Kojiro Otsuka

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.

Relationship between small airway function and health status, dyspnea and disease control in asthma.

Background: Small airways play important roles in the pathophysiology of asthma. However, relationships between small airway involvement and health status and dyspnea have not been investigated. Objectives: It was the aim of this study to assess the relationships between proximal and peripheral airway functions and health status, dyspnea and disease control in patients with asthma, using impulse oscillometry (IOS). Methods: We performed IOS, spirometry and assessment of health status (Asthma Quality of Life Questionnaire and St. George’s Respiratory Questionnaire), dyspnea (Baseline Dyspnea Index) and disease control (Asthma Control Questionnaire) in 65 asthmatics and evaluated their relationships. Results: Peripheral airway function as evaluated by IOS [R5–R20 (the fall in resistance from 5 to 20 Hz) and X5 (reactance at 5 Hz)], in addition to the proximal airway index (R20), significantly correlated with health status, dyspnea and disease control. Multiple regression analyses revealed that peripheral airway function significantly contributes to these, independently of the proximal airway index. In contrast, forced expiratory volume in 1 s did not significantly contribute to health status or dyspnea. Conclusions: IOS correlated better with clinical symptoms and asthma control than spirometry in patients with asthma. Peripheral and proximal airway functions as assessed separately by IOS independently contribute to health status, dyspnea and disease control, indicating that peripheral airways also represent an important therapeutic target.

Association of alveolar nitric oxide levels with pulmonary function and its reversibility in stable asthma.

Background: Inflammation of peripheral airways is implicated in the pathophysiology of severe asthma. However, contributions of peripheral airway inflammation to airway caliber/function in patients with stable asthma, including those with mild to moderate disease, remain to be confirmed. Objectives: To determine whether peripheral airway inflammation affects airway function in patients with asthma. Methods: In 70 patients with mild to severe asthma, alveolar nitric oxide [CANO(TMAD)] levels were examined as a noninvasive biomarker of peripheral airway/alveolar inflammation. CANO(TMAD) and maximal nitric oxide (NO) flux in the airway compartment, J’awNO, were estimated with a model that incorporated trumpet-shaped airways and axial diffusion using exhaled NO output at different flow rates. Measures of pulmonary function were then assessed by spirometry and an impulse oscillometry system, and their bronchodilator reversibility was examined. Results: CANO(TMAD) levels were not correlated with pre- or postbronchodilator spirometric values, but were significantly associated with prebronchodilator reactance at low frequency (Xrs5) (rho = –0.31, p = 0.011), integrated area of low-frequency Xrs (AX) (rho = 0.35, p = 0.003) and negative frequency dependence of resistance (Rrs5-Rrs20) (rho = 0.35, p = 0.004). Furthermore, CANO(TMAD) levels were associated with bronchodilator reversibility of FEV1, FEF25–75%, Xrs5 and AX (rho = 0.35, 0.31, –0.24 and –0.31, respectively; p ≤ 0.05 for all). No variables were related to J’awNO. Conclusions: Elevated CANO(TMAD), but not J’awNO, partly reflects reversible airway obstruction originating in the peripheral airway. These findings indicate the involvement of peripheral airway inflammation in physiological abnormalities in asthma.

Specific IgE response to Trichophyton and asthma severity.

BACKGROUND Sensitization to Trichophyton, a major dermatophyte, has been associated with asthma. Whether such sensitization is generally associated with the severity of asthma, like other molds such as Alternaria, is unknown. METHODS We compared 258 patients with asthma, which was classified by severity as mild (n = 123), moderate (101), or severe (34), and 114 healthy control subjects, with regard to specific IgE titers against Trichophyton rubrum and other common allergens such as mixed molds, house-dust mite, cat dander, dog dander, Japanese cedar pollen, mixed Graminea pollens and mixed weed pollens. RESULTS Positive rate of Trichophyton-specific IgE was higher in the patients with moderate asthma (15.8%) than in the control subjects (7.0%, p = 0.04) and patients with mild asthma (4.9%, p < 0.006), and it was also higher in the patients with severe asthma (32.4%) than in control subjects (p = 0.0001), and patients with mild asthma (p < 0.0001) and moderate asthma (p = 0.04), but it did not differ between the control subjects and patients with mild asthma. The positive rates of mixed molds, cat dander, and dog dander were almost invariably higher in patients in all asthma subgroups than in the control subjects but did not differ among patients in the three asthma subgroups. The positive rates of other allergens were not different in all groups. Reanalysis of positive rate of Trichophyton-specific IgE after excluding 52 subjects with positive results for mixed molds showed a similar statistical trend to that of the original cohort. This may negate the potential effect of cross-reactivity to these molds. Multivariate analysis of asthma subgroups identified positive IgE results for Trichophyton as an independent determinant of asthma severity. CONCLUSIONS Specific IgE response to Trichophyton may be associated with more severe asthma.

Sputum YKL-40 Levels and Pathophysiology of Asthma and Chronic Obstructive Pulmonary Disease

Background: Recent evidence suggests that YKL-40, also called chitinase-3-like-1 protein, is involved in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Details of sputum YKL-40 in asthma and COPD, however, remain unknown. Objectives: To clarify associations of sputum YKL-40 levels with clinical indices in asthma and COPD. Methods: Thirty-nine patients with asthma, 14 age-matched never-smokers as controls, 45 patients with COPD, and 7 age-matched smokers as controls were recuited for this study. Sputum YKL-40 levels were measured and YKL-40 expression in sputum cells was evaluated by immunocytochemistry. Results: Sputum YKL-40 levels were higher in patients with COPD (346 ± 325 ng/ml) than in their smoker controls (125 ± 122 ng/ml; p < 0.05), but were not significantly different between patients with asthma (117 ± 170 ng/ml) and their controls (94 ± 44 ng/ml; p = 0.15). In patients with asthma only, sputum YKL-40 levels were positively correlated with disease severity (r = 0.34, p = 0.034) and negatively correlated with pre- and postbronchodilator %FEV1 (r = –0.47 and –0.42, respectively; p < 0.01) and forced mid-expiratory flow (r = –0.48 and –0.46, respectively, p < 0.01). Sputum YKL-40 levels were positively correlated with sputum neutrophil counts in asthma (r = 0.55, p < 0.001) and with neutrophil and macrophage counts in COPD (r = 0.45 and 0.65, respectively, p < 0.01). YKL-40 was expressed in the cytoplasm of sputum neutrophils and macrophages in all groups. Conclusions: Elevated sputum YKL-40 reflects airflow obstruction in asthma whereas the roles of YKL-40 in the proximal airways in COPD remain to be elucidated.

Comprehensive efficacy of omalizumab for severe refractory asthma: a time-series observational study

BACKGROUND Omalizumab, a humanized anti-IgE monoclonal antibody, is reportedly an effective treatment for severe allergic asthma. However, there have been few comprehensive analyses of its efficacy, including assessments of small airways or airway remodeling. OBJECTIVE To comprehensively evaluate the efficacy of omalizumab, including its effects on small airways and airway remodeling, in adult patients with severe refractory asthma. METHODS In this prospective, time-series, single-arm observational study, 31 adult patients with severe refractory asthma despite the use of multiple controller medications, including high-dose inhaled corticosteroids (1,432 ± 581 μg/d of fluticasone propionate equivalent), were enrolled. Clinical variables, including Asthma Quality of Life Questionnaire, asthma exacerbations, exhaled nitric oxide, pulmonary function, methacholine airway responsiveness, induced sputum, and chest computed tomogram, were assessed at baseline and after 16 and 48 weeks of treatment with omalizumab. RESULTS Twenty-six of the 31 patients completed 48 weeks of treatment. For these patients, Asthma Quality of Life Questionnaire scores and peak expiratory flow values significantly and continuously improved throughout the 48 weeks (P < .001 for all comparisons). Unscheduled physician visits, asthma exacerbations requiring systemic corticosteroids, fractional exhaled nitric oxide at 50 mL/s and alveolar nitric oxide levels, sputum eosinophil proportions, and airway-wall thickness as assessed by computed tomography significantly decreased at 48 weeks (P < .05 for all comparisons). CONCLUSION Omalizumab was effective for adult patients with severe refractory asthma. Omalizumab may have anti-inflammatory effects on small airways and reverse airway remodeling. TRIAL REGISTRATION UMIN000002389.

Cytokeratin 19 fragment predicts the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor in non-small-cell lung cancer harboring EGFR mutation.

Background: EGFR gene mutation is independently associated with a favorable response in non–small-cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor -tyrosine kinase inhibitors (EGFR-TKIs), regardless of sex or smoking history. Squamous cell carcinoma patients harboring EGFR mutations show a significantly worse response to EGFR-TKIs compared with adenocarcinoma patients. We hypothesized that the serum cytokeratin 19 fragment (CYFRA 21-1) is associated with the efficacy of EGFR-TKIs in EGFR-mutated NSCLC patients. Methods: We retrospectively screened 160 NSCLC patients harboring EGFR mutations, who had received either gefitinib, or erlotinib between 1992 and 2011. Patients were screened for clinical characteristics, the efficacy of EGFR-TKI, and tumor markers (carcinoembryonic antigen [CEA]/CYFRA 21-1) at the initial diagnosis. Results: Of 160 eligible patients treated with EGFR-TKIs, 77 patients with high CYFRA 21-1 level (>2 ng/ml) showed significantly shorter progression-free survival (PFS) than the 83 patients with normal CYFRA 21-1 level (median PFS, 7.5 versus 13.3 months; p < 0.001). No significant difference in PFS was observed between the high-CEA group (>5 ng/ml) and the normal-CEA group (median PFS, 8.6 versus 11.2 months; p = 0.242). A multivariate analysis revealed that high CYFRA 21-1 level is independently associated with PFS (hazard ratio, 1.27; p = 0.002). No significant difference in overall survival was observed between the high- and the normal-CYFRA 21-1 groups (median overall survival, 24.8 versus 39.1 months; p = 0.104). Conclusions: Patients with a high CYFRA 21-1 level have significantly shorter PFS. CYFRA 21-1 is not a prognostic but a predictive marker of EGFR-TKI treatment in EGFR-mutated NSCLC patients.

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.

Pathophysiological characteristics of asthma in the elderly: a comprehensive study

BACKGROUND Comprehensive studies of the pathophysiologic characteristics of elderly asthma, including predominant site of disease, airway inflammation profiles, and airway hyperresponsiveness, are scarce despite their clinical importance. OBJECTIVE To clarify the pathophysiologic characteristics of elderly patients with asthma. METHODS Patients older than 65 years (elderly; n = 45) vs those no older than 65 years (nonelderly; n = 67) were retrospectively analyzed by spirometry, computed tomographic indices of large airway wall thickness and small airway involvement (air trapping), impulse oscillation measurements, exhaled nitric oxide levels, blood and induced sputum cell differentials, methacholine airway responsiveness, and total and specific serum IgE levels. RESULTS Elderly patients with asthma had significantly lower values for forced expiration volume in 1 second, mid-forced expiratory flow (percentage predicted), and ratio of forced expiration volume in 1 second to forced vital capacity than nonelderly patients with asthma (median 81.2% vs 88.8%, P = .02; 50.9% vs 78.6%, P = .03; 0.72 vs 0.78, P = .001, respectively). In computed tomographic measurements, elderly patients with asthma had significantly greater airway wall thickening and air trapping than nonelderly patients. Impulse oscillation measurements indicated that elderly patients with asthma showed significantly greater resistance at 5 Hz (used as an index of total airway resistance), greater decrease in resistance from 5 to 20 Hz, a higher ratio of decrease in resistance from 5 to 20 Hz to resistance at 5 Hz, higher integrated area between 5 Hz and frequency of resonance, greater frequency of resonance, and lower reactance at a frequency of 5 Hz (potential markers of small airway disease) than nonelderly patients. There were no significant differences in blood or sputum cell differentials, exhaled nitric oxide, or methacholine airway responsiveness between the 2 groups. Total serum IgE levels and positive rates of specific IgE antibodies against several allergens were significantly lower in elderly than in nonelderly patients with asthma. CONCLUSION Based on spirometric, computed tomographic, and impulse oscillation analyses, elderly patients with asthma have greater involvement of small and large airways than nonelderly patients with asthma.

Evaluation of the chronic obstructive pulmonary disease assessment test for measurement of health-related quality of life in patients with interstitial lung disease

Background and objective:  A well‐validated instrument that is simple to use is needed to assess health‐related quality of life in patients with interstitial lung disease (ILD). The COPD assessment test (CAT) is a recently introduced, short and simple questionnaire for COPD patients, which shows good and valid measurement properties. This study was conducted to evaluate the validity of the CAT in patients with ILD.