Yuji Tohda

Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids.

BACKGROUND Periostin, an extracellular matrix protein, contributes to subepithelial thickening in asthmatic airways, and its serum levels reflect airway eosinophilic inflammation. However, the relationship between periostin and the development of airflow limitation, a functional consequence of airway remodeling, remains unknown. OBJECTIVE We aimed to determine the relationship between serum periostin levels and pulmonary function decline in asthmatic patients on inhaled corticosteroid (ICS) treatment. METHODS Two hundred twenty-four asthmatic patients (average age, 62.3 years) treated with ICS for at least 4 years were enrolled. Annual changes in FEV1, from at least 1 year after the initiation of ICS treatment to the time of enrollment or later (average, 16.2 measurements over 8 years per individual), were assessed. At enrollment, clinical indices, biomarkers that included serum periostin, and periostin gene polymorphisms were examined. Associations between clinical indices or biomarkers and a decline in FEV1 of 30 mL or greater per year were analyzed. RESULTS High serum periostin levels (≥ 95 ng/mL) at enrollment, the highest treatment step, higher ICS daily doses, a history of admission due to asthma exacerbation, comorbid or a history of sinusitis, and ex-smoking were associated with a decline in FEV1 of 30 mL or greater per year. Multivariate analysis showed that high serum periostin, the highest treatment step, and ex-smoking were independent risk factors for the decline. Polymorphisms of periostin gene were related to higher serum periostin levels (rs3829365) and a decline in FEV1 of 30 mL or greater per year (rs9603226). CONCLUSIONS Serum periostin appears to be a useful biomarker for the development of airflow limitation in asthmatic patients on ICS.

Serum biomarkers as predictors of lung function decline in chronic obstructive pulmonary disease

BACKGROUND Recent studies show that COPD patients exhibit low-grade systemic inflammation, and that plasma fibrinogen and high neutrophil counts are related to faster declines in lung function. We examined correlations between serum biomarkers and the decline of lung function in COPD patients. METHOD Baseline levels of 9 serum biomarkers (TIMP-1, alpha1-antitrypsin, MMP-9, TNF-alpha, TGF-beta, IL-6, IL-8, neutrophil elastase and CRP), fibrinogen and white blood cell counts (WCC) were measured in 96 COPD patients. Lung function was measured at the time of blood sampling and every 3-6 months during the observation period (median 25.0 months). RESULTS Twenty patients were rapid decliners of lung function and 53 patients were non-decliners. Neutrophil counts, serum CRP and MMP-9 were significantly higher in the rapid decliners (p<0.05). The annual change of % predicted FEV(1) was inversely correlated with MMP-9 (r=-0.288; p<0.01) and CRP (r=-0.354; p<0.005) (partial correlation coefficients adjusted for age, sex, cardiovascular disease, smoking history, and baseline % predicted FEV(1)). The remaining biomarkers were not correlated with the annual change of % predicted FEV(1). CONCLUSION Serum CRP and MMP-9 levels were related to FEV(1) decline. These markers are good candidates as predictors for rapid decline of FEV(1) in COPD patients. Additional long-term and larger size studies of COPD patients could help determine the exact roles for these biomarkers.

Leukotriene receptor antagonist, montelukast, can reduce the need for inhaled steroid while maintaining the clinical stability of asthmatic patients.

Background Oral leukotriene receptor antagonists have been shown to have efficacy in chronic asthma.

Long-Term Once-Daily Tiotropium Respimat® Is Well Tolerated and Maintains Efficacy over 52 Weeks in Patients with Symptomatic Asthma in Japan: A Randomised, Placebo-Controlled Study

Background This study assessed the long-term safety and efficacy of tiotropium Respimat, a long-acting inhaled anticholinergic bronchodilator, in asthma, added on to inhaled corticosteroids (ICS) with or without long-acting β2-agonist (LABA). Methods 285 patients with symptomatic asthma, despite treatment with ICS±LABA, were randomised 2:2:1 to once-daily tiotropium 5 μg, tiotropium 2.5 μg or placebo for 52 weeks (via the Respimat SoftMist inhaler) added on to ICS±LABA, in a double-blind, placebo-controlled, parallel-group study (NCT01340209). Primary objective: to describe the long-term safety profile of tiotropium. Secondary end points included: trough forced expiratory volume in 1 second (FEV1) response; peak expiratory flow rate (PEFR) response; seven-question Asthma Control Questionnaire (ACQ-7) score. Results At Week 52, adverse-event (AE) rates with tiotropium 5 μg, 2.5 μg and placebo were 88.6%, 86.8% and 89.5%, respectively. Commonly reported AEs with tiotropium 5 μg, 2.5 μg and placebo were nasopharyngitis (48.2%, 44.7%, 42.1%), asthma (28.9%, 29.8%, 38.6%), decreased PEFR (15.8%, 7.9%, 21.1%), bronchitis (9.6%, 13.2%, 7.0%), pharyngitis (7.9%, 13.2%, 3.5%) and gastroenteritis (10.5%, 3.5%, 5.3%). In the tiotropium 5 μg, 2.5 μg and placebo groups, 8.8%, 5.3% and 5.3% of patients reported drug-related AEs; 3.5%, 3.5% and 15.8% reported serious AEs. Asthma worsening was the only serious AE reported in more than one patient. At Week 52, adjusted mean trough FEV1 and trough PEFR responses were significantly higher with tiotropium 5 μg (but not 2.5 μg) versus placebo. ACQ-7 responder rates were higher with tiotropium 5 μg and 2.5 μg versus placebo at Week 24. Conclusions The long-term tiotropium Respimat safety profile was comparable with that of placebo Respimat, and associated with mild to moderate, non-serious AEs in patients with symptomatic asthma despite ICS±LABA therapy. Compared with placebo, tiotropium 5 μg, but not 2.5 μg, significantly improved lung function and symptoms, supporting the long-term efficacy of the 5 μg dose. Trial Registration ClinicalTrials.gov NCT01340209

Assessment of Serum CYFRA 21-1 in Lung Cancer

Cytokeratins are the intermediate filaments of the cytoskeletal protein located in normal epithelia, tumor, and cultured cells. Recently, a fragment of cytokeratin subunit 19, referred to as CYFRA 21‐1, detected in the serum of patients with nonsmall cell lung cancer, has been reported as a new tumor marker. This article reports the results of a study of serum fragment CYFRA 21‐1, measured by immunoradiometric assay, as a marker of lung cancer.

Using Exhaled Nitric Oxide and Serum Periostin as a Composite Marker to Identify Severe/Steroid-Insensitive Asthma

At present, exhaled nitric oxide (FENO) is a clinically useful biomarker of eosinophilic airway inflammation (1); its levels increase during exacerbation and decrease with inhaled corticosteroid (ICS) treatment (2). Evidence has demonstrated that high FENO levels (>35 ppb) indicate the presence of a highly reactive phenotype among patients with asthma (3), which is useful for the management of patients. Nonetheless, additional markers are required for better characterization of patients with asthma with elevated FENO (>25 ppb), particularly to identify patients who may have steroid resistance (2). Serum periostin is a biomarker of helper T type 2/eosinophilic airway inflammation in asthma (4, 5) distinct from FENO (6). Periostin is a matricellular protein actively involved in airway remodeling (4, 7, 8), with partial steroid resistance (9), although steroid-sensitive aspects were initially highlighted (10). Indeed, high serum periostin levels are associated with refractory eosinophilic inflammation (5) and accelerated decline in pulmonary function in patients with asthma under ICS treatment (11, 12). Importantly, serum periostin levels are relatively stable and less variable than FENO (5, 6), which is advantageous for long-term monitoring of patients with asthma. Therefore, we hypothesized that high serum periostin could be used as a biomarker to efficiently identify ICS-insensitive patients among patients with elevated FENO. In the present study, we demonstrated the reliability of comeasurement of FENO and serum periostin to identify ICS-insensitive patients; they were defined as those with an accelerated decline in FEV1 of at least 30 ml/year (11) or a risk of asthma exacerbations requiring systemic corticosteroid bursts despite adequate ICS treatments in this study. This is a substudy of the Kinki Hokuriku Airway Disease Conference (KiHAC) study that investigated genobiological factors associated with pulmonary function decline in adults with asthma receiving ICS treatment; the patients had undergone 16.26 13.9 FEV1 measurements over 8.06 4.5 years (11). The study protocol (UMIN000002414) was approved by the ethics committee of each participating institution. The present study included the patients who agreed to FENO measurements with a chemiluminescence analyzer (NOA 280; Sievers, Boulder, CO) at enrollment. All patients underwent baseline examination, including a selfcompleted questionnaire, the asthma control test, spirometry, and blood tests at enrollment, as described previously (11). FENO levels were determined at an expiratory flow rate of 50 ml/second, according to the present guidelines (13, 14). The frequency of asthma exacerbation, requiring systemic corticosteroid bursts, was documented for 2 years after enrollment, except for one patient who was lost to follow-up 1 year after enrollment. Serum periostin levels were determined using an enzyme-linked immunosorbent assay at Shino-Test (Kanagawa, Japan), and a cutoff point of 95 ng/ml was used to define high serum periostin (11). Follow-up FENO and serum periostin measurements were not obligatory, but they were measured in several patients on various occasions during the subsequent 2 years (see the online supplement). Statistical analysis was performed with JMP version 9.0 software (SAS Institute Inc., Tokyo, Japan). FENO and serum periostin levels were log-transformed to achieve normal distribution. Pearson correlation coefficients were used to identify relationships between the parameters. Two data sets were compared, using the unpaired t test or Wilcoxon rank-sum test for numerical data and the x test or Fisher exact test for nominal data, as deemed appropriate. The comparison between high and low serum periostin groups or FENO groups regarding an accelerated decline in FEV1 was performed after adjustment for sex, height, age at enrollment, and FEV1 at the first measurement. Logistic regression analysis was performed to estimate the risk of subsequent asthma exacerbations (see the online supplement). Data are presented as means6 SD or percentage. P< 0.05 was considered statistically significant. The FENO levels, determined in 121 patients, were weakly associated with serum periostin levels (Figure 1). This relationship between FENO and serum periostin was stronger when the analysis was confined to patients undergoing treatment step 4 or 5 as

Interleukin‐18‐deficient mice exhibit diminished chronic inflammation and airway remodelling in ovalbumin‐induced asthma model

Interleukin (IL)‐18, which is produced by activated monocytes/macrophages and airway epithelial cells, is suggested to contribute to the pathophysiology of asthma by modulating airway inflammation. However, the involvement of IL‐18 on modulating chronic airway inflammation and airway remodelling, which are characterized in a refractory asthma model exposed to long‐term antigen, has not been investigated sufficiently. We examined the role of IL‐18 in chronic airway inflammation and airway remodelling by long‐term antigen exposure. IL‐18‐deficient and C57BL/6‐wild‐type mice were sensitized by ovalbumin (OVA) and were then exposed to aerosolized OVA twice a week for 12 weeks. We assessed airway inflammation by assessing the infiltration of cells into the airspace and lung tissues, and airway remodelling by airway mucus expression, peribronchial fibrosis and smooth muscle thickness. In IL‐18‐deficient mice, when exposed to OVA, the total cells and neutrophils of the bronchoalveolar lavage fluid (BALF) were diminished, as were the number of infiltrated cells in the lung tissues. IL‐18‐deficient mice exposed to OVA after 12 weeks showed significantly decreased levels of interferon (IFN)‐γ, IL‐13 and transforming growth factor (TGF)‐β1 in the BALF. The airway hyperresponsiveness to acetyl‐β‐methacholine chloride was inhibited in IL‐18‐deficient mice in comparison with wild‐type mice. In addition, IL‐18‐deficient mice exposed to OVA had fewer significant features of airway remodelling. These findings suggest that IL‐18 may enhance chronic airway inflammation and airway remodelling through the production of IFN‐γ, IL‐13 and TGF‐β1 in the OVA‐induced asthma mouse model.

The Strategy for Predicting Future Exacerbation of Asthma Using a Combination of the Asthma Control Test and Lung Function Test

Background. Various factors have been reported to be useful for predicting future exacerbations. Objective. This study was intended to determine a usefulness of a combination of a patient-based questionnaire, such as the Asthma Control Test (ACT) score with objective assessments, such as forced expiratory volume in 1 second (FEV1) and/or exhaled nitric oxide (FENO), for predicting future exacerbations in adult asthmatics. Methods. We therefore enrolled 78 subjects with mild to moderate asthma, who were clinically stable for 3 months who all had been regularly receiving inhaled steroid treatment. All subjects underwent a routine assessment of asthma control including the ACT score, spirometry, and FENO, and then were followed up until a severe exacerbation occurred. The predictors of an increased risk of severe exacerbation were identified and validated using decision trees based on a classification and regression tree (CART) analysis. The properties of the developed models were the evaluated with the area under the ROC curve (AUC) (95% confidence interval [CI]). Results. The CART analysis automatically selected the variables and cut-off points, the ACT score ≤23 and FEV1 ≤ 91.8%, with the greatest capacity for discriminating future exacerbations within one year or not. When the probalility was calculated by the likelihood ratio of a positive test (LP), the ACT score ≤23 was identified with a 60.3% probability, calculated by 1.82 of LP, whereas the combined ACT score ≤23 and the percentage of predicted FEV1 ≤ 91.8% were identified with an 85.0% probability, calculated by an LP score of 5.43, for predicting future exacerbation. Conclusion. These results demonstrated that combining the ACT score and percentage of predicted FEV1, but not FENO, can sufficiently stratify the risk for future exacerbations within one year.

Japanese Guideline for Adult Asthma 2014.

Adult bronchial asthma (hereinafter, asthma) is characterized by chronic airway inflammation, reversible airway narrowing, and airway hyperresponsiveness. Long-standing asthma induces airway remodeling to cause intractable asthma. The number of patients with asthma has increased, and that of patients who die from asthma has decreased (1.5 per 100,000 patients in 2012). The aim of asthma treatment is to enable patients with asthma to lead a normal life without any symptoms. A good relationship between physicians and patients is indispensable for appropriate treatment. Long-term management with antiasthmatic agents and elimination of the causes and risk factors of asthma are fundamental to its treatment. Four steps in pharmacotherapy differentiate between mild and intensive treatments; each step includes an appropriate daily dose of an inhaled corticosteroid, varying from low to high. Long-acting 02-agonists, leukotriene receptor antagonists, and sustained-release theophylline are recommended as concomitant drugs, while anti-immunoglobulin E antibody therapy has been recently developed for the most severe and persistent asthma involving allergic reactions. Inhaled 02-agonists, aminophylline, corticosteroids, adrenaline, oxygen therapy, and others are used as needed in acute exacerbations by choosing treatment steps for asthma exacerbations depending on the severity of attacks. Allergic rhinitis, chronic obstructive pulmonary disease, aspirin-induced asthma, pregnancy, asthma in athletes, and coughvariant asthma are also important issues that need to be considered.

Intrapleural Administration of Cisplatin and Etoposide to Treat Malignant Pleural Effusions in Patients with Non-Small Cell Lung Cancer

Background: To determine the efficacy, toxicity and pharmacokinetics of intrapleural cisplatin (CDDP) and etoposide as a treatment for malignant pleural effusions (MPE) in patients with non-small cell lung cancer (NSCLC). Methods: Seventy patients with MPE associated with NSCLC were enrolled in this study. In 68 patients, a catheter was inserted into the pleural cavity, within 24 h after complete drainage of the pleural effusion, CDDP (80 mg/m2) and etoposide (80 mg/m2) were simultaneously administered successfully via the catheter and the catheter was clamped. Seventy-two hours later, the catheter was unclamped to allow drainage. The catheter was removed when the accumulated intrapleural fluid decreased to 20 ml or less per day. Results: The pharmacokinetic profiles showed high maximum concentrations of CDDP (free form, 88 µg/ml) and etoposide (182.4 µg/ml) in intrapleural fluids. CDDP did not remain for a long period (free form, β-phase half-life = 10.51 h) in the fluids, while etoposide persisted for a long period (β-phase half-life = 62.53 h). The overall response rate was 46.2%, the median survival time 32.3 weeks, the 1-year survival rate 28.7% and the 2-year survival rate 12.8%. The most serious adverse reactions were WHO grade 3 anemia (3 patients), grade 3 nausea and vomiting (17 patients), grade 3 constipation (1 patient), grade 3 pulmonary toxicity (1 patient), grade 4 fever (1 patient), grade 3 infection (1 patient) and grade 3 mental disorder (1 patient). Conclusion: Intrapleural administration of CDDP and etoposide was an effective and acceptable regimen for patients with MPE due to NSCLC.