and backward translation. Patients completed the Japanese version of the MCLCS, the Leicester Cough Questionnaire (LCQ), and the cough visual analog scale (VAS). To confirm the reliability of the MCLCS, Cronbach's α coefficient was calculated, and for validity, the Spearman's rank correlation coefficient was used to assess the correlations between MCLCS and LCQ or cough VAS. Results Of the total 192 lung cancer patients enrolled in this study, 73 had a cough in the preceding week. The median MCLCS score was 28, demonstrating an excellent internal consistency (Cronbach's α coefficient = 0.83). MCLCS was strongly and significantly correlated with LCQ and cough VAS. Conclusions The Japanese version of MCLCS is a valid tool for assessing cough in lung cancer patients.

Background Cough and sputum are the major symptoms of pulmonary tuberculosis (TB). However, the relationship between these symptoms and treatment for TB is not fully understood. The aim of this prospective study was to clarify the cough- and sputum-related quality of life (QOL) in patients with pulmonary TB before and after initiation of treatment. Methods The study included 85 patients with active pulmonary TB who were hospitalized from July 2014 to August 2015. They completed the Leicester Cough Questionnaire (LCQ: range 3–21, the higher the better) and the Cough and Sputum Assessment Questionnaire (CASA-Q: range 0–100, the higher the better) on admission and at discharge after 2 months of treatment. Results The LCQ and CASA-Q scores were reduced on admission. A multivariate linear regression analysis revealed that younger age, more than two cavitary lesions, and the presence of bronchial TB were associated with reduced LCQ total score. However, each score significantly improved at discharge, regardless of the initial grade of the sputum smear, site of the lesion, number of cavitary lesions, and presence of bronchial TB. The change in the mean LCQ total score was 2.28 (95% confidence interval, 1.56–3.00). The changes in the mean CASA-Q cough symptoms, cough impact, sputum symptoms, and sputum impact scores were 22.84 (18.44–27.25), 10.96 (7.20–14.71), 17.25 (13.33–21.18), and 5.25 (2.49–8.00), respectively. Conclusions Cough- and sputum-related QOL was impaired in patients with pulmonary TB before treatment but improved after initiation of treatment regardless of the clinical characteristics.

Background: There are no standard cytotoxic treatments for non-small-cell lung cancer (NSCLC) patients beyond third-line therapy. The purpose of this study was to evaluate the efficacy and safety of amrubicin in pretreated NSCLC patients. Methods: The records of NSCLC patients who received amrubicin monotherapy as a third or later line of chemotherapy at Shizuoka General Hospital between April 2007 and March 2015 were retrospectively reviewed. Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1. Toxicities were evaluated according to the Common Terminology Criteria for Adverse Events version 3.0. Results: Overall, 69 patients were enrolled in this study; 16 patients were female and the median age was 67 years. The median number of treatment cycles was 3. The response rate was 7.2%, and the disease control rate was 63.8%. The median progression-free survival was 2.8 months. The median overall survival was 7.7 months. Hematological toxicities of ≥ grade 3 included leukopenia (59.4%) and neutropenia (62.3%). Non-hematological toxicities of ≥ grade 2 included anorexia (27.5%) and fatigue (24.6%). Conclusion: Although hematological toxicities were severe, these results suggested that amrubicin in NSCLC patients beyond third-line therapy shows sufficient clinical benefit.

Background The effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in preventing pneumococcal pneumonia has been controversial. Methods To evaluate the effectiveness of the PPSV23 in elderly outpatients with chronic respiratory diseases, we carried out a case–control study, including 4128 outpatients aged ≥ 65 years, in the respiratory department. Results There were 320 vaccinated patients, of which 164 were diagnosed with pneumococcal pneumonia. The adjusted odds ratio was 0.39 (95% confidence interval (CI), 0.17 to 0.89). In the subsets consisting of age groups ≥ 70 and ≥ 75 years, the adjusted odds ratio (95% CI) was respectively 0.16 (0.04 to 0.67) and 0.15 (0.02 to 1.12). Conclusion This real-world study suggests that PPSV23 can be useful in preventing pneumococcal pneumonia in the elderly with chronic respiratory diseases.

The usefulness of the oscillometry, known as forced oscillation technique, for predicting exercise tolerance in subjects with COPD is unknown. To test the hypothesis, we investigated whether oscillometry could predict a 6-minute walking distance (6MWD) 1, 61.0%). Modified MRC dyspnea scale (mMRC), COPD Assessment Test (CAT), oscillometry, spirometry, and 6MWT were performed in a stable condition. The participants were classified into subjects with 6MWD ≥350 m or 6MWD 1, IC, 6MWD, lowest SpO2, maximum Borg scale, respiratory resistance (Rrs), and reactance (Xrs). In multivariate regression analysis, a 6MWD 20/L/s. In conclusion, the oscillatory parameter, inspiratory R5, predicted low exercise tolerance in COPD subjects.

Background: Some patients present clinical features of both asthma and chronic obstructive pulmonary disease (COPD), which has led to the recent proposal of asthma-COPD overlap (ACO) as a diagnosis. Fractional exhaled nitric oxide (FeNO) is a candidate biomarker to diagnose ACO. We assessed the effect of an add-on treatment with budesonide/formoterol (BUD/FM) combination in patients with ACO, which was diagnosed by FeNO. Methods: This was a prospective, single-arm, open-label, before and after comparison study. Subjects included 83 patients with COPD who attended outpatient clinics for routine checkups at Shizuoka General Hospital between June and November 2016. All patients fulfilled the GOLD definition of COPD and were receiving long-acting muscarinic antagonist (LAMA) or LAMA/long-acting β2 agonist (LABA) combinations. After an 8-week run-in period, BUD/FM was added to the patients with FeNO levels of ≥35 ppb, defined as having ACO. For patients receiving LAMA/LABA, BUD/FM was added after the discontinuation of LABA. The modified British Medical Research Council (mMRC) score, COPD assessment test (CAT) score, spirometric indices, forced oscillation parameters, and FeNO were assessed before and after 8 weeks of BUD/ FM add-on treatment. Results: Twenty-four patients (28.9%) had FeNO levels ≥ 35 ppb, and 17 patients completed the study (mean age: 73 years and GOLD I/II/III/IV, 5/10/1/1). The mean CAT scores significantly improved (9.2 to 5.4, p = 0.015) and 10 patients (58.8%) showed ≥2 points improvement, a minimal clinically important difference. The mean FeNO levels significantly decreased from 63.0 to 34.3 ppb (p < 0.006). However, there were no changes in mMRC scores, spirometric indices, or forced oscillation parameters. Conclusions: FeNO-guided treatment with BUD/FM improves symptoms in patients with ACO.

Background Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases. The phenotypes that have clinical features of both asthma and COPD are still incompletely understood. Objective To clarify the best discriminators of the asthma-COPD overlap phenotype from asthma and COPD subgroups using a clustering approach. Methods This study assessed pathophysiological parameters, including mRNA expression levels of T helper cell-related transcription factors, namely, TBX21 (Th1), GATA3 (Th2), RORC (Th17), and FOXP3 (Treg), in peripheral blood mononuclear cells in asthma patients (n = 152) and in COPD patients (n = 50). Clusters were determined using k-means clustering. Exacerbations of asthma and COPD were recorded during the 1-year follow-up period. Results The cluster analysis revealed four biological clusters: cluster 1, predominantly patients with COPD; cluster 2, patients with an asthma-COPD overlap phenotype; cluster 3, patients with non-atopic and late-onset asthma; and cluster 4, patients with early-onset atopic asthma. Hazard ratios for exacerbation were 2.5 (95% confidence interval [CI], 1.1–5.6) in cluster 1 and 2.3 (95% CI, 1.0–5.0) in cluster 2 compared with patients in other clusters. Cluster 2 was discriminated from other clusters by total serum IgE level ≥ 310 IU/mL, blood eosinophil counts ≥ 280 cells/μL, a higher ratio of TBX21/GATA3, FEV1/FVC ratio < 0.67, and smoking ≥ 10 pack-years with an area under the curve of 0.94 (95% CI, 0.90–0.98) in the receiver operating characteristic analysis. Conclusions & Clinical Relevance The asthma-COPD overlap phenotype was characterized by peripheral blood eosinophilia and higher levels of IgE despite the Th2-low endotype. This article is protected by copyright. All rights reserved.

Our aims were to identify pericyte-specific markers for the analysis of formalin-fixed, paraffin-embedded human tissue samples, and to characterize perivascular myoid cell neoplasms phenotypically. Previously identified pericyte markers failed to distinguish pericytes from other cellular types, such as vascular smooth muscle cells (vSMCs) and fibroblasts, in immunohistochemistry analysis. However, we compared gene expression profiles between pericytes, vSMCs, and fibroblasts, and performed human skin vasculature immunohistochemistry analysis, which led to the identification of myosin 1B (MYO1B) as a novel pericyte marker. Afterward, we investigated the expression levels of MYO1B and h-caldesmon (h-CD) in perivascular myoid cell neoplasms, angioleiomyomas (n=28), glomus tumors (n=23), and myopericytomas (n=3). Angioleiomyomas were shown to contain MYO1B-negative and h-CD-positive (MYO1B-hCD+) tumor cells, with vSMC features. Glomus tumors were predominantly composed of the MYO1B+hCD+ tumor cells, with the intermediate features between pericytes and vSMCs, whereas MYO1B+hCD- tumor cells with pericytic features and/or the MYO1B-hCD+ tumor cells with vSMC features were frequently found in these tumors. The perivascular concentric pattern of 2 myopericytoma cases was composed of MYO1B+hCD+ tumor cells, whereas that of one myopericytoma contained MYO1B-hCD+ tumor cells. These results indicate that the ability to distinguish between these cell types may allow us to understand the differentiation and origin of perivascular myoid cell neoplasms. This is the first study to identify cell properties of perivascular myoid cell neoplasms by using a pericyte-specific marker with considerably lower expression in vSMCs and fibroblasts.