Prevalence and causes of chronic cough in Japan.

BACKGROUND: Chronic cough is one of the most common symptoms of respiratory diseases and can adversely affect patients' quality of life and interfere with social activities, resulting in a significant social burden. A survey is required to elucidate the frequency and treatment effect of chronic cough. However, clinical studies that cover all of Japan have not yet been conducted. METHODS: Patients who presented with a cough that lasted longer than 8 weeks and visited the respiratory clinics or hospitals affiliated with the Japan Cough Society during the 2-year study period were registered. RESULTS: A total of 379 patients were enrolled, and those who did not meet the definition of chronic cough were excluded. A total of 334 patients were analyzed: 201 patients had a single cause, and 113 patients had two or more causes. The main causative diseases were cough variant asthma in 92 patients, sinobronchial syndrome (SBS) in 36 patients, atopic cough in 31 patients, and gastroesophageal reflux (GER)-associated cough in 10 patients. The time required to treat undiagnosed patients and those with SBS was significantly longer and the treatment success rate for GER-associated cough was considerably poor. CONCLUSIONS: We confirmed that the main causes of chronic cough were cough variant asthma, SBS, atopic cough, and their complications. We also showed that complicated GER-associated cough was more likely to become refractory. This is the first nationwide study in Japan of the causes and treatment effects of chronic cough.

Pretreatment circulating MAIT cells, neutrophils, and periostin predicted the real-world response after 1-year mepolizumab treatment in asthmatics.

BACKGROUND: Mepolizumab treatment improves symptom control and quality of life and reduces exacerbations in patients with severe eosinophilic asthma. However, biomarkers that predict therapeutic effectiveness must be determined for use in precision medicine. Herein, we elucidated the dynamics of various parameters before and after treatment as well as patient characteristics predictive of clinical responsiveness to mepolizumab after 1-year treatment. METHODS: Twenty-seven patients with severe asthma were treated with mepolizumab for one year. Asthma control test scores, pulmonary function tests, fractional exhaled nitric oxide levels, and blood samples were evaluated. Additionally, we explored the role of CD69-positive mucosal-associated invariant T (MAIT) cells as a candidate biomarker for predicting treatment effectiveness by evaluating an OVA-induced asthma murine model using MR1 knockout mice, where MAIT cells were absent. RESULTS: The frequencies of CD69-positive group 1 innate lymphoid cells, group 3 innate lymphoid cells, natural killer cells, and MAIT cells decreased after mepolizumab treatment. The frequency of CD69-positive MAIT cells and neutrophils was lower and serum periostin levels were higher in responders than in non-responders. In the OVA-induced asthma murine model, CD69-positive MAIT cell count in the whole mouse lung was significantly higher than that in the control mice. Moreover, OVA-induced eosinophilic airway inflammation was exacerbated in the MAIT cell-deficient MR1 knockout mice. CONCLUSIONS: This study shows that circulating CD69-positive MAIT cells, neutrophils, and serum periostin might predict the real-world response after 1-year mepolizumab treatment. Furthermore, MAIT cells potentially have a protective role against type 2 airway inflammation.

Pretreatment Frequency of Circulating Th17 Cells and FeNO Levels Predicted the Real-World Response after 1 Year of Benralizumab Treatment in Patients with Severe Asthma.

Benralizumab treatment reduces exacerbations and improves symptom control and quality of life in patients with severe eosinophilic asthma. However, the determination of biomarkers that predict therapeutic effectiveness is required for precision medicine. Herein, we elucidated the dynamics of various parameters before and after treatment as well as patient characteristics predictive of clinical effectiveness after 1 year of benralizumab treatment in severe asthma in a real-world setting. Thirty-six patients with severe asthma were treated with benralizumab for 1 year. Lymphocyte subsets in peripheral blood samples were analyzed using flow cytometry. Treatment effectiveness was determined based on the ACT score, forced expiratory volume in 1 s (FEV1), and the number of exacerbations. Benralizumab provided symptomatic improvement in severe asthma. Benralizumab significantly decreased peripheral blood eosinophil and basophil counts and the frequencies of regulatory T cells (Tregs), and increased the frequencies of Th2 cells. To our knowledge, this is the first study to show benralizumab treatment increasing circulating Th2 cells and decreasing circulating Tregs. Finally, the ROC curve to discriminate patients who achieved clinical effectiveness of benralizumab treatment revealed that the frequency of circulating Th17 cells and FeNO levels might be used as parameters for predicting the real-world response of benralizumab treatment in patients with severe asthma.

Histological characteristics of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in asthmatic murine model during A(H1N1)pdm09 infection.

Pandemic influenza virus A(H1N1)pdm09 infection occurred in healthy children and young adults, but asthmatic patients presented more rapid progression of respiratory distress and plastic bronchitis. To investigate the pathogenesis of worsening respiratory symptoms after A(H1N1)pdm09 infection, we focused on matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1). MMP-9 and TIMP-1 levels in bronchoalveolar lavage fluid and serum from mice with and without asthma were evaluated after A(H1N1)pdm09 or seasonal A(H1N1) infection. MMP-9 levels were more elevated in Asthma/A(H1N1)pdm09-infected mice than in non-Asthma/A(H1N1)pdm09-infected mice on both 3 and 7 days post-infection. Immunohistochemical findings in this pneumonia model showed that MMP-9 and TIMP-1 positive cells were observed in blood vessels and bronchus of lung tissue in severe pathological findings of pneumonia with asthma. Microscopically, shedding cells and secretions were conspicuous in the trachea on days 3 and 7 post-infection, in the A(H1N1)pdm09-infected mice with asthma. Our results suggest that MMP-9 and TIMP-1 expressions are related to severe pneumonia in the A(H1N1)pdm09 infection with asthma, leading to cause epithelial cell shedding.

Effect of Japanese Cedar Pollen Sublingual Immunotherapy on Asthma Patients with Seasonal Allergic Rhinitis Caused by Japanese Cedar Pollen.

Allergen immunotherapy is a promising treatment for allergic diseases that induce immune tolerance through the administration of specific allergens. In this study, we investigate the efficacy of sublingual immunotherapy (SLIT) in asthmatic patients with SAR-JCP and the dynamics of the parameters before and after treatment in a real-world setting. This was a prospective single-center observational study. Patients with asthma and SAR-JCP (n = 24) were recruited for this study and assessed using symptom questionnaires before SLIT and a year after the SLIT. In addition, a respiratory function test, forced oscillation technique, and blood sampling test were performed during the off-season before and after SLIT. The one-year SLIT for asthma patients with SAR-JCP significantly improved not only allergic rhinitis symptoms, but also asthma symptoms during the JCP dispersal season, and significantly improved airway resistance during the off-season. The change in the asthma control test and the visual analog scale score during the season before and after SLIT was negatively and positively correlated with the change in peripheral blood γδ T cells off-season before and after SLIT, respectively. It was suggested that improvement in asthma symptoms during the JCP dispersal season after SLIT was associated with reduced peripheral blood γδ T cells.

Mepolizumab decreased the levels of serum galectin-10 and eosinophil cationic protein in asthma.

BACKGROUND: Mepolizumab, a humanized antibody targeting interleukin-5, decreases the number of blood eosinophils and the frequency of exacerbation of severe asthma. Galectin-10 is a protein within the cytoplasm of eosinophils and constitutes Charcot-Leyden crystals, which promotes key features of asthma. However, the relationship between time kinetics and clinical response of eosinophil-derived molecules such as galectin-10 or eosinophil cationic protein (ECP) has not been precisely investigated. OBJECTIVE: This study aimed to clarify the precise time course of the levels of serum galectin-10 and ECP after mepolizumab treatment and to analyze the relationship between the levels of eosinophil-derived molecules and the clinical background or response to mepolizumab treatment. METHODS: This multicenter, prospective open-label study recruited 20 patients with severe eosinophilic asthma. Mepolizumab was administered every 4 weeks for 32 weeks and the levels of various biomarkers were serially analyzed. RESULTS: The serum galectin-10 and ECP significantly and rapidly decreased 4 weeks after initial administration of mepolizumab. In contrast, basophil count, fractional exhaled nitric oxide, and the serum total IgE level were unchanged during treatment. Asthma Control Questionnaire-5, Asthma Health Questionnaire-33, and Lund-Mackay scores significantly improved after mepolizumab treatment. Both high ECP and eosinophil count related to better response in forced expiratory volume in 1 second (FEV1) and measurable ECP level at 4 weeks after administration of mepolizumab related to the further improvement in FEV1 toward week 32. No significant difference in improvement in FEV1 was observed in galectin-10 high group. The level of ECP at baseline was significantly related to the higher prevalence of nasal polyp and Lund-Mackay score. CONCLUSION: This study was the first to show that the levels of serum galectin-10 decreases after initial administration of mepolizumab. The significant relationship between serum ECP and better response in FEV1 suggested the potential role of serum ECP as a predictive biomarker for the efficacy of mepolizumab (UMIN000030466).

Chitin induces steroid-resistant airway inflammation and airway hyperresponsiveness in mice.

BACKGROUND: Previous reports have shown that pathogen-associated patterns (PAMPs) induce the production of interleukin (IL)-1ß in macrophages. Moreover, studies using mouse models also suggest that chitin, which acts as a PAMP, induces adjuvant effects and eosinophilic infiltration in the lung. Thus, we investigated the effects of inhaled chitin in mouse models. METHODS: We developed mouse models of inhaled chitin particle-induced airway inflammation and steroid-resistant ovalbumin (OVA)-induced airway inflammation. Some experimental groups of mice were treated additionally with dexamethasone (DEX). Murine alveolar macrophages (AMs), which were purified from bronchoalveolar lavage (BAL) fluids, were incubated with chitin, and treated with or without DEX. RESULTS: The numbers of total cells, AMs, lymphocytes, eosinophils, and neutrophils among BAL-derived cells, as well as the IL-1ß levels in BAL fluids and the numbers of IL-1ß-positive cells in lung, were significantly increased by chitin stimulation. Airway hyperresponsiveness (AHR) was aggravated in mice of the chitin inflammation model compared to control animals. The production of IL-1ß was significantly increased in murine AMs by chitin treatment, but DEX administration did not inhibit this chitin-induced IL-1ß production. Furthermore, in mouse models, DEX treatment inhibited the OVA-induced airway inflammation and AHR but not the airway inflammation and AHR induced by chitin or the combination of OVA and chitin. CONCLUSIONS: These results suggest that inhaled chitin induces airway inflammation, AHR, and the production of IL-1ß. Furthermore, our findings demonstrate for the first time that inhaled chitin induces steroid-resistant airway inflammation and AHR. Inhaled chitin may contribute to features of steroid-resistant asthma.

Enhanced airway hyperresponsiveness in asthmatic children and mice with A(H1N1)pdm09 infection.

BACKGROUND: Severe asthma exacerbation is an important comorbidity of the 2009 HIN1 pandemic (A(H1N1)pdm09) in asthmatic patients. However, the mechanisms underlying severe asthma exacerbation remain unknown. In this study, airway hyperresponsiveness (AHR) was measured in pediatric asthma patients infected with A(H1N1)pdm09. We also evaluated AHR in asthmatic mice with A(H1N1)pdm09 infection and those with seasonal influenza for comparison. METHODS: AHRs in asthmatic children were defined as the provocative acetylcholine concentration causing a 20% reduction in forced expiratory volume in 1 s (PC20 ). To investigate the pathophysiology using animal models, BALB/c mice aged 6-8 weeks were sensitized and challenged with ovalbumin. Either mouse-adapted A(H1N1)pdm09, seasonal H1N1 virus (1 × 105 pfu/20 µl), or mock treatment as a control was administered intranasally. At 3, 7, and 10 days after infection, each group of mice was evaluated for AHR by methacholine challenge using an animal ventilator, flexiVent. Lung samples were resected and observed using light microscopy to assess the degree of airway inflammation. RESULTS: AHRs in the children with bronchial asthma were temporarily increased, and alleviated by 3 months after discharge. AHR was significantly enhanced in A(H1N1)pdm09-infected asthmatic mice compared to that in seasonal H1N1-infected mice (p < .001), peaking at 7 days postinfection and then becoming similar to control levels by 10 days postinfection. Histopathological examination of lung tissues showed more intense infiltration of inflammatory cells and severe tissue destruction in A(H1N1)pdm09-infected mice at 7 days postinfection than at 10 days postinfection. CONCLUSION: Our results suggest that enhanced AHR could contribute to severe exacerbation in human asthmatic patients with A(H1N1)pdm09 infection.

Mobile Health App for Japanese Adult Patients With Asthma: Clinical Observational Study.

BACKGROUND: Inappropriate asthma control reduces quality of life and causes increased exacerbations. Mobile health (mHealth) employs information and communication technology for surveying health-related issues. OBJECTIVE: This noninterventional, observational study assessed current real-world asthma control levels among Japanese patients with asthma and cough variant asthma (CVA) using the Zensoku-Log app. METHODS: We developed the app using the ResearchKit platform and conducted a mobile-based, self-reporting, observational survey among patients with asthma and CVA. The app was downloaded 7855 times between February 2016 and February 2018, and enabled collection of data on symptoms, comorbidities, quality of life, medications, asthma control, and adherence. RESULTS: Of the 1744 eligible participants (median age 33 years; range 20-74 years; male-to-female ratio 38.7:61.3), 50.97% (889/1744) reported unscheduled visits, 62.84% (1096/1744) reported regularly scheduled visits, 23.14% (402/1737) smoked, and 40.75% (705/1730) had pets. In addition, 91.89% (1598/1739) of participants had atopic predisposition, including allergic rhinitis and atopic dermatitis. Daily inhaled corticosteroid and oral corticosteroid treatment had been prescribed for 89.45% (1552/1735) and 22.07% (383/1735) of participants, respectively. Although an asthma control questionnaire demonstrated poor asthma control in 58.48% (1010/1727), a leukotriene receptor antagonist, theophylline, and a long-acting muscarinic antagonist had been prescribed for only 30.66% (532/1735), 15.91% (276/1735), and 4.38% (76/1735), respectively. The Adherence Starts with Knowledge 12 total score was 29. In the 421 participants who repeated the questionnaire, asthma control increased significantly between the initial and last rounds (P=.002). CONCLUSIONS: Users of this mHealth app in Japan had poorly controlled asthma and may need more treatment for asthma and their comorbidities. Repeated app users demonstrated improved asthma control. TRIAL REGISTRATION: UMIN Clinical Trial Registry UMIN000021043; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000023913.

Using fractional exhaled nitric oxide to guide step-down treatment decisions in patients with asthma: a systematic review and individual patient data meta-analysis.

BACKGROUND: High exhaled nitric oxide fraction (F ENO) levels are associated with greater risk of asthma exacerbation. However, it is not clear how F ENO can be used to guide safe reductions in inhaled corticosteroid (ICS) doses in asthma patients. This study assesses the ability of F ENO to guide ICS reductions. METHODS: Systematic searching of electronic databases identified prospective observational studies and randomised controlled trials which recruited participants with mild-to-moderate asthma aged ≥12 years and measured F ENO before reducing ICS. We performed multilevel mixed-effects logistic regression in relation to acute exacerbations and estimated each participant's exacerbation risk using our logistic regression model. RESULTS: We included data from seven out of eight eligible studies, representing 384 participants. ICS doses were halved in four studies and withdrawn in three studies. A baseline F ENO measurement of ≥50 ppb was associated with increased risk of exacerbations (crude OR 3.14, 95% CI 1.41-7.00, p=0.005; adjusted OR 3.08, 95% CI 1.36-6.98, p=0.007) and corresponded to an estimated exacerbation risk cut-off of 15%. Reducing ICS when estimated exacerbation risk was <15% versus <10% would result in fewer patients remaining on the same ICS dose (40 (10.4%) out of 384 versus 141 (36.7%) out of 384), but similar proportions of patients avoiding exacerbations (222 (91.4%) out of 243, 95% CI 87.1-94.6% versus 311 (90.4%) out of 344, 95% CI 86.8-93.3%). CONCLUSION: In patients with mild-to-moderate asthma, gradual ICS reduction when F ENO is <50 ppb may help decrease ICS use without increasing exacerbations. Future research should aim to validate these findings in larger populations.

Difference between two exhaled nitric oxide analyzers, NIOX VERO® electrochemical hand-held analyzer and NOA280i® chemiluminescence stationary analyzer.

BACKGROUND: Fractional exhaled nitric oxide (FENO) is useful for the evaluation of eosinophilic airway inflammation, including that seen in asthma. Although a new electrochemical hand-held FENO analyzer, the NIOX VERO® (Aerocrine AB, Solna, Sweden), is clinically convenient to use, it has not been fully compared with the chemiluminescence stationary electrochemical analyzer NOA280i® (Sievers Instruments, Boulder, CO, USA) in terms of the level of measured FENO. The aim of this study was to determine whether there is a difference between the two analyzers. METHODS: The FENO levels measured with both NIOX VERO® and NOA280i® were evaluated in 1,369 adults at Juntendo University Hospital from May 2016 to October 2016. RESULTS: The median FENO level measured with the NIOX VERO® was significantly lower than that measured with the NOA280i® (41 ppb, range 5-368 ppb vs. 29 ppb, range 5-251 ppb; p < 0.001). There was a strong positive correlation in the measurement of FENO level between the NOA280i® and the NIOX VERO® (r = 0.942, p < 0.001). The following conversion equation was calculated: FENO (NOA280i®) = 1.362 (SE, 0.661) + 1.384 (SE, 0.021) × FENO (NIOX VERO®). CONCLUSIONS: To our best knowledge, we have provided the first report showing that the measured FENO level with the NIOX VERO® was approximately 30% lower than that with the NOA280i® and that there was a significant correlation between the measurements of these two devices. The correction equation that we provided may help assess the data obtained by these two analyzers. Abbreviations ATS American Thoracic Society BMI Body mass index ERS European Respiratory Society FENO Fractional exhaled nitric oxide GINA Global Initiative for Asthma NO Nitric oxide ppb Parts per billion ROC Receiver operating characteristic SD Standard deviation.

Characterization of tenascin-C as a novel biomarker for asthma: utility of tenascin-C in combination with periostin or immunoglobulin E.

BACKGROUND: Extracellular matrix proteins tenascin-C (TNC) and periostin, which were identified as T-helper cell type 2 cytokine-induced genes in human bronchial epithelial cells, accumulate in the airway basement membrane of asthmatic patients. Although serum periostin has been accepted as a type 2 biomarker, serum TNC has not been evaluated as a systemic biomarker in asthma. Therefore, the objective of this study was to evaluate whether serum TNC can serve as a novel biomarker for asthma. METHODS: We evaluated 126 adult patients with mild to severe asthma. Serum TNC, periostin, and total IgE concentrations were quantified using enzyme-linked immunosorbent assays. RESULTS: Serum TNC levels were significantly higher in patients with severe asthma and high serum total IgE levels. Patients with both high serum TNC (> 37.16 ng/mL) and high serum periostin (> 95 ng/mL) levels (n = 20) or patients with both high serum TNC and high serum total IgE (> 100 IU/mL) levels (n = 36) presented higher disease severity and more severe airflow limitation than patients in other subpopulations. CONCLUSIONS: To our knowledge, this is the first study to show that serum TNC levels in asthmatic patients are associated with clinical features of asthma and that the combination of serum TNC and periostin levels or combination of serum TNC and total IgE levels were more useful for asthma than each single marker, suggesting that serum TNC can serve as a novel biomarker for asthma.

Patients with Asthma Prescribed Once-Daily Fluticasone Furoate/Vilanterol or Twice-Daily Fluticasone Propionate/Salmeterol as Maintenance Treatment: Analysis from a Claims Database.

INTRODUCTION: There is a paucity of data describing prescribing patterns and adherence to therapy of inhaled corticosteroids (ICS) in combination with long-acting ß2-agonists (LABA) in the Japanese population in clinical practice. METHODS: This was a non-interventional, retrospective, cohort study of patients who were prescribed medication for asthma, using data from the Japan Medical Data Center Claims Database. Data from patients aged ≥ 15 years with a prescription of asthma drugs between December 2014 and October 2015 (Day 0, the index date when asthma medication was initiated) were analysed in 12-month pre-index and post-index periods. Part 1 focused on baseline characteristics and epidemiological outcomes in the pre- and post-index period in the overall asthma population, whereas comparing medication adherence [number of prescribed days per year and proportion of days covered (PDC)] between ICS/LABA-naïve patients treated with once-daily fluticasone furoate/vilanterol (FF/VI) and twice-daily fluticasone propionate/salmeterol (FP/SAL) was the primary endpoint in Part 2. RESULTS: Of the available patient data (N = 2,953,652), 28,699 patients were identified as having asthma. ICS/LABA was the main asthma treatment prescribed; 11,167 (38.9%) patients were continuous ICS/LABA users. In ICS/LABA-naïve asthma patients, treatment with once-daily FF/VI was associated with higher medication adherence compared with twice-daily FP/SAL; mean [standard deviation (SD)] number of prescribed days per year was 97.8 (115.9) for FF/VI versus 80.5 (92.7) for FP/SAL (p = 0.04), mean (SD) PDC was 26.7% (31.5) for FF/VI versus 21.9% (24.8) for FP/SAL (p = 0.04). FF/VI was also associated with a lower rate of treatment discontinuation and no difference in use of short-acting beta2-agonists or oral corticosteroids compared with FP/SAL. CONCLUSIONS: ICS/LABA was the major prescribed asthma treatment in Japan. Medication adherence was greater with FF/VI, which may indicate that patients are more likely to adhere to once-daily FF/VI versus twice-daily FP/SAL. FUNDING: This study was funded by GSK (study sponsor). STUDY REGISTRATION: GSK Study No. 207264, GSK Study Register site: https://www.gsk-clinicalstudyregister.com/search/?search_terms=207264 .

Combination of TWEAK and TGF-ß1 induces the production of TSLP, RANTES, and TARC in BEAS-2B human bronchial epithelial cells during epithelial-mesenchymal transition.

AIM OF THE STUDY: In patients with asthma, chronic inflammatory processes and the subsequent remodeling of the airways contribute to the symptoms and the pathophysiological changes. Epithelial-mesenchymal transition (EMT) is thought to play an important role in tissue remodeling. Previous reports show that tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a cytokine of the TNF superfamily, exerts pro-inflammatory effects, and enhances transforming growth factor (TGF)-ß-induced EMT in bronchial epithelial cells. In this study, we investigated the TWEAK-induced cytokine and chemokine production in the human bronchial epithelial cell line BEAS-2B during EMT. MATERIALS AND METHODS: Quantitative real-time RT-PCR, enzyme-linked immunosorbent assays, western blotting, and immunohistochemistry were used to define the production of cytokines and chemokines. RESULTS: We found that TWEAK increases mRNA and protein levels of thymic stromal lymphopoietin (TSLP), monocyte chemoattractant protein -1 (MCP-1), regulated upon activation normal T cell express sequence (RANTES), and IL-8 in BEAS-2B bronchial epithelial cells. Moreover, co-treatment with TWEAK and TGF-ß1 induces not only features of EMT but also enhances the production of TSLP and RANTES. Thymus- and activation-regulated chemokines (TARC) production is induced by the co-treatment of TWEAK and TGF-ß1 but not by TWEAK or TGF-ß1 stimulation alone. Furthermore, the increased mRNA expression of TSLP and RANTES after co-treatment with TWEAK and TGF-ß1 is prevented by inhibitors of Smad-independent signaling pathways. CONCLUSIONS: In the present study, we have revealed a novel mechanism for the production of asthma-related cytokines and chemokines in EMT driven by the co-stimulation with TWEAK and TGF-ß1. We conclude that cellular EMT processes caused by TWEAK and TGF-ß1 may contribute to chronic airway inflammation and remodeling.

Pulmonary inflammation and cytokine dynamics of bronchoalveolar lavage fluid from a mouse model of bronchial asthma during A(H1N1)pdm09 influenza infection.

Asthmatic patients present more rapid progression of respiratory distress after A(H1N1)pdm09 influenza infection than after seasonal infection. Here, we sought to clarify the pathophysiology of early deterioration in asthmatic patients after A(H1N1)pdm09 infection. Cytokine levels and virus titres in bronchoalveolar lavage fluid from mice with and without asthma after A(H1N1)pdm09 or seasonal H1N1 infection were examined. In asthma/A(H1N1)pdm09 mice, IL-6 and TNF-α levels peaked at 3 days post-infection and were higher than those in all other groups. IFN-γ levels in asthma/A(H1N1)pdm09 mice at 3 days post-infection were higher than in all other mice at any time point, whereas at 7 days post-infection, the levels were lowest in asthma/A(H1N1)pdm09 mice. Virus titres in asthma/A(H1N1)pdm09 mice were highest at 3 days post-infection, and decreased by 7 days post-infection, although the levels at this time point were still higher than that in any other group. Histopathological examination showed more inflammatory cell infiltration and lung tissue destruction in the asthma/A(H1N1)pdm09 group than in any other group. The distinct cytokine profiles in A(H1N1)pdm09-infected asthmatic mice indicated excessive inflammation and virus replication within a few days after infection. Thus, bronchial asthma could be a more exacerbating factor for pandemic influenza infection than for seasonal influenza infection.

Circulating activated innate lymphoid cells and mucosal-associated invariant T cells are associated with airflow limitation in patients with asthma.

BACKGROUND: A variety of innate subsets of lymphoid cells such as natural killer (NK) cells, several populations of innate lymphoid cells (ILCs), and mucosal-associated invariant T (MAIT) cells as innate-like T lymphocytes are involved in asthma and may have important effector functions in asthmatic immune responses. In the present study, we investigated whether NK cells, ILCs, and MAIT cells in the peripheral blood of patients with asthma would be associated with clinical asthma parameters. METHODS: We recruited 75 adult patients with mild to severe asthma. The peripheral blood mononuclear cells in peripheral venous blood samples from the patients were purified and stained with different combinations of appropriate antibodies. The cells were analyzed by flow cytometry. RESULTS: The percentage of activated (i.e., CD69+) NK cells in the total NK cell population was negatively correlated with FEV1% which is calculated by the forced expiratory volume in 1 s (FEV1)/the forced vital capacity (FVC). The percentages of CD69+ ILC1s and ILC2s were negatively correlated with FEV1% and %FEV1. The percentage of CD69+ ILC3s was positively correlated with BMI, and the percentage of CD69+ MAIT cells was negatively correlated with FEV1%. Moreover, the percentage of CD69+ NK cells, ILC1s, ILC2s, ILC3s, and MAIT cells were positively correlated with each other. CONCLUSIONS: For the first time, our data showed that activated NK cells, ILC1s, ILC2s, ILC3s, and MAIT cells were positively correlated with each other and may be associated with airflow limitation in patients with asthma.

Assessing usability of the "Adherence Starts with Knowledge 20" (ASK-20) questionnaire for Japanese adults with bronchial asthma receiving inhaled corticosteroids long term.

BACKGROUND: Maintaining high treatment adherence levels is critical for effective management of chronic diseases. The Adherence Starts with Knowledge 20 (ASK-20) questionnaire is the only linguistically validated patient-reported treatment adherence tool available in Japan. We conducted additional analyses on ASK-20 data from Japanese adults with asthma. METHODS: This was a prospective, non-interventional, single-visit, multi-centre study in Japanese adults (n = 300) with asthma receiving long-term treatment with inhaled corticosteroids (ICS) or ICS/long-acting beta-agonists. We tested the reliability, validity and the relationship between different adherence conditions and ASK-20 score. At one centre, ICS adherence prescription rate was calculated retrospectively based on 2-year percentage ICS adherence data contained within medical records. RESULTS: The ASK-20 had good internal consistency reliability (Cronbach's alpha = 0.76; n = 290). Discriminant validity was demonstrated with significant correlations between the percentage ICS adherence rates and both the mean ASK-20 total score and mean total barrier count (TBC) (r = -0.51 and -0.58, p < 0.001; n = 111). The ASK-20 total score discriminated between subjects with good and poor adherence measured by patients' reported questionnaire and between those of high and low percentage ICS adherence rates. All other factors that possibly affect adherence were correlated with the mean ASK-20 total score and mean TBC in addition to the number of medicines taken every day. CONCLUSIONS: The Japanese ASK-20 is a reliable tool for assessing possible medication adherence barriers and adherence behaviour in Japanese adults with asthma. Furthermore, our results are comparable with those obtained using the ASK-20 in the United States.

Antioxidant nutrients in plasma of Japanese patients with chronic obstructive pulmonary disease, asthma-COPD overlap syndrome and bronchial asthma.

BACKGROUND: Few studies to date have investigated the antioxidant nutrients such as vitamin C (ascorbic acid), vitamin E (α-tocopherol), retinol and carotenoids in plasma from patients with pulmonary disease in Japan. To clarify the role of antioxidant nutrients such as vitamin C, vitamin E, retinol and various carotenoids in plasma of Japanese patients with chronic obstructive lung diseases (COPD), asthma-COPD overlap syndrome (ACOS) and/or bronchial asthma (BA), we compared to healthy elderly controls. METHODS: Ascorbic acid (AA), carotenoids (lutein, zeaxanthin, ß-cryptoxanthin, α-carotene, ß-carotene and lycopene), retinol and α-tocopherol levels in plasma were determined by using a high performance liquid chromatography. Reduced glutathione (GSH), oxidised glutathione (GSSG) in whole blood and urinary 8-OHdG were also determined. RESULTS: Plasma AA level of COPD subjects was significantly lower than that of healthy elderly people. Conversely, ACOS and BA subjects showed no significant difference from healthy elderly people. Moreover, plasma lycopene and total carotenoid levels and GSH content in blood were significantly lower in COPD subjects than these in healthy elderly people. However, other redox markers such as GSSG, GSH/GSSG ratio and urinary 8-OHdG found no significant differences between COPD, ACOS and BA compared to healthy elderly people. CONCLUSIONS: These results suggested that COPD of Japanese patients may develop partly because of oxidative stress derived from a shortage of antioxidant nutrients, especially of AA and lycopene, as well as GSH while this may not be the case in both ACOS and BA.

Evaluation of switching low-dose inhaled corticosteroid to pranlukast for step-down therapy in well-controlled patients with mild persistent asthma.

OBJECTIVE: Treatment guidelines for asthma recommend step-down therapy for well-controlled asthma patients. However, the precise strategy for step-down therapy has not been well defined. We investigated whether well-controlled patients with mild persistent asthma can tolerate a step-down therapy of either a reduced dose of inhaled corticosteroid (ICS) or a switch to a leukotriene receptor antagonist (LTRA), pranlukast hydrate. METHODS: We recruited 40 adult patients with mild persistent asthma who were well-controlled for at least 3 months with a low-dose ICS therapy. The patients were randomly assigned to either an ICS dose reduction or a switch to pranlukast for 6 months. RESULTS: FeNO levels in the pranlukast group were significantly increased over that in the ICS group. There were no significant differences between the two groups for lung function, FOT, at the endpoint. The percentage of patients with controlled asthma was 72.2% in the pranlukast group and 90% in the ICS group. No statistically significant difference between the two groups in the percentages of patients with treatment failure was observed. CONCLUSIONS: Patients with mild persistent asthma that is well-controlled by a low dose of ICS can be switched to pranlukast safely for at least 6 months. However, 27.8% of the pranlukast group failed to maintain well-control, and FeNO levels increased with the switch to pranlukast at 6 months. This study was been limited by the small sample size and should therefore be considered preliminary. Further studies are needed to investigate the therapeutic efficacy of LTRA monotherapy as a step-down therapy.