Makiko Jinnai

High sensitivity C-reactive protein in asthma

Asthma is characterised by chronic inflammation of the airways, but the relevance of high-sensitivity assays for C-reactive protein (hs-CRP), which are known to be a sensitive marker of low-grade systemic inflammation, has not been fully studied in asthma. The objective was to examine serum hs-CRP levels in patients with asthma and their relationship to clinical characteristics and degree of airway inflammation. Serum hs-CRP levels were cross-sectionally examined in steroid-naive (n = 22) and steroid-inhaling (n = 23) adult patients with asthma and healthy controls (n = 14). All were nonsmokers. Serum hs-CRP levels were significantly increased in steroid-naive patients (mean±sd 1.33±1.48 mg·L−1) compared with controls (0.21±0.30 mg·L−1), but not in patients on inhaled corticosteroid. Among steroid-naive patients, serum hs-CRP levels significantly negatively correlated with indices of pulmonary function (forced expiratory volume in one second/forced vital capacity and forced mid-expiratory flow) and positively with sputum eosinophil count. Among patients on inhaled corticosteroid, hs-CRP levels did not correlate with any indices. In conclusion, an increase in serum C-reactive protein levels measured by high-sensitivity assays may be associated with airflow obstruction and airway inflammation, and may serve as a surrogate marker of airway inflammation in asthma.

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.

Prevalence and clinical manifestations of gastro-oesophageal reflux-associated chronic cough in the Japanese population

Gastro-oesophageal reflux (GOR) is one of the most common causes of chronic cough in Western countries, responsible for 10 to 40% of cases. In Japan, however, GOR-associated chronic cough (GOR-CC) has been rarely reported and its clinical manifestation including frequency of concomitant reflux laryngitis is poorly known.We have analyzed prevalence and clinical characteristics of patients who were diagnosed as having GOR-CC among adult patients with chronic cough (≥ 8 weeks) who visited our asthma and cough clinic over a period of 19 months. Diagnosis of GOR-CC was based on the response of coughing to a proton-pump inhibitor (lansoprazole™) and/or positive results of 24 h ambulatory esophageal pH monitoring. Laryngeal involvement was based on symptoms or objective diagnosis by specialists.GOR-associated chronic cough was diagnosed in 7.1% (8 of 112) of chronic cough patients. In addition to the demographic data which were consistent with the characteristics of patients with GOR-CC in the Western populations, including gender (6 females), age (mean ± SE, 56.9 ± 5.8 years), duration of cough (9.9 ± 3.3 months), lack of gastrointestinal symptoms (3 of 8) and complication with other causes of cough (5 of 8), we found the standard range of body mass index (23.9 ± 1.5 kg/m2) and high incidence of concomitant reflux laryngitis (5 of 8) in the present 8 patients. Among 4 patients who could stop treatment with temporal resolution of cough, cough recurred in 3 patients, 1 week to 8 months after the discontinuation.In conclusion, GOR-CC is a less frequent cause of chronic cough in Japan than in Western countries. Signs or symptoms of laryngitis may be important as clues to suspicion of GOR-CC.

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.

Clinical, Physiological and Anti- Inflammatory Effect of Montelukast in Patients with Cough Variant Asthma

Background: Cough variant asthma (CVA) is a phenotype of asthma presenting solely with coughing, characterized by airway hyperresponsiveness, eosinophilic inflammation and a cough response to bronchodilators. Leukotriene receptor antagonists (LTRAs) are antiasthma medications with anti-inflammatory and bronchodilatory properties. Although LTRAs exert antitussive effects in CVA, the mechanisms involved are unknown. Objectives: This study aimed to clarify the antitussive mechanisms of LTRAs in CVA patients. Methods: We prospectively observed the effect of montelukast (10 mg) daily for 4 weeks in 23 consecutive nonsmoking adults with anti-inflammatory treatment-naive CVA. We evaluated, before and after treatment, the cough visual analogue scale (VAS), pulmonary function (spirometry and impulse oscillation), methacholine airway responsiveness, cough receptor sensitivity, expressed by the concentration of capsaicin inducing 2 or more (C2) and 5 or more (C5) coughs, sputum eosinophil counts and levels of inflammatory mediators, including cysteinyl leukotrienes, leukotriene B4, prostaglandin (PG) D2, PGE2, PGF2α and thromboxane B2. We compared the baseline characteristics of the patients based on the symptomatic response to montelukast, defined as a decrease in the cough VAS of >25% (n = 15) or ≤25% (n = 8). Results: Montelukast significantly decreased the cough VAS (p = 0.0008), sputum eosinophil count (p = 0.013) and cough sensitivity (C2: p = 0.007; C5: p = 0.039), whereas pulmonary function, airway responsiveness and sputum mediator levels remained unchanged. Multivariate analysis showed that a better response to montelukast was associated solely with younger age (p = 0.032). Conclusion: The antitussive effect of montelukast in CVA may be attributed to the attenuation of eosinophilic inflammation rather than its bronchodilatory properties.

Features of cough variant asthma and classic asthma during methacholine-induced brochoconstriction: a cross-sectional study

BackgroundLittle is known regarding mechanistic and phenotypic differences between cough variant asthma (CVA), presenting with a chronic cough as the sole symptom that responds to bronchodilators, and classic asthma with wheezing during methacholine inhalation. Here we reported airway sensitivity, airway reactivity, and as the main concern, the appearance of cough and wheezes during methacholine inhalation in patients with CVA or classic asthma.MethodsWe cross-sectionally examined the degrees of airway sensitivity, the point where resistance started to increase, and reactivity, the slope of the methacholine-resistance curve, and the appearance of cough and wheezes in steroid-naïve adult patients with classic asthma (n = 58) or CVA (n = 55) while they were continuously inhaling methacholine during simultaneous measurement of respiratory resistance.ResultsPatients with CVA were less sensitive and less reactive to inhaled methacholine and wheezed less frequently but coughed more frequently during methacholine-induced bronchoconstriction than did patients with classic asthma. Multivariate analysis revealed that airway hypersensitivity and lower baseline FEV1/FVC were associated with the appearance of wheezes, whereas a diagnosis of CVA was associated with coughing.ConclusionThere are mechanistic and phenotypic differences between CVA and classic asthma during methacholine inhalation. Frequent coughing during bronchoconstriction may be a distinctive feature of CVA.

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.

Atopic features of cough variant asthma and classic asthma with wheezing

Background Cough variant asthma is a phenotype of asthma solely presenting with coughing. It involves airway inflammation and remodelling as does classic asthma with wheezing, and a subset of patients may progress to classic asthma. The atopic features of cough variant asthma remain unclear.