Modifications of airway responsiveness to adenosine 5'-monophosphate and exhaled nitric oxide concentrations after the pollen season in subjects with pollen-induced rhinitis

STUDY OBJECTIVE:s: To determine the effect of cessation of exposure to pollen on airway responsiveness to adenosine 5'-monophosphate (AMP) in subjects with pollen-induced rhinitis, and to explore the relationship between changes in airway responsiveness and changes in exhaled nitric oxide (ENO) levels. STUDY DESIGN: Subjects were studied during the pollen season and out of season. SETTING: Specialist allergy unit in a university hospital. PATIENTS: Fourteen subjects without asthma with pollen-induced rhinitis who showed bronchoconstriction in response to methacholine and AMP during the pollen season and 10 healthy nonatopic control subjects. MEASUREMENTS AND RESULTS: In subjects with pollen-induced rhinitis, ENO concentrations, provocative concentration of agonist causing a 20% fall in FEV(1) (PC(20)) methacholine, and PC(20) AMP were determined during the pollen season and out of season. Healthy control subjects were studied during the pollen season. In subjects with allergic rhinitis, PC(20) AMP increased from a geometric mean of 79.4 mg/mL (95% confidence interval [CI], 31.6 to 199.5 mg/mL) during the pollen season to 316.2 mg/mL (95% CI, 158.5 to 400.0 mg/mL) out of season (p = 0.004). The ENO concentrations decreased from 63.1 parts per billion (ppb) [95% CI, 50.1 to 79.4 ppb] during the pollen season to 30.2 ppb (95% CI, 23.4 to 38.0 ppb) out of season (p < 0.001). The ENO concentrations out of pollen season were still significantly increased in subjects with pollen-induced rhinitis when compared with healthy control subjects. There was no relationship between individual changes in ENO levels and changes in either PC(20) methacholine or PC(20) AMP. CONCLUSIONS: In pollen-sensitive subjects with allergic rhinitis, the cessation of exposure to pollen is associated with a significant reduction of airway responsiveness to inhaled AMP. However, no association was found between allergen-induced changes in ENO values and in airway responsiveness to either direct or indirect bronchoconstrictors. These findings suggest that modifications in ENO and in airway responsiveness are the consequence of different alterations induced by allergen exposure on the lower airways.     

Regular inhaled salbutamol : effect on airway responsiveness to methacholine and adenosine 5'-monophosphate and tolerance to bronchoprotection

OBJECTIVE: Regular treatment with inhaled beta(2)-agonists increases airway responsiveness consistently to indirect bronchoconstrictors (allergen, exercise, hypertonic saline solution, etc) and inconsistently to direct bronchoconstrictors (histamine, methacholine). Studies demonstrating tolerance to beta(2)-agonist bronchoprotection against the indirect bronchoconstrictor adenosine 5'-monophosphate (AMP) have not examined changes in baseline AMP responsiveness. This study assessed the effect of regular salbutamol on AMP and methacholine responsiveness and on tolerance to bronchoprotection. DESIGN: Double-blind, randomized, crossover study. SETTING: University hospital bronchoprovocation laboratory. PATIENTS: Fourteen atopic asthmatic subjects with FEV(1) > 65% predicted, and methacholine provocative concentration causing a 20% fall in FEV(1) (PC(20)) < 8 mg/mL. INTERVENTIONS: Salbutamol, 100 microg, and placebo inhalers, two puffs qid, each for 10 days. MEASUREMENTS: Methacholine PC(20) and AMP PC(20) measured 12 h after blinded inhaler after each treatment period. Methacholine PC(20) and AMP PC(20) repeated 10 min after salbutamol, 200 microg (eight subjects). RESULTS: There was no difference between placebo and salbutamol treatment in geometric mean methacholine PC(20) (0.85 mg/mL vs 0.82 mg/mL, p = 0.86) or AMP PC(20) (22 mg/mL vs 17.4 mg/mL, p = 0.21; n = 14). The acute bronchoprotective effect of salbutamol was greater vs. AMP than vs methacholine (5.1 doubling concentrations vs. 3.5 doubling concentrations, p = 0.06) and loss of protective effect of salbutamol (mean +/- SD) was greater vs AMP than vs. methacholine (2.4 +/- 0.33 doubling concentration loss vs 0.8 +/- 0.21 doubling concentration loss, p = 0.008; n = 8). CONCLUSION: Regular salbutamol (mean +/- SD) treatment did not enhance airway responsiveness to either the indirect bronchoconstrictor AMP or the direct bronchoconstrictor methacholine. Compared to its effect on methacholine, salbutamol had a greater acute protective effect vs AMP and produced greater loss of protection vs AMP when used regularly.     

Dissimilarity in methacholine and adenosine 5'-monophosphate responsiveness 3 and 24 h after allergen challenge

Bronchial hyperresponsiveness (BHR) to methacholine and adenosine 5'-monophosphate (AMP) was studied in 15 allergic asthmatic patients before and 3 and 24 h after allergen challenge with house dust mite (HDM). Subjects attended the clinic on 3 consecutive days. On the first day a control solution was inhaled, and methacholine or AMP challenge was performed 3 h later. The next day HDM was inhaled, and 3 and 24 h later methacholine or AMP challenge was performed again. There were no significant difference in FEV1 baseline value between any of the study days. PD20 HDM, percentage decrease in FEV1, and AUC for both the EAR and LAR were not significantly different in the methacholine and AMP studies. After HDM challenge, PC20 methacholine decreased significantly from a geometric mean (+/- SEM) starting value of 1.39 +/- 0.63 mg/ml to 0.30 +/- 0.78 mg/ml (p less than 0.001) at 3 h and to 0.22 +/- 0.75 mg/ml (p less than 0.001) at 24 h. The magnitude of the decrease in PC20 methacholine at 3 h correlated with the severity of the late asthmatic reaction (LAR) as measured by the percentage fall in FEV1 and area under the curve (AUC) (r = -0.60 and r = 0.55; p less than 0.05). A significant decrease was observed in the PC20 AMP at 3 h, from a geometric mean value of 12.2 +/- 0.96 mg/ml after challenge with the control solution to 4.47 +/- 0.99 mg/ml (p less than 0.05) after HDM challenge.(ABSTRACT TRUNCATED AT 250 WORDS)     

The inhibitory effect of nebulized albuterol on the early and late asthmatic reactions and increase in airway responsiveness provoked by inhaled allergen in asthma

It is widely held that inhaled beta 2-adrenoceptor agonists inhibit the early asthmatic response (EAR) but not the late response (LAR) or attendant increase in bronchial responsiveness. In this study of 10 atopic asthmatic subjects, we have investigated the effects of a high dose of nebulized albuterol (2.5 mg) on the allergen-provoked EAR, LAR, and increase in histamine responsiveness. In a randomized blinded fashion, study subjects inhaled the following combinations: albuterol followed 10 min later by allergen, placebo followed by allergen, albuterol followed by saline (albuterol, placebo, and control study periods, respectively). Airway caliber was measured as FEV1 and followed at regular intervals for 7.5 h postallergen. Bronchial responsiveness to histamine was measured and recorded as the PC20 value before and at 1.5, 3.5, 5.5, and 7.5 h after allergen or control challenge. During the placebo study period, allergen challenge caused mean 29.6 +/- 6.4 and 24.4 +/- 6.4% falls in FEV1 at 20 min and 7.5 h, respectively (both p less than 0.05), and a progressive decrease in PC20 amounting to a geometric mean of 1.9 doubling dilutions at 7.5 h (p less than 0.05). Albuterol followed by allergen resulted in a 13.1 +/- 2.2% increase in FEV1 prior to allergen followed by abolition of the EAR and inhibition of the LAR with only a 9.2 +/- 3.5% fall in FEV1 at 7.5 h, significantly different from that of placebo at 7.5 h (p = 0.048). Similarly, PC20 histamine fell by only 0.64 doubling dilutions at 7.5 h, not significantly different from baseline values but different from placebo values (p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)     

Roflumilast, a phosphodiesterase 4 inhibitor, reduces airway hyperresponsiveness after allergen challenge

BACKGROUND: Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, is currently in clinical development for the treatment of asthma. OBJECTIVES: This pilot study examined the effect of roflumilast on allergen-induced airway hyperresponsiveness (AHR) to histamine challenge and asthmatic response to allergen challenge. METHODS: In a randomized, double-blind, 2-period, crossover trial, 13 patients with mild allergic asthma [mean forced expiratory volume in 1 s (FEV(1)) % predicted = 86%] received a single dose of oral roflumilast 1,000 microg or placebo. Patients were administered roflumilast 60 min before allergen challenge, and asthmatic responses were assessed via change in FEV(1) 相似文献   

Exhaled nitric oxide, serum ECP and airway responsiveness in mild asthmatic children.

The purpose of the present study was to assess the possible relationships between exhaled nitric oxide (ENO), a circulating marker of eosinophil activation, serum eosinophil cationic protein (SECP), level of airway responsiveness to methacholine and lung function in asthmatic children, as well as to compare these markers between children with and without inhaled steroid therapy. In a cross-sectional study ENO, SECP and bronchial hyperresponsiveness to methacholine were evaluated in a group of 57 asthmatic children (21 without and 36 with regulator inhaled steroid therapy; aged 6-13 yrs). ENO was significantly lower in steroid treated children (p<0.01). No significant differences between steroid treated and untreated children were observed for the provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1; PC20), SECP and FEV1. In the whole study population significant increase correlations were observed between PC20 and SECP (r=-0.329, p=0.013) and between ENO and FEV1% of predicted (r=-0.348, p<0.01). In the group not receiving inhaled steroids the inverse relationship between PC20 and SECP was more evident (r=-0.581, p<0.001). In the steroid-treated group a significant inverse relationship was observed between ENO and FEV1 (r=-0.426, p=0.0011). The level of exhaled nitric oxide and the relationships between lung function, bronchial reactivity and markers of inflammation are different between steroid-treated and untreated asthmatic children. This has implications for the monitoring of asthma in childhood.     

Airway obstruction induced by inhaled acetaldehyde in asthma: repeatability relationship to adenosine 5'-monophosphate responsiveness.

Inhaled acetaldehyde and adenosine 5'-monophosphate (AMP) cause bronchoconstriction in asthmatics by a mechanism believed to involve histamine release from airway mast cells. This study investigates the repeatability of the acetaldehyde challenge and the relationship between airway responsiveness to acetaldehyde and AMP. To this end, we examined the effect of inhaled acetaldehyde on airway tone in comparison with either methacholine or AMP in 16 asthmatics. Furthermore, the repeatability of the acetaldehyde challenge was assessed in 14 subjects with mild asthma. The response to each bronchoconstrictor agent was measured by the PC20 (provocative concentration required to produce a 20% fall in FEV1). The geometric mean (range) PC20 values were 3.1 mmol/l (0.5-46.0 mmol/l) for methacholine, 883.1 mmol/l (190.7-1816.1 mmol/l) for acetaldehyde, and 50.1 mmol/l (3.2-1152.1 mmol/l) for AMP. Thus, acetaldehyde was 18-fold less potent than AMP in causing bronchoconstriction. A similar correlation was observed between PC20 acetaldehyde and either PC20 AMP (r = 0.58, p = 0.02) or PC20 methacholine (r = 0.56, p = 0.02). The challenge procedure with acetaldehyde was moderately repeatable (coefficient of repeatability = +/- 1.4 doubling concentrations, intraclass correlation coefficient = 0.64). We conclude that inhaled acetaldehyde is less potent than AMP in causing bronchoconstriction in asthma, and that the response to inhaled acetaldehyde is repeatable. Furthermore, the present data lends indirect support to the suggestion that acetaldehyde responsiveness and AMP responsiveness are not identifying the same alterations in the airways.     

Methacholine challenge: test-shortening procedures.

STUDY OBJECTIVES: Validation of test-shortening procedures for the 2-min tidal breathing methacholine challenge method. DESIGN: Retrospective chart review. SETTING: Tertiary-care university clinical pulmonary function laboratory. PATIENTS: One thousand subjects aged 10 to 85 years (mean +/- SD, 44.5 +/- 16.0 years), 44.5% male, referred for methacholine challenge. INTERVENTION: Two-minute tidal breathing methacholine challenge was performed, with both physician and technician access to published test-shortening procedures. MEASUREMENTS AND RESULTS: There were 315 positive test results (provocative concentration of methacholine causing a 20% fall in FEV(1) [PC(20)] < or = 8 mg/mL) and 685 negative test results. The subjects with positive test results were less likely to be male (39.1 vs 47.5%; p < 0.02) and had lower FEV(1) (91.8 +/- 14.9% predicted vs 97.2 +/- 13.9% predicted; p < 0.001). The average starting PC(20) was between 0.5 mg/mL and 1.0 mg/mL; the most common PC(20) was 1 mg/mL (67%). There were 431 skipped concentrations in 380 subjects. The mean number of methacholine inhalations was 3.7 +/- 1.1 (3.9 +/- 0.1 for negative test results vs 3.3 +/- 1.2 for positive test results; p < 0.001). Eighteen subjects had a > or = 20% FEV(1) fall on the first inhalation, and 11 subjects had a > or = 20% FEV(1) fall after a skipped concentration. In only one case (0.1%) an FEV(1) fall > or = 40% on the first concentration was reported, compared with no cases after a skipped concentration and seven cases with a > or = 40% FEV(1) fall after a routine doubling dose step-up. CONCLUSIONS: The 2-min tidal breathing methacholine test in clinical practice can be safely shortened to an average of less than four inhalations using starting concentrations based on FEV(1), asthma medication, and clinical features, and by occasionally omitting concentrations.     

A placebo-controlled clinical trial of regular monotherapy with short-acting and long-acting beta(2)-agonists in allergic asthmatic patients

BACKGROUND: Some recent studies suggest that regular beta(2)-agonist use may result in inadequate control of asthma. It has been hypothesized that this occurs particularly in allergic asthmatic patients exposed to relevant allergens. Moreover, it is still unclear whether this occurs during the use of both short-acting and long-acting beta(2)-agonists. METHODS: Asthmatic patients (n = 145) allergic to house dust mite (HDM) were randomly allocated to monotherapy with a short-acting beta(2)-agonist (SA; n = 48), a long-acting beta(2)-agonist (LA; n = 50), or placebo (n = 47), double blind, double dummy. The study covered three periods: (1) a 4-week run-in period, in which no changes took place; followed by (2) cessation of treatment with asthma medication including inhaled corticosteroids, introduction of allergen avoidance measures (active/placebo treatment) to lower HDM exposure in the active group, and an 8-week washout period to adjust patients to these changes; followed by (3) a 12-week study medication period. At the start of the 12-week medication period, and every 4 weeks thereafter, spirometric measurements (FEV(1) and provocative concentration of histamine causing a 20% fall in FEV(1) [PC(20)]) were performed. Peak flow and asthma symptoms were recorded daily. Additionally, at the start and every 6 weeks thereafter, dust samples were collected from mattresses and living room and bedroom floors to assess HDM (der p 1) concentrations. Effects on FEV(1), PC(20), peak flow, and asthma symptoms were analyzed with repeated-measurement analysis and corrected for the exposure to HDM allergens. RESULTS: There were no significant differences among the three medication groups after 12 weeks for FEV(1). However, a significant decrease in mean FEV(1) percent predicted (95% confidence interval [CI]) was observed within the SA group: - 6.6 (- 10.4 to - 2.8) (p = 0.0002). A decrease in geometric mean PC(20) (95% CI) of - 1.2 (- 1.96 to - 0.44) doubling concentration was observed within the SA group (p = 0.05). No significant changes in FEV(1) and PC(20) were observed > 12 weeks within the LA group or the placebo group. There were neither changes in peak flow and asthma symptom scores among the three medication groups nor within the groups. Moreover, none of the parameters showed interactive effects with allergen exposure. CONCLUSION: There were no significant differences among the three medication groups for FEV(1) and PC(20). The within-treatment group comparison showed a significant small decline in FEV(1) for the SA group (but not for the LA group), which could indicate that monotherapy with SAs might have negative effects on FEV(1). This was not seen during regular use of LAS: No clear pathophysiologic mechanism can explain these findings at the moment. Relatively high or low exposure to allergens did not alter these findings.     

Natural exposure to pollen reduces the threshold but does not change the pattern of response to the allergen in allergic subjects

It is known that exposure to seasonal allergen in sensitized asthmatics increases non-specific bronchial responsiveness, but it is controversial if exposure to seasonal allergen influences the presence and the severity of the late asthmatic response (LAR) to allergen. Fifteen asthmatic subjects sensitized to grass pollen performed a specific bronchial provocative test (sBPT) with Phleum pratensis extract before and during the pollen season. Changes of methacholine were also assessed. Allergen PD20FEV1 significantly decreased during the pollen season with respect to outside (allergen PD20FEV1, geometric mean: 0.10 vs. 0.23 biological units; P < 0.05), but the pattern of specific airway response did not change. Particularly, a consistent LAR was observed in three subjects outside the pollen season and in two subjects during the pollen season. Seven subjects with isolated early asthmatic response (EAR) outside the season did not show LAR after allergen inhalation during the pollen season. However, four of five subjects with slight LAR outside the pollen season (deltaFEV1% between 15 and 20%) lost LAR during season. Methacholine sensitivity increased slightly but significantly from outside to during the pollen season. This increase was greater in subjects with LAR outside the pollen season. The natural exposure to pollen induces an increase in bronchial sensitivity to allergen in sensitized subjects, but it does not induce LAR in subjects without LAR outside the pollen season.     

Effect of inhaled beclomethasone dipropionate on bronchial hyperreactivity in asthmatic children during maximal allergen exposure

In this double blind study we evaluated the effect of a 2 months long treatment with inhaled beclomethasone dipropionate (300 micrograms/day) on methacholine responses in asthmatic children, during a period of maximal allergen exposure. Baseline values of methacholine PC20-FEV1 were 0.66 +/- 0.22 mg/mL (mean +/- SEM) in 10 children treated with the active drug and 0.78 +/- 0.21 mg/mL in 10 children treated with placebo. After 1 month of treatment PC20-FEV1 was 1.91 +/- 0.64 and 0.80 +/- 0.33 mg/mL, respectively, in the groups treated with beclomethasone versus placebo. A statistically significant reduction in bronchial hyperreactivity (PC20-FEV1, 5.49 +/- 1.86 mg/mL) but no systemic side effects were observed after 2 months of treatment with beclomethasone dipropionate. This is compared with a PC20-FEV1 of 1.38 +/- 0.52 mg/mL in the placebo group. The results confirm the effect of inhaled corticosteroids in reducing bronchial hyperreactivity, even during a period of maximal allergen exposure.     

Nedocromil sodium inhibits the increase in airway reactivity induced by platelet activating factor in humans.

To investigate the effect of nedocromil sodium on changes in airway reactivity to methacholine induced by platelet activating factor, we studied 12 nonasthmatic, nonatopic subjects (24 to 41 years) in a double-blind trial. The FEV1 and airflow at 30 percent of vital capacity from a partial forced expiration (V30p) were used to assess changes in airway caliber. Two concentration-response curves to doubling concentrations of MCh (from 0.3 mg/ml) were performed 48 h apart. The concentrations of MCh causing a 20 percent fall in FEV1 (PC20FEV1) or a 40 percent fall in V30p (PC40V30p) were calculated. After the first MCh challenge, subjects were matched by airway reactivity and randomly assigned to nedocromil sodium (two puffs qid 2 mg/puff) or placebo treatment. Two days after the second MCh challenge, PAF was inhaled, and changes in airway caliber were recorded. Administration of either nedocromil sodium or placebo was ended at this time and airway response to MCh was assessed two days after PAF. The two concentration-response curves to MCh obtained before PAF exposure were superimposable. The PAF caused a dose-related bronchoconstriction in both groups; the maximal fall in V30p was 27.6 +/- 6.6 percent (mean +/- SE) in the nedocromil sodium group and 37.4 +/- 4.6 percent in the placebo group. Two days after PAF, the PC20FEV1 did not change in subjects who received nedocromil sodium (4.86 vs 4.32 mg/ml; geometric mean), but it fell from 6.59 to 1.12 mg/ml (p less than 0.05) in placebo-treated subjects. These results indicate that nedocromil sodium inhibits PAF-induced increase in airway reactivity.     

Salmeterol does not alter increased bronchial responsiveness caused by organic dust exposure

BACKGROUND: Exposure in a swine house induces airway inflammation and increases bronchial responsiveness to methacholine in healthy subjects. STUDY OBJECTIVES: The aim was to investigate whether a long-acting beta2-agonist, salmeterol, alters the increased bronchial responsiveness induced in healthy subjects following exposure to organic dust in a swine barn. DESIGN AND SUBJECTS: The study includes three separate parts. In the first part (part 1), healthy subjects inhaled salmeterol (50 microg bid, n = 8) or placebo (n = 8) over 2 weeks. In part 2, healthy subjects inhaled one single dose of salmeterol (100 microg, n = 6) or placebo (n = 6) 1 h prior to exposure in a swine barn, which was followed by a bronchial methacholine challenge. In part 3, eight healthy individuals inhaled placebo or salmeterol (100 microg), 2 h or 8 h prior to a bronchial methacholine provocation, without being exposed in the swine barn. RESULTS: Exposure caused an increase of bronchial responsiveness to methacholine by 3.2 doubling concentration steps (25 to 75th percentiles, 2.8 to 4.1) and 2.6 doubling concentration steps (25 to 75th percentiles, 1.4 to 3.7) in the placebo and salmeterol groups (2 weeks), respectively, with no significant differences between the groups (p = 0.3; part 1). Similar results were obtained when salmeterol was administered as a single dose (part 2) prior to exposure. However, salmeterol significantly attenuated the bronchial responsiveness to methacholine by 1.2 doubling concentration steps (0.8 to 1.7) 8 h after inhalation (part 3). CONCLUSIONS: Salmeterol inhalation did not protect against the increased bronchial responsiveness induced in healthy subjects following exposure to organic dust when administered for 2 weeks or as a single dose prior to exposure. This lack of protection cannot be explained by homologous beta2-adrenoceptor desensitization. We hypothesize that exposure to organic material may alter the airway response to beta2-agonists.     

Effect of nedocromil sodium and sodium cromoglycate against bronchoconstriction induced by inhaled adenosine 5'-monophosphate

In this randomized, double-blind, placebo controlled study, the effect of prior inhalation of nebulized sodium cromoglycate (SCG) (7.3 +/- 0.6 mg) and nedocromil sodium (NED) (7.5 +/- 0.6 mg) was observed on adenosine 5'-monophosphate (AMP)-induced bronchoconstriction in 11 non-atopic asthmatic subjects. The geometric mean provocation doses of methacholine and AMP required to produce a 20% decrease in forced expiratory volume in one second (FEV1) (PD20FEV1) were 0.6 (0.1-18.8) and 5.1 (0.8-130.7) mumole respectively. The repeatability of the AMP challenge procedure for PD20FEV1 was within one doubling dose difference. SCG and NED, administered 30 min prior to bronchoprovocation with AMP, displaced the AMP dose-response curve to the right by 9.6 (1.5-41.6) (p less than 0.01) and 22.2 (3.7-89.1) (p less than 0.01)-fold, respectively, the difference between the two drugs being significant (p less than 0.05). There was a significant correlation (r = 0.7, p = 0.02) between the log dose ratios for PD20FEV1 for SCG and NED. We conclude that both SCG and NED protect against AMP-induced bronchoconstriction, NED being at least 2.3 (0.7-11.5)-fold more potent than SCG, and that they achieve this effect by a similar mechanism(s).     

Changes in bronchial reactivity in asthmatic children after treatment with beclomethasone alone or in association with salbutamol

Airway inflammation is consistently present in patients with severe asthma. The combination of inhaled steroids and bronchodilators may be useful both for treating symptoms and improving the underlying inflammatory condition. We have compared the effect of beclomethasone dipropionate (BDP) combined with salbutamol (S), BDP alone, and placebo, on the severity of bronchial responsiveness in 30 children with allergic asthma during the period of specific allergen exposure. In children treated with BDP alone, PC20-FEV1 methacholine was 0.66 +/- 0.54 at the beginning and 1.91 +/- 2.11 at the end of the study period (p greater than 0.05). In children treated with BDP + S PC20, methacholine was 1.21 +/- 1.43 at the beginning and 4.22 +/- 3.88 at the end of the study (p less than 0.05). The group of children treated with placebo had a PC20-FEV1 methacholine of 0.79 +/- 0.61 at the beginning of the study and 0.80 +/- 0.46 at the end of the study. The results of the present study show that maintenance treatment with inhaled beclomethasone combined with salbutamol may lead to greater improvement in bronchial hyperreactivity than treatment with inhaled beclomethasone dipropionate alone.     

Exhaled nitric oxide and bronchial responsiveness to adenosine 5'-monophosphate in subjects with allergic rhinitis

STUDY OBJECTIVES: To determine differences in exhaled nitric oxide (ENO) between subjects with allergic rhinitis with and without increased responsiveness to direct and indirect bronchoconstrictor agents. STUDY DESIGN: Cross-sectional study with the order of challenge tests randomized. SETTING: Specialist allergy unit in a university hospital. PATIENTS: Thirty-eight subjects without asthma with allergic rhinitis and 10 healthy nonatopic control subjects. MEASUREMENTS AND RESULTS: Participants were challenged with increasing concentrations of adenosine 5'monophosphate (AMP) and methacholine. ENO was measured with the single-exhalation method. A positive response to both bronchoconstrictor agents was detected in nine subjects with allergic rhinitis, whereas four subjects showed increased responsiveness to AMP but not to methacholine. The geometric mean (range) ENO values were significantly higher in subjects with allergic rhinitis with increased responsiveness to either methacholine or AMP than in subjects with normal responsiveness to both agonists: 51.3 parts per billion (ppb) [22.0 to 108.5 ppb] vs 25.1 ppb (5.7 to 102.9 ppb, respectively; p = 0.007) and healthy control subjects (11.2 ppb [5.0 to 31.9 ppb], p < 0.001). Subjects with allergic rhinitis with normal responsiveness to both agonists also had higher concentrations of ENO than healthy control subjects (p = 0.007). No correlation was found between ENO and either of the provocative concentrations of methacholine or AMP causing a 20% fall in FEV(1). CONCLUSIONS: In subjects without asthma but with allergic rhinitis, the presence of bronchoconstriction in response to methacholine or AMP is associated with increased ENO concentrations. However, elevated concentrations of ENO are detected even in subjects with allergic rhinitis without airway hyperresponsiveness. These results suggest that the presence of airway hyperresponsiveness is not the only factor that determines the increased NO levels detected in subjects with allergic rhinitis.     

Seasonal variability of non-specific bronchial responsiveness in asthmatic patients with allergy to house dust mites.

The aim of the study was to assess the seasonal variability of non-specific bronchial responsiveness to methacholine in allergic asthma. One hundred sixty-five patients (83 male and 82 female) entered the study: 86 subjects (group A) with allergy exclusively to mites and 79 (group B) with concomitant allergy to pollens, e.g., "Graminae" and "Parietaria." Inclusion criteria were the absence of sensitization to other allergens, no smoking habit, withdrawal from steroids, bronchodilators, sodium cromoglycate, and antihistamines for at least four weeks before enrollment, FEV1 > 70% of the predicted value, and absence of other respiratory diseases and of upper and lower respiratory tract infections for at least one month before the methacholine challenge. None of the patients had been previously treated with specific immunotherapy. Subjects of each group (A and B) underwent methacholine challenge at first visit and were divided into four subgroups according to the period when the challenge was performed. Subgroups A1 and B1 performed the challenge in December, January, and February; subgroups A2 and B2 in March, April, and May; subgroups A3 and B3 in June, July, and August; subgroups A4 and B4 in September, October, and November. PD20 values were expressed as the natural logs of the cumulative dose of methacholine causing at least a 20% fall in FEV1. Statistical analysis was carried out using multiple group analysis and Student's t-test. Results showed that the highest non-specific bronchial responsiveness was observed in autumn (ln PC20 = 4.54 +/- 1.51) in patients allergic to mites only (group A), and in summer (ln PC20 = 4.72 +/- 2.11) in those of group B. Multiple group analysis showed statistical significant differences between subgroups within each group (group A, p = 0.039; group B, p < 0.001). In patients allergic exclusively to house dust mites (group A), multiple comparisons and Student's t-test showed statistically significant differences between non-specific bronchial responsiveness (NSBR) assessed in autumn and those of other seasons (winter, p = 0.002; spring, p < 0.001; summer, p = 0.082). These results confirm that the level of allergen exposure may influence NSBR. Mite-allergic patients showed an increase of NSBR in autumn, possibly as a consequence of higher indoor mite concentration. However, mite- and grass-allergic patients had wider variations of NSBR, possibly reflecting changes in seasonal pollen concentration.     

Lack of tachyphylaxis to methacholine at 24 h

OBJECTIVE: To examine for tachyphylaxis to methacholine at 24 h and to use these data to assess the repeatability of the provocative concentration of a substance causing a 20% fall in FEV1 (PC20) for methacholine and to obtain statistical power calculations. DESIGN: Retrospective review of four double-blind, placebo-controlled studies with two methacholine PC20 values measured at 24-h intervals. SETTING: Tertiary university hospital bronchoprovocation laboratory. PATIENTS: Thirty-two subjects with mild-to-moderate well-controlled asthma. INTERVENTIONS: The placebo arms of the four studies were examined. MEASUREMENTS: Methacholine PC20 (using 2-min tidal breathing method) initial determination and repeat testing at 24 h. RESULTS: The geometric mean PC20 values were 1.57 mg/mL (95% confidence interval [CI], 1.0 to 2.4 mg/mL) and 1.62 mg/mL (95% CI, 1.0 to 2.6 mg/mL NSD; p = 0.64). The mean absolute difference between the two measurements was < 0.4 doubling concentrations, and 31 of 32 measurements had both values within one doubling concentration. These data provide a statistical power of 92% for 10 subjects to show a one-half concentration deltaPC20 and a mean power of 99 +/- 1% to show a one-concentration deltaPC20. CONCLUSIONS: There is no evidence for methacholine tachyphylaxis at 24 h in subjects with asthma. At 24 h, the average repeatability was well within a one-half concentration change, and individually 31 of 32 measurements (97%) were within one doubling concentration.     

Predictors of late asthmatic response. Logistic regression and classification tree analyses

To identify predictors of the late asthmatic response (LAR), we reviewed data from 60 asthmatic subjects who had undergone allergen challenge over the past 5 yr (33 females, age 31.4 +/- 6.7 yr [mean +/- SD], FEV(1) 90% +/- 14% predicted). Variables considered likely predictors of LAR included baseline FEV(1), PC(20) methacholine (PC(20)), sputum eosinophil percent, and the decrease in FEV(1) within 20 min of allergen challenge. A LAR (FEV(1) >/= 15% fall between 3 and 7 h after challenge) was documented in 57% of subjects. A variety of logistic regression methods revealed a significant inverse association between LAR and PC(20) (odds ratio [OR] = 0.14 [95% CI = 0.03-0.66]) and a positive association between LAR and the decrease in FEV(1) at 20 min (OR = 1.18 [1.04 -1.33]). Classification tree analysis revealed that a threshold of 0.25 mg/ml for PC(20) was most predictive of LAR; LAR developed in 87% of those with PC(20) 0.25 mg/ml (n = 37). Notably, in subjects with PC(20) > 0.25 mg/ml, the incidence of LAR increased from 38% to 57% if the allergen-induced decline in FEV(1) at 20 min was >/= 27%. Surprisingly, baseline FEV(1) and percent eosinophils in induced sputum were not significantly associated with LAR. We conclude that a threshold value of 0.25 mg/ml for PC(20) methacholine is a good predictor of LAR. Measuring the PC(20) methacholine may be useful as a screening method to improve the efficiency of identifying asthmatic subjects with a LAR.