Tomoko Tajiri

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.

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

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.

Smoking attenuates the age-related decrease in IgE levels and maintains eosinophilic inflammation

Epidemiological studies have shown that smoking increases the propensity for atopy and asthma. However, the effects of smoking on atopy and eosinophilic inflammation in asthmatics, including the elderly, remain unknown.

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.

Efficacy of omalizumab in eosinophilic chronic rhinosinusitis patients with asthma

Disclosures: Authors have nothing to disclose. [3] Yesudian PD, Penny M, Azurdia RM, King CM. Ibuprofen-induced acute generalized exanthematous pustulosis. Int J Dermatol. 2004;43:208e210. [4] Rastogi S, Modi M, Dhawan V. Acute localized exanthematous pustulosis (ALEP) caused by Ibuprofen: a case report. Br J Oral Maxillofac Surg. 2009;47: 132e134. [5] Romano A, Torres MJ, Castells M, Sanz ML, Blanca M. Diagnosis and management of drug hypersensitivity reactions. J Allergy Clin Immunol. 2011;127 (3 Suppl):S67eS73. [6] Drew AC, Eusebius NP, Kenins L, de Silva HD, Suphioglu C, Rolland JM, et al. Hypoallergenic variants of the mayor latex allergen Hev b 6.01 retaining human T lymphocyte reactivity. J Immunol. 2004;173:5872e5879. [7] Speeckaert MM, Speeckaert R, Lambert J, Brochez L. Acute generalized exanthematous pustulosis: an overview of the clinical, immunological and diagnostic concepts. Eur J Dermatol. 2010;20:425e433. [8] Torres MJ, Mayorga C, Blanca M. Nonimmediate allergic reactions induced by drugs: pathogenesis and diagnostic tests. J Invest Allergol Clin Immunol. 2009; 19:80e90.

Utility of serum periostin and free IgE levels in evaluating responsiveness to omalizumab in patients with severe asthma

Omalizumab, a humanized anti‐IgE monoclonal antibody, has demonstrated efficacy in patients with severe allergic asthma. However, treatment responses vary widely among individuals. Despite a lack of data, free serum IgE levels following omalizumab treatment have been proposed as a marker of treatment responsiveness.

Prevalence and Clinical Relevance of Allergic Rhinitis in Patients with Classic Asthma and Cough Variant Asthma

Background: A clinically relevant relationship between classic asthma and allergic rhinitis has been reported. However, the possible link between cough variant asthma (CVA) and allergic rhinitis remains unknown. Objectives: To clarify the prevalence and clinical relevance of perennial allergic rhinitis or seasonal allergic rhinitis in CVA patients compared to classic asthma patients. Methods: We retrospectively studied adult patients with classic asthma (n = 190) and those with CVA (n = 83). The prevalence of perennial allergic rhinitis or seasonal allergic rhinitis and associations of concomitant perennial or seasonal allergic rhinitis with asthma severity, forced expiratory volume in 1 s (% predicted), fractional exhaled nitric oxide (FeNO) levels, and eosinophil proportions in sputum and blood were analyzed in the two groups. Results: The prevalence of perennial allergic rhinitis and/or seasonal allergic rhinitis was significantly higher in classic asthma patients than in CVA patients (all p < 0.05). Concomitant perennial allergic rhinitis was associated with higher FeNO levels and eosinophil proportions in sputum and blood in classic asthma patients (p = 0.035, p = 0.036, and p = 0.008, respectively) and with higher asthma severity, FeNO levels, and sputum eosinophil proportions in CVA patients (p = 0.031, p = 0.007, and p = 0.010, respectively). Concomitant seasonal allergic rhinitis was only associated with higher sputum eosinophil proportions in CVA patients with active rhinitis symptoms during the sensitized pollen season (p = 0.025). Conclusions: Perennial allergic rhinitis may be relevant for CVA patients as well as classic asthma patients by consistently augmenting eosinophilic lower airway inflammation.