Hitoshi Nakaji

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.

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.

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

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Plasma Substance P Levels in Patients with Persistent Cough

Background: Substance P (SP) is involved in the pathogenesis of cough in animal models. However, few studies in humans have been reported and the roles of SP in clinical cough remain obscure. Objectives: To clarify the relevance of plasma levels of SP in patients with persistent cough. Methods: We studied 82 patients with cough persisting for at least 3 weeks and 15 healthy controls. Patients were classified as having asthmatic cough (cough-variant asthma and cough-predominant asthma; n = 61) or nonasthmatic cough (n = 21; postinfectious cough, n = 6; gastroesophageal reflux disease, n = 5; idiopathic cough, n = 5, and others, n = 5). Correlations were evaluated between plasma SP levels as measured with ELISA and methacholine airway hyperresponsiveness (airway sensitivity and airway reactivity), capsaicin cough sensitivity, sputum eosinophil and neutrophil counts, and pulmonary function. Results: Plasma SP levels were significantly elevated in patients with both asthmatic and nonasthmatic cough compared with controls [31.1 pg/ml (range 18.0–52.2) and 30.0 pg/ml (range 15.1–50.3) vs. 15.4 pg/ml (range 11.3–23.7); p = 0.003 and p = 0.038, respectively] but did not differ between the two patient groups (p = 0.90). Plasma SP levels correlated with airway sensitivity (threshold dose of methacholine) in the patients with asthmatic cough (r = –0.37, p = 0.005) but not with airway reactivity, cough sensitivity, FEV1 values, or sputum eosinophil and neutrophil counts in either group. Conclusions: Increased levels of SP in plasma are associated with persistent cough in humans and might be related to airway sensitivity in asthmatic cough.

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.

Effects of 24-week add-on treatment with ciclesonide and montelukast on small airways inflammation in asthma

BACKGROUND Eosinophilic inflammation of the small airways is a key process in asthma that often smolders in treated patients. The long-term effects of add-on therapy on the persistent inflammation in the small airways remain unknown. OBJECTIVE To examine the effects of add-on therapy with either ciclesonide, an inhaled corticosteroid with extrafine particles, or montelukast on small airway inflammation. METHODS Sixty patients with stable asthma receiving inhaled corticosteroid treatment were enrolled in a randomized, open-label, parallel comparison study of 24-week add-on treatment with ciclesonide or montelukast. Patients were randomly assigned to 3 groups: ciclesonide (n = 19), montelukast (n = 22), or no add-on as controls (n = 19). At baseline and at weeks 4, 12, and 24, extended nitric oxide analysis; pulmonary function tests, including impulse oscillometry; blood eosinophil counts; and asthma control tests (ACTs) were performed. RESULTS A total of 18 patients in the ciclesonide group, 19 in the montelukast group, and 15 in the control group completed the study and were analyzed. With repeated-measures analysis of variance, ciclesonide produced a significant decrease in alveolar nitric oxide and a significant improvement in ACT scores over time. Montelukast produced significant decreases in alveolar nitric oxide concentrations and blood eosinophil counts over time and slightly improved ACT scores, whereas no such changes were observed in the control group. Alveolar nitric oxide concentrations with ciclesonide and reactance area at low frequencies with montelukast produced greater improvements over time compared with control. CONCLUSION Ciclesonide add-on therapy and montelukast add-on therapy may act differently, but both separately can improve small airway abnormalities and provide better asthma control. TRIAL REGISTRATION umin.ac.jp/ctr Identifier: UMIN000001083.