Noriyuki Ohkura

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.

Transformation to small-cell lung cancer following treatment with EGFR tyrosine kinase inhibitors in a patient with lung adenocarcinoma.

We report the case of a 52-year-old woman with lung adenocarcinoma treated with EGFR tyrosine kinase inhibitor (TKI) therapy. After disease progression, histological examination of a secondary biopsy specimen revealed small-cell lung cancer (SCLC) that was sensitive to standard SCLC treatment. Tumor markers, including ProGRP and NSE, were elevated. Transformation to SCLC is a mechanism for acquired resistance to EGFR-TKI therapy. Secondary biopsy is important for evaluation of genetic and histological changes and selection of appropriate treatment. Furthermore, ProGRP and NSE may be useful for early detection of SCLC transformation in cases resistant to EGFR-TKI therapy.

Integrating longitudinal information on pulmonary function and inflammation using asthma phenotypes.

From the Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md; the Clinical Research Directorate/CMRP, Leidos Biomedical Research (formerly SAIC-Frederick), Frederick National Laboratory for Cancer Research, Frederick, Md; the Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; the Clinical Center and the Department of Laboratory Medicine, National Institutes of Health, Bethesda, Md; and the Department of Internal Medicine, Virginia Commonwealth University, Richmond, Va. E-mail: jdmilner@ niaid.nih.gov. Or: twilson@mail.nih.gov. Supported by National Institutes of Health (NIH) U19AI77435, and in part by grants from Food Allergy Research and Education (formerly the Food Allergy and Anaphylaxis Network [FAAN], the Food Allergy Project [FAP], and the Food Allergy Initiative [FAI]), the Buckeye Foundation, and the Campaign Urging Research for Eosinophilic Diseases (CURED) Foundation. This project has been funded in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the NIAID. Disclosure of potential conflict of interest: N. Jones has received a grant from LEIDOS. J. P. Abonia has received grants from the National Institutes of Health (NIH), Food Allergy Research and Education (FARE), the Food Allergy & Anaphylaxis Network, the Buckeye Foundation, and the Campaign Urging Research for Eosinophilic Diseases Foundation. M. E. Rothenberg has received research support from the NIH, the CURED Foundation, FARE, and the Buckeye Foundation; is a board member of the International Eosinophil Society Steering Committee and the APFED Medical Panel; has consultant arrangements with Immune Pharmaceuticals, Pluristem Pharmaceuticals, Receptos, and Novartis; is an inventor on patents submitted and owned by Cincinnati Children’s Hospital Medical Center; receives royalties from Teva Pharmaceuticals; and has stock/stock options in Immune Pharmaceuticals and Receptos. L. B. Schwartz is on the board of directors for the Clinical Immunology Society and the Asthma and Allergy Foundation of America; has consultant arrangements with Sanofi Aventis, Dyax, and Viropharma; has received grants from CSL Behring and Dyax; receives royalties for licensing arrangements through VCU Tech Transfer; and receives honorarium as Associate Editor of the Journal of Clinical Immunology. The rest of the authors declare that they have no relevant conflicts of interest.

Exhaled nitric oxide levels in patients with atopic cough and cough variant asthma

Background and objective:  Atopic cough (AC) is an established clinical entity in Japan, in which patients present with a chronic persistent non‐productive cough. Exhaled nitric oxide (NO) is a biomarker of eosinophilic airway inflammation. The present study examined whether exhaled NO levels were increased in AC in comparison with cough variant asthma (CVA) and bronchial asthma (BA).

Effect of Pressure Stress Applied to the Airway on Cough-Reflex Sensitivity in Guinea Pigs

RATIONALE We hypothesized that cough stress of the airway wall results in a self-perpetuating cough-reflex cycle in which antigen-induced increase in cough-reflex sensitivity results in pathologic cough, and the cough in turn further amplifies cough-reflex sensitivity. OBJECTIVES To examine cough-reflex sensitivity in an experimental animal model. METHODS We developed an experimental guinea pig model in which airway collapse similar to that in cough was induced by rapid negative pressure applied to the airway of artificially ventilated animals. We examined the influence of this stimulus on cough-reflex sensitivity to inhaled capsaicin and bronchoalveolar lavage (BAL) cell components. After the termination of artificial ventilation, the number of coughs due to capsaicin was measured, and BAL was performed. MEASUREMENTS AND MAIN RESULTS Capsaicin cough-reflex sensitivity and the number of BAL neutrophils were increased 6 hours after stimulus application, decreasing to control levels by 24 hours. Cough-reflex sensitivity or BAL cell components were not changed in the absence of stimulus application. The number of BAL neutrophils correlated significantly with the number of coughs. Hydroxyurea inhibited the stimulus-induced increase in the number of coughs and airway neutrophil accumulation. CONCLUSIONS Our findings suggest that cough itself is a traumatic mechanical stress to the airway wall that induces neutrophilic airway inflammation and cough-reflex hypersensitivity. Cough stress to the airway wall results in a self-perpetuating cough-reflex cycle.

GLCCI1 variant accelerates pulmonary function decline in patients with asthma receiving inhaled corticosteroids

In steroid‐naive patients with asthma, several gene variants are associated with a short‐term response to inhaled corticosteroid (ICS) treatment; this has mostly been observed in Caucasians. However, not many studies have been conducted for other ethnicities. Here, we aimed to determine the relationship between the annual decline in forced expiratory flow volume in one second (FEV1) and the variant of the glucocorticoid‐induced transcript 1 gene (GLCCI1) in Japanese patients with asthma receiving long‐term ICS treatment, taking into account the effect of high serum periostin levels, a known association factor of pulmonary function decline and a marker of refractory eosinophilic/Th2 inflammation.

Bronchoconstriction-triggered cough in conscious guinea pigs.

The aim of the present study was to investigate the relation between bronchoconstriction and cough induced by methacholine (Mch) inhalation and to elucidate the role of C-fibers and rapidly adapting irritant receptors (RARs) in these reactions in conscious guinea pigs. The authors measured enhanced pause (Penh) as an index of bronchoconstriction and also measured the number of coughs induced by Mch inhalation in conscious guinea pigs. The authors also examined the effects of pretreatment with procaterol, capsaicin desensitization and moguisteine on these responses. There was a significant positive correlation between the increase in Penh and the number of coughs induced by Mch inhalation. Procaterol (0.1 mg/kg, intraperitoneal [i.p.]) completely abolished both the Mch-induced increase in Penh and cough. Capsaicin desensitization had no effect on Penh or the number of coughs. Moguisteine (0.02, 0.2, or 2 mg/kg, i.p.) dose-dependently inhibited the number of coughs but not the increase in Penh induced by Mch inhalation. Bronchoconstriction causes cough via RARs, but not C-fibers. Neither RARs nor C-fibers are involved in Mch-induced bronchoconstriction itself.

Sputum Eosinophilia, Airway Hyperresponsiveness and Airway Narrowing in Young Adults with Former Asthma

BACKGROUND 30-80% of outgrown asthma subjects develop symptoms again later in life. We investigated inflammation and function of lower airway in adolescents with former asthma. METHODS 326 never-smoking young adults (mean age 24.0 years) were interviewed with special emphasis on history of asthma. Diagnosis of asthma was based on GINA guidelines. Former asthma subjects consisted of ones with a history of physician-diagnosed childhood asthma, who had been free of asthma symptoms without the use of medication for at least 10 years prior to the study. Provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 second (FEV(1))(PC(20)) and eosinophil percentage in induced sputum were measured. RESULTS 31 subjects were former asthma subjects (FBA), 11 subjects were current asthma subjects (CBA) and 284 subjects had no history of asthma (non-BA). PC(20) and FEV(1)/FVC ratio were significantly lower in the FBA group than in the non-BA group (P < 0.01). Maximal mid-expiratory flow (MMF) was significantly lower in the FBA group than in the non-BA group (P < 0.05). Sputum eosinophil percentage was significantly increased in the FBA group compared with the non-BA group (P < 0.01). PC(20) was significantly lower in the CBA group than in the FBA and non-BA groups (P < 0.01). FEV(1), FEV(1)/FVC ratio and MMF were significantly lower in the CBA group than in the FBA group (P < 0.05, P < 0.05 and P < 0.05, respectively) and the non-BA group (P < 0.01, P < 0.01 and P < 0.05, respectively). Sputum eosinophils were significantly higher in the CBA group than in the FBA and non-BA groups (P < 0.01). CONCLUSIONS This study shows that subjects with long-term outgrown asthma continue to have airway eosinophilic inflammation, airway hyperresponsiveness and airway narrowing.

Heightened cough response to bronchoconstriction in cough variant asthma

Background and objective:  The pathophysiology of cough variant asthma (CVA) is poorly understood. We compared bronchoconstriction‐triggered cough between CVA patients and normal control (NC) subjects.

Bronchoconstriction-triggered Cough Is Impaired in Typical Asthmatics

Background and objective. Cough is an essential innate protective behavior, which is experienced by even healthy individuals. The mechanism of cough triggered by bronchoconstriction is not yet clear. The aim of this study was to investigate the relation between bronchoconstriction and cough caused by methacholine (Mch) inhalation in typical asthmatics and normal healthy subjects. Methods. We measured bronchial responsiveness to Mch and counted the number of coughs induced by Mch inhalation in 15 typical asthmatics and 20 normal subjects. Results. After inhalation of Mch at the concentration causing 20% or more decrease in forced expiratory volume in 1 second (FEV1) (PC20-FEV1), coughs were provoked in normal subjects (number of cough: 22.5/32 min, range: 3.3–45). Conversely, coughs were hardly provoked in typical asthmatics (median number of cough: 2/32 min, range: 0–4). Conclusions. Although typical asthmatics have increased airway responsiveness, their cough response to bronchoconstriction is impaired.