Associations between asthma history, atopy, and non-specific bronchial responsiveness in young adults

In 105 subjects taken from a student population and aged between 15 and 30 there was a strong positive association between the presence of the atopic state, defined by skin tests, and a high level of non-specific bronchial responsiveness to methacholine (χ²= 10·5, d.f. = 2, P= 0·01). Regression analysis showed a history of asthma, and the symptom of wheeze, to be predominantly predicted by the degree of bronchial responsiveness (R²= 31%), with only a minor independent contribution from the degree of atopy (R² a furthur 5%). The genetic or other reasons for the association between bronchial responsiveness and atopy may have importance in understanding the aetiology of allergic asthma.     

Severity assessment in asthma: An evolving concept

BACKGROUND: Guidelines for the clinical management of asthma base specific treatment recommendations on the assessment of disease severity. Thus, the accuracy of such assessments is essential for proper clinical management. The consistency of asthma severity assessment in patients with difficult-to-treat disease is unknown. OBJECTIVE: The objectives of this analysis were to compare the asthma severity assessment according to 3 methodologies in patients from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study. METHODS: Asthma severity on the basis of the National Asthma Education and Prevention Program and the Global Initiative for Asthma guidelines was compared with physician assessment and benchmarked against asthma-related health care use. Guideline-based asthma severity symptom components were derived from patient-reported questionnaires. Lung function levels were determined by prebronchodilator FEV(1) measurements; asthma-related medication and recent health care use were reported by patients. RESULTS: There was a clear lack of agreement among the asthma severity assessment modalities. Asthma severity was associated with asthma-related health care use, and patients considered to have severe asthma according to both sets of guidelines and physicians' assessment had the highest health care and medication use. CONCLUSION: Classification of asthma severity on the basis of current asthma symptoms and lung function may be useful but not completely reflective of a patient's true asthma condition. Clinical assessment of asthma severity should consider a patient's medication use and consumption of health care resources for asthma exacerbations. Additional studies that apply criteria for asthma severity longitudinally are needed to support recommendations for optimal assessment of asthma severity.     

Eosinophil activation status and corticosteroid responsiveness in severe asthma

BACKGROUND: Since eosinophils are implicated in asthma pathogenesis, we investigated whether these cells were activated in severe asthma. METHODS: Twenty-six asthmatics with different clinical responses to oral corticosteroid (CS), i.e. sensitive [change in forced expiratory volume in 1 s (DeltaFEV(1)) >/= 25% after oral methylprednisolone, 40 mg daily, for 14 days, n = 7], resistant (DeltaFEV(1) /= 20 mg oral prednisone daily for acceptable asthma control, n = 10), were studied. RESULTS: Calcium ionophore-induced leukotriene (LT) C(4) release of purified blood eosinophils was similar in the three groups. Cell incubation with granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced ionophore-induced LTC(4) release, and this effect was higher in CS-sensitive (5-fold) than in CS-resistant subjects (1.7-fold) (p = 0.02). CS treatment decreased blood eosinophil counts in these two groups of subjects (p 相似文献   

Severity of asthma in skin test-negative and skin test-positive patients

The standardized records of 144 asthmatic patients have been analyzed to determine whether the severity of their condition was correlated with the presence or absence of positive intradermal skin test reactions to a panel of seven allergen extracts (dust, feathers, Alternaria, Hormodendrum, mixed tree pollen, mixed grass pollen, and ragweed pollen). The skin tests were totally negative in 71 of the subjects, whereas in 73 subjects there was a strongly positive response to two or more allergens. The skin test-negative patients were older than the skin test-positive ones and had a shorter duration as well as a later onset of asthma. Also, they had lower serum-IgE levels and a lower frequency of a family history of atopic disease. Moreover, the skin test-negative group lost more time from their normal activities, required more visits to their doctor as a result of asthma, and were more frequently treated with oral corticosteroids. They additionally had greater air trapping on pulmonary function tests. However, when the groups were adjusted for the discordance in their age and duration of asthma, they tended to converge in the level of the variables that described the severity of their asthma. Thus the severity of asthma was found to be relatively similar in skin test-negative and skin test-positive patients.     

Biomarkers of therapy responsiveness in asthma: pitfalls and promises

Asthma is one of the most common chronic diseases worldwide. There is a large inter‐individual variability in response to asthma treatment. Most patients respond well to standard therapy; however, a small proportion of the patients remain symptomatic despite treatment with high dosages of corticosteroids. Uncontrolled asthma leads to a decreased quality of life. Therefore, it is important to identify individuals who will respond poorly to standard asthma medication, especially to standard maintenance therapy with inhaled corticosteroids, at an early stage. Response to anti‐inflammatory therapy is generally monitored by the assessment of clinical symptoms, which only partially correlates with underlying airway inflammation. The identification of specific inflammatory biomarkers might help to guide treatment or predict a corticosteroid response more accurately. Some inflammatory biomarkers are already finding their way into clinical practice (e.g. fraction of nitric oxide in exhaled breath), whereas others are predominantly used as a research tool (e.g. profiles of volatile organic compounds). Currently, there is no inflammatory biomarker used in routine clinical practice to predict a corticosteroid response. More knowledge on the underlying biological mechanism(s) of heterogeneous therapeutic responses could help to identify novel biomarkers. This review will focus on inflammatory patterns and genetic variations that may underlie differences in treatment response in patients with asthma, and will provide an overview of inflammatory biomarkers that could potentially serve as response predictors. Cite this as: S. J. H. Vijverberg, L. Koenderman, E. S. Koster, C. K. van der Ent, J. A. M. Raaijmakers and A.‐H. Maitland‐van der Zee, Clinical & Experimental Allergy, 2011 (41) 615–629.     

Severity and associated risk factors in adult asthma patients in Turkey.

BACKGROUND: The prevalence of asthma of varying severity and associated risk factors are unknown in Turkey. OBJECTIVE: The study investigated the distribution of asthma severity, the factors having roles in asthma severity, and the relationship between serum eosinophil cationic protein (ECP) levels and disease severity. METHODS: Three hundred patients with asthma (73 male, 227 female) were enrolled in the study. The patients were surveyed for their smoking habits, educational levels, household incomes, asthma duration, occupations, and accompanying diseases. ECP levels were also determined in certain patients representing different disease severities (n: 76) and in a control group (n: 9). RESULTS: Patients were classified as mild intermittent (n: 14, 5%), mild persistent (n: 220, 73%), moderate (n: 44, 15%), and severe asthma (n: 22, 7%). Cigarette consumption and educational status were similar in all groups. A longer duration of disease and an older population predominated in patients with moderate and severe asthma. Analgesic sensitivity was seen in 7%, 10%, 6%, and 31% of mild intermittent, mild persistent, moderate and severe asthma patients, respectively, with the highest ratio in severe asthma (P < .05). Nasal polyps were significantly higher in severe asthmatics. Atopy was diagnosed in 85%, 57%, 56% and 10% of mild intermittent, mild persistent, moderate and severe asthma patients, respectively. ECP levels were significantly higher in moderate and severe asthma patients. CONCLUSIONS: Mild asthma was the most common clinical presentation and was associated with atopy. The factors associated with severe asthma included prolonged asthma duration, advanced age, nonatopy, analgesic intolerance and nasal polyps. ECP levels also reflected disease severity.     

Atopy in childhood. II. Relationship to airway responsiveness, hay fever and asthma

While airway hyperresponsiveness is usually associated with a diagnosis of asthma or symptoms of wheezing, some individuals with rhinitis show airway hyperresponsiveness as do some with no symptoms whatsoever. We have studied the correlations between symptoms, airway hyperresponsiveness and atopy as determined by skin-prick tests in a cohort of New Zealand children. A total of 662 members of a birth cohort were studied at age 13 years using a respiratory questionnaire, skin-prick tests to 11 common allergens, and an abbreviated validated methacholine challenge test to determine airway responsiveness. Airway hyperresponsiveness (methacholine PC20 FEV1 < or = 8 mg/ml) was strongly correlated with reported asthma and current wheezing (P<0.0001) and also with atopy, especially to house dust mite and cat (P<0.0001). As weal size for both house dust mite and cat increased, so did the proportion of children with airway hyperresponsiveness. All children with diagnosed asthma and airway hyperresponsiveness were atopic. Skin-test reactions to house dust mite and cat were strongly correlated with any degree of measurable airway responsiveness (PC20 FEV1 < or = 25 mg/ml) in children with rhinitis (P<0.00001), and remained significantly correlated even in children without current asthma, without asthma ever and without rhinitis (P<0.001). Atopy is a major determinant of airway hyperresponsiveness in children, not only in those with reported histories of asthma and wheezing, but also in the absence of any history suggesting asthma and rhinitis.     

Acute exercise decreases airway inflammation, but not responsiveness, in an allergic asthma model

Previous studies have suggested that the asthmatic responses of airway inflammation, remodeling, and hyperresponsiveness (AHR) are interrelated; in this study, we used exercise to examine the nature of this interrelationship. Mice were sensitized and challenged with ovalbumin (OVA); mice were then exercised via running on a motorized treadmill at a moderate intensity. Data indicate that, within the lungs of OVA-treated mice, exercise attenuated the production of inflammatory mediators, including chemokines KC, RANTES, and MCP-1 and IL-12p40/p80. Coordinately, OVA-treated and exercised mice displayed decreases in leukocyte infiltration, including eosinophils, as compared with sedentary controls. Results also show that a single bout of exercise significantly decreased phosphorylation of the NFkappaB p65 subunit, which regulates the gene expression of a wide variety of inflammatory mediators. In addition, OVA-treated and exercised mice exhibited decreases in the levels of Th2-derived cytokines IL-5 and IL-13 and the prostaglandin PGE(2), as compared with sedentary controls. In contrast, results show that a single bout of exercise had no effect on AHR in OVA-treated mice challenged with increasing doses of aerosolized methacholine (0-50 mg/ml) as compared with sedentary mice. Exercise also had no effect on epithelial cell hypertrophy, mucus production, or airway wall thickening in OVA-treated mice as compared with sedentary controls. These findings suggest that a single bout of aerobic exercise at a moderate intensity attenuates airway inflammation but not AHR or airway remodeling in OVA-treated mice. The implication of these findings for the interrelationship between airway inflammation, airway remodeling, and AHR is discussed.     

Mannitol challenge for assessment of airway responsiveness,airway inflammation and inflammatory phenotype in asthma

Background Assessment of airway inflammation in asthma is becoming increasingly important, as the inflammatory phenotype underpins the treatment response. Objective This study aimed to evaluate mannitol as a tool for assessing airway responsiveness and airway inflammation in asthma, compared with hypertonic saline. Methods Fifty‐five subjects with stable asthma completed a hypertonic (4.5%) saline challenge and a mannitol challenge at two separate visits, performed 48–72 h apart, in random order. Results Induced sputum was obtained from 49 (89%) subjects during the saline challenge and 42 (76%) subjects during the mannitol challenge (P>0.05). There was a significant correlation between the greatest percentage fall in forced expiratory volume in 1 s (FEV₁) (r=0.6, P<0.0001), the dose–response slope (r=0.73), cumulative dose (r=0.55) and PD15 (r=0.46) for mannitol and hypertonic saline. The greatest percentage fall in FEV₁ to mannitol was less in non‐eosinophilic asthma. There was a lower total cell count in mannitol vs. hypertonic‐saline‐induced sputum. However, sputum eosinophils and neutrophils were not significantly different. Using mannitol, a higher proportion of subjects were classified as having eosinophilic asthma. There were no differences in IL‐8, neutrophil elastase or matrix‐metalloproteinase 9 concentrations in sputum samples induced with mannitol or hypertonic saline. Conclusion We conclude that mannitol can be used to induce good‐quality sputum, useful for analysis of inflammatory mediators and for predicting the inflammatory phenotype in asthma. Cite this as: L. G. Wood, H. Powell and P. G. Gibson, Clinical & Experimental Allergy, 2010 (40) 232–241.     

Relationship of asthma, atopy, and bronchial responsiveness to serum eosinophil cationic proteins in early childhood

BACKGROUND: The relationship between atopy, asthma, and eosinophilic inflammation is less clear in early childhood than later in life. OBJECTIVE: We sought to determine the relationships between asthma, atopy, and serum eosinophil cationic protein (ECP), a biomarker of eosinophil activation, in 6-year-old children. METHODS: Serum ECP levels were available from 968 six-year-old children who were part of a longitudinal birth cohort being assessed for asthma and atopy. Detailed clinical history and examination, lung function testing, methacholine challenge, and skin prick testing to 4 common allergens were undertaken. Subgroups of the children were compared by using t tests, ANOVA, chi 2 tests, and regression analysis. RESULTS: One hundred ninety-one (19.7%) children had current asthma, with 114 (59.7%) of these being atopic. The mean serum ECP level for the entire group was 18.0 mug/L (range, 2.0-146.0 mug/L), with no difference between male and female patients. Serum ECP was higher in atopic children (20.5 +/- 18.4), those with asthma (22.4 +/- 19.6), and those with asthma and atopy (26.6 +/- 22.4; all P < .001 compared with children with no asthma or atopy [16.1 +/- 15.9]). Serum ECP levels were highest in children with severe asthma ( P < .001), especially in those with concurrent atopy. Severity of atopy, judged on the basis of wheal size or derived variables combining wheal size and the number of positive skin tests, was a major determinant of serum ECP. Heightened methacholine responsiveness was not associated with increased serum ECP levels. CONCLUSION: The higher serum ECP levels seen in 6-year-old children with current asthma and more severe atopy suggest that atopy and eosinophilic inflammation are important in driving this clinical phenotype and that this might represent asthma that persists.     

Expression of nonmuscle cofilin-1 and steroid responsiveness in severe asthma

BACKGROUND: Glucocorticoids are the mainstay of asthma therapy; however, a proportion of patients with asthma has a severe form of the disease that fails to respond to therapy. Understanding the molecular mechanisms behind glucocorticoid-insensitive asthma is therefore of clinical importance. Evidence in glucocorticoid-unresponsive Henrietta Lack (HeLa) cells indicated that cofilin-1 could act as an inhibitor of glucocorticoid function. OBJECTIVE: To determine whether cofilin-1 expression is abnormally expressed in cells from patients with severe glucocorticoid-insensitive asthma and examine the effect of cofilin-1 overexpression on glucocorticoid function. METHODS: Peripheral blood CD4(+) T cells were purified from 16 subjects with severe glucocorticoid-insensitive asthma and 16 subjects with mild glucocorticoid-sensitive asthma, and cofilin-1 expression was determined by quantitative real-time RT-PCR and Western blotting. The effect of dexamethasone on cofilin-1 expression was determined in Jurkat T cells, and the effect of cofilin-1 overexpression on anti-CD3/CD28-stimulated IL-2 release was measured. RESULTS: Peripheral blood CD4(+) T cells from subjects with severe glucocorticoid-insensitive asthma are less responsive to dexamethasone than cells from subjects with mild glucocorticoid-sensitive asthma. Cells from these patients express significantly (P < .05) higher levels of cofilin-1 than cells from subjects with mild asthma. Dexamethasone did not affect cofilin-1 expression in Jurkat T cells. Functionally, dexamethasone suppression of anti-CD3/CD28-stimulated IL-2 was attenuated in Jurkat cells overexpressing cofilin-1. CONCLUSION: These results suggest that increased cofilin-1 expression may be important in the regulation of glucocorticoid sensitivity in peripheral blood lymphocytes of patients with severe treatment-insensitive asthma. CLINICAL IMPLICATIONS: Understanding the mechanisms of enhanced cofilin-1 expression may lead to the development of new therapies for severe treatment-insensitive asthma.     

Green tea-induced asthma: relationship between immunological reactivity, specific and non-specific bronchial responsiveness

BACKGROUND: The relationships between immunological reactivity and bronchial responsiveness to allergen and non-specific bronchial responsiveness are unclear in occupational asthma caused by low molecular weight substances. OBJECTIVE: We assessed the above relationships in green tea-induced asthma, an occupational asthma of green tea factory workers, in which epigallocatechin gallate (EGCg), a low molecular weight component of green tea leaves, is the causative agent. METHODS: Subjects consisted of 21 patients suspected of having green tea-induced asthma, on whom skin test and inhalation challenge with EGCg were performed. The skin sensitivity or end-point titration to EGCg as a measure of immunological reactivity, together with the provocative concentrations causing a 20% or greater fall in forced expiratory volume in 1 s (PC20) of EGCg and methacholine, were determined. RESULTS: We found that 11 patients had green tea-induced asthma, with immediate asthmatic reactions in eight and dual asthmatic reactions in three. We also found that 11 of 13 patients (85%) with immunological reactivity and bronchial hyper-responsiveness to methacholine experienced an asthmatic reaction and that no subject without immunological reactivity reacted. There were significant correlations among skin sensitivity, EGCg PC20 and methacholine PC20. Multiple linear regression analysis showed the relationship: log (EGCg PC20)=0.42 log (skin sensitivity)+1.17 log (methacholine PC20)+0.93 (r=0.796, P<0.05). CONCLUSION: It is concluded that bronchial responsiveness to EGCg can be highly satisfactorily predicted by skin sensitivity to EGCg and bronchial responsiveness to methacholine.     

Airway responsiveness to acetaldehyde in patients with asthma: relationship to methacholine responsiveness and peak expiratory flow variation

BACKGROUND: Although airway hyperresponsiveness to inhaled acetaldehyde has been documented in Japanese patients with asthma, the response to this bronchoconstrictor agent has never been studied in Caucasians. OBJECTIVES: The objectives of the study were to determine differences in airway responsiveness to acetaldehyde between asthmatic and healthy subjects, and to examine the relationship between acetaldehyde responsiveness and the variability of peak expiratory flow (PEF). METHODS: The response to methacholine and acetaldehyde challenges was measured in 81 non-smoking adults (61 asthmatics and 20 normal controls). Subjects recorded PEF morning and evening for 14 days. The response to both bronchoconstrictor agents was measured by the PC20 (provocative concentration required to produce a 20% fall in FEV1). PEF variation was expressed as amplitude percentage mean, and as low percentage best (lowest PEF expressed as a percentage of the best PEF recorded). RESULTS: The two types of challenge yielded a similarly high level of sensitivity (100% for methacholine and 92% for acetaldehyde) and specificity (90 and 100%, respectively) to distinguish between asthma and controls. Asthmatic subjects were on average 265-fold less sensitive to acetaldehyde than to methacholine. PC20 acetaldehyde correlated weakly but significantly with both indices of PEF variation (amplitude percentage mean: rho = - 0.36, P = 0. 004; low percentage best: rho = 0.42, P = 0.001). CONCLUSIONS: These results indicate that airway hyperresponsiveness to acetaldehyde is a sensitive and specific indicator for separating asthmatic and normal subjects. Airway responsiveness to methacholine or acetaldehyde and PEF variation are not reflecting the same pathophysiological process in the airways.     

Asthma Control Test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists

BACKGROUND: The development of the Asthma Control Test (ACT), a short, simple, patient-based tool for identifying patients with poorly controlled asthma, was recently described in patients under the routine care of an asthma specialist. OBJECTIVES: We sought to evaluate the reliability and validity of the ACT in a longitudinal study of asthmatic patients new to the care of an asthma specialist. METHODS: Patients (n=313) completed the ACT and the Asthma Control Questionnaire (ACQ) at 2 physician visits (4-12 weeks apart). Pulmonary function was measured, and asthma specialists rated asthma control. RESULTS: Internal consistency reliability of the ACT was 0.85 (baseline) and 0.79 (follow-up). Test-retest reliability was 0.77. Criterion validity was demonstrated by significant correlations between baseline ACT scores and baseline specialists' ratings of asthma control (r=0.52, P<.001) and ACQ scores (r=-0.89, P<.001). Discriminant validity was demonstrated, with significant (P<.001) differences in mean ACT scores across patients differing in asthma control, pulmonary function, and treatment recommendation. Responsiveness of the ACT to changes in asthma control and lung function was demonstrated with significant correlations between changes in ACT scores and changes in specialists' ratings (r=0.44, P<.001), ACQ scores (r=-0.69, P<.001), and percent predicted FEV1 values (r=0.29, P<.001). An ACT score of 19 or less provided optimum balance of sensitivity (71%) and specificity (71%) for detecting uncontrolled asthma. CONCLUSIONS: The ACT is reliable, valid, and responsive to changes in asthma control over time in patients new to the care of asthma specialists. A cutoff score of 19 or less identifies patients with poorly controlled asthma. CLINICAL IMPLICATIONS: In a clinical setting the ACT should be a useful tool to help physicians identify patients with uncontrolled asthma and facilitate their ability to follow patients' progress with treatment.     

Bronchial responsiveness to mite allergen in atopic dermatitis without asthma

Eight patients with atopic dermatitis (AD) without a history of asthmatic episodes and 8 patients with mite-allergic bronchial asthma (BA) were subjected to bronchial inhalation challenge with a nonspecific stimulus (acetylcholine) and an immunologically specific stimulus (house dust mite allergen). AD patients had a significantly greater concentration of IgE (p less than 0.01) and antimite IgE antibody (p less than 0.05) than BA patients. Nonspecific bronchial hyperreactivities of AD patients distributed from normal to asthmatic range. After allergen challenge, all 8 AD patients and all 8 BA patients showed an immediate asthmatic response (IAR). The mite extract concentration to induce an IAR was significantly (p less than 0.01) greater in AD patients than in BA patients. A late asthmatic response was observed in 6 out of 8 BA patients, whereas it was not observed in any AD patient. Our results showed that AD patients are less reactive to a specific mite allergen than BA patients in spite of greater concentrations of antimite IgE antibody. They suggest that this difference in the bronchial reactivity to the allergen concerns the difference in the onset of clinical symptoms and that a certain level of bronchial hyperreactivity to the allergen is a prerequisite for the development of asthmatic symptoms.