Pathophysiological relevance of sputum MUC5AC and MUC5B levels in patients with mild asthma.

BACKGROUND: Airway mucus hypersecretion is an important pathophysiological feature of asthma. MUC5AC and MUC5B are the major secreted polymeric mucins in airways, and their compositions affect mucus properties. Despite the increasing appreciation of MUC5AC and MUC5B compositions in asthmatic airways, their pathophysiological relevance remains to be fully understood in humans. METHODS: In this cross-sectional study, we prospectively enrolled newly referred steroid-untreated patients with mild asthma and healthy controls. We compared induced sputum MUC5AC and MUC5B levels between patients and controls. Subsequently, we assessed the correlation between MUC5AC and MUC5B levels and clinical indices in patients. Sputum MUC5AC and MUC5B levels were measured using enzyme-linked immunosorbent assays. RESULTS: Sputum MUC5AC and MUC5B levels were significantly higher in patients (n = 87) than in controls (n = 22) (p = 0.0002 and p = 0.006, respectively). The ratio of sputum MUC5AC to MUC5B tended to be higher in patients than in controls (p = 0.07). Sputum MUC5AC levels significantly and positively correlated with fractional exhaled nitric oxide at expiratory flow of 50 mL/s (Spearman's rho = 0.29, p = 0.006), sputum eosinophil proportion (rho = 0.34, p = 0.0013), and airway sensitivity (rho = 0.39, p = 0.0005). By contrast, sputum MUC5B levels significantly and positively correlated with airway sensitivity (rho = 0.35, p = 0.002) and negatively correlated with airway reactivity (rho = -0.33, p = 0.004). CONCLUSIONS: Sputum MUC5AC is increased by protein levels and involved in airway type 2/eosinophilic inflammation and airway hyperresponsiveness in steroid-untreated patients with mild asthma.

Imbalance of endogenous prostanoids in moderate-to-severe asthma.

BACKGROUND: Inhalation studies suggested "protective" roles of exogenous prostaglandin E2, but the clinical relevance of endogenous prostanoids in asthma is poorly known. The objective of this study is to measure sputum levels of prostanoids in asthmatic patients to correlate with clinical indices. METHODS: Mild (n = 41) or moderate-to-severe (19) asthmatics and 27 normal controls were examined for pulmonary function (FEV1 and mid-forced expiratory flow), sputum cell differentials, and sputum levels of prostaglandins D2, E2, F2α, and thromboxane B2 measured by sandwich enzyme immunoassay. RESULTS: Each prostanoid level did not differ among the three groups. Sputum number of bronchial epithelial cells was greater in moderate-to-severe asthmatics than in the other two groups, suggesting epithelial desquamation. Levels of prostaglandin F2α, D2, and thromboxane B2 positively correlated with the severity of airflow obstruction in the 60 asthmatic patients, whereas prostaglandin E2 levels were unrelated to pulmonary function. The ratio of combined "contractile" prostanoids (prostaglandin D2/prostaglandin F2α/thromboxane B2) to prostaglandin E2 was 2.5-fold greater in moderate-to-severe asthmatics than in controls (p = 0.001) or in mild asthmatics (p = 0.0002) but did not differ between the latter two groups. In the two asthmatic groups combined, this ratio positively correlated with the sputum number of epithelial cells. The combined "contractile" prostanoids levels positively correlated with prostaglandin E2 levels in controls and in mild asthmatics but not in moderate-to-severe asthmatics. CONCLUSIONS: An imbalance in production, breakdown, or both between prostaglandin E2 and other prostanoids possibly due to epithelial damage may be involved in the pathogenesis of moderate-to-severe asthma.

CT-assessed large airway involvement and lung function decline in eosinophilic asthma: The association between induced sputum eosinophil differential counts and airway remodeling.

OBJECTIVES: Eosinophilic asthma (EA) is a distinct clinical phenotype characterized by eosinophilic airway inflammation and airway remodeling. Few studies have used computed tomography (CT) scanning to assess the association between sputum eosinophil differential counts and airway involvement. We aimed to investigate the clinical characteristics and airway involvement of EA, and to examine the correlation between induced sputum eosinophil differential counts and CT-assessed airway remodeling. METHODS: We retrospectively divided 63 patients with stable asthma receiving inhaled corticosteroids into 2 groups: 26 patients with EA (sputum eosinophil >3%) and 37 patients with non-eosinophilic asthma (NEA). Clinical measurements such as spirometry, fractional exhaled nitric oxide levels (FeNO), and CT-assessed indices of airway involvement were compared between the groups. Multivariate analysis was performed to identify determinants of the percentage of wall area (WA%). RESULTS: The EA group had significantly longer asthma duration, lower pulmonary function, and higher FeNO than the NEA group. Also, the EA group had higher WA% and smaller airway luminal area than the NEA group. Sputum eosinophil differential counts and WA% were positively correlated. The multivariate linear regression analysis showed that the factors associated with WA% included sputum eosinophil differential counts, age, and body mass index. However, asthma duration was not associated with WA%. Our CT-assessed findings demonstrated large airway involvement in EA, and we observed a positive association between induced sputum eosinophil differential counts and WA%. CONCLUSIONS: The findings indicate that induced sputum eosinophil differential counts may be associated with airway remodeling in patients with stable asthma.

Assessment of Small Airways with Computed Tomography: Mosaic Attenuation or Lung Density?

BACKGROUND: Computed tomography (CT) assessment of air trapping has been considered useful as a measure of small airway disease. Mean lung density (MLD) and the percentage of the lung field occupied by low attenuation area (LAA%) can be evaluated automatically, and their expiratory/inspiratory (E/I) ratios correlate with asthma severity and spirometry parameters. However, mosaic attenuation, another indicator of air trapping, has been assessed visually, and its functional relevance remains controversial. OBJECTIVES: This retrospective study was conducted to correlate mosaic attenuation, which was assessed visually and automatically, and the E/I ratios of MLD and LAA% (defined as areas <-960 Hounsfield units) with clinical and physiological variables, including impulse oscillometry (IOS) indices. MATERIAL AND METHODS: In 36 nonsmoking patients with stable asthma, the lungs were scanned at full inspiration and full expiration. Mosaic attenuation was measured visually and automatically, by counting areas with CT values higher than the surrounding areas. MLD and LAA% were measured using our validated method. Spirometry, IOS, exhaled NO and the sputum eosinophil count were evaluated. RESULTS: The automatic results and visual scores of mosaic attenuation correlated well on expiratory scans (r = 0.894) and to a lesser degree on inspiratory scans (r = 0.629; p < 0.0001 for both). However, only the E/I ratios of MLD and LAA% correlated with forced expiratory volume in 1 s/forced vital capacity of spirometry and the IOS indices of resistance from 5 to 20 Hz and the integrated area of low-frequency reactance. CONCLUSIONS: Our automatic method for analysis of mosaic attenuation is likely useful, but the results themselves may not be reflecting small airway involvement of asthma, unlike the E/I ratios of MLD and LAA%.

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.

Cough triggers and their pathophysiology in patients with prolonged or chronic cough.

BACKGROUND: The character or timing of chronic cough is considered to be unpredictable for diagnosing its cause. However, the associations of cough triggers with cough pathophysiology remains unknown. METHODS: We developed a closed questionnaire listing 18 triggers that were reported by ≥1% of 213 patients in a retrospective survey. Using this questionnaire, patients with cough-predominant or cough-variant asthma (n = 140) and those with non-asthmatic cough (54) were asked whether their cough was induced by the listed triggers. Associations of triggers with causes of cough, airway sensitivity to inhaled methacholine, exhaled nitric oxide (NO) levels, number of sensitizing allergens, and scores from gastroesophageal reflux (GER) questionnaires were examined. Factor analysis was used to categorize variables, including the 12 most common cough triggers, diagnosis of asthmatic cough, airway sensitivity, and exhaled NO levels. RESULTS: "Cold air" and "fatigue/stress" induced cough more often in asthmatic coughers than in non-asthmatic coughers. "Spices" and "meals" induced cough more frequently in GER-coughers (n = 19). Patients who marked "cold air" as the trigger were more sensitive to inhaled methacholine and showed higher exhaled NO levels than those who did not mark this trigger. The "post-nasal drip" trigger was associated with elevated exhaled NO levels, and this association was mainly exhibited by patients with cough-predominant asthma. The triggers "pollen" and "mold smell" were associated with a number of sensitizing allergens. The number of triggers was weakly associated with GER scores. By factor analysis, "cold air," "fatigue/stress," asthmatic cough, airway hypersensitivity, and elevated NO levels were categorized into the same factor. CONCLUSIONS: Several cough triggers may reflect the pathophysiology of prolonged or chronic cough.

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 %FEV(1) (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 B(4), prostaglandin (PG) D(2), PGE(2), PGF(2)(α) and thromboxane B(2). 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.

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.

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 FEV(1), FEF(25-75%), 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.

Inflammatory subtypes in cough-variant asthma: association with maintenance doses of inhaled corticosteroids.

BACKGROUND: Sputum cell-subtype profiles in cough-variant asthma (CVA) are unknown. METHODS: Ninety-eight inhaled corticosteroid (ICS)-naive CVA patients were classified according to sputum eosinophil (eos)/neutrophil (neu) counts, as reported in subjects with asthma, as eosinophilic (E) (eos ≥ 1.0%, neu < 61%; n = 28), neutrophilic (N) (eos < 1.0%, neu ≥ 61%; n = 31), mixed granulocytic (M) (eos ≥ 1.0%, neu ≥ 61%; n = 12), and paucigranulocytic (P) (eos < 1.0%, neu < 61%; n = 27) subtypes. Patient characteristics; sputum levels of eosinophil cationic protein (ECP), IL-8, and neutrophil elastase (NE); and daily ICS doses required to maintain control during follow-up (6, 12, 18, and 24 months) were compared, retrospectively. RESULTS: Subtype N patients, predominantly women, were marginally older than the other subtypes, but FEV(1), airway responsiveness, and total and specific IgE results did not differ. ECP levels were higher in M and E than in N and P subtypes, being similar between M and E or N and P subtypes. Levels of IL-8 and NE were higher in M than in other subtypes, being similar among the latter. ICS doses were initially similar in all subtypes (800 µg equivalent of beclomethasone) but were higher in M than in N and P subtypes throughout follow-up, with E being intermediate between M and N or P subtypes. ICS doses decreased (halved or quartered) in E, N, and P patients followed for 24 months (P < .0001 for all) but remained unchanged in M subjects. IL-8 and NE levels correlated positively with ECP levels. CONCLUSIONS: In addition to eosinophils, neutrophils, which are possibly activated in the presence of eosinophils, may participate in the pathophysiology of CVA.

Induced sputum concentrations of mucin in patients with asthma and chronic cough.

BACKGROUND: Mucus hypersecretion is an important pathophysiologic index of airway disease. Measurement of secreted mucin in sputum has been reported in asthma, but not in chronic cough with or without increased sputum production. METHODS: We studied 49 patients with classic asthma (CA), 39 with cough-variant asthma (CVA), nine and five with chronic cough associated with sinobronchial syndrome (SBS) and gastroesophageal reflux disease (GERD), respectively, and 11 healthy controls. Seventeen patients with CA, but none from the other groups, were taking antiinflammatory medications. Mucin levels in induced sputum supernatants were measured by enzyme-linked immunosorbent assay, which detects airway mucin, probably including MUC5AC and MUC5B. RESULTS: Mucin levels were higher in patients with CA (674.2 +/- 548.8 microg/mL) and SBS (638.4 +/- 650.7 microg/mL) than in controls (212.0 +/- 167.1 microg/mL) (P = .0037 and .044). They were also higher in patients with CA than in those with CVA (350.4 +/- 374.0 microg/mL) and GERD (134.3 +/- 93.1 microg/mL) (P = .0016 and 0.015), but results did not differ between the latter groups and controls. When the four disease groups were combined, patients with frequent sputum production had greater mucin levels than those with occasional (P = .0023) or no sputum production (P < .0001). Patients with CA showed negative correlations of mucin levels with respiratory resistance indices on impulse oscillation and with airway sensitivity to methacholine. CONCLUSIONS: Sputum mucin levels differ in various respiratory conditions when compared with controls, primarily reflecting the degree of sputum production. Airway mucin might possibly exert protective effects in asthma, at least between exacerbations, but this issue needs to be further clarified by future studies.

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.

Effect of inhaled corticosteroids on small airways in asthma: investigation using impulse oscillometry.

BACKGROUND: Small airways appear to have an important role in asthma. Hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) has ultrafine particles and accordingly greater deposition in the small airways than chlorofluorocarbon (CFC)-BDP. Impulse oscillometry systems (IOS), a new and non-invasive measure of pulmonary function, can examine the resistance of total (R5), large (R20), and small airways (R5-R20) separately, and low-frequency reactance area (AX), also considered a measure of small airways dysfunction. METHODS: Mild-to-moderate asthmatics who were inhaled corticosteroid naïve were randomized to receive 200 mcg HFA-BDP bid (n 1/4 26) or 400 mcg CFC-BDP bid (n 1/4 12) for 12 weeks in an open-label manner. Following baseline measurements, IOS and spirometry were repeated every 4 weeks, and methacholine challenge to separately assess airway sensitivity and airway reactivity and lung volumes at 12 weeks. RESULTS: Moderate correlations were found between R5-R20 or AX and spirometry and lung volume indices of small airways, and between R20 and peak expiratory flow at baseline. The two groups did not significantly differ in baseline clinical or functional parameters. At 12 weeks, all IOS indices improved in the HFA-BDP group, whereas all but R5-R20 improved with CFC-BDP. R5-R20 and AX progressively improved with HFA-BDP; these changes achieved statistical significance at 12 weeks versus the CFC-BDP group. Other IOS and spirometry indices failed to show such trends. HFA-BDP significantly attenuated methacholine airway sensitivity; the degree of this attenuation strongly correlated with R5-R20 and AX baseline values, and with improvement of AX with treatment. CONCLUSION: HFA-BDP is an effective treatment of small airways in asthma. Prolonged treatment provides a progressive effect over time, which is associated with an attenuation of airway responsiveness.

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

BACKGROUND: Little 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. METHODS: We 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. RESULTS: Patients 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. CONCLUSION: There are mechanistic and phenotypic differences between CVA and classic asthma during methacholine inhalation. Frequent coughing during bronchoconstriction may be a distinctive feature of CVA.

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.

Gastroesophageal reflux-associated chronic cough in an adolescent and the diagnostic implications: a case report.

A 15-year-old girl was referred with a 2-year history of perennial non-productive cough, which had been preceded by Mycoplasma pneumoniae pneumonia and subsequent asthma. Symptoms were only partially responsive to anti-asthma treatment including an inhaled corticosteroid and a leukotriene receptor antagonist. The patient's BMI was 27.8; she had gained over 10 kg in the previous two years. Typical symptoms of gastroesophageal reflux disease were not evident except for belch. Coughing worsened on eating and rising from bed. Although esophagography failed to disclose reflux esophagitis, esophageal pH monitoring revealed significant acid reflux. Asthma was considered well controlled. Treatment with the proton-pump inhibitor rabeprazole resulted in disappearance of cough. Frequency Scale for the Symptoms of Gastroesophageal reflux disease (FSSG) score, a questionnaire evaluating the symptoms of gastroesophageal reflux disease, was initially high but normalized after treatment. Capsaicin cough sensitivity also diminished with treatment.Chronic cough due to gastroesophageal reflux disease has been considered rare in adolescents, but this condition might be increasing in line with the recent trend in adults. Clinical features of gastroesophageal reflux disease-associated cough typical for adult patients and a specific questionnaire for evaluating gastroesophageal reflux disease validated in adults may also be useful diagnostic clues in adolescents.

TGFB1 promoter polymorphism C-509T and pathophysiology of asthma.

BACKGROUND: TGF-beta1 can modulate airway inflammation and exaggerate airway remodeling. A polymorphism of a promoter region of TGFB1, C-509T, might be associated with the development of asthma, but its pathophysiologic relevance remains poorly understood. OBJECTIVE: We investigated relations of the C-509T polymorphism to airflow obstruction, sputum eosinophilia, and airway wall thickening, as assessed by means of computed tomography, in 85 patients with stable asthma. METHODS: The CC, CT, and TT genotypes were examined by means of PCR and restriction enzyme fragment length polymorphism. At a selected bronchus, 3 indices of airway wall thickness were measured with an automatic method. RESULTS: The CC, CT, and TT genotypes were found in 22, 46, and 17 patients, respectively. Serum TGF-beta1 levels were significantly associated with the polymorphism and were increased in the CT/TT genotypes. FEV(1) and sputum eosinophil percentages were also significantly associated with the polymorphism and were both decreased in the CT/TT genotypes. The polymorphism was unrelated to airway wall thickness. CONCLUSION: In addition to increased serum TGF-beta1 levels, the T allele of the C-509T polymorphism is related to increased airflow obstruction but attenuated eosinophilic inflammation. The former relation is not attributed to thickening of the central airway walls. The latter relation might reflect the anti-inflammatory effect of TGF-beta1. The C-509T polymorphism has a complex role in asthma pathophysiology, presumably because of the diverse functions of TGF-beta1 and its various interactions with cells and humoral factors in vivo.

Airway wall thickening in patients with cough variant asthma and nonasthmatic chronic cough.

BACKGROUND: Chronic cough, which may be of asthmatic or nonasthmatic origin, is an important clinical issue. Airway inflammation, and remodeling demonstrated by subbasement membrane thickening has been associated with cough variant asthma (CVA) as well as with nonasthmatic chronic cough (NAC). CT studies have shown airway wall thickening in patients with asthma who wheeze. We examined airway wall thickness by CT in adult patients with chronic cough and examined its pathophysiologic implication. METHODS: Nonsmoking, steroid-naïve patients with CVA (n = 27), NAC (n = 26), and healthy control subjects (n = 15) were studied. Airway dimensions were assessed by a validated CT technique, in which we measured airway wall area (WA) corrected by body surface area (BSA), the ratio of WA to outer wall area (percentage of wall area [WA%]), absolute wall thickness (T)/ square root BSA, and airway luminal area/BSA of a segmental bronchus. Correlations between CT parameters and clinical indexes such as disease duration and cough sensitivity were examined. RESULTS: In patients with CVA, WA/BSA, WA%, and T/ square root BSA were all significantly greater than those in control subjects. In patients with NAC, WA/BSA and T/ square root BSA were significantly greater than in control subjects. The increase of WA/BSA and T/ square root BSA of NAC patients was less than that of CVA patients. In a subset of patients with NAC, WA% correlated with capsaicin cough sensitivity (n = 9, r = 0.75, p = 0.034). CONCLUSIONS: Walls of central airways are thickened in patients with CVA, and also to a lesser degree in patients with NAC. Airway wall thickening in NAC may be associated with cough hypersensitivity.