Provocative Dose Of Methacholine Research Articles

Furry Animal Allergen Component Sensitization and Clinical Outcomes in Adult Asthma and Rhinitis

Sensitization to allergen components has been linked to asthma in children, but studies in adults are lacking. To study the relation of sensitization to furry animal allergen components to risk of asthma, rhinitis, and markers of asthma severity in adults. From the West Sweden Asthma Study, a random population-representative sample of adults aged 16 to 75 years, 2006 participants were clinically examined; 1872 were analyzed for serum IgE level to a mix of aeroallergens. Those with an IgE level of more than 0.35 kUA/L to cat, dog, or horse allergen components were analyzed for specific cat (Felis domesticus [Fel d 1, Fel d 2, and Fel d 4]), dog (Canis familiaris [Can f 1, Can f 2, Can f 3, and Can f 5]), and horse (Equus caballus [Equ c 1]) allergen components. We defined monosensitization, double sensitization, and polysensitization (>2 components) patterns and applied cluster analysis to derive distinct sensitization clusters. Sensitization to each allergen component, lipocalins, each sensitization pattern, and each sensitization cluster (nonsensitized, Fel d 1-driven sensitized, and multisensitized clusters) was associated with substantial increased risk of asthma, rhinitis, concomitant asthma and rhinitis, and Asthma Control Test-controlled asthma. Fel d 1, Can f 1, Can f 2, Can f 3, polysensitization, and multisensitized cluster were further associated with increased fractional exhaled nitric oxide and eosinophil levels, but with lower PD20 methacoline (provocative dose of methacholine causing a 20% drop in FEV1) values. There was no association with asthma exacerbations, FEV1 predicted values, emergency visits or regular oral steroid use, and neutrophil levels. Sensitization to furry animal allergen components is an important predictor of asthma, rhinitis, and markers of asthma severity with increased blood eosinophils, fractional exhaled nitric oxide, and airway hyperreactivity.

Bronchial hyperresponsiveness, airway inflammation, and reversibility in patients with chronic obstructive pulmonary disease.

BackgroundBronchial hyperresponsiveness (BHR), sputum eosinophilia, and bronchial reversibility are often thought to be a hallmark of asthma, yet it has been shown to occur in COPD as well.ObjectivesTo evaluate the relationship between BHR, lung function, and airway inflammation in COPD patients.MethodsThirty-one, steroid-free patients with stable, mild and moderate COPD were studied. The following tests were carried out: baseline lung function, reversibility, provocative dose of methacholine causing a 20% fall in forced expiratory volume in 1 second, a COPD symptom score, and sputum induction.ResultsTwenty-nine patients completed the procedures. About 41.4% had BHR, 31.0% had increased sputum eosinophils, and 37.9% had bronchial reversibility. Some of the patients had only one of these characteristics while others had two or the three of them. Patients with BHR had higher sputum eosinophils than patients without BHR (P=0.046) and those with sputum eosinophils ≥3% had more exacerbations in the previous year and a higher COPD symptom score than patients with sputum eosinophils <3% (P=0.019 and P=0.031, respectively). In patients with BHR, the cumulative dose of methacholine was negatively related to the symptom score and the number of exacerbations in the previous year. When patients with bronchial reversibility were considered, bronchodilation was positively related to sputum eosinophils.ConclusionOur study showed that BHR, sputum eosinophilia, and bronchial reversibility were not clustered in one single phenotype of COPD but could be present alone or together. Of interest, BHR and airway eosinophilia were associated with clinical data in terms of exacerbations and symptoms. Further investigation is needed to clarify this topic.

Prenatal and postnatal genetic influence on lung function development

It is unknown to what extent adult lung function genes affect lung function development from birth to childhood. Our aim was to study the association of candidate genetic variants with neonatal lung function and lung function development until age 7 years. Lung function measurement by means of spirometry with the raised-volume thoracoabdominal compression technique and bronchial responsiveness to methacholine challenge were assessed in 411 high-risk newborns from the Copenhagen Prospective Study on Asthma in Childhood 2000 (COPSAC2000) cohort. Measures were repeated at age 7 years. Genetic risk scores were calculated based on reported single nucleotide polymorphisms for adult lung function (FEV1/forced expiratory vital capacity [FVC] ratio and FEV1) as the number of risk alleles weighted on known effect size. These genetic risk scores were analyzed against lung function measures as z scores at birth (forced expiratory volume in 0.5 seconds [FEV0.5], forced expiratory flow at 50% of functional vital capacity [FEF50], and provocative dose of methacholine causing a 15% decrease in lung function [PD15]) and at age 7 years (FEV1, FEF50, and provocative dose of methacholine causing a 20% decrease in lung function [PD20]) and with development from birth to age 7 years (FEV0.5/1, FEF50, and PD15/20). The genetic risk scores were not associated with lung function measures at age 1 month, but the FEV1/FVC genetic risk score was associated with reduced FEF50 values at age 7 years (P = .01) and similarly with reduced growth in FEF50 from birth to age 7 years (P = .02). This score was also associated with increased bronchial responsiveness (reduced PD20) at age 7 years (P = .02) and change in responsiveness from birth to age 7 years (P = .05). Lung function genetic variants identified in adults were not associated with neonatal lung function or bronchial responsiveness but with the development of these lung function measures during early childhood, suggesting a window of opportunity for interventions targeting these genetic mechanisms.

Factors associated with elevated exhaled nitric oxide fraction in infants with recurrent respiratory symptoms

Exhaled nitric oxide fraction (F(eNO)) has been proposed as a noninvasive marker of eosinophilic bronchial inflammation in active asthma, and supposed to reflect responsiveness to corticosteroid therapy. There are several factors influencing F(eNO), and its role in early childhood respiratory disorders needs to be established. Between 2004 and 2008, 444 children aged <3 yrs with recurrent lower respiratory tract symptoms were referred to a tertiary centre for further investigation. 136 full-term, steroid-free, infection-free infants, median age of 16.4 months (range 4.0-26.7 months), successfully underwent measurement of F(eNO), lung function tests, and a dosimetric methacholine challenge test. The median level of F(eNO) was 19.3 ppb (interquartile range 12.3-26.9 ppb). Elevated F(eNO) (≥ 27 ppb, the highest quartile) was associated with maternal history of asthma (adjusted OR 3.2, 95% CI 1.3-8.1; p=0.012), and increased airway responsiveness (the provocative dose of methacholine causing a 40% fall in maximal expiratory flow at functional residual capacity ≤ 0.30 mg) (adjusted OR 4.1, 95% CI 1.4-12.7; p=0.012). Atopy, blood eosinophilia and lung function were not associated with elevated F(eNO). In conclusion, maternal history of asthma, and increased airway responsiveness are associated with elevated F(eNO) in infants with recurrent lower respiratory tract symptoms.

Combination Therapy Salmeterol/Fluticasone Versus Doubling Dose of Fluticasone in Children With Asthma

To determine if the addition of a long-acting bronchodilator is noninferior to doubling the dose of inhaled corticosteroids in children whose asthma is not controlled with use of low-to-moderate doses of inhaled corticosteroids alone.Children aged 6 to 16 years who were using fluticasone propionate (100 μg twice daily) to treat their asthma were enrolled in this study (N = 257). A 4-week run-in period was used to monitor these children. Those who were still symptomatic despite regular use of fluticasone propionate were included in the randomization of study groups (n = 158). The study was conducted at multiple pediatric medical centers throughout Europe.Symptomatic children were randomly assigned to 1 of 2 treatment groups: fluticasone propionate (200 μg twice per day) or salmeterol/fluticasone propionate (50/100 μg twice per day), used for a 26-week treatment period. Lung-function measurements were recorded at the start of the run-in period, at time of randomization, and at all visits during the treatment period. The provocative dose of methacholine that causes a 20% decrease (PD20) in the forced expiratory volume in 1 second (FEV1) and exhaled nitric-oxide levels were measured at the start and end of the treatment period. The number of symptom-free days and asthma exacerbations were logged at each clinic visit. Exacerbations were classified as mild, moderate, or severe on the basis of the medical interventions needed.There was no significant difference between the treatment groups in the percentage of symptom-free days. Each treatment group had an increase in symptom-free days by ∼25% while on treatment compared to baseline (P < .001). Furthermore, no significant difference was seen in the percentage of days in which rescue salbutamol was used; both groups had a gradual decline in use of the salbutamol. A combined ranked assessment of all exacerbations among the treatment groups revealed no statistically significant difference between the 2 groups. Lung-function parameters did not differ between groups other than a slightly greater effect on maximal expiratory flow seen in the salmeterol/fluticasone group during the first week of treatment. The 2 groups did not differ in statural growth or number of adverse events.The results of this study indicate that the combination of a long-acting bronchodilator with inhaled corticosteroid has equal efficacy in controlling symptoms and preserving lung function when compared with doubling the dose of inhaled corticosteroids in children who were symptomatic on a moderate dose of inhaled corticosteroids. Therefore, combination of a long-acting bronchodilator is likely an appropriate alternative in step-up therapy.This study provides us with an adequate alternative step 3 treatment option. The results of this study are in line with those of previous work. Further study is now needed to evaluate whether there might be specific asthma phenotypes that respond more favorably to 1 treatment option versus another. The fear of increased severe asthma exacerbations and asthma-related deaths associated with use of long-acting β2 agonists in children is still present. Further data from large numbers of children are needed to make a more definite conclusion about this possible risk.

Methacholine challenge – Comparison of an ATS protocol to a new rapid single concentration technique

Bronchial methacholine challenge is well established in asthma diagnostics and research. ATS guidelines propose a five step standard dosimeter (SDM) protocol with incremental concentrations of methacholine to calculate the concentration causing a 20% drop in FEV(1) in an individual (PC(20)FEV(1)). In contrast, the aerosol provocation system (APS) by Viasys automatically determines the administered dose of methacholine by measuring the effective nebulisation time and referring it to drug concentration and nebuliser power. Therefore, it offers a feasible and less time-consuming provocation procedure by applying incremental doses (PD(20)) of methacholine using a single concentration (16mg/mL methacholine, APS-SC). In this study we compared these two methods in 52 young adults (25+/-5.8 years). Following a screening visit, subjects were randomly assigned to undergo either SDM or APS-SC followed by the other method within 1 week. A close correlation between concentration and dosage causing a 20% fall of FEV(1) was found (r=0.69, p<0.001). Using the ATS categorisation of bronchial responsiveness we interpreted the results of the APS-SC method as follows: PD(20) methacholine<0.3mg as "moderate to severe BHR", 0.3 - 0.6mg as "mild BHR", 0.6 - 1.0mg as "borderline BHR", and>1.0mg as "normal bronchial response". We conclude that the five-step APS-SC is a suitable method, providing reliable results. In clinical practice the APS-SC is a timesaving procedure and less prone to errors since only one dilution of methacholine is necessary compared to the SDM.

Effect of formoterol with or without budesonide in repeated low-dose allergen challenge

The use of combination therapy in mild asthma is debated. The current authors evaluated the effects of formoterol alone and a formoterol/budesonide combination inhaler on asthma deterioration induced by repeated low-dose allergen exposure. In total, 15 subjects with intermittent allergic asthma inhaled low doses of allergen on seven consecutive weekdays in a three-period, crossover, double-blind, double-dummy comparison between formoterol 4.5 microg Turbuhaler, budesonide 160 microg/formoterol 4.5 microg Turbuhaler and placebo, each taken as two puffs 30 min after allergen dosing. The outcome variables were: provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second (PD(20)), exhaled nitric oxide fraction (F(eNO)), sputum eosinophils and prostaglandin D(2), and diary card recordings of symptoms (on a scale of 0-10), short-acting beta(2)-agonist use and evening forced expiratory volume in one second (FEV(1)). With placebo treatment, allergen exposure caused significant increases in airway hyperresponsiveness (geometric mean (coefficient of variation) PD(20): 397 (98) microg before versus 168 (82) microg after), F(eNO) (mean+/-sd 46+/-31 ppb before versus 73+/-46 ppb after) and asthma symptom score (mean+/-sd 0.39+/-0.55 before versus 0.68+/-0.67 after). Budesonide/formoterol abolished these changes and significantly improved baseline FEV(1). Formoterol alone, while providing symptom relief, was no better than placebo in protecting against the allergen-induced increase in airway inflammation. Signs of deteriorating asthma, provoked by low-dose allergen, are prevented by short-term use of budesonide/formoterol but not by temporary use of formoterol alone.

Airway hyperresponsiveness and airway inflammation in elite swimmers

The prevalence of respiratory symptoms and airway hyperresponsiveness (AHR) is high in elite athletes; swimmers have one of the highest prevalences. No consensus exists on what airway challenge to use when identifying AHR in elite athletes. Further, knowledge is sparse about when during their active sport career AHR develops and if there is an acute effect on the airway inflammation of a swimming training session. We aimed to (i) evaluate the airway response to a methacholine challenge, a eucapnic voluntary hyperpnoea (EVH) test, a field-based exercise test (FBT) and a laboratory-based exercise test (LBT) in adult elite swimmers; (ii) investigate airway responsiveness and airway inflammation in adolescent elite swimmers; and (iii) evaluate the acute effect of a training session in an indoor swimming pool on airway inflammation in adolescent elite swimmers. Two groups were studied. (i) In adult elite swimmers (n = 16), we examined airway response in four airway provocation tests: methacholine challenge, EVH test, FBT and LBT. (ii) In adolescent elite swimmers (n = 33), we examined airway responsiveness to EVH and methacholine, and airway inflammation and compared the findings with those in asthmatic adolescents (n = 32) and unselected adolescents (n = 35). Further, we examined the acute effect of swimming on airway inflammation in a subpopulation of the adolescent swimmers (n = 21). Airway inflammation was evaluated using sputum induction, measurements of exhaled nitric oxide (FeNO) and exhaled breath condensate (EBC). Of 16 adult swimmers, eight (50%) had AHR; five of the eight (63%) were identified with the EVH test, four (50%) with the FBT, four (50%) with the LBT and none with the methacholine challenge [provocative dose of methacholine causing a 20% fall in FEV1 (PD(20)) <or= 2 micromol]. There were no differences in the prevalence of AHR to either EVH or methacholine (PD(20) <or= 8 micromol) among the adolescent swimmers, the asthmatic adolescents and the unselected adolescents. When looking at airway responsiveness as a continuous variable, the swimmers were more responsive to EVH than were the unselected subjects, and less responsive to methacholine than were the asthmatic adolescents. There were no differences in FeNO, EBC pH or in the cellular composition of the sputum among the three groups. Lung function, FeNO, EBC pH, EBC lactate and differential cell counts in sputum were not acutely affected by the swimming session. We found that the EVH test is the most sensitive test for identifying AHR in elite athletes when using the diagnostic criteria set forward by the International Olympic Committe. Whereas a high prevalence of AHR in adult swimmers was found, the prevalence of AHR in the adolescent swimmers did not differ from that in unselected adolescents nor did the adolescent swimmers have signs of airway inflammation. There was no acute effect of a swimming training session in an indoor chlorinated pool on lung function or airway composition in adolescent swimmers. We believe that elite swimming results in airway changes with AHR and airway inflammation.

Low Attenuation Area Is Associated with Airflow Limitation and Airway Hyperresponsiveness

Background. Asthma is a chronic inflammatory disorder of the airways characterized by airflow limitation and airway hyperresponsiveness. Lung density indices on quantitative computed tomography (QCT) are assumed to reflect the degree of air trapping originated from airflow limitation in airway diseases. Purpose. The present study investigated the availability of lung density indices on QCT in clinical evaluation of asthma. Methods. Eleven asthmatic patients and 48 healthy control subjects were prospectively evaluated by QCT, pulmonary function testing, and a methacholine challenge test. High-resolution computed tomography scans were performed at full-inspiratory and full-expiratory phases, and percentage of lung field occupied by low attenuation area (LAA%) and mean lung density (MLD) at both inspiratory and expiratory phases were measured. Results. MLD values at inspiratory phase were significantly increased in asthmatic patients compared with those in healthy control subjects. Inspiratory LAA% values were significantly decreased in asthmatics compared with the values in control subjects. On expiratory scans, MLD values of asthmatics were significantly lower than the values of control subjects. Expiratory LAA% values of asthmatics were significantly higher than the values of control subjects. The LAA% in the expiratory phase showed significant negative correlation with forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity, and the provocative dose of methacholine causing a 20% decrease in FEV1 in asthmatic patients. Conclusion. These results suggest that lung density indices on QCT may be useful for clinical evaluation of asthmatic patients and increased LAA% in the expiratory phase is associated with airflow limitation and airway hyperresponsiveness in asthma.

Paternal Asthma, Mold Exposure, and Increased Airway Responsiveness Among Children With Asthma in Costa Rica

Little is known about the determinants of airway hyperresponsiveness (AHR) among children with asthma in Hispanic America. We examined the relations among selected familial and environmental factors, markers of allergy, spirometric measures of lung function, and AHR in a cross-sectional study of 403 Costa Rican children with asthma between the ages of 6 and 14 years. Study participants completed a protocol that included questionnaires, spirometry, measurements of serum total and allergen-specific IgE, peripheral blood eosinophil count, and body mass index, and the assessment of airway responsiveness to methacholine (ie, a methacholine challenge test [MCT]). AHR to MCT was defined as the provocative dose of methacholine causing a 20% fall in FEV(1). Linear regression was used for the univariate and multivariate analyses. Of the 403 asthmatic children who underwent an MCT, 350 (86.8%) had AHR to methacholine. In a multivariate analysis, paternal asthma (p = 0.004), parental report of mold/mildew in the child's home (p = 0.04), FEV(1)/FVC ratio (p < 0.0001), and a positive IgE response to Der p 1 (p = 0.008) were significantly associated with AHR among Costa Rican children with asthma. Our results suggest that paternal asthma and environmental exposure to mold/mildew are strong determinants of AHR in Costa Rican children with asthma. FEV(1)/FVC ratio may be a useful measure of AHR (a marker of asthma severity) among Costa Ricans and other Hispanic Americans for whom reference values for FEV(1) are not currently available.

The Physical and Biological Doses of Methacholine Are Different for Mefar MB3 and Jaeger APS Sidestream Nebulizers

Within a study on respiratory symptoms in rural areas, we used the European Community Respiratory Health Survey methacholine challenge protocol. For quicker and more reliable handling, we had to change the nebulizer in the bronchial challenge system from Mefar model MB3 (Bovezzo, Italy) to Jaeger APS Sidestream (similar to Mefar; Würzburg, Germany). Therefore, we compared the physical properties of the two systems, adapted the challenge protocol, and compared the results of both systems in subjects with and without airway hyperresponsiveness to methacholine. The physical properties of both systems were characterized by the residual method indicating a similar particle size distribution and an average output of 6 muL/s for Mefar MB3 and 1.25 muL/s for APS Sidestream. In the comparison study, 34 subjects were included. Airway responsiveness was quantified by provocative dose of methacholine causing a 20% fall in FEV(1). A significant difference was found between the two challenge systems (p =0.004, McNemar test). Nine subjects reached a 20% drop in FEV(1) with the APS Sidestream only. The FEV(1) dropped by > 20% using either system in eight subjects. In 17 subjects, none of the two systems caused a 20% decrease in FEV(1). Even if the physical dose is determined with elaborate methods, the biological dose may vary between two nebulizer systems, causing incomparable outcomes for subjects tested with different systems.

Ultrastructure of bronchial biopsies from patients with allergic and non-allergic asthma

Epithelial damage is commonly found in airways of asthma patients. The aim of this study was to investigate epithelial damage in allergic and non-allergic asthma at the ultrastructural level. Bronchial biopsies obtained from patients with allergic asthma (n=11), non-allergic asthma (n=7), and healthy controls (n=5) were studied by transmission electron microscopy. Epithelial damage was found to be extensive in both asthma groups. Both in basal and in columnar cells, relative desmosome length was reduced by 30-40%. In columnar cells, half-desmosomes (i.e., desmosomes of which only one side was present) were frequently noticed. Eosinophils showing piece-meal degranulation were commonly observed in allergic asthma. Degranulating mast cells were more often observed in allergic asthma. Goblet cell hyperplasia was only found in allergic asthma. Lymphocytes were increased in both groups. In both groups, the lamina densa of the basal lamina was thicker than the control by about 40-50%. In allergic asthma the lamina densa was irregular with focal thickening. While there was always a tendency for changes (epithelial damage, desmosomes, degranulating mast cells, basal lamina) to be more extensive in allergic asthma compared to non-allergic asthma, there was no significant difference between the two groups in this respect. Reduced desmosomal contact may be an important factor in the epithelial shedding observed in patients with asthma.

Outcome of Occupational Asthma in Patients With Continuous Exposure: A 3-Year Longitudinal Study During Pharmacologic Treatment

To evaluate the effect of treatment with beclomethasone dipropionate (500 microg bid) and salmeterol (50 microg bid) on lung function and respiratory symptoms in 20 subjects with occupational asthma (OA) still exposed to the work environment cause of their disease. At enrollment and every 6 months for 3 years, respiratory symptom score (from 0 [no symptoms] to 2 [moderate-to-severe symptoms]), spirometry, methacholine challenge, peak expiratory flow (PEF) variability, and the use of rescue salbutamol were evaluated. During the 3 years of follow-up, 10 subjects were excluded from the study because they retired or changed jobs. Symptoms of work-related asthma started 12.6 +/- 13.1 years (mean +/- SD) before diagnosis. At baseline, mean FEV(1) was 80.2% of predicted values and provocative dose of methacholine causing a 20% fall in FEV(1) (PD(20)) was 1,001 +/- 1,275 microg; the workers received 2.1 +/- 2.4 puffs of salbutamol per day. After 3 years, no significant differences in any of the morbidity outcomes (FEV(1), PD(20), PEF variability, use of rescue salbutamol, respiratory symptom score) were found as compared with baseline or run-in values. Regular treatment with inhaled corticosteroids and long-acting bronchodilators seems to prevent respiratory deterioration over a 3-year period in workers with mild-to-moderate persistent OA who were still exposed at work to the environmental cause of their disease.

Relationship among pulmonary function, bronchial reactivity, and exhaled nitric oxide in a large group of asthmatic patients

Bronchial reactivity and exhaled nitric oxide (eNO) are not often used to monitor control and severity of asthma in clinical practice. To evaluate the relationship among different physiologic measures (pulmonary function, nonspecific bronchial reactivity, and eNO) in asthmatic patients. Cross-sectional, hospital-based study conducted in patients with varied asthma severity. A total of 392 patients participated in the study. There was no difference in eNO levels between patients taking inhaled corticosteroids (ICS group) and patients not receiving inhaled corticosteroids (NICS group). However, the percentage of predicted forced expiratory volume in 1 second (FEV1) and the provocative dose of methacholine causing a 20% decrease in FEV1 were significantly lower in the ICS group compared with the NICS group (mean, 83.2%; 95% confidence interval [CI], 80.4%-86.0%; vs mean, 94.1%; 95% CI, 91.1%-97.1%; P = .001; and geometric mean, 0.32 mg; 95% CI, 0.23-0.45 mg; vs geometric mean, 0.58 mg; 95% CI, 0.42-0.81 mg; P = .01; respectively). Patients with more severe bronchial hyperresponsiveness had a lower percentage of predicted FEV1 values (P < .001) and levels of eNO were significantly increased with increasing bronchial hyperresponsiveness (P < .001). There was no relationship between the percentage of predicted FEV1 and eNO. Atopic patients had significantly higher eNO levels than nonatopic patients (geometric mean, 11.21 ppb; 95% CI, 10.07-12.49 ppb; vs geometric mean, 7.76 ppb; 95% CI, 6.11-9.85 ppb; P = .006; respectively). eNO values are not related to the degree of airway obstruction but are related to airway reactivity and atopic status independent of inhaled corticosteroid use. Higher values of eNO are seen with increased airway reactivity.

Airway reactivity and diving in healthy and atopic subjects.

The short- and long-term effects of self-contained underwater breathing apparatus (SCUBA) dives on airway responsiveness in nonasthmatic atopic subjects have not been systematically investigated. To compare the effect of SCUBA diving at 50-m depth on lung function and airway responsiveness to methacholine (MCh) in atopic nonasthmatics and healthy subjects. We studied 15 atopic nonasthmatic subjects and 15 controls who underwent the visit for the professional SCUBA-diving license at the Navy Medical Center, La Spezia, Italy. All subjects underwent spirometry and skin-prick test for common environmental allergens. MCh challenge was performed 24 h before, and 20 min and 24 h after a standardized SCUBA-dive test and after hyperbaric-chamber test. At 20 min, the provocative dose of MCh causing 20% fall of the forced expiratory volume at the first second (MCh PD20 - FEV1) was significantly reduced in atopic, asymptomatic subjects from 1712 x 2.6 microg (mean x geometric standard deviation) to 1202 x 2.2 microg (P < 0.0005) after the hyperbaric-chamber test and to 1204 x 2.3 microg (P < 0.005) after SCUBA diving. In healthy subjects, the baseline value of MCh PD20 was 2977 x 1.1 microg, and this value did not change significantly after the hyperbaric-chamber test (2575 x 1.4 microg) and after SCUBA dives (2553 x 1.4 microg, P > 0.1 for both comparisons). In atopic subjects, the MCh PD20 returned near to the baseline value 24 h after the hyperbaric-chamber test (1776 x 2.4 microg) and after the SCUBA test (1500 x 2.67 microg). No significant change in FEV1 was observed after the tests in both groups. SCUBA diving is associated with development of early airway hyperresponsiveness to MCh in atopic subjects.

Fifty μg b.i.d. of inhaled fluticasone propionate (FP) are effective in stable asthmatics previously treated with a higher dose of FP

Twenty-seven subjects with moderate asthma at the time of diagnosis, well controlled under regular fluticasone propionate (FP) (250 μg b.i.d.) for 6 months at least, were randomized to receive in double-blind fashion: FP 125 μg b.i.d. (Group 1) or FP 50 μg b.i.d. (Group 2) or placebo (Group 3) for 3 months or until symptom recurrence. Daily symptom score and peak expiratory flow were monitored. At the beginning and at the end of the study, subjects underwent methacholine challenge and sputum induction. Recurrence of symptoms occurred shortly after randomization in all subjects receiving placebo. None from Group 1 or 2 experienced symptom recurrence during the study. No significant difference in clinical and functional data, and in sputum eosinophil percentages was observed between the beginning and the end of the study in both Groups 1 and 2. Subjects from Group 3 showed a significant increase of sputum eosinophils ( P<0.05) and a significant decrease in provocative dose of methacholine ( P<0.05) when asthma symptoms recurred. Therefore, very low doses of FP (50 μg b.i.d.) are effective in maintaining for 3 months a good control of the disease in asthmatics already stable under high-dose fluticasone, considering both clinical and functional outcomes and markers of airway inflammation.

Sputum Eosinophilia and Maximal Airway Narrowing in Dermatophagoides pteronyssinus Allergic Rhinitis Patients: Only Rhinitis or Rhinitis Plus Mild Asthma?

To study the existence of bronchial disease among rhinitis patients. To evaluate the laboratory test or set of tests (ie, symptoms, exposure, and sensitization to the allergen, and the provocative dose of methacholine [Mth] causing a 20% fall in FEV(1) [PD(20)] and the maximal response plateau [MRP] to Mth) that best identifies a case of mild asthma. Cross-sectional analysis in 52 Dermatophagoides pteronyssinus-monosensitized patients who were consulting a physician for perennial rhinitis. Allergy Department, Hospital Doctor Negrín, Las Palmas, Grand Canary Island, Spain. Patients filled out a standardized asthma symptom questionnaire, and underwent sputum induction and Mth challenge in which 40% falls in FEV(1) were attained. Dose-response curves were expressed in terms of both PD(20) values and the level of the MRP. D pteronyssinus allergen exposure was assessed in dust samples from patients' beds. No difference between patients who positively responded to the questionnaire and those who did not was observed. Mth-PD(20) values were not detected in 13% of the patients reporting bronchial symptoms, and an MRP was not identified in 59% of the subjects who did not respond positively. A higher degree of allergen sensitization (ascertained from skin test results, and total and specific serum IgE levels) and higher degree of sputum eosinophilia were detected in subjects in whom an MRP had not been identified. The presence of sputum eosinophilia provided the best differentiation between those patients who presented with an MRP and those who did not. The individual perception of bronchial symptoms is highly variable among perennial allergic rhinitis patients. The lack of a maximal airway-narrowing plateau is related to the presence of sputum eosinophilia, which might be useful in the detection of patients susceptible to anti-inflammatory therapy. Prospective studies evaluating whether these patients are more likely to develop symptomatic asthma in the future and if the early anti-inflammatory treatment prevents its development are needed.

Fluticasone Propionate via the Diskhaler or Hydrofluoroalkane-134a Metered-Dose Inhaler on Methacholine-Induced Airway Hyperresponsiveness

s: To compare the effect of 4 weeks of treatment with fluticasone propionate (FP), 100 micro g bid, delivered either via the Diskhaler (GlaxoSmithKline; Middlesex, UK) or a hydrofluoroalkane (HFA)-134a pressurized metered-dose inhaler (pMDI) on airway responsiveness. A single-center, randomized, double-blind, double-dummy, placebo-controlled crossover study. Outpatients. Patients with mild asthma who had not received corticosteroids for 4 weeks prior to the study. FP, 100 micro g bid, via the Diskhaler, HFA-134a pMDI, or placebo for periods of 4 weeks. The primary efficacy variable was the provocative dose of methacholine causing a 20% fall in FEV(1) (PD(20)) at the end of each 4-week treatment period. The FP formulations were defined as equivalent if the treatment difference was within +/- 1 doubling dose of methacholine. Forty-seven patients were included in the per-protocol population. The baseline PD(20) geometric mean was 0.21 mg, which increased to 0.55 mg with FP via the HFA-134a pMDI and to 0.68 mg with FP via the Diskhaler. The treatment difference between adjusted means was - 0.16 doubling doses (95% confidence interval, - 0.62 to 0.31 doubling doses; p = 0.503). Both significantly decreased airway responsiveness compared to placebo (p < 0.001), and also significantly increased lung function with no difference between the two active groups. FP was well tolerated with few adverse events and no effect on serum cortisol levels. FP delivered via the HFA-134a pMDI is equivalent to FP via the Diskhaler in reducing airway responsiveness.

Therapeutic Ratio of Hydrofluoroalkane and Chlorofluorocarbon Formulations of Fluticasone Propionate

To compare the therapeutic ratio of chlorofluorocarbon (CFC) and hydrofluoroalkane-134a (HFA) formulations of fluticasone propionate (FP). We performed a randomized, placebo-controlled, crossover study comparing 6 weeks of treatment with FP using 500 micro g/d and 1,000 microg/d formulations of CFC and HFA. The primary end points were provocative dose of methacholine causing a 20% fall in FEV1 (PD20) and overnight urinary cortisol/creatinine excretion. Eighteen patients with mild-to-moderate asthma and geometric mean (SEM) PD20 of 82.3 micro g (19.2 micro g) completed the study. All treatments significantly improved PD20 values and morning peak expiratory flow vs placebo, while 1,000 microg/d was significantly better than 500 microg/d for the CFC formulation of FP (CFC-FP) but not the HFA formulation of FP (HFA-FP). Only 1,000 microg/d of CFC-FP caused significant suppression of overnight urinary cortisol/creatinine compared to placebo. There were no differences between formulations at either dose. The increased airway benefit with CFC-FP > 500 microg/d was offset by greater systemic effects. Although HFA-FP had fewer systemic effects than CFC-FP at 1,000 microg/d, there was no benefit to increasing HFA-FP to > 500 microg/d.

Effects of Adding Either a Leukotriene Receptor Antagonist or Low-Dose Theophylline to a Low or Medium Dose of Inhaled Corticosteroid in Patients With Persistent Asthma

To evaluate the effect of adding zafirlukast or low-dose theophylline to a beclomethasone dipropionate (BDP) extra-fine hydrofluoroalkane aerosol on bronchial hyperresponsiveness as the primary outcome variable. Twenty-four patients with mild-to-moderate asthma were studied using a randomized crossover design with the following three treatment blocks: (1) beclomethasone, 100 microg/d, alone for the first 2 weeks followed by 400 microg/d alone for the next 2 weeks; (2) beclomethasone, 100 microg/d, followed by 400 microg/d, with the addition of zafirlukast, 20 mg bid; (3) beclomethasone, 100 microg/d, followed by 400 microg/d, with the addition of theophylline, 200 to 300 mg bid. Measurements were made after 2 and 4 weeks of each treatment and at pretreatment baseline. The mean trough plasma theophylline concentration was 6.7 mg/L, coinciding with the anti-inflammatory target range (ie, 5 to 10 mg/L). The provocative dose of methacholine causing a 20% fall in FEV(1) (as doubling dose difference from baseline) was significantly (p < 0.05) greater with beclomethasone, 100 microg, plus zafirlukast (1.1 doubling dose) but not with beclomethasone, 100 microg, plus theophylline (0.7 doubling dose) compared to beclomethasone, 100 microg alone (0.4 doubling dose), but not compared to beclomethasone, 400 microg alone (1.1 doubling dose). There were also significant (p < 0.05) differences between beclomethasone, 100 microg, plus zafirlukast (but not BDP, 100 microg, plus theophylline) vs beclomethasone, 100 microg, alone in terms of nitric oxide level, midexpiratory phase of forced expiratory flow, and peak expiratory flow. There were no further significant improvements observed with the addition of zafirlukast or theophylline to beclomethasone, 400 microg. A leukotriene receptor antagonist, but not low-dose theophylline, conferred significant additive anti-inflammatory effects to therapy with a low-dose inhaled corticosteroid but not to that with a medium dose of an inhaled corticosteroid. Thus, optimizing the dose of inhaled corticosteroid as monotherapy would seem to be the logical first step, which is in keeping with current guidelines.