Nitric oxide metabolites in induced sputum: a marker of airway inflammation in asthmatic subjects

BACKGROUND AND OBJECTIVE: The role of nitric oxide (NO) needs to be further clarified in allergic inflammation. This study was designed to investigate the relationships between NO metabolites and eosinophil count, eosinophil cationic protein (ECP), interleukin (IL)-5 in induced sputum from asthmatics. METHODS: Hypertonic saline-induced sputum was obtained in 25 asthmatic subjects, among which 13 patients were examined before and after anti-asthmatic medications including steroid preparations. Ten normal subjects were enrolled as controls. Fresh expectorated sputum separated from saliva was treated with equal volume of dithiothreitol 0.1%, cytospinned for cell count, and the supernatant was collected for biochemical assay. NO metabolites were assayed by using modified Griess reaction. ECP was measured by fluoroimmunoassay, and detected IL-5 by a sandwich ELISA. RESULTS: Asthmatic subjects, compared with controls, had significantly higher concentration of NO metabolites (1035.4 +/- 125.3 vs 557.2 +/- 101.5 micromol/L, P < 0.01), higher percentage of eosinophils (25.6 +/- 4.6 vs 1.7 +/- 0.2%, P < 0.01), and higher levels of ECP (1117.8 +/- 213.9 vs 154.6 +/- 47.4 microg/L, P < 0.01) in the induced sputum. IL-5 was detected more frequently in asthmatic subjects than in control subjects (11/25 [44%] vs 1/10 [10%], P < 0.05). According to asthma severity, moderate to severe asthmatic subjects (n = 18) had higher level of NO metabolites (1143.8 +/- 156.3 vs 575.5 +/- 89.5 micromol/L, P < 0. 01), higher levels of ECP and IL-5 (P < 0.01, respectively) in the induced sputum than in those of mild asthmatic subjects (n = 7). NO metabolites, the percentage of eosinophils, the levels of ECP, and IL-5 were reduced following treatment with anti-asthmatic drugs (P < 0.01, respectively). There were significant positive correlations between NO metabolites and percentage of eosinophils or ECP (r = 0. 34, P < 0.05; r = 0.28, P < 0.05). Negative correlations were noted between FEV1, FEV1/FVC and proportion of eosinophils, ECP, or IL-5 levels. CONCLUSION: These findings confirmed that the level of NO metabolites was increased in the tracheobronchial secretion of asthmatic subjects and was paralleled with severity of asthma. Measurement of NO metabolites in induced sputum may be used for monitoring the degree of airway inflammation in asthmatics.     

Morning-to-evening variation in exercise-induced bronchospasm

BACKGROUND: Exercise is one of the most common triggers of asthmatic symptoms. Many factors, including hyperventilation, determine the prevalence and severity of exercise-induced bronchospasm (EIB). However, the influence of time of day has not been adequately described. OBJECTIVE: We sought to compare morning and evening EIB and minute ventilation during exercise (VE). METHODS: Twenty-two patients with stable asthma and 12 control subjects underwent exercise challenge at 7 am and 6 pm. The time of the first challenge was randomly assigned; the second challenge was performed within 1 week of the first. The primary outcomes were EIB intensity (maximum fall in FEV(1)) and VE. RESULTS: The asthma group exhibited lower EIB values in the morning: 14.8% +/- 3.7% at 7 am vs 21.4% +/- 4.2% at 6 pm (P =.004)-ie, 0.37 +/- 0.09 L vs 0.53 +/- 0.10 L, respectively (P =.002). VE was higher at 7 am (55.4 +/- 4.7 L/min) than at 6 pm (52.4 +/- 4.3 L/min; P =.03). Baseline FEV(1) increased from 2.33 +/- 0.13 L (morning) to 2.49 +/- 0.15 L (evening; P =.04), and a significant correlation between baseline FEV(1) and EIB was found in the evening (r = +0.5; P =.049) but not in the morning. Post-exercise FEV(1) was similar at 7 am (1.96 +/- 0.13 L) and 6 pm (1.97 +/- 0.14 L). For the control group, no changes were detected in FEV(1) fall or VE. CONCLUSION: Baseline airway caliber contributes to the mechanisms of the morning-to-evening EIB enhancement.     

Effect of ciclesonide dose and duration of therapy on exercise-induced bronchoconstriction in patients with asthma

BACKGROUND: Inhaled corticosteroid therapy improves exercise symptoms in asthmatic subjects. OBJECTIVE: We sought to evaluate exercise-induced bronchoconstriction (EIB) as a method of determining the dose and time responses of inhaled corticosteroid therapy. METHODS: In this double-blind, randomized, cross-over study with 2 parallel arms, 4 doses of inhaled ciclesonide (40 microg and 160 microg or 80 microg and 320 microg) were compared over 3 weeks of treatment. Twenty-six asthmatic subjects (age range, 14-27 years) with baseline FEV1 values of greater than 70% of predicted value were enrolled. The primary outcome was the maximum percentage decrease in FEV1 after standardized exercise challenge. RESULTS: After 1 week of therapy, the mean +/- SEM reduction in maximum decrease in FEV1 in the ciclesonide 40-microg/80-microg dose group was 9% +/- 2.6% (95% CI, 3.9% to 14%), with no additional reduction thereafter. In the ciclesonide 160-microg/320-microg dose group, there was an 8.7% +/- 2.5% (95% CI, 3.7% to 13.7%) reduction in maximum decrease in FEV1 after week 1, which continued in a linear fashion during subsequent weeks of treatment. No difference was found between the 2 treatment arms in the temporal response of EIB to ciclesonide treatment. The maximum percentage attenuation in EIB achieved was 51.1% +/- 7.9%, which was achieved by using the 320-microg dose after 3 weeks of treatment. CONCLUSIONS: A significant improvement in EIB was demonstrated for all doses of ciclesonide. Use of 160 microg/320 microg of ciclesonide resulted in a continuing improvement in FEV1 with time, and no plateau was seen in protective effect during 3 weeks of treatment. CLINICAL IMPLICATIONS: Attenuation in exercise-induced decrease can be seen as early as after 1 week of therapy with inhaled ciclesonide at doses greater than 40 microg. However, maximal attenuation in exercise response continues to increase at doses greater than or equal to 200 microg, even after 3 weeks of therapy.     

Exhaled breath condensate cysteinyl leukotrienes are increased in children with exercise-induced bronchoconstriction

BACKGROUND: It is recognized that airway inflammation has a central role in the pathogenesis of asthma, but how it relates to exercise-induced bronchoconstriction (EIB) is not completely understood. OBJECTIVE: The aim of our study was to investigate the relationship between EIB and baseline concentrations of cysteinyl leukotrienes (Cys-LTs) and other inflammatory markers in exhaled breath condensate (EBC). METHODS: EBC was collected, and the fraction of exhaled nitric oxide (FE NO ) was measured in a group of 19 asthmatic children, after which they performed a treadmill exercise test. Fourteen healthy children were enrolled as control subjects. RESULTS: The asthmatic children were divided into the EIB group (decrease in FEV 1 , > or =12%) and the non-EIB group. The EBC was analyzed for the presence of Cys-LTs, leukotriene B 4 , and ammonia. Asthmatic patients with EIB (mean FEV 1 decrease, 23% +/- 3%) had higher Cys-LT concentrations than either asthmatic patients without EIB or control subjects (42.2 pg/mL [median] vs 11.7 pg/mL and 5.8 pg/mL; P < .05 and P < .001, respectively). Ammonia concentrations were lower in both the EIB and non-EIB groups than in control subjects (253.2 microM and 334.6 microM vs 798.4 microM; P < .01 and P < .05, respectively). No difference in EBC leukotriene B 4 levels was found among the 3 groups. Both asthmatic groups had higher FE NO levels than control subjects ( P < .001). EBC Cys-LT ( P < .01; r = 0.7) and FE NO ( P < .05; r = 0.5) values both correlated significantly with the postexercise FEV 1 decrease. CONCLUSION: this study shows that EBC Cys-LT values are higher in asthmatic children with EIB and correlate with the decrease in FEV 1 after exercise. These findings suggest that the pathways of both Cys-LT and nitric oxide are involved in the pathogenesis of EIB.     

Protection against exercise-induced bronchoconstriction by montelukast in aspirin-sensitive and aspirin-tolerant patients with asthma

BACKGROUND: Montelukast, a cysteinyl-leukotriene receptor antagonist, was reported to have a protective effect against exercise-induced bronchoconstriction (EIB). Aspirin-induced asthma (AIA) is characterized by overproduction of cysteinyl-leukotrienes. OBJECTIVE: The aim of the study was to compare the response to exercise and the effect of montelukast on EIB in AIA as compared to aspirin-tolerant asthma (ATA). METHODS: A placebo-controlled, double blind, cross-over randomized study was performed in 19 AIA and 21 ATA patients with stable asthma. A single dose of montelukast (10 mg) or placebo (PL), was given orally one hour prior to exercise challenge. FEV1 was measured before and 5, 10, 15 min after exercise and then at 15-minute intervals for 4 h. Urinary LTE4 excretion and blood eosinophil count were measured at baseline, 2 h and 4 h following exercise challenge. RESULTS: Positive bronchial response to exercise was observed in 47.5% of all patients studied. Exercise led to almost identical maximal fall in FEV1 in AIA and ATA patients (23.5% +/- 6.8% vs. 21.8% +/- 12.0%, respectively; P = 0.7). Montelukast, as compared to PL, significantly attenuated EIB in 63.2% of 19 patients with positive exercise test preceded by PL. The mean of maximum fall in FEV1 from the pre-exercise value was 10.2% +/- 13.8 after montelukast as compared to 22.5% +/- 10.2 after placebo (P < 0.001). No significant differences between protective effect of montelukast was observed in AIA as compared to ATA patients (P = 0.63, anova). Urinary LTE4 excretion showed no change following exercise, irrespective of the result of the test in all subjects. CONCLUSION: Patients with AIA and ATA react similarly to exercise challenge and obtain similar protection against EIB by montelukast.     

Increased levels of vascular endothelial growth factor in induced sputum in asthmatic patients

BACKGROUND: Vascular endothelial growth factor (VEGF) is highly expressed in the airway of asthmatic patients. As VEGF increases airway vascular permeability, consequent thickening of the airway wall mucosa may lead to narrowing of the airway lumen. OBJECTIVE: We evaluated the relationship between VEGF levels in induced sputum and eosinophilic inflammatory profiles, and the degree of airway vascular permeability in asthmatic patients and we evaluated the effect of inhaled corticosteroids on VEGF levels in induced sputum. METHODS: Induced sputum specimens were obtained from 28 glucocorticosteroids free asthmatics and 11 healthy control subjects. We examined VEGF levels and airway vascular permeability index in induced sputum. After the initial sputum induction, 21 asthmatics received 8-week inhaled beclomethasone dipropionate (BDP, 800 micro g/day) therapy, then sputum induction was repeated. RESULTS: The VEGF levels in asthmatics were significantly higher than in healthy control subjects (P < 0.0001). The VEGF levels were negatively correlated with forced expiratory volume of 1 s (FEV1, % predicted, r = - 0.68, P < 0.001), the percentage of eosinophils (r = 0.51, P < 0.01) and ECP levels (r = 0.39, P < 0.05). Moreover, the VEGF levels were significantly correlated with airway vascular permeability index (r = 0.61, P < 0.001). After 8-week inhaled BDP therapy, the VEGF levels were significantly decreased compared to pretreatment levels (P < 0.0001) and the VEGF levels were significantly correlated with airway vascular permeability index even in post-treatment asthmatics (r = 0.62, P < 0.01). CONCLUSION: The VEGF levels in induced sputum were increased in asthmatics and its levels were associated with degree of airway narrowing and airway vascular permeability. These findings provide strong evidence that VEGF may play an important role in the pathogenesis of bronchial asthma.     

Effect of a single dose of the selectin inhibitor TBC1269 on early and late asthmatic responses

BACKGROUND : Selectins participate in the initial phase of leucocyte migration from circulation to inflamed tissues and may play a role in inflammatory cellular influx into airways in asthma. In the sheep asthma model, TBC1269, a pan-selectin antagonist, reduced late allergen response by 74%. OBJECTIVE : To determine whether a single dose of TBC1269 inhibits early (EAR) and late (LAR) asthmatic responses, and whether it inhibits sputum leucocyte influx after inhalation allergen challenge in atopic asthmatic subjects treated with bronchodilators only. METHODS : Twenty-one asthmatic subjects (mean+/-SD, age=32.5+/-6.7 years, 8 males, FEV1 percent predicted=84+/-15%) with known late asthmatic response based on a screening inhalation allergen challenge were randomly assigned to receive intravenous treatment with either placebo (n=11) or TBC1269 (n=10, 30 mg/kg) infused over 15 min immediately prior to a second (post-treatment) allergen challenge at least 4 weeks after the screening challenge. After each challenge, EAR and LAR were monitored for 7 h. In addition, sputum was induced 1 day before and 1 day after each allergen challenge. RESULTS : TBC1269 did not attenuate the EAR compared with placebo (largest fall in FEV1 within 1 h of 34.1+/-13.9% vs. 31.8+/-12.2% for TBC1269 and placebo groups respectively, P=0.61) or the LAR (largest fall in FEV1 between 3 and 7 h of 39.3+/-15.3% vs. 32.6+/-13.8%, P=0.24). TBC1269 had only minor effects on allergen-induced sputum eosinophilia. CONCLUSION : We conclude that TBC1269 administered before allergen challenge as a single intravenous dose does not attenuate early or late asthmatic responses to allergen in asthmatic subjects.     

Albuterol HFA is as effective as albuterol CFC in preventing exercise-induced bronchoconstriction.

BACKGROUND: Secondary to the phase-out of chlorofluorocarbons (CFCs), the albuterol (Ventolin, GlaxoSmithKline, Uxbridge, Middlesex, United Kingdom) pressurized metered-dose inhaler (MDI) has been formulated in a non-ozone-depleting propellant, hydrofluoroalkane (HFA) 134a. OBJECTIVE: To compare the efficacy of albuterol HFA to albuterol CFC and placebo HFA in protecting patients from exercise-induced bronchospasm (EIB). METHODS: Randomized, double-blind, placebo-controlled, three-way crossover study in patients with documented EIB. Patients (n = 24) aged 18 to 45 years old received albuterol HFA or albuterol CFC, (total dose of 180 microg ex-actuator), or placebo HFA via an MDI, 30 minutes before a standardized exercise challenge. Serial forced expiratory volume in 1 second (FEV1) measurements were made 5 minutes before exercise and 5, 10, 15, 20, 25, 30, and 60 minutes postexercise. The primary outcome measure was the maximum percentage fall in FEV1 over the 60 minutes after exercise. RESULTS: The adjusted mean maximum percentage falls in FEV1 postexercise for albuterol HFA and CFC groups were 15.4% and 14.9%, respectively. The two formulations were comparable with a treatment difference of -0.5% (P = 0.848; 95% confidence interval, -5.3 to 4.4%). When compared with the fall in FEV1 for placebo (33.7%), both active treatments demonstrated a significantly smaller fall in FEV1 postexercise (P < 0.001). Safety profiles were similar among the three treatment groups. CONCLUSIONS: The results provide assurance to prescribers that the formulation of albuterol in the non-ozone-depleting propellant HFA 134a has not affected its efficacy in the treatment of EIB in asthmatic patients. Single doses of albuterol HFA and CFC from an MDI are comparable in terms of efficacy and safety on a microgram per microgram basis.     

Airway immunopathology of asthma with exercise-induced bronchoconstriction

BACKGROUND: Exercise-induced bronchoconstriction (EIB) is a common cause of symptoms in a subgroup of asthmatic subjects. The pathobiology that makes this group of asthmatic subjects susceptible to bronchoconstriction after a brief period of exercise remains poorly understood. OBJECTIVE: We sought to determine whether there are differences in lower airway inflammation and production of cytokines and eicosanoids between asthmatic subjects with and without EIB. METHODS: Two distinct groups of asthmatic subjects based on a priori definitions were identified, one with moderate-to-severe EIB and the other without significant bronchoconstriction after exercise challenge. Both groups met the definition of asthma on the basis of bronchodilator response, bronchial hyperresponsiveness, or both. A comparative immunopathology study was conducted by using induced sputum to identify differences in lower airway inflammation and production of cytokines and eicosanoids. RESULTS: The groups had similar baseline lung function and bronchodilator response and did not have any asthma exacerbations within the prior year. The concentration of columnar epithelial cells was markedly higher in the group with EIB (1.4 x 10(5) vs 2.9 x 10(4) cells/mL, P=.01). The concentration of eosinophils was higher in the group with EIB (3.6 x 10(4) vs 4.9 x 10(3) cells/mL P=.04). Cysteinyl leukotrienes (CysLTs; 727.7 vs 151.9 pg/mL, P=.01) and the ratio of CysLTs to prostaglandin E(2) (1.85 vs 1.04, P=.002) in the airways were higher in the group with EIB. CONCLUSION: Injury to the airway epithelium, overexpression of CysLTs, relative under production of prostaglandin E(2), and greater airway eosinophilia are distinctive immunopathologic features of asthma with EIB.     

Effects of azelastine on allergen- and exercise-induced asthma

The effects of the new anti-allergic drug, azelastine, on allergen- and exercise-induced asthma were studied. In six allergen inhalation tests for five asymptomatic asthmatic patients, the maximum percentage fall in FEV1.0 immediately after inhalation of allergen extract was 37.2 +/- 6.4 per cent (mean +/- SEM). As compared with a placebo, the maximum percentage fall in FEV1.0 with azelastine after inhalation of allergen extract in the same manner as with the placebo was 17.3 +/- 6.9 per cent. The difference was statistically significant (p less than 0.05). The percentage fall in FEV1.0 with placebo and azelastine in late asthmatic response (n = 4) was 36.0 +/- 5.3 per cent and 10.0 +/- 5.2 per cent, respectively. The difference was also statistically significant (p less than 0.01). An exercise test was carried out on seven asymptomatic asthmatic patients using an inclined treadmill. The maximum percentage fall in FEV1.0 without drugs, with diphenhydramine and azelastine was 38.9 +/- 5.0 per cent, 20.1 +/- 3.8 per cent and 11.3 +/- 3.1 per cent, respectively. Significant differences were found among each group (p less than 0.05). Azelastine was regarded as having sufficient potency to inhibit exercise-induced asthma; however, placebo effects cannot be ruled out with regard to the effects of diphenhydramine. These results suggests that chemical mediator release is involved not only in allergen-induced asthma but also in exercise-induced asthma, suggesting the clinical utility of azelastine.     

Atopy may be related to exercise-induced bronchospasm in asthma

BACKGROUND: Recent studies suggest that atopy may be associated with exercise-induced bronchospasm (EIB) in asthma. However, it is not clear whether atopy is related to EIB, regardless of airway hyper-responsiveness (AHR) to methacholine, because asthmatic subjects often show AHR to exercise and methacholine simultaneously. OBJECTIVE: To investigate whether atopy is related to EIB in asthmatic subjects, independently of AHR to methacholine. METHODS: Fifty-eight male asthmatic subjects were studied. Initial spirometry was performed. Skin prick test was carried out, using 53 common allergens including mites dust antigen. Atopy score was defined as a sum of mean weal diameters to all allergens tested. Methacholine bronchial provocation testing was performed. Twenty-four hours later, free running test was performed. Positive EIB was defined as a 15% reduction or more in FEV1 from baseline after exercise. RESULTS: All subjects had AHR to methacholine. The degree of AHR to methacholine in asthmatics with EIB was similar to that in asthmatics without EIB. However, atopy score and skin reaction to Dermatophagoides pteronyssinus significantly increased in asthmatics with EIB compared with those without EIB (P < 0.05, respectively). Furthermore, the degree of EIB significantly correlated with atopy score in all subjects (r = 0.35, P < 0.01). This relationship was maintained even after the exclusion of EIB-negative asthmatic subjects. CONCLUSION: Atopy defined as skin test reactivity may contribute to the development of EIB in asthma, independently of AHR to methacholine.     

Influence of a single antigenic challenge on the pattern of airway response to exercise in asthma.

We studied 14 atopic subjects with mild asthma (six men and eight females) to document whether allergen exposure can change the pattern of response to exercise. Each had an exercise test at 80% of the VO2 max for six minutes before (exercise 1) and 48 hours (exercise 2) after an allergen inhalation test (AIT). FEV1 was measured at regular intervals up to eight hours after each challenge. On the day following AIT, spontaneous changes in FEV1 were measured for eight hours (control day). Airway responsiveness (AR) to histamine was measured at the beginning of the study, then 24 hours after AIT and at the end of the 2nd exercise. Mean early fall in FEV1 after exercise 1, AIT and exercise 2 were, 24.9 +/- 3.2%, 24.5 +/- 2.2%, and 27.6 +/- 3.8%, respectively. Airway responsiveness to histamine was increased at 32 and 56 hours post-AIT with a mean PC20 (SEM) of 0.50 (0.40, 0.62) and 0.93 (0.74, 1.17) mg/mL compared with 1.87 (1.33, 2.61) at baseline (P less than .05). Allergen inhalation test induced an isolated early asthmatic response (EAR) in four subjects, an equivocal response (late fall in FEV1: 5% to 15%) in four and a definite late asthmatic response (LAR) in six. No subject had a LAR before the AIT but two with a LAR after allergen exposure developed a late response to exercise after the AIT. This last was only partly explained by an increased diurnal variation of expiratory flows.(ABSTRACT TRUNCATED AT 250 WORDS)     

Imbalance between vascular endothelial growth factor and endostatin levels in induced sputum from asthmatic subjects

BACKGROUND: Angiogenesis has recently attracted considerable attention as a component of airway remodeling in bronchial asthma. Vascular endothelial growth factor (VEGF) is highly expressed in asthmatic airways, and its contribution to airway remodeling has been reported. Although angiogenesis is regulated by a balance of angiogenic and antiangiogenic factors, the relative levels of antiangiogenic factors in asthmatic airways have not been evaluated. OBJECTIVE: We sought to determine whether an imbalance between angiogenic and antiangiogenic factors exists in asthmatic airways. METHODS: We simultaneously measured VEGF and endostatin levels and evaluated their correlation and balance in induced sputum from 18 steroid-naive asthmatic subjects and 11 healthy control subjects. After initial sputum induction, asthmatic subjects underwent 8 weeks of inhaled beclomethasone dipropionate (BDP; 800 microg/d) therapy, and sputum induction was then repeated. RESULTS: VEGF and endostatin levels in induced sputum were significantly higher in asthmatic subjects than in control subjects (P <.001). There was a significant correlation between VEGF and endostatin levels in both control subjects (r = 0.995, P <.001) and asthmatic subjects (r = 0.923, P <.001). Moreover, the VEGF/endostatin level ratio in asthmatic subjects was significantly higher than that in control subjects (P <.0001). After 8 weeks of inhaled BDP therapy, the VEGF level in induced sputum in asthmatic subjects was significantly decreased (P <.001), whereas the endostatin level was not. A correlation between VEGF and endostatin levels existed even after BDP therapy (r = 0.861, P <.001). Moreover, the VEGF/endostatin level ratio was significantly decreased to the same level as in the control subjects after BDP therapy (P <.0001). CONCLUSION: There was an imbalance between VEGF and endostatin levels in induced sputum from asthmatic subjects. This imbalance might play an important role in the pathogenesis of bronchial asthma through its effects on angiogenesis.     

Sputum induction in corticosteroid-dependant asthmatics: risks and airway cellular profile

Sputum induction with nebulized hypertonic saline is increasingly being used to evaluate airway inflammation. We investigated the procedure-associated risk in 16 asthmatics that were still symptomatic despite on high doses of regular corticosteroid (CS) therapy (7 on daily inhaled CS > or = 800 microg budesonide or equivalent; 9 on additional daily oral CS) and their sputum cellular profile. For comparison, 12 mild stable asthmatics and 10 normal healthy subjects were included. All subjects inhaled 3%, 4% and 5% hypertonic saline sequentially via ultrasonic nebulizer as a means to induce sputum. Maximal percentage fall of Forced Expiratory Volume on One Second (FEV1) during sputum induction was significantly greater in CS-dependent asthmatics (median % [IQR]: 16.0 [11.0-32.3]) than in mild asthmatics (5.3 [4.2-10.8], p = 0.002] and in normal subjects (4.6 [3.4-6.4]), p = 0.0001). The maximal percentage FEV1 fall was inversely correlated with baseline FEV1 (Rs= -0.69; p < 0.0001). Compared to mild asthmatics, induced sputum from CS-dependant asthmatics had proportionately fewer eosinophils (2.2 [0.8-7.0] versus 23.3% [10.7-46.3], p = 0.003) and greater neutrophils (64.2 [43.9-81.2] versus 28.7 [19.0-42.6], p = 0.009). Sputum neutrophils showed a significant inverse correlation to FEV1 (Rs = -0.51, p = 0.01). We concluded that sputum induction using nebulized hypertonic saline should be performed with caution in CS-dependant asthmatics. The airway cellular profile observed suggests that the immunopathology underlying CS-dependant asthmatics may be different or a consequence of CS therapy.     

Immediate and delayed bronchoconstriction after exercise in patients with asthma

Although an immediate asthmatic response after exercise is known to occur in some patients with asthma, the existence of a delayed asthmatic response after exercise is controversial. Accordingly, we studied 53 patients who had an immediate mean (+/- SD) decrease in forced expiratory volume at one second (FEV1) of 36 +/- 13 percent, which was maximal 13 +/- 12 minutes after the completion of treadmill exercise. Eight of these patients also had a delayed asthmatic response (a 32 +/- 5 percent decrease in FEV1 occurring 5.0 +/- 1.8 hours after exercise). During a control day, on which the FEV1 was measured serially but no exercise was performed, the same delayed asthmatic response was observed in all but one patient. This finding suggests that the delayed asthmatic response observed in these patients after exercise was not specifically related to the performance of exercise. We conclude that in patients who have bronchoconstriction immediately after exercise, a second asthmatic response occurring later after the exercise is uncommon.     

Exercise in elite summer athletes: Challenges for diagnosis

BACKGROUND: There is a high prevalence of asthma and exercise-induced bronchoconstriction (EIB) in elite athletes when the diagnosis is based on symptoms and medication use. Objective measurements are now required by some sporting bodies to support a diagnosis of asthma or EIB to justify use of beta-agonists. Such measurements could include bronchial provocation with methacholine, with eucapnic voluntary hyperpnea (EVH) of dry air (a surrogate for exercise), or both. OBJECTIVE: The aim of the study was to investigate the relationship between asthma symptoms and responses to methacholine and the EVH challenge in a group of unselected elite summer-sport athletes. The outcome would be to inform practitioners of a suitable objective approach to identifying those with asthma and EIB. METHODS: Fifty elite summer-sport athletes with or without asthma were recruited from sporting teams and sports medicine centers throughout Melbourne, Australia. All subjects completed a respiratory questionnaire and, on separate days, underwent a bronchoprovocation challenge test with methacholine and EVH. RESULTS: Forty-two subjects reported one or more respiratory symptoms in the past year, 9 had positive methacholine challenge results (mean PD(20) of 1.69 +/- 2.05 micromol), and 25 had positive EVH challenge results (mean fall in FEV(1) of 25.4% +/- 15%). Although all subjects with positive methacholine challenge results had positive EVH challenge results, methacholine had a negative predictive value of only 61% and a sensitivity of 36% for identifying those responsive to EVH. CONCLUSION: These findings suggest that the pathogenesis of EIB in elite athletes might be different from that of asthma, and as such, neither symptoms nor the methacholine challenge test should be used exclusively for identifying EIB.     

激素治疗对运动诱发性哮喘患者痰嗜酸性粒细胞计数的影响

目的探讨气道嗜酸性粒细胞性炎症和运动诱发的支气管痉挛（EIB）之间的关系,及其对吸入糖皮质激素（ICS）治疗的反应。方法本研究为随机、双盲、二阶段交叉试验,将26例有运动诱发性支气管痉挛发作史且从未接受过激素治疗的哮喘患者随机分为两组,每组分别给予两个剂量水平的布地奈德吸入：①100μg/d与400μg/d对比;②200μg/d与800μg/d对比。每一阶段为3周,洗脱期3～8周。治疗前及开始治疗后每隔1周进行1次运动激发试验并留取痰液标本行嗜酸性粒细胞计数。结果高剂量ICS治疗（400μg/d和800μg/d）可显著减少痰嗜酸性粒细胞比例。痰嗜酸性粒细胞百分比与运动诱发性支气管痉挛严重程度相关,且对EIB的严重程度有预测作用;高剂量ICS治疗时,尚可预测EIB对激素治疗有效,而对低剂量ICS组（100μg/d和200μg/d）则无预测作用。低剂量ICS治疗,不管基线痰嗜酸性粒细胞计数是否增多,EIB在第1周末发作显著减轻,尔后几无改善。而高剂量ICS治疗对EIB的改善作用在痰嗜酸性粒细胞增多的患者中显著优于嗜酸性粒细胞计数小于5%者,这种明显的差异在开始治疗1周后即显现,且随时间的推移而继续加大。结论气道嗜酸性粒细胞性炎症可能在EIB的发生及其对ICS治疗有效的调节机制中起重要的作用。测定痰嗜酸性粒细胞计数在预测EIB的严重程度及其对不同剂量ICS治疗的反应具有一定的临床应用价值。     

The effect of nedocromil sodium on the bronchoconstrictor effect of neurokinin A in subjects with asthma

We have previously demonstrated that the neuropeptide, neurokinin A (NKA) (substance K), causes bronchoconstriction in subjects with asthma. In a double-blind, crossover study we investigated the effect of nedocromil sodium on NKA-induced bronchoconstriction in subjects with asthma. Twelve patients with mild asthma (mean FEV1 percent predicted +/- SE, 87.3 +/- 3.4) inhaled on 2 separate days either nedocromil sodium, 4 mg, or placebo, as two puffs from a metered-dose aerosol, 30 minutes before challenge with NKA. NKA was inhaled at three concentrations (10(-7), 3.10(-7), and 10(-6) mol/ml). The specific airway conductance (SGaw) and FEV1 were measured before and 5 and 15 minutes after each concentration step. On the placebo-treatment day, NKA caused a concentration-dependent decrease in SGaw and FEV1 (mean log for the provocative concentration of NKA causing a 35% fall in SGaw [10(-7) mol/ml], 0.49; mean log for the provocative concentration of NKA causing a 15% fall in SGaw [10(-7) mol/ml], 0.90). The inhalation of 4 mg of nedocromil sodium reduced the decrease in both SGaw and FEV1. The maximal percentage decrease in SGaw on the nedocromil sodium-treatment day was 27 +/- 5.2 (versus placebo, 53.3 +/- 5.4; p less than 0.05), and the maximal percentage decrease in FEV1 was 5.5 +/- 1.4 (versus placebo, 12.4 +/- 2.3; p less than 0.05). The dose-response curves for NKA after nedocromil sodium treatment were significantly shifted to the right compared to the curve after placebo-treatment. We conclude that nedocromil sodium protects against NKA-induced bronchoconstriction in subjects with asthma.     

Effect of anti-asthmatic drugs on the response to inhaled endotoxin.

BACKGROUND: Endotoxin is a pro-inflammatory agent contaminating the dust that has been associated with the risk to develop pulmonary diseases. There is no data on the protective efficacy of anti-asthmatic drugs on the response induced by inhaled endotoxin in human. METHODS: Twelve mildly asthmatic subjects were submitted weekly to bronchial challenge tests with 20 microg endotoxin. The response was evaluated by the changes in FEV1, blood cells count, neutrophils activation (measured with the luminol-enhanced chemiluminescence) and blood concentration in the acute phase proteins, C-reactive protein (CRP) and haptoglobin. In a double-blind randomized cross-over placebo-controlled design, a single dose each of 500 microg beclomethasone dipropionate, 200 microg salbutamol, and 50 microg salmeterol were administered 30 minutes before the endotoxin challenge test. RESULTS: The 20-microg endotoxin challenge test induced a significant decrease in FEV1 and luminol-enhanced chemiluminescence (P < .001 and <.05, respectively). There was an increase in the blood neutrophils count (P < .05), in CRP (P < .02) and in haptoglobin (P < .03) concentrations. Pretreatment with beclomethasone dipropionate did not have any significant effect on the response to inhaled endotoxin. Salbutamol and salmeterol completely prevent the FEV1 decline due to their potent bronchodilatation activity. Salmeterol and salbutamol did not have any significant effect on the blood inflammation induced by endotoxin inhalation. CONCLUSION: The bronchodilating properties of beta2-agonists prevent the lung function response to inhaled endotoxin. When given in a single dose, an inhaled corticosteroid does not have protective activity on the endotoxin-induced blood inflammation.     

Autonomic regulation after exercise evidenced by spectral analysis of heart rate variability in asthmatic children.

BACKGROUND: Bronchial asthma is associated with abnormal autonomic nervous function in childhood. Exercise is one of the most common precipitating factors of acute asthmatic crises although the exact mechanism of autonomic regulation in asthmatic children after exercise is unclear. OBJECTIVE: The aim of this study was to investigate the features of autonomic regulation after exercise in asthmatic and control children. METHODS: Pulmonary function tests and heart rate variability spectral analysis were performed in 15 asthmatic children and 7 control children (age 6 to 15 years) during and after an exercise challenge. RESULTS: The maximum % fall of forced expiratory volume in 1 second (FEV1) was significantly greater (P < .01) in asthmatic subjects (9.1 +/- 5.1%) than in normal control subjects (1.0 +/- 2.5%). The high frequency band (HF) amplitude, an index of cardiac vagal tone, 5 minutes after exercise was significantly higher (P < .05) in the asthmatic subjects (14.4 +/- 7.9 msec) than in control subjects (5.9 +/- 2.6 msec). Furthermore, the difference in the HF amplitude between the control group and the exercise-induced asthma group was significant both 5 minutes (P < .01) and 10 minutes (P < .05) after challenge. There was a significant correlation (P = .565, P = .0165) between HF amplitude 5 minutes after exercise and the magnitude of the decrease in FEV1. On the other hand, no significant difference was observed in the low frequency band amplitude between the controls and the asthmatic subjects. The ratio of low frequency to high frequency power, which is suggested to correlate with cardiac sympathetic activity, did not differ between the two groups. CONCLUSION: These findings suggest that autonomic nervous activities, particularly vagal response after exercise, in asthmatic children is different from that in control children.