Chronic hyperplastic eosinophilic sinusitis as a predictor of aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a disease of intense eosinophilic inflammation that can produce fibrosis, hyperplasia, and remodeling. OBJECTIVE: To investigate the usefulness of quantifying severity of chronic hyperplastic eosinophilic sinusitis in predicting the presence of AERD. METHODS: Data were compared between asthmatic patients who reported exacerbations after aspirin ingestion and those who did not. The primary outcome measure was severity of sinusitis using a validated computed tomography (CT) scan-based scoring system. Indices of lower airway remodeling and other markers of inflammation were also evaluated. RESULTS: Twenty-one patients with AERD were compared with 19 patients with aspirin-tolerant asthma (ATA). Patients were well matched for asthma severity as shown by their similar lung function as measured by postbronchodilator forced expiratory volume in 1 second. Patients with AERD were distinguished by their sinus CT scores (AERD patients: 16.9; 95% confidence interval [CI], 13.4-21.3; ATA patients: 6.2; 95% CI, 4.2-9.1; P < .001), and they were considerably more likely to have nasal polyps (AERD patients: 90%; ATA patients: 26%; P < .001). In addition, AERD patients demonstrated increased total lung capacity (AERD patients: 107.9%; 95% CI, 99.9%-117.6%; ATA patients: 98.0%; 95% CI, 93.7%-102.5%; P = .05), reflecting a trend toward increased air trapping. No significant differences occurred in diffusing capacity, exhaled nitric oxide, eosinophilia, or exhaled breath condensate pH. CONCLUSIONS: AERD can be distinguished from ATA by the extent of hyperplasia on CT scan and the presence of nasal polyps. We hypothesize that AERD represents a remodeling process that affects both the upper and lower airways.     

Irreversible lung function deficits in young adults with a history of childhood asthma

BACKGROUND: Asthma, traditionally characterized as reversible airway obstruction, might lead to structural changes and permanent impairment. OBJECTIVE: We sought to study the frequency, severity, and reversibility of pulmonary deficits in adults with a history of moderate-to-severe childhood allergic asthma. METHODS: Subjects (n = 121) previously enrolled in a randomized trial of immunotherapy for childhood asthma were recalled. Eighty-four young adults (age, 17-30 years; 78% male) were reevaluated by means of spirometry. Subjects with a postbronchodilator FEV1, forced vital capacity, or FEV1/forced vital capacity ratio less than or equal to the 5th percentile or 2 or more indices less than or equal to the 10th percentile (National Health and Nutrition Examination Survey III normative data) were invited to undergo complete pulmonary function testing, physical examination, and chest radiography after 1 week of 1 mg/kg daily prednisone. RESULTS: Of 84 subjects reevaluated, 40 (48%) had one or more spirometric indices less than or equal to the 5th and 10th percentiles (P < .0001). Twenty-eight of the 40 subjects were reassessed after prednisone treatment, of whom 21 (75%) did not improve. Adult and childhood (age 5-12 years) spirometric results were positively correlated (r = 0.49-0.72, P < .001). Abnormal adult spirometric results were associated with a longer duration of asthma at enrollment in the original trial (4.6 vs 6 years, P=.02), increased childhood methacholine sensitivity (PC20, 0.11 vs 0.18 mg/mL; P = .01), and birth prematurity (adjusted odds ratio, 10.7; 95% CI, 1.4-84.5). Immunotherapy status was unrelated to adult lung function. CONCLUSIONS: Many adults with a history of moderate-to-severe allergic asthma in childhood have irreversible lung function deficits. Childhood spirometry, duration of asthma, methacholine sensitivity, and birth prematurity might identify such individuals at a young age.     

Lipoxin A4 levels in asthma: relation with disease severity and aspirin sensitivity

BACKGROUND: Lipoxin (LX) A4, an endogenous anti-inflammatory eicosanoid, has been found to be low in patients with severe asthma. However, few studies also suggested more diminished LX A4 levels in aspirin-exacerbated respiratory disease (AERD) when compared with aspirin-tolerant asthma (ATA). It is, therefore, currently not clear whether the asthma severity or the presence of AERD has a primary role in the disturbed LX metabolism. OBJECTIVE: To detect LX A4 and 15-epi-LX A4 levels in asthma patients with and without AERD of comparable severity. METHODS: The study groups consisted of 22 subjects with AERD, 22 subjects with ATA and 10 volunteers without asthma and aspirin sensitivity. Whole-blood samples were stimulated with calcium ionophore, A23187 (5 x 10(-5) m) and A23187 (5 x 10(-5) m)+aspirin (10(-4) m). LX A4 and 15-epi-LX A4 levels were analysed by the enzyme immune assay method. RESULTS: Severe asthma patients in both AERD [0.5 (0.8)] ng/mL and ATA [0.5 (0.45) ng/mL] groups showed diminished generation for LX A4 to stimulation with A23187 in comparison with other severity degrees in their groups (P=0.02 and 0.046, respectively). LX A4 generation in both severe groups was comparable with each other (P>0.05). Although severe cases with AERD showed a diminished capacity to generate 15-epi-LX A4, this did not reach statistical significance. CONCLUSION: This study indicated that diminished LX A4 generation was unique to severe asthma phenotype regardless of comorbid aspirin sensitivity. Clinical Implications Lower LX A4 levels in severe asthma would suggest a possibility for LX analogues as future treatment options in these patients.     

Vascular remodeling is a feature of asthma and nonasthmatic eosinophilic bronchitis

RATIONALE: Increased vascularity and expression of vascular endothelial growth factor (VEGF) are recognized features of the asthmatic airway. The association of vascular remodeling with airway hyperresponsiveness (AHR) is unclear. OBJECTIVE: To assess vascular remodeling and sputum VEGF concentration in subjects with asthma, subjects with nonasthmatic eosinophilic bronchitis (EB), and healthy controls. METHODS: In cohort 1, 19 patients with asthma (Global Initiative for Asthma [GINA] 1-2, n = 9; GINA 3-5, n = 10), 10 patients with EB, and 11 healthy matched controls were recruited. Expression of the endothelial marker EN4 was assessed in bronchial biopsy samples. Vessels were counted using the validated mean Chalkley count by a blind observer. For cohort 2, a second independent cohort of 31 patients with asthma (GINA 1-2, n = 11; GINA 3-5, n = 20), 14 patients with EB, and 15 matched controls was recruited. Induced sputum supernatant VEGF was measured by ELISA. RESULTS: The mean chalkley count was significantly greater in GINA 3-5 asthma (5.2 [0.4]) and EB (4.8 [0.3]) compared with controls (3.5 [0.5]) and demonstrated a significant inverse correlation with the postbronchodilator FEV(1)% predicted in patients with asthma (R(2) = 0.28; P = .02). Sputum VEGF concentration was also increased in GINA 3-5 asthma (2365 [1361-4110] pg/g) and EB (4699 [2818-7834] pg/g) compared with controls (1094 [676-1774] pg/g) and was inversely related to postbronchodilator FEV(1)% predicted in asthma (R(2) = 0.2; P = .01). CONCLUSION: Vascular remodeling is a feature of asthma, and EB and is inversely associated with the postbronchodilator FEV(1) in asthma, suggesting that vascular remodeling is associated with airflow obstruction but not AHR. CLINICAL IMPLICATIONS: Vascular remodeling is dissociated from AHR in asthma and associated with airflow limitation.     

Specificity of basement membrane thickening in severe asthma

BACKGROUND: Reticular basement membrane (RBM) thickness is considered a hallmark for airway remodeling in airway diseases such as asthma. It is still unclear whether this measurement could be associated with disease severity or apply to chronic obstructive pulmonary disease (COPD). A wide range of results, at baseline or after therapeutic intervention, have been reported using different measurement methods. OBJECTIVE: To determine whether increased RBM thickness could be associated specifically with severe asthma and in COPD in large samples. METHODS: We blindly measured RBM thickness in endobronchial biopsies from 50 patients with severe asthma (mean age, 53 years; FEV(1) 66% predicted, inhaled steroids > or =1500 microg and 20 mg daily dose of oral corticosteroids, lifelong nonsmokers), 50 untreated patients with mild asthma (mean age, 33 years; FEV(1) 93%pred, lifelong nonsmokers), 50 patients with COPD (mean age, 57 years; FEV(1) 53%pred, all current smokers), and 18 control subjects using 2 different validated quantitative and computer-assisted methods (repeated multiple point-to-point vs area by length ratio). RESULTS: Reticular basement membrane thickness was higher in severe asthma compared with mild asthma and COPD (P = .0053). On the basis of receiver operating characteristic curves, RBM thickness was effective in differentiating severe asthma from other groups (sensitivity and specificity, 98% and 95%, respectively, above a threshold of 5 microm vs control, 70% and 75% at 7 microm vs mild, 83% and 68% at 6 microm vs COPD). CONCLUSION: Increased RBM thickness was specifically associated with severe asthma, whereas surprisingly, COPD and mild asthma had similar remodeling features. CLINICAL IMPLICATIONS: Reticular basement membrane thickness can be considered a hallmark of severe asthma.     

The blocking effect of essential controller medications during aspirin challenges in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: The blocking effect of controller medications for asthma could have an effect on the outcome of aspirin challenges in patients suspected of having aspirin-exacerbated respiratory disease (AERD). OBJECTIVE: To evaluate whether there was any blocking effect of long-acting beta2-agonists, systemic corticosteroids, and/or inhaled corticosteroids alone or as co-therapy with leukotriene modifier drugs (LTMDs). METHODS: Between 1981 and 2004, 678 patients with suspected AERD were admitted for aspirin challenge and desensitization. All patients had asthma, chronic sinusitis, nasal polyposis, and at least 1 historical reaction to a nonsteroidal anti-inflammatory drug. Asthma controller medications taken during aspirin challenge were recorded and analyzed with respect to their potential effects on 4 possible outcomes of aspirin challenge, namely, naso-ocular reaction, lower airway reaction, classic upper and lower airway reaction, or a negative challenge result. RESULTS: When compared with AERD patients who received no controller medications, the combined use of LTMDs, inhaled corticosteroids, and long-acting beta2-agonists led to a statistically significant change in aspirin challenge outcomes (P = .009), mainly shifting the reaction from a classic upper and lower respiratory tract reaction to naso-ocular reactions only. LTMDs appeared to have the strongest effect (P < .001) in blocking lower respiratory tract reactions. Systemic corticosteroids did not have the same effects. Blocking of both upper and lower respiratory tract reactions to aspirin as a result of taking controller medications did not occur. CONCLUSION: Controller medications are frequently needed to stabilize airways of patients with AERD. LTMDs alone or in combination with other controllers blocked lower respiratory tract reactions during aspirin challenge in some patients with AERD but did not change the overall rate of positive aspirin challenge results and did not lead to false-negative challenges.     

The relationship between historical aspirin-induced asthma and severity of asthma induced during oral aspirin challenges

BACKGROUND: Historical aspirin- or nonsteroidal anti-inflammatory drug (NSAID)-induced reactions might provide predictive information about the severity of reactions in patients with aspirin-exacerbated respiratory disease (AERD) undergoing oral aspirin challenge (OAC). OBJECTIVE: We sought to assess the relationship between historical aspirin- or NSAID-induced bronchial reactions and the severity of bronchial reactions during OAC in patients with AERD. METHODS: Data regarding the provoking doses, treatments, and treatment settings of historical aspirin/NSAID-induced reactions were recorded, analyzed, and compared with the provoking doses, maintenance regimens, and observed decreases in FEV(1) that occurred during OAC in 210 consecutive patients referred with suspected AERD. RESULTS: Of 147 patients who reported seeking acute medical care for their historical aspirin/NSAID-induced asthma attacks, 101 (69%) were treated in an emergency department and released, and 46 (31%) required hospitalization. During OAC in these 147 subjects, 23 (16%) had a 20% to 29% decrease and 14 (10%) had a 30% or greater decrease in FEV(1) values from baseline. Of the 46 patients previously hospitalized for aspirin/NSAID-induced asthma attacks, 9 (20%) had a 20% to 29% decrease and 6 (13%) had a 30% or greater decrease in FEV(1) during OAC. By contrast, of the 63 patients who treated their prior aspirin/NSAID-induced reactions at home, 5 (8%) had a 20% to 29% decrease and 5 (8%) had a 30% or greater decrease in FEV(1) during OAC (P = not significant for both). CONCLUSION: The severity of the historical aspirin/NSAID-induced asthma attack was not predictive of asthma severity during OAC. CLINICAL IMPLICATIONS: These data provide further reassurance regarding the safety of outpatient aspirin desensitization.     

Adult asthma severity in individuals with a history of childhood asthma

BACKGROUND: Childhood asthma can have a range of outcomes in adulthood. OBJECTIVE: To identify clinical features and exposures associated with persistence and severity of childhood asthma in adulthood. METHODS: Eighty-five of 121 subjects previously enrolled in a study of immunotherapy for childhood allergic asthma (age 5-12 years) were re-evaluated with allergy skin testing, spirometry, and interviews about asthma symptoms and medications. These young adults (age 17-30 years; 74% male) all had moderate to severe childhood asthma. Adult asthma severity was scored by using a modified version of National Heart, Lung, and Blood Institute severity categories. RESULTS: Thirteen (15.3%) of 85 adult subjects were in remission despite persistent childhood asthma. Another 19 subjects (22.4%) had only intermittent asthma. The remaining 53 had persistent asthma, of whom 12 (14.1%) had mild asthma, 25 (29.4%) had moderate asthma, and 16 (18.8%) had severe asthma. Subjects in remission, compared with subjects with intermittent or persistent asthma, had lower total serum IgE in childhood (412 ng/mL vs 1136 ng/mL vs 968 ng/mL; P = .02) and fewer positive allergy skin tests (7 vs 9 vs 10 from panel of 18; P = .02). Subjects in remission also had milder childhood asthma, indicated by lower average daily medication usage scores (1.6 vs 3.5 vs 4.4; P = .005) and lower percentage of days on inhaled corticosteroids (13.7% vs 24.7% vs 40.9%; P = .008). No significant association was found between current asthma severity and childhood immunotherapy ( P = .46). CONCLUSION: The prognosis of childhood allergic asthma in adulthood is largely determined early in life. The degree of atopy appears to be a critical determinant of asthma persistence.     

Diagnostic value of clinical parameters in the prediction of aspirin-exacerbated respiratory disease in asthma

Purpose

Aspirin-exacerbated respiratory disease (AERD) has attracted a great deal of attention because of its association with increased asthma severity. However, oral aspirin challenge (OAC) to diagnose AERD is a time-consuming procedure, and some patients experience serious complications. Thus, we evaluated diagnostic values of non-invasive clinical parameters to predict AERD in asthmatic patients.

Methods

A total of 836 Korean subjects were recruited from an asthma cohort. They underwent OAC, and clinical parameters including the history of aspirin hypersensitivity, nasal polyposis, and chronic sinusitis of aspirin-tolerant asthma (ATA) and AERD asthmatic patients were compared.

Results

Significant differences (P<0.01) were found in eight parameters: age at diagnosis, body mass index, FEV1%, PC20, history of urticaria, nasal polyps, chronic sinusitis, and history of aspirin hypersensitivity. After logistic regression analysis based on the eight clinical parameters, nasal polyps, history of aspirin intolerance, sinusitis, and log [PC20 methacholine] remained significantly associated with AERD (P<0.05). The sensitivity and specificity of the history of aspirin hypersensitivity to predict AERD were 64.7% and 92.0%, respectively, and the positive and negative predictive values were 56.9% and 94.1%, respectively. Overall, the accuracy of the test was 88.2%. The accuracy of the tests for nasal polyps and chronic sinusitis were 67.3% and 60.4%, respectively.

Conclusions

Among clinical parameters associated with AERD, the history of aspirin hypersensitivity has the best positive and negative predictive values for the oral aspirin challenge test. Because the false-positive and -negative rates were still high, additional non-invasive methods are needed to reduce the rate of false outcomes.     

Aspirin intolerance and allergy to house dust mites: important factors associated with development of severe asthma.

BACKGROUND: Although the occurrence of bronchial asthma is still increasing, the possible factors associated with the development of severe asthma have not been completely determined. OBJECTIVE: To measure the incidence of severe asthma and its determinants in outpatients. Aspirin intolerance, house dust mite (HDM) allergy, male sex, age older than 65 years, and duration of asthma exceeding 10 years were investigated as factors potentially related to the severity of asthma. METHODS: The study population included 598 women and 408 men, mean age of 44.59 years (SD +/- 16.45 years), randomly chosen from patients with asthma under follow-up surveillance in an outpatient clinic. Their medical histories were reviewed; spirometry and skin prick tests were performed. RESULTS: The asthma was diagnosed as intermittent in 35.39%, persistently mild in 33.40%, moderate in 23.76%, and severe in 7.45% of the study cohort. In the patients with atopy, HDM allergy was a significant factor associated with the development of severe asthma [odds ratio (OR) = 5.65]. Of the 1,006 patients, 341 (33.90%) had had asthma for at least 10 years, which was a significant factor in the overall study group (OR = 3.64). We found 95 cases (9.44% of the study group) of aspirin intolerance, including 23 of the 75 patients with severe asthma (30.67%; OR = 5.44). Logistic regression analysis showed that aspirin intolerance was most closely associated with severe asthma (beta = 5.79; P < .001). CONCLUSIONS: The data from this study show that aspirin intolerance, HDM allergy, and asthma duration exceeding 10 years are major factors associated with severe asthma in outpatients.     

Differences in airway remodeling between subjects with severe and moderate asthma

BACKGROUND: Airway remodeling in asthma comprises a range of structural changes. Several studies have suggested an association between these changes and disease severity. The relationship between the extent of remodeling and lung function is not well defined. OBJECTIVE: We sought to contrast the structural changes in the airways of well-defined groups of subjects with severe and moderate asthma and to correlate the extent of remodeling with disease severity. METHODS: Endobronchial biopsy specimens were obtained from 15 subjects with severe and 13 subjects with moderate asthma. Epithelial integrity, cell-layer areas, subepithelial fibrosis, and the distance between epithelial and airway smooth muscle (ASM) layers were measured by means of image analysis. Collagen was identified by using Van Giesen stain, and ASM was defined by using smooth muscle alpha-actin immunostaining. Specific immunostains were performed for the evaluation of RANTES, IL-8, and eotaxin expression as markers of ASM phenotype. RESULTS: ASM area was greater in subjects with severe (0.24+/- 0.03 mm(2)) than in subjects with moderate (0.05+/- 0.01 mm(2)) asthma (P<.001). The distance between the epithelial and ASM layers was less in the severe group (0.12+/- 0.01 mm) than in the moderate group (0.24+/- 0.02, P<.001). A trend toward greater subepithelial fibrosis in subjects with severe asthma did not reach statistical significance. IL-8 and eotaxin expression, but not RANTES expression, were increased in the ASM of subjects with severe asthma compared with in subjects with moderate asthma. CONCLUSION: Smooth muscle alteration is the key structural change that distinguishes severe from moderate asthma, and phenotypic change in ASM might contribute to the difficulty in obtaining adequate control in some subjects with severe asthma.     

Persistent airflow limitation in adult-onset nonatopic asthma is associated with serologic evidence of Chlamydia pneumoniae infection

BACKGROUND: Persistent airflow limitation may develop in patients with asthma, particularly in adults with nonatopic (intrinsic) disease. Although the underlying mechanisms are still unknown, respiratory infections might be involved. OBJECTIVE: We investigated the annual loss of lung function in relation to seropositivity to Chlamydia pneumoniae in different subgroups of patients with severe asthma according to age at onset of asthma and atopic status. METHODS: One hundred one nonsmoking outpatients with a pulmonologist's diagnosis of severe asthma (32 men and 69 women; mean age, 46.0 years; range, 18-75 years) were included in a cross-sectional study. C pneumoniae-specific serum IgG and IgA were measured by means of ELISA. The estimated decline in lung function was calculated from the relationship between postbronchodilator FEV(1)/vital capacity (percent predicted) and the duration of asthma and expressed as the slope of the regression line. RESULTS: Patients with adult-onset nonatopic asthma and positive IgG antibodies to C pneumoniae had a significantly steeper slope of the regression line compared with the other subgroups of asthmatic patients (P =.001), being indicative of a 4-fold greater estimated decline in postbronchodilator FEV(1)/vital capacity (2.3% vs 0.5% predicted per year of asthma duration). CONCLUSION: These results suggest that C pneumoniae infection might promote the development of persistent airflow limitation in patients with nonatopic adult-onset asthma. It remains to be established whether viable pathogens that are accessible for therapeutic intervention are still present in the lower airways.     

Mild to moderate asthma affects lung growth in children and adolescents

BACKGROUND: The effect of childhood asthma on lung growth is unclear. OBJECTIVE: To show the effect of mild to moderate childhood asthma on lung growth. METHODS: A total of 1041 children with mild to moderate asthma from the Childhood Asthma Management Program (CAMP) were compared with 5415 children without asthma from the Harvard Six Cities Study (H6CS). Sex-age-specific comparisons of lung growth in CAMP with the H6CS were made by using repeated-measures multiple linear regression models. Sex-age-specific percentages of children with asthma with abnormal (<5th percentile of H6CS) pulmonary function values were calculated. RESULTS: In both boys and girls, the ratio of FEV(1) to forced vital capacity (FVC) was significantly lower for children with than without asthma (P < .001), with corresponding increases for children with asthma in FVC (P < .001). FEV(1) was lower for boys with asthma than for boys without asthma (P < .001), but not for girls (P = .14). Percentages of CAMP children with abnormal FEV(1)/FVC ratios increased with age for both sexes (P < .001). The patterns of lung growth for children with asthma compared with children without asthma did not differ among children treated for 4.3 years with budesonide or nedocromil and placebo during the CAMP trial. CONCLUSION: Mild to moderate asthma results in a pattern of airway obstruction that increases in magnitude from age 5 to 18 years. CLINICAL IMPLICATIONS: Periodic spirometry is needed to monitor children with asthma for signs of increasing airway obstruction with appropriate intervention following national guidelines.     

Gene expression of vascular endothelial growth factor and its receptors and angiogenesis in bronchial asthma

BACKGROUND: Angiogenesis is a feature of airway remodeling in bronchial asthma. The mechanism responsible for this angiogenesis is unknown. Vascular endothelial growth factor (VEGF) is a potent inducer of endothelial cells, which may contribute to chronic inflammation and angiogenesis. OBJECTIVE: We sought to investigate the molecular mechanisms underlying increased vascularity, and we examined the mRNA expression of VEGF and its receptors (flt-1 and flk-1) within bronchial biopsy specimens from asthmatic patients and normal control subjects. METHODS: Endobronchial biopsy specimens were examined immunocytochemically by staining with anti-type IV collagen mAb to evaluate vessel density by using computer-assisted image analysis. Specimens were also analyzed for the presence of the mRNAs of VEGF and its receptors with in situ hybridization. RESULTS: The extent of airway vascularity was increased in asthmatic subjects compared with that in control subjects (P <.01). Asthmatic subjects exhibited a greater expression of VEGF, flt-1, and flk-1 mRNA(+) cells in the airway mucosa compared with that in control subjects (P <.001 for each comparison). The degree of vascularity was associated with the number of VEGF, flt-1, and flk-1 mRNA(+) cells. Numbers of cells expressing VEGF mRNA inversely correlated with airway caliber (r = -0.83, P <.01) and airway hyperresponsiveness (r = -0.97, P <.001). Colocalization studies showed that macrophages, eosinophils, and CD34(+) cells were the major sources of VEGF; CD34(+) cells, macrophages, and T cells expressed both flt-1 and flk-1. CONCLUSION: These findings provide evidence that VEGF may play an important role in angiogenesis and subsequent airway remodeling in bronchial asthma.     

Increased nasal mucosal swelling in subjects with asthma

OBJECTIVE: The objective of this study was to evaluate nasal mucosal swelling with acoustic rhinometry in subjects with asthma and in healthy controls. METHODS: We examined 184 individuals with asthma and compared with 156 randomly selected controls outside the pollen season, where 144 subjects in the asthma group and 80 controls had a previous history of non-infectious rhinitis (NIR). Nasal mucosal swelling was assessed with acoustic rhinometry before and after nasal decongestion with oxymetazoline and was analysed for the crosssectional area (4cm from the nostril) and the volume between 3.3 and 4cm from the nostril. Symptom scores for nasal blockage, secretion, itching and sneezing were assessed on a 0-10 visual analogue scale as well as peak nasal inspiratory flow and spirometry. RESULTS: Before decongestion there was a decrease in the cross-sectional area at 4 cm (1.32 cm2 vs. 1.59 cm2, mean left + right P = 0.04) and in the volume (1.70 vs. 1.91 cm3 P = 0.03) in the asthma group compared with healthy controls. After decongestion there were no significant differences in cross-sectional area at 4cm (1.66 vs. 1.73cm2 P=0.32) or volume (2.12 vs. 2.24cm3 P=0.32). Combined nasal symptom scores were higher in the asthma group (1.8 vs. 0.8, P=0.0001) and peak nasal inspiratory flow was lower (119 vs. 124 L/min, P = 0.38) than the healthy controls. FEV1 (% predicted) was also lower in asthma group (84 vs. 93% P < 0.0001). CONCLUSION: We have been able to demonstrate an increased nasal mucosal swelling in a population sample of persons with asthma compared to healthy controls. These data support previous reports of a generalized airway inflammation in patients with asthma and suggest that acoustic rhinometry can be used to monitor the nasal mucosal swelling in these patients.     

Identification of alpha-enolase as an autoantigen associated with severe asthma

BACKGROUND: Approximately 5% to 10% of patients with asthma have severe disease that is not effectively controlled by typical therapies. The existence of an autoantigen associated with severe asthma has been previously reported. OBJECTIVE: We attempted to identify the autoantigen. METHODS: Severe asthma was defined as patients having at least 1 severe asthmatic exacerbation requiring an emergency department visit or admission in the last year despite continuous typical therapies. Autoantibodies to airway epithelial cells (A549) were examined in sera from patients with severe asthma by immunoblot analysis. RESULTS: IgG autoantibodies to the 52-kd airway epithelial cell antigen were detected in sera from 32 of 78 patients with severe asthma (41%), 9 of 83 patients with mild-to-moderate asthma (11%), and 2 of 58 healthy controls (3%; P < .001). The 52-kd autoantigen was identified as alpha-enolase by mass spectrometry analysis and confirmed by using recombinant human alpha-enolase protein. The detection of IgG autoantibodies to alpha-enolase was the most significant indicator for distinguishing severe asthma from mild-to-moderate asthma, even after adjusting for the effects of other clinical variables, including age, sex, atopy, and FEV(1) (adjusted odds ratio, 5.2; 95% CI, 2.1-12.9; P < .001). CONCLUSION: The alpha-enolase was identified as an autoantigen associated with severe asthma. Further studies are needed to determine the significance of this autoantigen in severe asthma. CLINICAL IMPLICATIONS: IgG autoantibodies to alpha-enolase could be a biological marker for severe asthma.     

Symptoms, spirometry, exhaled nitric oxide, and asthma exacerbations in clinical practice

BACKGROUND: Patient symptoms, spirometry measurements, exacerbation rates, and exhaled nitric oxide (FE(NO)) levels have all been used to quantify asthma severity. OBJECTIVE: To determine the relationships among these disease surrogates in clinical practice. METHODS: Data were collected from 5 primary care asthma clinics on patient symptoms, reliever use, spirometry measurements, maintenance pharmacotherapy, disease severity (British Thoracic Society treatment step), and FE(NO) level. Exacerbation data (asthma-related unscheduled health care contact or rescue oral corticosteroid therapy) for the 12 months before and 3 months after the clinic visit were then obtained. RESULTS: A total of 267 adult asthmatic patients (mean [SEM] age, 51.6 [1.1] years; forced expiratory volume in 1 second, 86.3% [1.2%] of predicted) participated, and 157 exacerbations were captured. For the 12 months before the clinic visit, exacerbation rate was positively correlated with dose of inhaled corticosteroid (P < .001), treatment step (P < .001), reliever use (P = .002), and symptom score (P < .001) but was negatively correlated with FE(NO) level (P = .04); only symptom scores correlated with exacerbation rate in the 3 months after the visit. Levels of FE(NO) were significantly lower in frequently exacerbating patients receiving higher doses of maintenance inhaled corticosteroids compared with patients with mild disease who were corticosteroid naive (19.7 vs 40.4 ppb, P < .001). Measurement of FE(NO) was an insensitive method (sensitivity, 66.7%; specificity, 51.9% at a cutoff value of 20 ppb) for identifying patients who subsequently exacerbated. CONCLUSION: Levels of FE(NO) are paradoxically decreased in patients with more severe asthma and frequent exacerbations and may, therefore, be of limited utility in primary care.     

High-resolution computed tomography scan and airway remodeling in children with severe asthma

BACKGROUND: Children with severe asthma have a significantly higher bronchial wall thickness (BWT) on high-resolution computed tomography scan than control children. OBJECTIVE: We sought to determine whether a BWT score correlates with markers of airway remodeling and inflammation. METHODS: In 37 children with severe asthma, we determined reticular basement membrane thickness; number of intraepithelial neutrophils and eosinophils on bronchial biopsy; IFN-gamma, IL-4, IL-5, and eosinophil cationic protein levels and IFN-gamma/IL-4 ratio on bronchoalveolar lavage specimen; and alveolar nitric oxide (NO) concentration and the maximum airway wall NO flux. RESULTS: The BWT score significantly correlated with reticular basement membrane thickening (r = 0.34; P = .04) and NO production by the airway wall (r = 0.45; P = .02). The correlation with the eosinophil cationic protein level was just significant (r = 0.40; P = .05), whereas there was no correlation with IFN-gamma/IL-4 ratio (r = -0.31; P = .08). The BWT score did not correlate with FEV(1) or forced expiratory flow at 25% to 75% of forced vital capacity. CONCLUSION: High-resolution computed tomography scan is a noninvasive technique that might be valuable for quantifying airway remodeling in children with severe asthma. The new generations of multislice computed tomography scanners will allow higher definition and lower radiation exposure and probably give a better assessment of airway remodeling and efficacy of treatment in children with asthma.     

Analysis of vascular endothelial growth factor levels in induced sputum samples from patients with cough variant asthma.

BACKGROUND: We previously found that vascular endothelial growth factor (VEGF) levels in induced sputum samples are increased in patients with classic asthma and are associated with the degree of airflow obstruction and airway microvascular permeability. OBJECTIVE: To examine VEGF levels and the degree of airway microvascular permeability in patients with cough variant asthma (CVA). METHODS: Levels of VEGF in induced sputum samples and airway microvascular permeability were examined in 12 controls, 16 patients with CVA, and 16 patients with classic asthma. We also evaluated the relationship between VEGF level and the clinical features of these 2 disorders. RESULTS: Mean (SD) VEGF levels and airway vascular permeability index values were significantly higher in patients with CVA (VEGF: 2,520 [1,050] pg/mL; P < .001; vascular permeability index: 0.017 [0.006]; P = .003) and classic asthma (4,750 [1,260] pg/mL; P < .001; 0.028 [0.009]; P < .001) than in controls (1,420 [1,230] pg/mL; 0.009 [0.003]). Furthermore, these values were significantly higher in patients with classic asthma vs CVA. We also found significant correlations between VEGF level and airway vascular permeability index in patients with CVA (r = 0.60; P = .02) vs classic asthma (r = 0.83; P = .001). Furthermore, VEGF levels were inversely correlated with the degree of airflow obstruction and airway hyperresponsiveness to methacholine in patients with CVA and classic asthma. CONCLUSIONS: Airway microvascular hyperpermeability induced by elevated VEGF levels contributes to abnormal airway function in CVA and classic asthma, and differences in the clinical features of these 2 disorders may depend on airway VEGF levels.