A controlled trial of immunotherapy for asthma in allergic children. Effect of specific immunotherapy added to pharmacologic treatment and allergen avoidance in asthmatic patients allergic to house dust mite. Immunotherapy vs inhaled budesonide in bronchial asthma: an open, parallel, comparative trial. Relative effects of inhaled corticosteroids on immunopathology and physiology in asthma: a controlled study. [Effects of high doses of beclomethasone dipropionate in bronchial asthma]. High-dose inhaled steroids in the management of asthma. A comparison of the effects of budesonide and beclomethasone dipropionate on pulmonary function, symptoms, bronchial responsiveness and the adrenal function. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma. The American Academy of Allergy, Asthma and Immunology Beclomethasone Dipropionate-Theophylline Study Group. Repository dexamethasone in the treatment of acute bronchial asthma. Effect of inhaled beclomethasone dipropionate on bronchial responsiveness in patients with asthma. Effects of immunotherapy on symptoms, PEFR, spirometry, and airway responsiveness in patients with allergic asthma to house-dust mites (D. pteronyssinus) on inhaled steroid therapy. Allergic bronchial asthma due to Dermatophagoides pteronyssinus hypersensitivity can be efficiently treated by inoculation of allergen-antibody complexes. Fluticasone propionate induced alterations to lung function and the immunopathology of asthma over time. Short course of steroids in home treatment of children with acute asthma. Immunotherapy in children with allergic asthma: effect on bronchial hyperreactivity and pharmacotherapy. Immunotherapy in cat-induced asthma. Double-blind trial with evaluation of in vivo and in vitro responses. A comparison of regular with intermittent bronchodilators in asthma patients on inhaled steroids. The efficacy of inhaled corticosteroids in the management of non asthmatic chronic airflow obstruction. Corticosteroids in status asthmaticus. Placebo-controlled immunopathologic study of four months of inhaled corticosteroids in asthma. Significant reduction of nonspecific bronchial reactivity in patients with Dermatophagoides pteronyssinus-sensitive allergic asthma under therapy with allergen-antibody complexes. Effect of inhaled corticosteroids on bronchial hyperresponsiveness in patients with mild asthma. Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics. Benefits of immunotherapy with a standardized Dermatophagoides pteronyssinus extract in asthmatic children: a three-year prospective study. An inhaled steroid improves markers of airway inflammation in patients with mild asthma. Continuous and on demand use of bronchodilators in patients with non-steroid dependent asthma and chronic bronchitis: four-year follow-up randomized controlled study. Treatment with inhaled steroids in patients with symptoms suggestive of asthma but with normal lung function. Specific immunotherapy with a standardized latex extract versus placebo in allergic healthcare workers. Effect of beclomethasone dipropionate on bronchial responsiveness to histamine in controlled nonsteroid-dependent asthma. Randomised trial of an inhaled beta2 agonist, inhaled corticosteroid and their combination in the treatment of asthma. Slowing the deterioration of asthma and chronic obstructive pulmonary disease observed during bronchodilator therapy by adding inhaled corticosteroids. A 4-year prospective study. Impact of sublingual immunotherapy on seasonal asthma and skin reactivity in children allergic to Parietaria pollen treated with inhaled fluticasone propionate. Immunotherapy with dog and cat extracts in children. Grass pollen immunotherapy for seasonal rhinitis and asthma: a randomized, controlled trial. Allergen specific immunotherapy attenuates early and late phase reactions in lower airways of birch pollen asthmatic patients: a double blind placebo-controlled study. Immunotherapy in cat-induced asthma. Double-blind trial with evaluation of bronchial responses to cat allergen and histamine. High doses of inhaled corticosteroids in unstable chronic asthma. A multicenter, double-blind, placebo-controlled study. Treatment of acute asthmatic exacerbations with an increased dose of inhaled steroid. A comparison of bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airways disease. Dutch Chronic Non-Specific Lung Disease Study Group. Efficacy of short-term corticosteroid therapy in outpatient treatment of acute bronchial asthma. Treatment of steroid-dependent bronchial asthma with cyclosporin. Placebo controlled trial of systemic corticosteroids in acute childhood asthma. Immunotherapy in allergy to dog: a double-blind clinical study. Protection by budesonide and fluticasone on allergen-induced airway responses after discontinuation of therapy. A double-blinded, comparative study of the effects of short preseason specific immunotherapy and topical steroids in patients with allergic rhinoconjunctivitis and asthma. Treatment of acute, episodic asthma in preschool children using intermittent high dose inhaled steroids at home. Effect of specific immunotherapy with house dust mite extract on the bronchial responsiveness of paediatric asthma patients. Long-term effects of budesonide on airway responsiveness and clinical asthma severity in inhaled steroid-dependent asthmatics. Effect of immunotherapy in bronchial asthma: treatment with extracts of house dust and mite. Initiation of maintenance treatment of persistent asthma: salmeterol/fluticasone propionate combination treatment is more effective than inhaled steroid alone. Specific immunotherapy with Dermatophagoides pteronyssinus and D. farinae results in decreased bronchial hyperreactivity. Effect of addition of inhaled salmeterol to the treatment of moderate-to-severe asthmatics uncontrolled on high-dose inhaled steroids. European Respiratory Study Group. Changes in bronchial reactivity in asthmatic children after treatment with beclomethasone alone or in association with salbutamol. Regular versus symptomatic aerosol bronchodilator treatment of asthma. [Ion generators and bronchial asthma. A double-blind placebo controlled study]. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Short-term regular beta 2-adrenergic agonists treatment is safe in mild asthmatics taking low doses of inhaled steroids. Asthma control during and after cessation of regular beta 2-agonist treatment. Beclomethasone dipropionate dry-powder inhalation compared with conventional aerosol in chronic asthma. Effects of salmeterol on mucosal inflammation in asthma: a placebo-controlled study. A controlled trial of hyposensitization with adsorbed tyrosine Dermatophagoides pteronyssinus antigen in childhood asthma: in vivo aspects. Effects of inhaled beclomethasone dipropionate on beta 2-receptor function in the airways and adrenal responsiveness in bronchial asthma. Combined treatment with ipratropium bromide and beta-2-adrenoceptor agonists in childhood asthma. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Chrysotherapy in the treatment of corticosteroid-dependent asthma. Long-term treatment with fluticasone propionate/salmeterol via Diskus improves asthma control versus fluticasone propionate alone. Steroid-dependent asthma treated with inhaled beclomethasone dipropionate. A long-term study. Aerosol beclomethasone dipropionate compared with theophylline as primary treatment of chronic, mild to moderately severe asthma in children. Inhaled steroids in patients with bronchiectasis. Immunotherapy with a depigmented, polymerized vaccine of Olea europaea pollen allergens. Significantly reduces specific bronchial and skin test reactivity in sensitized patients after one year of treatment. Specific immunotherapy with a standardized latex extract in allergic workers: a double-blind, placebo-controlled study. Adding salmeterol to an inhaled corticosteroid: long term effects on bronchial inflammation in asthma. Ipratropium bromide, salbutamol and prednisolone in bronchial asthma and chronic bronchitis. Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma. Intramuscular methylprednisolone acetate for the prevention of relapse in acute asthma.
Injections of allergens are widely prescribed for patients with asthma, but little is known about the effectiveness of immunotherapy.
                We conducted a double-blind, placebo-controlled trial of multiple-allergen immunotherapy in 121 allergic children with moderate-to-severe, perennial asthma. The children, who required daily medication for their asthma, were randomly assigned to receive subcutaneous injections of either a mixture of up to seven aeroallergen extracts or a placebo. Maintenance injections were continued for 18 months or longer. Medications were adjusted every two to three weeks on the basis of peak flow rates and symptoms. The principal outcome was the daily medication score. Bronchial sensitivity to methacholine (the concentration provoking a 20 percent decrease in the forced expiratory volume in one second [PC20]) was measured twice yearly.
                The median medication score declined from 5.4 to 4.9 in the immunotherapy group (P<0.001) and from 5.2 to 5.0 in the placebo group (P<0.001), but there was no significant difference between the groups (P>0.6). The number of days on which oral corticosteroids were used was similar in the two groups. Partial or complete remission of asthma occurred in 31 percent of the immunotherapy group and in 28 percent of the placebo group (P>0.5). There was no difference between the groups in the use of medical care, symptoms, or peak flow rates. The median PC20 increased significantly in both groups, but again with no difference between the two groups.
                Immunotherapy with injections of allergens for over two years was of no discernible benefit in allergic children with perennial asthma who were receiving appropriate medical treatment. Although several studies support the efficacy of specific immunotherapy in allergic asthma, its benefit compared with that of standardized pharmacologic intervention remains unknown.
                A double-blind, placebo-controlled trial in 72 patients with mild-to-moderate asthma and allergy to house dust mite (HDM; Dermatophagoides species) was conducted to assess the effects of specific immunotherapy added to guideline-adjusted pharmacologic treatment and allergen avoidance.
                After 1 observational year of pharmacologic treatment and standard measures of HDM avoidance, 2 groups of asthmatic subjects were randomly assigned to receive specific immunotherapy consisting of subcutaneous injections of either a mixture of Dermatophagoides pteronyssinus and Dermatophagoides farinae vaccine (n=41) or placebo (n=31) for 3 years. Medications were adjusted every 3 months according to the Global Initiative for Asthma guidelines.
                The adjustment of treatment was associated with a reduction in asthma symptom scores in all subjects. The addition of specific immunotherapy was associated with a decrease in the number of subjects requiring rescue bronchodilators, an increase in morning and evening peak expiratory flow, and a reduced skin sensitivity to HDM extracts. The addition of specific immunotherapy had no significant effects on the cumulative dose of inhaled corticosteroids, asthma symptoms, lung volumes, or bronchial responsiveness to methacholine.
                These results suggest that specific immunotherapy added to pharmacologic treatment and HDM avoidance provides marginal but statistically significant clinical benefits, possibly by reducing the allergic response of asthmatic patients sensitized to HDM. Budesonide, an inhaled corticosteroid and specific immunotherapy, are both routinely used in the treatment of bronchial asthma. However, there are as yet, no studies comparing the effects of budesonide vs immunotherapy.
                The aim of this study is to compare the effects of budesonide with immunotherapy in patients having perennial asthma.
                This study is an open, parallel, comparative trial, in which 51 young patients were administered either immunotherapy or budesonide for 1 year and their global symptom scores and FEV1 values assessed. Both treatments were abruptly discontinued after 12 months and the effects of cessation analysed.
                The use of budesonide resulted in a faster and more striking improvement during the first few months as compared to immunotherapy, with an even more rapid decline in benefits on cessation of budesonide. Immunotherapy on the other hand, resulted in slow but steady improvement which did not decline as rapidly as budesonide on cessation.
                Although this was an open trial, it could be concluded that relief with inhaled corticosteroids in bronchial asthma is more rapid than immunotherapy; however the decline in benefit on cessation of inhaled corticosteroid is even more rapid, a phenomenon not seen with immunotherapy. Although corticosteroids are recognised as the most efficacious treatment for bronchial asthma, their mode of action remains unclear. A placebo controlled trial was undertaken of the effect of inhaled corticosteroids on physiological and immmunopathological parameters in asthmatic patients in whom the correlations between these indices were tested after treatment.
                Sixteen patients (two women) with asthma entered a double blind, placebo controlled, parallel study during which they inhaled either budesonide 800 micrograms twice daily or matching placebo for six weeks. Spirometric parameters and bronchial reactivity to histamine and terbutaline were measured and endobronchial biopsy samples were taken before and after treatment. Patients recorded morning and evening flow rates during the treatment period. The biopsy samples were subjected to immunohistological analysis to determine the disposition of inflammatory cells within the bronchial wall.
                Treatment with budesonide resulted in a significant improvement in the 25-75% forced expiratory flow (FEF25-75) from a mean of 133 l/min before treatment to 169 l/min after treatment, and in the morning peak expiratory flow rate (PEFR) from a mean of 384 l/min before treatment to 415 l/min after treatment. No changes were seen in the placebo group. Comparison between the changes in the immunopathological indices after six weeks of treatment with placebo or budesonide showed a significant reduction in the numbers of mast cells (0.5/unit area to 0.2/ unit area), activated eosinophils, and the expression of HLA-DR antigens (relative density -1.9 before to 1.02 after treatment) on inflammatory cells in response to treatment with budesonide. Although reductions in the numbers of other inflammatory cells within the bronchial wall were recorded using immunohistological analysis, these changes were not statistically significant. Significant correlations were found between changing immunological indices and lung physiology.
                This controlled study shows that inhaled corticosteroids cause improvement in physiological and immunopathological parameters in patients with stable asthma that are not seen with placebo, and that cause and effect relationships may exist between these two measures of disease status. To evaluate the clinical efficacy of high dose inhaled steroids, we examined the effects of standard doses (400 micrograms/day) and high doses (800 micrograms/day) of inhaled beclomethasone dipropionate (BDP, Becotide Inhaler), and the dose for regular use (800 micrograms/day) of salbutamol (Salb. Asmidon Air) on pulmonary function, bronchial hyperresponsiveness and asthma attack score. The subjects were 17 out-patients with mild or moderate bronchial asthma who were not receiving any anti-allergics or steroids. The patients were randomly allocated into three groups i.e., Group I: BDP 400 micrograms/day, Group II: BDP 800 micrograms/day and Group III: Salb. 800 micrograms/day. The administration period was 8 weeks. Pulmonary function test were performed and bronchial hyperresponsiveness was examined before and after the 8 weeks of treatment and attack scores were recorded during this period. It was found that inhalations of 400 micrograms/day and 800 micrograms/day BDP improved FEV1.0% value, peak flow, F-V curve, Dmin. and SGrs/Grs cont. Particularly, inhalation of 800 micrograms/day of BDP significantly improved these values and reduced attack scores in the early stages of the 8 week treatment. In contrast, there was a trend for inhalation of Salbutamol to enhance bronchial hyperresponsiveness and not to improve pulmonary function and asthma attack score. In conclusion, 800 micrograms/day of inhaled BDP is considered to be useful in the treatment of mild or moderate bronchial asthma. The efficacy of budesonide (800 micrograms b.d.) and beclomethasone dipropionate (750 micrograms b.d.) in controlling the symptoms of asthma, pulmonary function, bronchial responsiveness to histamine, and adrenal function, was assessed in a double-blind, double-dummy cross-over study of 36 adult chronic asthmatic patients. The patients, the majority of whom were assessed to be affected to a severe degree, were insufficiently controlled in their current regimen of inhaled steroids and/or inhaled and oral bronchodilators. A 2 weeks baseline period preceded 6 weeks of treatment with each of the study drugs. Both treatment groups showed improvements from baseline in clinical assessment of lung function carried out after the first 6 weeks of treatment. No significant differences were seen throughout the entire 12 weeks study, when comparing the effects of the treatments on FEV1, FVC, PEF or the histamine PC20. Asthma severity, symptom score and inhaled bronchodilator use showed the same results after both treatments. It is concluded that inhalations of budesonide and beclomethasone dipropionate in high doses are equally potent in the treatment of severe asthma. There is no significant influence on the adrenal function and no significant side effects during a period equal to that of the present study. Inhaled corticosteroids and oral theophylline are effective treatments for moderate asthma.
                We sought to compare the benefits and adverse reactions of theophylline and aerosol beclomethasone spray.
                A multicenter, double-blind, double-placebo, randomized, controlled trial of 1-year duration was performed. Seven hundred forty-seven patients with asthma received either beclomethasone dipropionate aerosol spray (84 microg four times per day) or sustained-release theophylline twice per day in doses adjusted for optimum control of the disease. The main outcome measures were daily diary of symptoms and peak flow rates (recorded on a mark-sense computer-readable form); supplemental bronchodilator use; doctor's office or hospital visits and absence from work or school; spirometry; methacholine testing; adverse experiences; and cortisol blood measurements.
                Both treatment strategies reduced symptoms promptly and achieved low absenteeism from work or school and low rates of emergency treatment for asthma. Both maintained nearly normal pulmonary function. Beclomethasone was statistically significantly more effective in reducing symptoms, supplemental bronchodilator and systemic glucocorticoid doses, bronchial hyperresponsiveness, and eosinophilia. However, the magnitude of these differences was small. Theophylline caused more headache, nervousness, insomnia, and gastrointestinal distress, and more patients discontinued treatment because of side effects. Beclomethasone caused more oropharyngeal candidiases and hoarseness and reduced morning plasma cortisol levels before and after cosyntropin. It reduced the rate of growth in children. No new cataracts or glaucoma developed.
                Theophylline effectively controlled symptoms at lower than the customarily recommended blood level. The risk/ benefit profiles of these agents suggest that inhaled corticosteroids may be the preferred agent for most adult patients and for some children. Fifty-two patients with acute asthma requiring immediate therapy but not hospitalization were studied in an emergency department following conventional therapy with bronchodilators. After discharge, the patients were treated with a controlled regimen of long-acting theophylline and beta-agonist inhalation as necessary. They were randomly assigned to one of three groups using a double blind model. Group A received intramuscular and oral placebos. Group B received intramuscular dexamethasone injection along with oral placebo treatment. Group C received oral dexamethasone by a tapering schedule associated with placebo intramuscular injection. Follow-up was carried out 7 days after the treatment in the emergency room. There were no significant statistical differences in the relapse rate among the three groups. Those patients who received oral or intramuscular dexamethasone had a decrease in the need for beta-agonist inhalation and fewer respiratory symptoms. However, there was no significant statistical difference between groups B and C. It was concluded that repository steroids could reduce the respiratory symptoms and frequency of beta-agonist usage as effectively as oral steroid treatment. However, the steroids do not improve the relapse rate in patients with only mild symptoms. We investigated the effect of 300 micrograms of inhaled beclomethasone dipropionate (BDP) daily on bronchial responsiveness to methacholine and pulmonary function of 22 subjects with asthma in a single-blind, crossover study. The severity of bronchial hyperresponsiveness lessened significantly during treatment with BDP (P < .01). No significant changes occurred in FEV1 or in the control value of airway conductance. We conclude that a 300-micrograms total daily dose of BDP is an efficacious treatment for patients with asthma. Because suppression of adrenal function and systemic adverse effects can occur in asthmatic patients treated with inhaled corticosteroids, especially children, long-term treatment with inhaled steroids should employ minimal daily doses necessary. The present study was designed to investigate the effects of immunotherapy (IT) with an extract of Dermatophagoides pteronyssinus (Alergo-Merck Depot) during a 27-month period in patients with allergic asthma to house-dust mites. We included 11 patients (mean age 18 years) treated with a combination of IT and inhaled beclomethasone dipropionate (BDP) in comparison to another 11 (mean age 22 years) treated with BDP alone. We evaluated symptom scores, salbutamol use, peak expiratory flow rates (PEFR), spirometry, and bronchial hyperresponsiveness (BHR) during 18 months of therapy with BDP and in the 9 months after BDP interruption. The two kinds of treatment were efficient and comparable in relation to symptom score, salbutamol use, morning PEFR, FVC, and FEV1, but patients treated with IT and BDP had a faster improvement of BHR and PEFR variability. The interruption of BDP after 18 months of therapy was linked to an impairment of all end points, which were more pronounced in patients previously treated only with BDP. These findings suggest that in selected asthmatic patients allergic to house-dust mites, the association of IT and BDP is more effective than therapy with this inhaled steroid alone due to a faster and more striking improvement during the first months of treatment and to a lower rate of relapse after the interruption of therapy with BDP. Antigen-antibody complexes were made from allergens of the common house dust mite, Dermatophagoides pteronyssinus (Dpt) and an excess of purified autologous specific antibodies. These complexes have been used to treat Dpt-hypersensitive patients who suffered from chronic bronchial asthma. Clinical symptoms and medication intake were followed by filling in diary cards. Peak expiratory flow, measured four times a day, was also followed. Intradermal skin tests and bronchial challenge tests were performed with allergen together with an evaluation of nonspecific bronchial reactivity. Specific IgE and IgG antibodies were assayed after separation from the bulk of serum immunoglobulins by immunoadsorption. The study was carried out over two years according to a double-blind protocol. Intradermal inoculation of antigen-antibody complexes resulted in a marked reduction of both clinical and medication scores. No systemic side-effects were observed and only mild wheal and flare reactions were noted at the injection site. The treatment showed a drastic reduction of specific skin and bronchial reactivities with only marginal effects on nonspecific bronchial reactivity. Concentrations of specific IgE antibodies decreased significantly during the first weeks of treatment and remained at these lower values throughout the study. Specific IgG antibodies actually decreased in the majority of treated patients. The total amount of allergen used in this study was less than 1% of the amount currently used for conventional hyposensitization with the same allergen. These findings show that antigen-antibody complex inoculation is an efficient and safe means of treating allergic bronchial asthma and that the mechanism of action is likely to differ from conventional hyposensitization. Inhaled corticosteroids are the most widely used treatment for asthma, a disease characterised by both functional and immunopathological abnormalities. This study investigated the relative effects of inhaled corticosteroids on these two features of asthma over time.
                A randomised, double blind, placebo controlled, parallel group study with inhaled fluticasone propionate, (FP 2 mg daily) was conducted in 27 patients with asthma. Following baseline analysis, the study tested the effects of short term (two weeks) and longer term (eight weeks) treatment. At each time point (0, 2, and 8 weeks) lung function tests were performed and endobronchial biopsy specimens obtained to determine the distribution and number of lymphocyte, macrophage and eosinophil subsets using immunohistological analysis. Twenty three patients completed the study, 11 on FP and 12 placebo.
                FEV1, delta FEV1, FEF25-75, and FEV1/FVC all improved after two weeks of FP treatment. This improvement was maintained but not increased after eight weeks. PC20FEV1 showed a trend to increase but was not significantly improved at eight weeks. No significant changes were seen in the placebo group. The numbers of T cells, macrophages, and eosinophils in the bronchial wall were reduced by two weeks of treatment with FP but were unaltered by placebo. The improvement offered by FP continued over the eight week period. Reductions in CD4:CD8 ratio and numbers of activated (EG2+) eosinophils were only significant after eight weeks of treatment.
                These results reveal that FP influences both functional and immunopathological parameters of asthma. Temporal relationships suggest that these are parallel but not necessarily interrelated effects. While short term treatment is effective in "normalising" the functional abnormalities in asthma, the impact of FP on bronchial inflammation appears to be progressive, taking up to eight weeks and more. A double blind, randomised, placebo controlled study of the treatment of children with acute asthma at home showed that a three day course of prednisolone hastened improvement of both asthmatic symptoms and peak expiratory flow rates. Thus all asthmatic children who present with an acute attack should be considered for treatment with corticosteroids in addition to bronchodilators not only to prevent possible deterioration but also to speed recovery. Immunotherapy has been shown to reduce allergen sensitivity to allergens such as cat and dust mite. The aim of this study was to investigate the effect of cat or dust mite immunotherapy on bronchial hyperreactivity and the need for inhaled corticosteroids in children with asthma, cat or dust mite allergy, and hay fever.
                Twenty-nine children, 7 to 16 years old, completed the 3-year study. They were randomly allocated to receive cat/dust mite or placebo and birch/timothy immunotherapy.
                Before immunotherapy was begun and then once each year, bronchial histamine challenges were performed. Bronchial allergen challenge with the perennial allergen was done before and after the 3-year study. Pharmacotherapy was given according to a standardized protocol.
                PC20 allergen increased significantly in both the active immunotherapy group (P <.001) and in the placebo-pollen group (P <.05). PC20 histamine increased continuously in the active immunotherapy group (P <.05 and P =.002 after 1 and 3 years, respectively) and had also increased after 3 years in the placebo-pollen group (P <.05). The difference between the 2 groups was significant for PC20 allergen (P =.001) but not for PC20 histamine. There was no significant change in the dose of inhaled budesonide needed for symptom control in either of the groups.
                Pollen immunotherapy combined with inhaled corticosteroids results in improvement of both cat/dust mite bronchial sensitivity and hyperresponsiveness to histamine. The combination of cat or dust mite, pollen immunotherapy, and inhaled budesonide enhances this improvement. Cat immunotherapy also induces cat allergen tolerance. The efficacy of immunotherapy in cat-induced asthma was studied by use of a purified fraction of cat-pelt extract and a double-blind protocol. Nine active-treatment subjects who received a mean cumulative dose of cat allergen, 1 of 10.9 units, and eight placebo-treatment subjects completed the study. Active treatment resulted in significant reductions in bronchial sensitivity (p less than 0.05) and prick test titer (p less than 0.01). In addition, active treatment resulted in a significant delay in the onset of ocular (p less than 0.05) and pulmonary (p less than 0.02) symptoms on exposure to living cats. Significant increases in IgG antibody to cat allergen 1 (p less than 0.001) and cat albumin (p less than 0.01) also occurred with active treatment. There was no significant change in bronchial reactivity to methacholine or in the sensitivity of circulating basophils. These results confirm the validity of immunotherapy in allergic asthma where there is careful patient selection and well defined treatment preparations. The aim of this study was to compare the effect of regular versus intermittent (p.r.n.) bronchodilators on bronchial reactivity and asthma control in patients on concomitant inhaled corticosteroids. We studied 12 patients with asthma in a prospective, randomised, single-blind, single-dummy, three-period crossover trial comparing placebo (2 puffs t.d.s.), salbutamol (200 micrograms t.d.s.) and oxitropium bromide (200 micrograms t.d.s.) for 28 days each. Computerised spirometry and bronchial reactivity to histamine were obtained on entry and after each treatment period. Symptom scores, use of rescue bronchodilator and peak expiratory flow rates were recorded daily. There were no significant differences in bronchial hyperreactivity between the salbutamol, oxitropium and placebo treatment periods. There were no significant differences in baseline FEV1, FEF25-75%, symptom scores, use of rescue bronchodilator or morning and evening PEFR between treatment periods. Intermittent beta agonist therapy is as effective as regular therapy in terms of asthma control and bronchial hyperreactivity in patients on concomitant inhaled corticosteroid therapy. Since intermittent therapy achieves similar results with significantly lower beta agonist consumption, the data support current recommendations that beta agonists should be taken on a p.r.n. basis in asthma patients on inhaled steroids. The aims of this investigation were to evaluate the efficacy of regular inhaled beclomethasone in the control of symptoms and lung function with non-asthmatic smoking related obstructive pulmonary disease and to evaluate the relationship between clinical responses to a short course of oral prednisone and longer term outcomes using inhaled steroid.
                The study was a randomised, double blind, placebo controlled, crossover investigation in 18 patients. The active treatment was inhaled beclomethasone 1000 micrograms given twice daily for three months by metered dose inhaler. At the end of each treatment period, patients received oral prednisone 30 mg/day for ten days. The two treatment phases were separated by a one month washout interval. Peak flow rates, symptom scores and "rescue" bronchodilator use were recorded twice daily. Lung function (FEV1, FVC and lung volumes) and bronchial hyperresponsiveness (PC20 methacholine) were measured at monthly visits. The number of exacerbations requiring intervention therapy were also recorded.
                There were no consistent benefits attributable to beclomethasone. Lung function was not significantly better as a result of active treatment. Sputum production improved but other symptom scores were similar during active and placebo therapy. Three patients exhibited an increase in FEV1 of 15% or more during active treatment but did not do so when oral prednisone was administered immediately after the period of placebo treatment. A further three patients showed an improvement in FEV1 of 15% or more with oral prednisone but failed to improve during treatment with inhaled beclomethasone. The predictive value of the "trial of steroid" was 0% and 81.3% for positive and negative outcomes respectively.
                Our results indicate that in non-asthmatic chronic obstructive pulmonary disease inhaled corticosteroid fails to achieve significant improvements in either lung function or symptoms. The response to a "trial of steroid" using oral prednisone is not clinically helpful in selecting the small number of patients who may subsequently benefit from this form of therapy. Nineteen children who were not steroid dependent and were hospitalized in status asthmaticus were studied to evaluate the effect of corticosteroids. They were randomized into two groups. Each group received salbutamol inhalations and intravenous aminophylline therapy. One group received 7 mg/kg hydrocortisone intravenously every six hours; the other group served as a control. Each group showed significant improvement in clinical score and peak expiratory flow rate after 36 hours; there was no statistical difference in the degree of improvement. Six of ten steroid-treated children and six of nine controls achieved a PEFR of 50% predicted by 36 hours. The response to inhaled salbutamol was similar in each group. The results show that in the first 36 hours of therapy, corticosteroids have no additive effect on the bronchodilator response of aminophylline and salbutamol and do not hasten the recovery of nonsteroid-dependent children in status asthmaticus. Although the results show that an inhaled sympathomimetic drug is beneficial in status asthmaticus, corticosteroid therapy does not increase the responsiveness of the airways to these agents. The effect of prolonged inhaled corticosteroid treatment on bronchial immunopathology was assessed in 25 nonsmoking mildly asthmatic subjects previously receiving intermittent inhaled beta 2-agonist alone. Inhaled beclomethasone dipropionate (BDP), 500 micrograms twice per day or placebo was administered for 4 mo in a double-blind parallel group study. Histamine bronchial provocation, fiberoptic bronchoscopic biopsy, and bronchoalveolar lavage (BAL) were performed before and after treatment. There was no difference in bronchial responsiveness or lung function between groups. In patients treated with BDP compared with placebo, there was a significant reduction in toluidine blue-staining mast cells (p = 0.028) and total (p = 0.005) and activated eosinophils (p = 0.05) in biopsies but no difference in eosinophils or eosinophil cationic protein in BAL. Granulocyte-macrophage colony-stimulating factor expression was significantly reduced in the bronchial epithelium, and the thickness of Type III collagen deposition in the bronchial lamina reticularis reduced from 29.7 +/- 4.4 to 19.8 +/- 3.4 microns (mean +/- 95% confidence interval) (p = 0.04). No change in helper or activated helper T cells occurred. Prolonged BDP treatment reduces inflammatory infiltration, proinflammatory cytokine expression, and subepithelial collagen deposition, a recognized abnormality in asthma. Thirty-nine asthmatic patients hypersensitive to Dermatophagoides pteronyssinus were treated for a total of 4 yr with injections of complexes made of allergen and autologous specific antibodies. The results obtained throughout the first 2 yr of a double-blind placebo-controlled trial have been published (1) and we now report the results of such therapy during an additional 2 yr. Three groups of patients had been defined: Groups A and B were comprised of patients treated with either "higher" doses of complexes (Group A) or "lower" doses (Group B), whereas Group C received the placebo preparation. Four injections of complexes were performed during the third yr and none during the fourth yr. The clinical benefit resulting from such injections was maintained until the end of the study, whereas medication intake, especially systemic or high doses of inhaled corticosteroids, was much reduced. Skin reactivity to allergen was significantly decreased in both treated groups. Bronchial provocation tests were carried out at 1-yr intervals with either allergen or acetylcholine (ACh). Reactivity to allergen inhalation was significantly decreased at each time point. Reactivity to ACh was significantly decreased at the end of Years 3 and 4. Fifty percent of treated patients who underwent bronchial challenges lost their bronchial reactivity to the highest concentrations of both allergen and ACh. A significant improvement in the basal lung function was observed in both treated groups. The long-term effects of immunotherapy with allergen-antibody complexes in allergic asthma patients thus include reduction in nonspecific bronchial reactivity. We studied the effect of inhaled budesonide on bronchial hyperresponsiveness (BHR) in twenty mild asthmatic patients. The study was conducted as a randomized, double-blind, placebo-controlled study. Before entering the study, the patients performed methacholine inhalation challenge (MIC) using a reservoir method to assess BHR. Then, they were randomly allocated to receive budesonide turbuhaler (200 micrograms/dose) or placebo turbuhaler two inhalations, twice daily for eight weeks. During the study, each patient recorded daily asthma score and daily number of puffs of beta 2 agonist and they were assessed at weeks 4 and 8. At the end of the treatment, MIC was repeated again. Patients receiving budesonide showed a significant improvement in airway responsiveness compared with those receiving placebo (p < 0.05). They also showed a significant improvement in asthma severity score and a significant decrease in beta 2 agonist bronchodilator use. This study also suggested that inhaled corticosteroids may be the primary treatment in patients, even with mild asthmatic and well-controlled symptoms. Several short-term studies have shown that inhaled steroids can reduce airway hyper-responsiveness in asthma. To evaluate whether prolonged treatment can bring about full recovery, this double-blind, randomized, controlled trial examined the effect of budesonide, 400 micrograms daily for 1 yr, on airway hyperresponsiveness. The time course and characteristics of improvements and associated changes in clinical asthma severity were also evaluated. Thirty-two stable adult asthmatics, requiring bronchodilators alone, were selected. Before and monthly throughout the study, airway responsiveness to methacholine was measured and clinical asthma severity assessed by questionnaire, daily bronchodilator use, and number of asthma exacerbations. Patients receiving budesonide showed a fourfold mean improvement in airway responsiveness compared with those receiving placebo (p less than 0.0005), whose responsiveness remained very stable. Fifteen of the 16 budesonide subjects improved and 5 returned to the normal range. Largest improvements occurred during the first 3 months but, in some, were still progressing slowly at 1 yr. Improvements in responsiveness were accompanied by significant improvements in asthma symptoms, bronchodilator use, and number of asthma exacerbations. The results show that regular, prolonged use of inhaled steroid can produce marked improvements in airway hyperresponsiveness, sometimes with full resolution, and these improvements are accompanied by clinically significant improvements in clinical asthma. Although widely practiced for over 80 years, the role of specific immunotherapy (SIT) in pediatric asthma treatment is still controversial. We assessed the effects of a 3-year period of subcutaneous administration of a standardized preparation of Dermatophagoides pteronyssinus (D pt) on the respiratory health in a group of asthmatic children monosensitized to house dust mite (HDM).
                A randomized clinical trial was performed after 1-year run-in period. Fifteen children receiving SIT for HDM and 14 controls (four drop-outs), matched for age, allergen sensitization, asthma severity, lung function, and non-specific bronchial reactivity (BHR), were studied during the 3-year treatment period. During the whole trial, respiratory symptoms, pharmacological and respiratory function parameters were regularly evaluated. Skin prick tests and methacholine challenge were performed at the beginning and end of the study.
                In the SIT group significant improvement in asthmatic symptoms and marked reduction in drug intake was observed. The SIT group also showed a significant decrease in non-specific bronchial BHR. No new sensitivity occurred during the study period in the SIT group only. No major local or systemic side-effects were reported during the study.
                Our results confirm that SIT is effective in asthmatic children sensitive to mites. It is associated with a decrease in BHR and it may prevent the development of new sensitizations in monosensitized subjects. Airway inflammation can be demonstrated in mildly asthmatic patients who are not treated with inhaled steroids. Current guidelines recommend that inhaled steroids should be introduced in mild asthmatics who use an inhaled beta2-agonist more than once daily. It was postulated that inhaled steroids can have anti-inflammatory effects in patients with even milder disease. The effect of 4 weeks of treatment with budesonide (800 microg twice daily by Turbohaler) was studied in 10 steroid-naive mildly asthmatic patients (forced expiratory volume in one second (FEV1) = 96+/-1.4% predicted) who required an inhaled beta2-agonist less than one puff daily, in a double-blind, placebo-controlled, crossover fashion. Spirometry, exhaled nitric oxide (NO), bronchial responsiveness (provocative concentration causing a 20% fall in FEV1 (PC20)), and sputum induction were performed before and after each treatment period. Following budesonide treatment, there were significant improvements in FEV1, and PC20, in association with a significant reduction in the percentage of eosinophils in induced sputum. Exhaled NO levels tended towards reduction, but the change was nonsignificant. There were also nonsignificant reductions in sputum eosinophil cationic protein and tumour necrosis factor-alpha levels. In conclusion inhaled budesonide can lead to improvements in noninvasive markers of airway inflammation, in association with a small improvement in lung function, even in mildly asthmatic patients who require an inhaled beta2-agonist less than once daily. This suggests a potential benefit of inhaled corticosteroids, even in relatively asymptomatic asthma. A previous two-year study of continuous and on demand bronchodilator therapy in patients with moderate asthma and chronic bronchitis showed a deterioration in lung function in those on continuous therapy.
                A two-year follow-up study was undertaken of patients who had been shown in the previous study to have non-steroid dependent (mild) asthma and chronic bronchitis, in order to investigate the effect of continuous and on-demand treatment with bronchodilator therapy.
                Patients for the study were drawn from 29 general practices in the catchment area of the University of Nijmegen, the Netherlands. A total of 83 patients (27 with asthma and 56 with chronic bronchitis) were selected from a group of 160 patients who had completed the previous two-year bronchodilator trial. During these first two years the selected subjects had been shown to be non-steroid dependent (no rapid decline in lung function and a low number of exacerbations of their condition per year), and they were followed up for another two years of treatment with bronchodilator therapy. At the start of the four-year study, patients were randomly assigned to one of two parallel treatment groups: continuous treatment (dry powder inhalations of either salbutamol 1600 micrograms or ipratropium bromide 160 micrograms daily) or treatment on demand (only during exacerbations or periods of dyspnoea). Outcome parameters were the annual decline in lung function, changes in peak flow rate, bronchial hyper-responsiveness, exacerbation rate, respiratory symptoms and reported health.
                After correction for possibly confounding variables and for regression to the mean, the decline in lung function was 49 ml year in patients taking bronchodilators continuously and 51 ml year in patients using bronchodilators on demand, irrespective of the drug use. Continuously treated patients, whether suffering from asthma or chronic bronchitis, did not differ from patients treated on demand with respect to mean morning peak flow rate, diurnal (and week to week) variation of the peak flow rate, bronchial hyper-responsiveness, exacerbation rate and reported health. There was no difference between the long-term effects of salbutamol and ipratropium.
                Continuous use of bronchodilators over four years in patients with non-steroid dependent asthma or chronic bronchitis does not increase the decline in lung function which had been observed previously in patients with moderate asthma or chronic bronchitis during two years of continuous treatment with bronchodilators. A total of 144 patients with lower airway symptoms suggestive of asthma, but who did not fulfil the functional criteria of asthma, were included in a randomised, double-blind, placebo-controlled 8-week "proof-of-concept" study with mometasone furoate (MF), 400 microg once daily. The primary efficacy variable was the mean change from baseline in six morning and evening weekly symptom scores: cough, sputum production, wheeze, shortness of breath, chest tightness and exercise-induced cough/wheeze. Total symptom scores were calculated after treatment for 4 and 8 weeks. Compared with placebo, MF improved total morning symptom score at 8 weeks. Changes in total evening symptom scores did not differ between treatments. MF improved all individual symptom scores more than placebo, although the differences in changes between treatments were not always statistically significant. Morning and evening peak expiratory flow rates increased with MF compared with placebo. MF reduced eosinophils and the levels of eosinophilic cationic protein in induced sputum. The results show that symptoms suggestive of asthma exist in patients without significant beta(2)-agonist reversibility or diurnal variability in peak flow. Once-daily MF may benefit some of these patients and a short course with inhaled corticosteroids may be tried. Responders should be better identified in further studies. The prevalence of allergy to natural rubber latex proteins has increased over recent years among healthcare professionals but also in children undergoing multiple operations. Exposure to the antigen mainly occurs through the respiratory mucosa and the percutaneous route. Clinical manifestations range from urticaria to angioedema, rhinoconjunctivitis, bronchial asthma, or anaphylactic shock. Preventive measures have been proposed to reduce the risk of sensitization by using only powder-free or synthetic gloves and latex-free material in operating units, but this is not always possible.
                The aim of this study was to investigate the efficacy and safety of specific immunotherapy in sensitized workers.
                Seventeen patients with latex skin allergy and rhinitis (9 of whom also had asthma) were included in this randomized, double-blind, placebo-controlled trial (9 in the active group and 8 in the placebo group) for 1 year. Treatment started with a 2-day course of rush immunotherapy in hospital. Treatment efficacy was assessed after 6 and 12 months by means of symptom and medication scores recorded on diary cards. Conjunctival provocation tests were also performed.
                Patients in the active treatment group had a significantly lower total rhinitis score after 6 (P <. 04) and 12 months (P <.05), conjunctivitis score after 6 months (P <. 02), and cutaneous score after 12 months (P <.03) than in the placebo group. Asthma symptoms after 6 or 12 months of treatment were not significantly different between the two groups after adjustment for baseline values. The global medication score was markedly decreased in the latex-treated group. A significant difference in conjunctival reactivity was observed in favor of the active group: the number of patients for whom the threshold dose was increased after 12 months of treatment was significantly greater in the active group than in the placebo group (P <.02). Most injections were well tolerated, but several adverse effects, including hypotension, urticaria, wheezing, and pharyngeal edema, were observed.
                The clinical benefits observed during the present study included a significant improvement of rhinitis, conjunctivitis, and cutaneous symptoms. Immunotherapy also decreased allergen-specific conjunctival reactivity. Latex-specific immunotherapy may allow sensitized personnel to remain at work, but further trials need to be conducted in a larger number of patients. We investigated the possibility that corticosteroids can reduce bronchial responsiveness to histamine by mechanisms other than change in airway caliber. Ten adult asthmatic subjects were selected because their symptoms were controlled by bronchodilators alone, they had no recent respiratory infection or allergen exposure that might have temporarily altered responsiveness, their spirometry was more than 70% predicted, and they had a range of histamine bronchial hyperresponsiveness. They received, in random order and double-blind manner, beclomethasone dipropionate (400 micrograms daily) or placebo for 4 wk and then, after a 2-week washout period, they crossed over to the other treatment for 4 wk. Treatment with beclomethasone induced a small but significant reduction in bronchial responsiveness to histamine (p = 0.014). Although the improvement was too small to be considered of clinical significance, its importance lies in the mechanisms by which it was produced. Part of the improvement was related to improvement in airway caliber, but, even when the data was adjusted for this, there was still a significant difference between beclomethasone and placebo treatment (p = 0.018). The results suggest that regular treatment with corticosteroids can alter bronchial responsiveness through mechanisms other than change in airway caliber. Although many asthmatic patients are treated with a combination of beta2 agonist and corticosteroid inhalers, the clinical effects of combining the drugs are unknown. Studies on the early asthmatic response to allergen suggest that beta2 agonists may reduce the benefit of inhaled corticosteroids. A study of the effects of combining the drugs on asthma control was undertaken.
                Sixty one subjects with mild to moderate asthma were randomised to a double blind crossover comparison of inhaled budesonide (200-400 microg twice daily), terbutaline (500-1000 microg four times daily), combined treatment, and placebo. Each treatment was given for six weeks following a four week washout period. Ipratropium was used for symptom relief. Treatments were ranked from worst (1) to best (4) based on need for oral steroid, mean morning peak flow, nocturnal awakening, ipratropium use, and asthma symptoms. Lung function and bronchial hyperresponsiveness were measured before and after each treatment.
                Evaluable data for all four treatments were obtained from 47 subjects. The mean rank of each treatment was: placebo = 2.05; terbutaline = 2.13; budesonide = 2.48; combined treatment = 3.34. Combined treatment was ranked significantly better than any other treatment (p<0.01). Mean (95% CI) morning and evening peak flows were 14 (5 to 23) and 24 (15 to 34) l/min higher, respectively, during combined treatment than during budesonide, and 27 (17 to 37) and 15 (7 to 23) l/min higher than during terbutaline. Asthma symptoms tended to be least frequent during combined treatment but were not significantly different from budesonide alone. There was no significant difference between combined treatment and budesonide alone for lung function and bronchial hyperresponsiveness.
                In this group of mild to moderate asthmatic subjects the combination of beta2 agonist and corticosteroid gave better asthma control than either treatment alone. There was no evidence that regular beta2 agonist treatment impaired the beneficial effect of inhaled corticosteroid. To determine if deterioration in patients with asthma or chronic obstructive pulmonary disease (COPD) during bronchodilator therapy could be slowed by additional treatment with an inhaled corticosteroid.
                A 4-year prospective study.
                Twenty-nine general practices in the catchment area of the University of Nijmegen, Nijmegen, the Netherlands.
                The study included 56 patients (28 with asthma and 28 with COPD) who showed an annual decrease in the forced expiratory volume in 1 second (FEV1) of at least 80 mL in combination with at least two exacerbations per year during bronchodilator therapy alone. Forty-eight patients completed the study.
                During the first 2 years of treatment, patients received only bronchodilator therapy (salbutamol, 400 micrograms, or ipratropium bromide, 40 micrograms). During years 3 and 4, they received additional treatment with beclomethasone dipropionate, 400 micrograms two times daily.
                Prebronchodilator FEV1 increased 458 mL/y (95% CI, 233 to 683 mL/y) during the first 6 months of beclomethasone treatment; FEV1 then decreased 102 mL/y (CI, 57 to 147 mL/y) during months 7 to 24. The annual decline in FEV1 during beclomethasone treatment was less than the decline of 160 mL/y seen before beclomethasone therapy (difference, 58 mL/y; 95% CI, 2 to 87 mL/y). Only in patients with asthma did beclomethasone treatment improve bronchial hyperresponsiveness (assessed by determining the concentration of histamine that provoked a 20% decrease in FEV1 [PC20]) by 3.0 doubling doses per year (95% CI, 0.8 to 5.2 doses per year). Beclomethasone treatment was associated with improvement in peak expiratory flow rate, alleviation of symptoms, and a decrease in the number of exacerbations in both patient groups.
                Adding beclomethasone, 800 micrograms daily, slowed the unfavorable course of asthma or COPD seen with bronchodilator therapy alone. This effect was most evident in asthmatic patients. Immunotherapy is a recognized treatment for allergic respiratory diseases.
                To study the usefulness of immunotherapy in combination with optimal pharmacological therapy.
                Thirty-eight children (8-14 years) suffering from seasonal asthma+/-rhinoconjunctivitis due to Parietaria poorly controlled by anti-allergic drugs treatment were selected. After randomization according to a double-blind placebo-controlled design they received active sublingual immunotherapy (15 children) or placebo (15 children) for 13 months combined with inhaled fluticasone twice a day during the pollen season. Eight children were taken as control, whereas all patients were instructed to take symptomatic drugs on need. Early and late skin response to the allergen were assessed in all patients before and after treatment. Drug and symptom scores, as well as visual analogue scores (VASs) and Parietaria pollen counts were assessed during the pollen season.
                Groups were well balanced for age, gender, early and late skin response before treatment. Four children dropped out, in one case in relationship with active sublingual immunotherapy (SLIT) administration. Chest and nose symptoms, as well as drug scores and VASs were significantly better in both the active or placebo SLIT+fluticasone (S+F) as compared to the control group (P between <0.001 and 0.043). Eye symptoms were significantly better in the active S+F group as compared to control (P=0.025). The VASs were significantly better in the active S+F group as compared to the placebo S+F group (P=0.037). The early skin response decreased significantly in the active S+F group (P<0.001), whereas the late skin response changed significantly in all groups, with an increase in the placebo+fluticasone group (P=0.019) and in the control group (P=0.037) and a decrease (P<0.0001) in the active S+F group.
                The clinical efficacy of S+F is equal to that of fluticasone alone, but the addition of SLIT has effects also on non-bronchial symptoms. Hypersensitivity to dogs and cats causes asthma in many children. In this open controlled clinical study we wanted to establish whether immunotherapy can be recommended as a supplement to conventional medical therapy in dog- and cat-induced asthma in children. Twenty-seven children with mean age 10 7/12 years and with allergy to dog or cat according to anamnesis, skin prick test (SPT), specific IgE (RAST) and bronchial provocation test (BPT) entered the study. On the basis of age and bronchial sensitivity they were randomly allocated to either immunotherapy with dog or cat extract (active group, n = 14) or conventional medical therapy (control group, n = 13). Immunotherapy comprised subcutaneous injections with an alum-adsorbed depot extract (Alutard-SQ), and a maintenance dose of 100,000 SQ-U or the maximum tolerated dose. Before entering the study and after 9 months' therapy the patients were evaluated by BPT, SPT, RAST - and IgG4 analyses. The active group showed statistically significant change in bronchial tolerance (P less than 0.02), whereas no such change was found in the control group (P greater than 0.05). The change in skin sensitivity was significantly greater in the active group than in the control group (P less than 0.05), whereas no significant differences were found in RAST and IgG4. However, a significant (P = 0.05) increase in IgG4 was seen in the active but not in the control group. Frequency and degree of side effects in this study were acceptable. Grass pollen immunotherapy significantly reduces hay fever symptoms and medication requirements. Effects on seasonal asthma are less clear, and concerns over safety persist.
                The goal of this study was to assess the effects of grass pollen immunotherapy on symptoms, bronchial hyperresponsiveness, and quality of life in seasonal rhinitis and asthma.
                Forty-four patients with severe summer hay fever (of whom 36 reported seasonal chest symptoms and 28 had seasonal bronchial hyperresponsiveness) participated in a randomized, double-blind, placebo-controlled, parallel group study. After symptom monitoring for one summer, participants received injections of a depot grass pollen vaccine (n = 22) or matched placebo injections (n = 22) in a rapid updosing cluster regimen for 4 weeks, followed by monthly injections for 2 years. Outcome measures included hay fever symptoms and medication use, health-related quality of life, and measurements of nonspecific bronchial responsiveness.
                Significant reductions were observed in the immunotherapy group compared with the placebo group in hay fever symptoms (49%, 15%; P =.01), medication scores (80%, 18%; P =.007), and seasonal chest symptoms (90%, 11%; P <.05). Impairment of overall quality of life (mean score of 7 domains) during the pollen season was less in the immunotherapy group than in the placebo group (median difference [95% CI], 0.8 [0.18-1.5]; P =.02). During the pollen season there was no change in airway methacholine PC(20) (provocation concentration producing a 20% fall in FEV(1)) in the immunotherapy-treated group (P =.5), compared with an almost 3 doubling-dose decrease in the placebo-treated group (P =.01, between-group difference). There were no significant local or systemic side effects during the study.
                Grass pollen immunotherapy improves quality of life in seasonal allergic rhinitis and reduces seasonal asthma symptoms and bronchial hyperresponsiveness. Few placebo-controlled studies have examined the effect of allergen specific immunotherapy (SIT) on early and late phase asthmatic reactions. In this placebo-controlled study we have investigated the effect of 1 year of SIT with standardized birch pollen extract on early and late phase asthmatic reactions in adult asthmatic patients.
                Nineteen patients with a history of birch-pollen-induced seasonal symptoms from upper and lower airways, positive skin prick test and in vitro specific immunoglobulin E to birch pollen extract were included. Allergen and methacholine bronchial challenges were performed and blood samples obtained for analyses of total eosinophil count and eosinophil cationic protein (ECP) in serum, before and after 1 year of immunotherapy treatment.
                All patients developed early and 16 of 19 both early and late phase asthmatic reactions. A significant increase in allergen dose was required to evoke early asthmatic reaction in the immunotherapy group (P < 0.01) after 1 year of treatment. The difference between the groups was significant (P < 0.01). Also the size of late asthmatic reaction was significantly reduced in the SIT group compared with placebo treated patients (P < 0.01). Twenty-four hours after allergen challenge methacholine sensitivity, number of total eosinophils and ECP increased significantly in the placebo (P < 0.02, P < 0.05 and P < 0.05 respectively), but not in the SIT group.
                Allergen SIT with standardized birch pollen extract decreased early and late asthmatic responses following bronchial challenge in pollen allergic patients, thus confirming anti-inflammatory effect of the treatment. Ten asymptomatic patients with normal pulmonary function were selected for a double-blind trial of immunotherapy in cat-induced asthma. Each patient had a positive prick test to cat pelt extract and also a positive bronchial challenge response to the same extract. Patients were randomly assigned to active treatment or placebo groups and received weekly or biweekly injections over a 3 to 4-month period. The 5 patients who received the active treatment received a cumulative dose of cat pelt extract that ranged from 16.4 to 44.8 mg of total solid containing 1.7 to 4.7 mg of cat allergen 1. Apparent systemic reactions were observed in 3 patients who received the placebo and 3 patients who received the active treatment. The 5 patients who received the active treatment showed a reduction in skin reactivity to cat pelt extract as well as a significant mean reduction in bronchial sensitivity to the same extract. The 5 patients who received the placebo showed no significant changes in skin reactivity or bronchial sensitivity to cat pelt extract. Bronchial response to histamine did not change significantly in either the active treatment of the placebo group. In a multicenter, randomized, double-blind study, inhaled beclomethasone dipropionate (BDP) 1,500 micrograms/day was compared to placebo in 43 chronic asthmatic patients uncontrolled by inhaled salbutamol and oral theophylline. During the prestudy period, a test of maximal steroid reversibility with oral prednisolone 0.5 mg/kg/day for 14 days was performed. The therapeutic response was measured over an 8-wk period as the ability to maintain the clinical improvement and the optimal pulmonary function induced by prednisolone. During the study, severe asthma exacerbation occurred in one (5%) of the 21 patients who received BDP and in 15 (78%) of the 22 patients who received placebo (p less than 0.001). In patients who received BDP, FEV1 and peak expiratory flow (PEF) remained above the optimal postprednisolone value, with a trend to improvement during the 8-wk study period. In patients who received placebo, FEV1 and PEF decreased and remained below the optimal value. We conclude that, in chronic asthma, inhaled BDP 1,500 micrograms/day maintains the optimal pulmonary function in addition to the clinical benefit induced by a short course of oral corticosteroids. To investigate the efficacy of an increased dose of inhaled steroid used within the context of an asthma self management plan for treating exacerbations of asthma.
                Randomised, double blind, placebo controlled, crossover trial.
                Twenty eight children aged 6-14 years with asthma of mild to moderate severity were studied for six months. Eighteen pairs of exacerbations were available for analysis, during which subjects took an increased dose of inhaled steroids or continued on the same dose.
                There was no significant difference between increasing inhaled steroids or placebo on morning or evening peak expiratory flow rates (PEFRs), diurnal peak flow variability, or symptom scores in the two weeks following an asthma exacerbation. Difference (95% confidence intervals) in baseline PEFR on days 1-3 were 3.4% (-3.5% to 10.4%) and -0.9% (-4.7% to 2.9%) for inhaled steroid and placebo, respectively. Spirometric function and the parents' opinion of the effectiveness of asthma medications at each exacerbation were also not significantly different between inhaled steroid or placebo.
                This study suggests that increasing the dose of inhaled steroids at the onset of an exacerbation of asthma is ineffective and should not be included in asthma self management plans. The morbidity from obstructive airways disease (asthma and chronic obstructive pulmonary disease) is considerable, and the mortality rate is rising in several countries. It has been hypothesized that long-term improvement in prognosis might result from vigorous bronchodilator or antiinflammatory therapy.
                In a multicenter trial we compared three inhalation regimens in which a beta 2-agonist (terbutaline, 2000 micrograms daily) was combined with a corticosteroid (beclomethasone, 800 micrograms daily), an anticholinergic bronchodilator (ipratropium bromide, 160 micrograms daily), or placebo. Patients with airways hyperresponsiveness and obstruction who were 18 to 60 years old were followed for 2 1/2 years.
                Of the 274 patients enrolled, 56 percent had allergies. The mean forced expiratory volume in one second (FEV1) was 64 percent of the predicted value. The mean PC20 (the concentration of inhaled histamine causing a 20 percent decrease in FEV1, a measure of hyperresponsiveness) was 0.26 mg per milliliter. Withdrawal from the study, due mainly to pulmonary symptoms, was less frequent in the corticosteroid group (12 of 91 patients) than in the anticholinergic-drug group (45 of 92 patients) or the placebo group (44 of 91 patients; P < 0.001). The mean FEV1 (+/- SE) increased by 10.3 +/- 1.3 percent of the predicted value in the corticosteroid group within three months and remained stable thereafter, whereas it did not change in the other two groups (P < 0.001). The PC20 increased by 2.0 doubling concentrations in the corticosteroid group but did not change in the other groups (P < 0.001). In the corticosteroid group, patients who did not smoke, who had allergies, or who were less than 40 years old benefited more from their treatment than did those who smoked, did not have allergies, or were over 40, but all subgroups of the corticosteroid group had improvement as compared with the anticholinergic-drug or placebo group.
                The addition of an inhaled corticosteroid--but not an inhaled anticholinergic agent--to maintenance treatment with a beta 2-agonist (terbutaline) substantially reduced morbidity, hyperresponsiveness, and airways obstruction in patients with a spectrum of obstructive airways disease. A group of adults with 76 episodes of acute asthma needing emergency therapy, but not requiring hospitalization, were discharged from an emergency department following standardized therapy with bronchodilators. Upon discharge, the patients were treated with a controlled regimen of oral theophylline, and were randomly assigned in double-blind manner to either a placebo treatment (42 patient episodes) or a corticosteroid treatment group (34 patient episodes). The latter were given an intravenous bolus of methylprednisolone followed by an eight-day tapering course of oral methylprednisolone, starting at 32 mg twice a day. Follow-up was carried out seven or 10 days after treatment in the emergency department. Relapse could not be predicted on the basis of peak expiratory flow rates measured during care in the emergency department. Those patients who received corticosteroids had a decrease in the need for repeated emergency care (5.9 percent versus 21 percent for placebo) and fewer respiratory symptoms (15.6 percent versus 36.4 percent for placebo). It is concluded that a short course of high-dose corticosteroids in outpatients reduces the relapse rate and symptoms following an acute asthmatic attack. The treatment of chronic severe asthma is unsatisfactory for many patients. The aim of the study was to determine the effects of treatment of steroid-dependent asthma with cyclosporin. We performed a double-blind, placebo-controlled, randomized, parallel group trial on the effect of cyclosporin on pulmonary function, asthma severity and tapering of prednisone in 34 steroid-dependent asthmatics (mean oral prednisone dose: 16 mg.day-1). The study consisted of: 1) baseline period (12 weeks); 2) experimental period divided into two parts: Part I (12 weeks) cyclosporin or placebo treatment; Part II (22 weeks) cyclosporin or placebo treatment and oral prednisone reduction; and 3) follow-up observation (8 weeks). Asthma symptoms score, pulmonary function tests (daily peak expiratory flow (PEF) and bi-weekly forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and maximal mid-expiratory flow (MEF50), biochemical profile and blood cyclosporin levels were monitored throughout the study. Following cyclosporin administration, a slight beneficial effect on some subjective parameters of asthma severity was observed. At the same time, no beneficial effect on pulmonary function was noted. The time trends analysis of mean daily prednisone doses between the treatment groups revealed a statistically significant difference indicating that, during prednisone reduction, cyclosporin seemed to be slightly more efficient than placebo in reducing the requirement for systemic corticosteroid, even though the steroid reduction was accompanied by slight impairment of some pulmonary function. However, there was no significant difference in the final dose reduction between the treatment groups. These data and the known toxicity of the drug suggest a limited place for cyclosporin treatment in steroid-dependent bronchial asthma. In a randomised controlled trial 38 asthmatic children aged 2-11 yr who had not received regular oral or inhaled steroids during the previous year, were treated with a standard regime of nebulised salbutamol and intravenous aminophylline plus either hydrocortisone and oral prednisolone for 5 days, or placebo. The children were observed throughout their hospital stay and for 3 months afterwards. There was a greater fall in heart rates in the steroid treated group on the second day of treatment (mean diff. 16 beats/min) and at discharge (mean diff. 13 beats/min); p less than 0.025. Peak Expiratory Flow Rates recorded in 26 children, 13 in each group, showed more improvement on day 2 in those given steroids (mean diff 16% predicted); p less than 0.05. This difference was not apparent at discharge but 9 children treated with steroids were clinically wheeze-free when they left hospital compared with 3 in the placebo group, p less than 0.05. There were no differences in respiratory rate, pulsus paradoxus and arterial oxygen saturation. Trends in duration of hospital stay and relapse rate during the succeeding 3 months favoured active treatment. These findings support the use of systemic corticosteroids in addition to high dose bronchodilators to treat 'non steroid dependent' children hospitalised with acute severe asthma. Twenty-seven asthmatic children allergic to dog were included in the study. Their allergy to dog was confirmed by positive results from the skin prick, radioallergosorbent and provocation tests. The subjects were randomly assigned to active and placebo groups. Fifteen subjects received immunotherapy with a commercial standardized aluminum hydroxide-bound dog dander extract and 12 subjects received placebo injections containing histamine. After one year's therapy the conjunctival sensitivity to dog dander extract had decreased significantly (p less than 0.001) in the active treatment group compared to the placebo group. The hyposensitization effect was already observable after six to eight months of treatment. The decrease in bronchial sensitivity was less marked than that in conjunctival sensitivity and statistically not significant. Immunotherapy was observed to be safe and effective. No systemic adverse reactions occurred and local reactions were mild. Treatment with inhaled steroids is an effective method of reducing bronchoconstriction and airway inflammation after allergen challenge. However, the duration of the protective effects of inhaled steroids after discontinuation of therapy has not been established.
                We sought to evaluate the protective effect of 1 week of inhaled steroid therapy against inhaled allergen challenge 12 hours after discontinuation of therapy.
                In this randomized, double-blind, placebo-controlled crossover trial, 26 asthmatic subjects (>18 years old) not using inhaled steroids were administered 200 microg of budesonide twice daily, 200 microg of fluticasone twice daily, or placebo twice daily for 1 week. Twelve hours after discontinuation of therapy, subjects were administered an inhaled allergen challenge. Each treatment period was separated by a 3-week washout period.
                When compared with placebo (26% +/- 14%), there was a slight but significant protection against the allergen-induced early response after fluticasone treatment (19% +/- 10%, P = .001) but not after budesonide treatment (23% +/- 13%, P = .08). However, when the area under the curve for the early airway response was examined, there was no difference between the 2 drugs in the amount of protection ( P = .62). Partial protection was demonstrated against the late-response allergen-induced sputum eosinophilia with both treatments ( P = .001). By contrast, no protection was observed against allergen-induced airway hyperresponsiveness for either treatment.
                The protective effects of inhaled steroids against allergen-induced early responses, airway eosinophilia, and allergen-induced airway hyperresponsiveness are partially or completely lost as early as 12 hours after discontinuation of therapy. Both specific immunotherapy (SIT) and nasal steroid (NS) have been shown to effectively reduce symptoms of allergic rhinitis. Although a number of investigators have convincingly shown anti-inflammatory effects of both treatments in separate studies, few comparative studies have been performed.
                The purpose of this study was to compare the effects of preseason SIT with a standardized allergen extract and NS in seasonal allergic disease (rhinoconjunctivitis and asthma).
                We examined 41 patients allergic to birch pollen, 21 with rhinoconjunctivitis and 20 with both rhinoconjunctivitis and asthma; they were treated in a randomized, double-blinded comparative study with birch SIT and NS (budesonide 400 microg daily). Bronchial hyperresponsiveness was measured before and during the season. Changes in eosinophil number, eosinophil cationic protein, and eosinophil chemotactic activity (ECA) in peripheral blood were investigated.
                Symptoms of rhinoconjunctivitis increased significantly less in the NS-treated patients than in the SIT-treated patients during the final 2 weeks of the season (P = .03 and P = .04, respectively). Seasonal peak expiratory flow values decreased significantly only in the NS-treated patients (P = .01). In the NS-treated patients, bronchial hyperresponsiveness increased significantly during the season (P = .0001); however, SIT treatment prevented seasonal PC(20) increase in the asthmatic patients. Measurement of blood eosinophils, eosinophil cationic protein, and eosinophil chemotactic activity demonstrated significant seasonal increase only in the NS-treated asthmatic patients.
                Treatment with NS was more effective than short-course preseason SIT in reducing symptoms of rhinoconjunctivitis; however, the 2 therapies were equivalent in terms of the need for rescue medication. SIT prevented seasonal increase in bronchial hyperresponsiveness, eosinophil number, eosinophil cationic protein, and eosinophil chemotactic activity only in asthmatic patients. The mechanisms underlying bronchial hyperresponsiveness developing during allergen exposure in rhinitis might be different from those operating in asthma. In a double blind, controlled trial, the effect of high dose beclomethasone dipropionate (750 micrograms three times daily for five days) administered by metered dose inhaler and valved spacer, was compared with placebo, during 70 paired episodes of acute asthma in 24 preschool children. Treatment commenced at home at the first sign of an attack. Parents' blind preference for active treatment was significant. Data from 17 pairs of treatment, however, were affected by interventions such as hospital admission or oral corticosteroid treatment. These events occurred similarly in active and control periods. An intrasubject comparison was made of diary scores from the 18 pairs of episodes in which no intervention occurred in either the active or placebo treatment. Both daytime and night symptoms over the first week of the attack were significantly reduced by active treatment. Intermittent high dose inhaled beclomethasone dipropionate is beneficial in modifying the severity of acute episodic asthma in preschool children able to use a spacer device. Allergic asthma is common in children, and house dust mite (HDM) is an important source of perennial allergens. Bronchial hyperresponsiveness is a functional hallmark of asthma. Specific immunotherapy (SIT) with HDM extracts were shown to decrease symptoms, but its effect on bronchial responsiveness, as measured by non-pharmacological challenges, has not been evaluated.
                Twenty-six paediatric asthma patients allergic to HDM participated in this study. Fourteen patients received SIT with a HDM extract (Alavac, Bencard) for 2 years, and 12 served as controls. Bronchial responsiveness was assessed non-pharmacologically by cold dry air challenge (CACh) before and 3, 6, 12 and 24 months after SIT, and 12 months after termination of SIT.
                After 24 months, the SIT group showed a statistically significant reduction of the mean CACh-induced changes of both forced expiratory volume in one second (-21.8+/-2.7% vs. -13.7+/-2.4%; P = 0.03) and maximal expiratory flow at 25% remaining vital capacity (-48.9+/-4.9% vs. -27.9+/-6.2%; P = 0.01). In contrast, no significant changes of bronchial responsiveness were observed in the control group. In the SIT group more patients lost their bronchial hyperresponsiveness than in the control group (6/14 vs. 1/12; P<0.05). One year after terminating SIT, the treatment group showed a tendency towards returning bronchial hyperresponsiveness.
                These results demonstrate that during 2 years of SIT there was a reduction of bronchial hyperresponsiveness in HDM-allergic paediatric asthma patients. Budesonide 400 micrograms daily, in nonsteroid-dependent asthma, can produce improvements in airway responsiveness and clinical asthma severity, with some patients returning to normal responsiveness and becoming asymptomatic. This study examined whether similar improvements occur when asthmatics, who are dependent upon inhaled steroids, take either a regular maintenance dose of inhaled steroid or twice that amount for a year. Thirty two asthmatics were each stabilized on the minimum amount of inhaled steroid that would keep symptoms non-troublesome. In a double-blind, randomized manner, half were assigned to remain on a maintenance dose (MD) and the rest received twice that dose (MDx2) for one year. Before and monthly throughout the study, airway responsiveness to methacholine was measured and clinical asthma severity assessed by questionnaire, inhaled bronchodilator use and number of asthma exacerbations. There was a significant improvement in airway responsiveness and clinical asthma severity in both treatment groups. Those on MDx2 showed the greatest improvement but the difference between the two groups did not reach significance. This study provides strong evidence that prolonged use of inhaled steroids is associated with improvement in airway responsiveness and clinical asthma severity in inhaled steroid-dependent asthma with a suggestion that the improvements are dose related. nan To determine whether initiation of maintenance treatment with the salmeterol (S)/fluticasone propionate (FP) combination (Seretide/Viani/Advair) is more effective than inhaled steroid alone in patients with asthma symptomatic on short-acting bronchodilator alone.
                150 asthma patients with symptoms and prn use of short-acting bronchodilator at least once a week were randomised to 24 weeks' treatment with either S/FP 50/100 microg bd (n = 78) or FP 100 microg bd (n = 72). The primary endpoint was the percentage of symptom-free 'day + night's.
                The percentage of symptom-free 'day + night's increased significantly more for S/FP (20 to 64%) compared to FP (24 to 51%). The treatment difference was 15.3%, P = 0.008. In the sub-group of patients with mild asthma the treatment difference was also statistically significant in favour of S/FP (P = 0.0245, n = 74). S/FP was also significantly superior to FP alone for: lung function, salbutamol use prn, day symptom score, symptom-free days, and episode-free 'day + night's. Treatments were equally well tolerated.
                Initial maintenance treatment with S/FP is significantly more effective than with inhaled steroid alone for patients symptomatic when treated with short-acting bronchodilator alone. This also apply to patients with mild persistent asthma. To evaluate the tolerability and efficacy of specific immunotherapy with mite extracts, we performed a double-blind, placebo-controlled immunotherapy study in 30 patients with proven allergy to mite allergens. The specific immunotherapy with standardized extracts of Dermatophagoides pteronyssinus and D. farinae by a clustered rush protocol was well tolerated. After 1 year of treatment, the actively treated group showed a significant improvement compared to their starting value as well as to the placebo-treated patients with regard to skin prick test, conjunctival provocation test, and subjective rhinitis score. The subjective asthma score and bronchial hyperreactivity, measured by the methacholine provocation test, was improved in comparison to the starting value, but not to the placebo group, after 12 months. However, a further, open comparison of the placebo- and verum-treated groups at 18 months revealed a significant reduction. The drug intake was not increased in the verum-treated group. Exposure to mite levels was constant throughout this time period, as revealed by antigen measurement. We conclude that specific immunotherapy in perennial, mite-allergen-induced asthma may reduce not only immediate, IgE-mediated symptoms but, after a rather long time period of 12-18 months, also the inflammatory component of bronchial asthma, thus leading to a reduction of unspecific hyperreactivity. The aim of this study was to assess the efficacy and safety of inhaled salmeterol 100 micrograms b.d. (SM) versus inhaled salbutamol 400 micrograms q.d.s. (SB), both via the Diskhaler, when added to concurrent treatment, in asthmatic patients who were not controlled on high doses of inhaled steroids (> or = 1,500 micrograms beclomethasone dipropionate (BDP) or equivalent daily). This was a multicentre, parallel group, double-blind study in which 190 patients with a forced expiratory volume in one second (FEV1) or peak expiratory flow rate (PEFR) of 30-75% predicted and 15% reversibility to inhaled bronchodilator were randomized to treatment for 6 weeks. In the SM group, morning PEFR increased from 281 to 315 L-min-1 during treatment and in the SB group from 311 to 315 L.min-1 (p < 0.001). The SM group showed significantly better reduction in diurnal variation, from 39 to 22 L.min-1 during treatment, than the SB group (34 to 37 L.min-1) (p < 0.001). There was a significantly greater improvement in FEV1 in the SM group (from 1.63 to 1.85 L) than in the SB group (from 1.79 to 1.84 L). The SM group had significantly more symptom-free nights than the SB group (p < 0.001), and also more "rescue-free" nights (p = 0.04). The adverse event profile was similar in both groups. This study indicates that in asthmatic patients, not controlled on high-dose inhaled steroids, inhaled salmeterol 100 micrograms b.d. significantly improves lung function and reduces asthma symptoms. 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. Regular treatment with salbutamol or placebo aerosols was compared in a double-blind study in 18 asthma patients. Although symptom scores and respiratory function tests were not significantly different, wheezing attacks requiring additional puffs of a standard salbutamol aerosol were significantly more frequent during the period on placebo when patients were receiving symptomatic treatment only. Thus regular treatment with bronchodilator aerosols provides better control of asthma than symptomatic use alone. In this double blind, placebo-controlled study we examined the value of using a device for ionizing the air in the immediate environment as a therapy for asthma bronchiale. Nineteen adult patients with stable, reversible asthma were randomised to blind treatment with either an active device or an inactive placebo-device. After four weeks treatment the patients were given the alternative device for another period of four weeks. We measured daily peak-flow, symptomscore, use of medicine and spirometry and found no differences between the two periods. Therapy with ionization of the environmental air in patients with bronchial asthma should not be recommended. The clinical benefit and steroid-sparing effect of treatment with the anti-immunoglobulin-E (IgE) antibody, omalizumab, was assessed in patients with moderate-to-severe allergic asthma. After a run-in period, 546 allergic asthmatics (aged 12-76 yrs), symptomatic despite inhaled corticosteroids (500-1,200 microg daily of beclomethasone dipropionate), were randomized to receive double-blind either placebo or omalizumab every 2 or 4 weeks (depending on body weight and serum total IgE) subcutaneously for 7 months. A constant beclomethasone dose was maintained during a 16-week stable-steroid phase and progressively reduced to the lowest dose required for asthma control over the following 8 weeks. The latter dose was maintained for the next 4 weeks. Asthma exacerbations represented the primary variable. Compared to the placebo group, the omalizumab group showed 58% fewer exacerbations per patient during the stable-steroid phase (p<0.001). During the steroid-reduction phase, there were 52% fewer exacerbations in the omalizumab group versus the placebo group (p<0.001) despite the greater reduction of the beclomethasone dosage on omalizumab (p<0.001). Treatment with omalizumab was well tolerated. The incidence of adverse events was similar in both groups. These results indicate that omalizumab therapy safely improves asthma control in allergic asthmatics who remain symptomatic despite regular use of inhaled corticosteroids and simultaneous reduction in corticosteroid requirement. Regular treatment with beta 2-adrenergic agonists is controversial in bronchial asthma. To investigate whether beta 2-adrenergic agonists can be used safely if associated with low doses of inhaled steroids, for a short period, without a deterioration of asthma control, we have examined 24 mild asthmatics. In a parallel, double-blind, placebo-controlled study, 1 week of run-in and run-out period framed 3 weeks of treatment. All patients received inhaled beclomethasone dipropionate (BDP 250 micrograms t.i.d.); after 1 week, 12 patients inhaled 400 micrograms of broxaterol and 12 patients received placebo t.i.d. FVC, FEV1, PD20-FEV1 methacholine, morning and evening PEF, and PEF amplitude % mean were measured before, during, and after treatment. No significant changes were noted in patients receiving inhaled broxaterol. There were no differences in symptoms and the use of rescue medication (salbutamol spray). We conclude that short-term regular treatment with beta 2-adrenergic agonists is not associated with a deterioration in asthma control in mild asthmatics inhaling low doses of steroids. It has been suggested that regular treatment with high doses of beta 2-agonists might result in poorer control of asthma and increased bronchial responsiveness. We have examined change in FEV1 (delta FEV1), bronchial reactivity, peak expiratory flow (PEF), and symptoms during and after 3 wk of regular treatment with a relatively low dose of albuterol and broxaterol, a new beta 2-agonist. Eleven subjects 18 to 50 yr of age with mild asthma inhaled albuterol (200 micrograms), broxaterol (400 micrograms), or placebo three times a day for 3 wk with a 2- to 4-wk run-in/washout period between treatments. Ipratropium bromide was allowed for symptomatic relief. The PD20 (dose of histamine causing a 20% fall in FEV1) was measured before and 11, 35, and 59 h after cessation of treatment and a bronchodilator dose-response study before and 83 h after cessation of treatment. Change from baseline after albuterol and broxaterol are compared with change after placebo. Diurnal change in PEF (amplitude % mean) increased during treatment with albuterol by 6.5% (95% CI, 1.7-12.3; p < 0.02) mainly because of a fall in morning PEF. Cessation of treatment with both beta 2-agonists was associated with a fall in FEV1 and PD20 compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS) In a double-blind study beclomethasone dipropionate inhaled as a dry powder in doses of 100 microgram four times daily and 150 microgram four times daily was compared with the conventional aerosol dose of 100 microgram four times daily in 20 outpatients with chronic asthma. Each of the three treatments was given for four weeks. The dry powder in a dose of 150 microgram four times daily had advantages over the other two treatments in terms of FEV1 and the number of exacerbations of asthma during the study. There were no adverse reactions to inhaling dry-powder beclomethasone. It was concluded that this new way of administering the drug was effective in chronic asthma, and should allow most patients with chronic asthma who cannot use conventional pressurised aerosols efficiently to benefit from inhaled corticosteroid treatment. Although the anti-inflammatory effects of inhaled corticosteroids in the treatment of asthma are established, the effects of long-acting beta2-adrenergic receptor agonists on inflammation are the subject of debate. The aim of the present study was to determine the effect of salmeterol on the numbers of inflammatory cells in biopsy samples of distinct immunophenotype and those expressing the genes for interleukin-4 and -5, regulatory cytokines particularly relevant to asthma. Twenty patients (aged 18-55 yrs) with mild stable asthma were randomised in a three-way crossover study to 6 weeks of treatment with: 1) salmeterol (50 microg b.d.; SM50); 2) fluticasone propionate (250 microg b.d.; FP250), or 3) placebo. Compared with placebo, SM50 significantly reduced the numbers of neutrophils in bronchial biopsy samples and the concentrations of myeloperoxidase and soluble E-selectin in serum, each of which reflect neutrophil involvement. Compared with FP250, SM50 reduced neutrophil number and human neutrophil lipocalin level in bronchial lavage fluid and intercellular adhesion molecule-1 level in bronchoalveolar lavage fluid. Compared with placebo, FP250 significantly reduced the numbers of (CD3+) T-lymphocytes, (CD4+) T-helper cells, (CD45RO+) activated T-helper cells and eosinophils in the biopsy samples; it also reduced the percentage of eosinophils and soluble intercellular adhesion molecule-1 in serum. The percentage of symptom-free days and nights and airways hyperresponsiveness improved significantly after SM50 compared to both placebo and FP250. In conclusion, a novel antineutrophilic effect of the inhaled long-acting beta2-adrenergic receptor agonist, salmeterol, in mild asthma is reported. Continuing study for a second year and further analysis of a double-blind placebo controlled trial, already briefly reported, of injections of tyrosine-adsorbed, glutaraldehyde-modified Dermatophagoides pteronyssinus antigen in fifty-one children with perennial asthma and positive bronchial challenge to the antigen, confirms that the patients receiving the treatment reduced their symptomatic medication more than controls, without deterioration of symptoms. Some became symptom-free, when off all treatment. A double-blind placebo controlled trial of continuing treatment for a second year gave evidence of deterioration when the treatment was stopped. Within the treatment group, the improvement was associated with loss of late (6 hr) reaction to bronchial provocation with the antigen, but was not associated with change of immediate (20 min) reaction in lungs or skin. Those who improved in the placebo group did not lose their late reaction. There was a trend for similar benefit from active treatment in the control group, during the second year, though less than in the original active group, and only one lost his late reaction. Only one of the six children with very severe early onset asthma improved. Local reactions to either active or placebo (tyrosine) were seen in half the patients; these were mild and did not influence the treatment. Systemic symptoms occurred shortly after four active injections and after two placebo injections; only one patient stopped the treatment. Sixteen patients suffering from bronchial asthma, with or without chronic bronchitis, sufficiently severe to be treated with inhaled corticosteroids, were studied in a single-blind trial (blind observer) of beclomethasone dipropionate (BDP) given in three randomized dosage regimens: 500, 1000 and 2000 micrograms per day, each for 4 weeks. The beta 2-adrenergic agonist response curve showed a dose-dependent increase in FEV1 which was not affected by different doses of BDP. A small but significant reduction in basal cortisol levels was observed after BDP 500 micrograms/day. There was no significant difference between the various doses of BDP in reducing cortisol level and stimulation with tetracosactide remained unchanged. The study showed a gradual, dose-dependent improvement in lung function, statistically significant for morning peak expiratory flow rate at BDP 2000 micrograms/day. Dyspnoea score and beta 2-agonist use decreased, reflecting the anti-asthmatic effects. An increase in total leukocyte count was observed, together with a decrease in the eosinophil count. Oral candidiasis was seen in 2 out of 16 patients. It is concluded that the clinical anti-asthmatic effects of corticosteroid treatment by inhalation are not due to modulation of beta 2-receptor function in the airways. The effect of adding ipratropium bromide to treatment with beta-2-adrenoceptor agonists was studied in 13 asthmatic children in a double-blind cross-over trial. In the acute phase of the study inhalation of salbutamol 0.1 mg/kg followed by inhalation of 0.25 mg of ipratropium bromide was found to improve pulmonary function variables to a significantly greater extent than salbutamol followed by placebo. The combined therapy also provided significantly better protection than salbutamol plus placebo against exercise-induced asthma. Maintenance treatment with ipratropium bromide (two inhalations four times daily, 20 micrograms per inhalation) in combination with oral terbutaline and aerosolized salbutamol did not alleviate asthmatic symptoms or pulmonary function variables to a degree beyond that achieved with the beta-stimulants alone. There were no side effects associated with the ipratropium bromide treatment. These data suggest that higher doses of ipratropium bromide than are presently used should be tested for maintenance treatment of chronic asthma. IgE plays an important role in allergic asthma. We hypothesized that reducing IgE in the airway mucosa would reduce airway inflammation. Forty-five patients with mild to moderate persistent asthma with sputum eosinophilia of 2% or more were treated with humanized monoclonal antibody against IgE (omalizumab) (n = 22) or placebo (n = 23) for 16 weeks. Outcomes included inflammatory cells in induced sputum and bronchial biopsies, and methacholine responsiveness. Treatment with omalizumab resulted in marked reduction of serum IgE and a reduction of IgE+ cells in the airway mucosa. The mean percentage sputum eosinophil count decreased significantly (p < 0.001) from 6.6 to 1.7% in the omalizumab group, a reduction significantly (p = 0.05) greater than with placebo (8.5 to 7.0%). This was associated with a significant reduction in tissue eosinophils; cells positive for the high-affinity Fc receptor for IgE; CD3+, CD4+, and CD8+ T lymphocytes; B lymphocytes; and cells staining for interleukin-4, but not with improvement in airway hyperresponsiveness to methacholine. This study shows antiinflammatory effects of omalizumab treatment and provides clues for mechanisms whereby omalizumab reduces asthma exacerbations and other asthma outcomes in more severe asthma. The lack of effect of omalizumab on methacholine responsiveness suggests that IgE or eosinophils may not be causally linked to airway hyperresponsiveness to methacholine in mild to moderate asthma. The efficacy of parenteral gold therapy was evaluated in patients with steroid-dependent asthma. Five of eight patients improved in terms of reduced steroid requirement while they were maintaining or improving lung function. Two patients developed significant proteinuria that resolved with cessation of gold. Chrysotherapy appears to have a corticosteroid-sparing effect in some patients and may have a useful role in the management of severe refractory asthma. This 52-week study was designed to assess the safety and efficacy of fluticasone propionate/salmeterol combination (FSC) 250/50 micrograms versus fluticasone propionate (FP) 250 micrograms in subjects with persistent asthma symptomatic on open-label FP 100 micrograms. The primary objective of this study was to show that FSC 250/50 micrograms was superior to FP 250 micrograms at increasing pulmonary function as measured by forced expiratory volume in 1 second over a 52-week treatment period. A secondary objective was to compare the rate of asthma attacks defined as (1) a sustained 2-day decrease in morning peak expiratory flow or increase in albuterol use for 2 consecutive days, (2) an asthma exacerbation requiring systemic corticosteroids, or (3) an unscheduled clinic or hospital visit for acute asthma symptoms. Three hundred six subjects received FSC 250/50 micrograms and 315 subjects received FP 250 micrograms. Both treatments were administered twice daily. Treatment with FSC 250/50 micrograms resulted in a significant improvement in lung function compared with FP 250 micrograms (p < 0.001). Additionally, treatment with FSC 250/50 micrograms resulted in a reduction in the rate of exacerbations of asthma (i.e., requiring systemic corticosteroids or unscheduled urgent care intervention) compared with FP 250 micrograms (0.170 versus 0.273, respectively; p = 0.017). There was no differentiation between treatments for less severe attacks of asthma. FSC 250/50 micrograms showed consistently greater improvement in lung function, symptom control, and decreased albuterol use. In addition, FSC 250/50 micrograms-treated subjects experienced fewer severe asthma exacerbations than subjects treated with FP 250 micrograms. The efficacy of inhaled beclomethasone dipropionate has been examined in 44 steroid-dependent asthmatics observed for 9 months to 2 years. A 3-month double-blind trial found that subjects treated with beclomethasone had a significant diminution in symptoms, were able to reduce their use of medication, and had improved maximum expiratory flow rates. Approximately one half were able to discontinue the use of oral prednisone within 9 months after starting beclomethasone, and a further one third reduced their dose by at least 50%. No characteristics could be defined to predict responsiveness to beclomethasone. The effectiveness of beclomethasone was sustained for as long as 2 years and was not associated with any abnormal urine, blood, or serum values or chest X-ray findings. Candidiasis of the palate appeared in approximately one third of the subjects and was usually transient. The chronic use of beclomethasone did not result in endocrine suppression. To compare the benefits and adverse reactions of theophylline and beclomethasone (BDP) in the long-term control of mild to moderate chronic asthma in children.
                Multicentered, double-blind, double-placebo, randomized, controlled trial.
                One hundred ninety-five children between the ages of 6 and 16 years with mild to moderate asthma.
                Treatment with either BDP, 84 micrograms four times a day, or sustained-release theophylline administered twice daily in doses adjusted for optimum control of symptoms.
                Daily diary record of symptoms, peak flow rates, supplemental bronchodilator and glucocorticoid treatment, doctor and hospital visits, absence from work and school, and side effects.
                Aerosol BDP and sustained-release theophylline were effective primary treatments for mild to moderate chronic asthma. Beclomethasone resulted in comparable symptom control with less bronchodilator use and fewer courses of systemic steroids than did theophylline. Side effects were observed significantly more frequently with theophylline than with BDP. Growth velocity suppression was noted with BDP and was more pronounced in boys. Suppression was not associated with alterations in cortisol measurements either at baseline or following stimulation.
                Both theophylline and BDP are effective therapy for mild to moderate asthma. Caution must be used with the administration of BDP in children because of possible growth velocity suppression. The effect of inhaled beclomethasone diproprionate (1500 micrograms day-1) on symptoms, pulmonary function and sputum production was examined in a double-blind, placebo-controlled, cross-over study in 20 patients with bronchiectasis. An 18% reduction in daily sputum production (P less than 0.003) was observed on treatment with inhaled steroid compared to placebo. A small, significant, improvement in morning peak expiratory flow rate (P less than 0.03) and forced expiratory volume in 1 s (P less than 0.03) was seen but the absolute changes are unlikely to be of clinical importance. Symptom scores for cough improved significantly (P less than 0.02). Inhaled steroids may have a role in the management of bronchiectasis by reducing cough and sputum production. Clinical manifestations after the inhalation of Olea europaea pollen are very frequent in Spain. Forty-five patients with a clinical history of asthma and sensitivity to O. europaea pollen were included in a randomized trial to evaluate the safety and the clinical efficacy of immunotherapy with a new chemically modified extract (depigmented and glutaraldehyde-polymerized) of Olea europaea. The study was conducted following good clinical practices and appropriate consent forms were signed. Patients were divided into three groups of 15 individuals: Group A received a maximum concentration of 44 micrograms/ml of the depigmented, polymerized allergen extract (equivalent to 100 HEPL of the native unmodified extract). Group B received 10 times less; Group C did not receive any specific immunotherapy. Any adverse event was recorded to assess safety. Efficacy was evaluated by measuring the amount of allergen needed to elicit a positive response in specific bronchial challenges before and after 12 months of immunotherapy. The treatment schedule consisted of an incremental phase of five injections and a maintenance dosage of 0.5 ml per month. Each patient received a total of 14 injections during this period. No moderate or serious adverse events related to immunotherapy were recorded. At the beginning of the study, no significant differences were observed between the three groups in specific bronchial hyperreactivity (p > 0.05). A significant difference (p < 0.05) was obtained after 12 months. Patients in Group A needed four times more native unmodified allergen than Group C to elicit the same degree of bronchoconstriction. The analysis of the individual groups before and after 12 months of treatment showed that patients in Groups B and C did not improve. Patients in Group A showed a significant improvement (p < 0.05) in specific bronchial hyperreactivity, and at the end of the study needed 5.5 times more native unmodified allergen to obtain the same degree of bronchial response as in the beginning. Depigmented and glutaraldehyde-polymerized vaccines of Olea europaea pollen are very safe for treating patients with asthma and clinical sensitivity to allergens of this pollen. The clinical efficacy of this new allergen vaccine seems to be dose-dependent as shown by specific bronchial challenges as well as by symptom and medication scores. These modified extracts induce protection against unmodified native allergens. Preventive measures have been proposed to reduce the risk of sensitization to natural rubber latex (NRL), but this is not always feasible.
                The aim of this study was to determine the efficacy and safety of specific immunotherapy with a standardized latex extract in sensitized workers.
                Twenty-four patients allergic to NRL with contact urticaria (n = 8) and rhinitis or asthma (n = 16) were included (16 in the active group and 8 in the placebo group). Treatment started in a cluster immunotherapy protocol, with injections every week for 3 months and then every other week for another 3 months.
                Patients in the active group had significantly lower values than patients in the placebo group in skin terms of reactivity to NRL (P <.01), rubbing test results (P =.047), and latex glove use test results (P =.046) after 6 months of treatment. There were no significant differences between the active and placebo groups in symptom scores, use of medication, self-assessment, or methacholine test results either before or after treatment. Differences in nasal and bronchial symptoms during specific inhalation challenges (P = not significant and P =.05, respectively) were observed in favor of the active group. In the active group 32 systemic reactions were observed (8% of doses), mostly during the build-up period, being more frequent in patients with respiratory symptoms (P =.004). All reactions responded promptly to treatment.
                Clinical efficacy was shown mainly on cutaneous symptoms, although an improvement in rhinitis and asthma symptoms was also observed during specific inhalation challenges. Latex-specific immunotherapy might be a useful approach for the treatment of latex allergy in sensitized workers. Addition of the long acting beta2 agonist salmeterol to inhaled corticosteroids leads to better symptomatic asthma control than increasing the dose of inhaled corticosteroids. However, little is known about the long term effects of adding salmeterol on the asthmatic inflammatory process, control of which is considered important for the long term outcome of asthma.
                After a 4 week fluticasone run-in period, 54 patients with allergic asthma were randomised to receive twice daily treatment with fluticasone 250 microg with or without salmeterol 50 microg for 1 year in a double blind, parallel group design (total daily dose of fluticasone 500 microg in both treatment groups). Primary outcomes were sputum eosinophil numbers and eosinophil cationic protein concentrations. Secondary outcomes were neutrophil associated sputum parameters and a respiratory membrane permeability marker. The effects on allergen induced changes were determined before and at the end of the treatment period.
                Adding salmeterol to fluticasone resulted in improved peak expiratory flow, symptom scores, rescue medication usage, and bronchial hyperresponsiveness (p < 0.05 for all). There was no sustained effect on sputum cell differential counts and cytokine concentrations during the treatment period or on changes induced by allergen challenge at the end of treatment (p > 0.05). However, adding salmeterol significantly reduced sputum ratios of alpha2-macroglobulin and albumin during the treatment period (p = 0.001).
                The addition of salmeterol to fluticasone produces no sustained effect on allergen induced cellular bronchial inflammation but leads to a significant improvement in size selectivity of plasma protein permeation across the respiratory membrane. This may contribute to the improved clinical outcome seen in patients with allergic asthma when a long acting beta2 agonist is combined with inhaled corticosteroids. Eleven patients with bronchial asthma and 10 with chronic bronchitis were treated over four consecutive 3-day periods, firstly with aerosols either of ipratropium bromide (40 microgram four times a day) or of salbutamol (200 microgram four times daily) by random allocation, then the alternate drug, next by both drugs together, and finally with prednisolone (10 mg three times daily) in addition to both drugs. The effects of these four treatment periods were assessed both clinically and by measuring ventilatory capacity, nitrogen slope and progressive exercise testing. Ipratropium bromide and salbutamol produced approximately equal improvements in both diseases, with salbutamol showing a marginal advantage in patients with asthma. The combination of both drugs together more than doubled the FEV1 change in both groups of patients. The addition of prednisolone to both drugs produced a marginal advantage only in those with asthma. Patients with severe asthma are often inadequately controlled on existing anti-asthma therapy, constituting an unmet clinical need.
                This randomized, double-blind, placebo-controlled trial evaluated the ability of omalizumab, a humanized monoclonal anti-IgE antibody, to improve disease control sufficiently to enable inhaled corticosteroid reduction in patients with severe allergic asthma.
                After a run-in period when an optimized fluticasone dose (> or =1000 microg/day) was received for 4 weeks, patients were randomized to receive subcutaneous omalizumab [minimum 0.016 mg/kg/IgE (IU/mL) per 4 weeks; n=126] or matching placebo (n=120) at intervals of 2 or 4 weeks. The study comprised a 16-week add-on phase of treatment followed by a 16-week fluticasone-reduction phase. Short-/long-acting beta(2)-agonists were allowed as needed.
                Median reductions in fluticasone dose were significantly greater with omalizumab than placebo: 60% vs. 50% (P=0.003). Some 73.8% and 50.8% of patients, respectively, achieved a > or =50% dose reduction (P=0.001). Fluticasone dose reduction to < or =500 microg/day occurred in 60.3% of omalizumab recipients vs. 45.8% of placebo-treated patients (P=0.026). Through both phases, omalizumab reduced rescue medication requirements, improved asthma symptoms and asthma-related quality of life compared to placebo.
                Omalizumab treatment improves asthma control in severely allergic asthmatics, reducing inhaled corticosteroid requirements without worsening of symptom control or increase in rescue medication use. To examine the hypothesis that an IM long-acting steroid injection will decrease the relapse rate of asthma patients.
                A randomized, single-blind, placebo-controlled trial.
                The emergency department of an urban academic medical center.
                Acute asthma patients aged 18 to 45 years who were treated successfully in the ED.
                Participants received either IM saline placebo or 240 mg methylprednisolone acetate suspension at the time of discharge. MEASUREMENTS AND MAIN OUTCOME: Relapse, defined as the need to seek nonroutine medical care for asthma within seven days of discharge, was the main outcome measure. Of 70 patients entered, 56 (80%) completed follow-up, including 30 in the steroid group and 26 in the placebo group. The groups had similar characteristics and peak expiratory flow values on arrival and at discharge. Relapse occurred in two steroid patients (6.7%) and eight placebo recipients (30.8%) (P < .05). There was one death in the placebo group. Reported side effects were similar.
                IM long-acting steroids reduced the rate of relapse in patients with acute asthma.
Immunotherapy reduces asthma symptoms and use of asthma medications and improves bronchial hyper-reactivity.  One trial found that the size of the benefit is possibly comparable to inhaled steroids. The possibility of local or systemic adverse effects (such as anaphylaxis) must be considered.