Initial corticosteroid therapy for asthma

PURPOSE OF REVIEW: This review examines the commencement of maintenance pharmacotherapy for asthma: inhaled corticosteroids alone or in combination with long-acting beta2 agonists. RECENT FINDINGS: A systematic review of randomized controlled trials has examined the starting dose of inhaled corticosteroids (high, moderate, low) and the dose regimen (step down versus constant) in asthma. There was no significant difference in key asthma outcomes for step down compared with a constant inhaled corticosteroid dose. There was no significant difference between high or moderate dose inhaled corticosteroid groups (n=11) for morning peak expiratory flow, symptoms and rescue medication use. There may be a benefit from high-dose inhaled corticosteroids for airway hyperresponsiveness. There was a significant improvement in peak expiratory flow and nocturnal symptoms in favour of a moderate inhaled corticosteroid dose compared with low-dose treatment. Long-acting beta2 agonists combined with inhaled corticosteroids as initial asthma therapy has been examined in a systematic review of nine randomized controlled trials. Inhaled corticosteroids combined with long-acting beta2 agonists led to significant improvements in forced expiratory volume in 1 s, morning peak expiratory flow, symptom score and symptom-free days but no difference in exacerbations requiring oral corticosteroids. A randomized controlled trial of patients with uncontrolled asthma found a benefit of escalating doses of salmeterol/fluticasone compared with fluticasone on asthma control. SUMMARY: Initial inhaled corticosteroid therapy should begin with a constant, moderate dose. Initial therapy with long-acting beta2 agonist and inhaled corticosteroids achieves superior improvement in symptoms and lung function, and at a quicker rate than inhaled corticosteroids alone. There is no benefit in terms of reduced exacerbations unless an escalating inhaled corticosteroid dose strategy is used.     

Clinical implications of combination therapy on the future of asthma management.

Current guidelines for the treatment of moderate persistent asthma list the combination of long-acting beta-agonists and inhaled corticosteroids (ICSs) as the treatment of choice. This decision is based on their efficacy compared with other dual controller combinations such as increased doses of ICSs or adding leukotriene modifiers, especially when the forced expiratory volume in 1 second value is used as the primary comparator. The main purpose of this study is to examine this form of dual controller therapy in terms of anti-inflammatory effects. One of the concerns with the combination of long-acting beta-agonists and ICSs is what happens to patients on this therapy during an asthma exacerbation. The existing data indicate that when combination therapy was compared with high-dose ICSs alone, it did not alter the ability to detect deteriorating asthma, it led to faster recovery after an exacerbation, it did not disguise deteriorating asthma, and it did not increase/mask airway inflammation. This study also examines how to approach patients placed on this dual controller therapy after control of their asthma is attained. Suggestions for the transition from initial therapy to maintenance therapy that may involve single controller medications are made. Innovative methods of handling asthma exacerbations with dual controller therapy also are made.     

Safety and effectiveness of long-acting inhaled beta-agonist bronchodilators when taken with inhaled corticosteroids

Long-acting beta-agonists are a pillar of therapy for many patients with asthma because they are the preferred add-on therapy to inhaled corticosteroids. However, a recent meta-analysis documented a substantial increase in severe exacerbations requiring hospital admission and life-threatening asthma exacerbations in patients treated with long-acting beta-agonists. A careful evaluation of this meta-analysis raises several concerns about its applicability to current practice. Pivotal trials evaluating the benefit of adding long-acting beta-agonists to inhaled corticosteroids were not included. The authors of the current paper call for physicians to continue their usual practice of using long-acting beta-agonists as adjunctive therapy, as well as for an independent meta-analysis of individual patients using inhaled corticosteroids and long-acting beta-agonists concomitantly.     

Treatment strategies for asthma

Asthma is characterized by variable and reversible airflow limitation and bronchial hyperresponsiveness due to chronic airway inflammation. Asthma treatment is based on the patients' asthma control status. Central to treatment recommendations is anti-inflammatory therapy with inhaled corticosteroids plus a rapid-acting β(2)-agonist as required. If this is not sufficient to achieve at least partial asthma control, the dose of the inhaled corticosteroid should be increased and a long-acting β(2)-agonist should be added. Other controllers, such as leukotriene antagonists or slow-release theophylline are alternative or additive options. Systemic treatment with corticosteroids and/or the monoclonal anti-IgE antibody omalizumab are reserved for patients with severe asthma. Strategies aimed at preventing airway irritation, reducing exposure to exogenous allergens and inhaled irritants as well as asthma education are other key elements of asthma management.     

Therapiestrategien bei Asthma

Asthma is characterized by variable and reversible airflow limitation and bronchial hyperresponsiveness due to chronic airway inflammation. Asthma treatment is based on the patients’ asthma control status. Central to treatment recommendations is anti-inflammatory therapy with inhaled corticosteroids plus a rapid-acting β₂-agonist as required. If this is not sufficient to achieve at least partial asthma control, the dose of the inhaled corticosteroid should be increased and a long-acting β₂-agonist should be added. Other controllers, such as leukotriene antagonists or slow-release theophylline are alternative or additive options. Systemic treatment with corticosteroids and/or the monoclonal anti-IgE antibody omalizumab are reserved for patients with severe asthma. Strategies aimed at preventing airway irritation, reducing exposure to exogenous allergens and inhaled irritants as well as asthma education are other key elements of asthma management.     

Effects of terbutaline and budesonide on sputum cells and bronchial hyperresponsiveness in asthma

Previous studies have shown that the regular administration of short acting beta-agonists can be associated with adverse effects on airway caliber and bronchial hyperresponsiveness (BHR) and that this may occur through a proinflammatory mechanism. The aim was to explore possible adverse effects of high-dose beta-agonist therapy and to assess any adverse interaction with corticosteroids. We undertook a randomized, crossover study to investigate the effects of 6 wk of treatment with regular terbutaline (1 mg four times a day), regular budesonide (400 microg twice a day), combined treatment, and placebo in subjects with mild to moderate asthma. Major endpoints were PD(15) saline, PD(20) methacholine, and induced sputum differential cell counts. Thirty-four subjects were randomized and 28 completed the study. PD(15) saline decreased on terbutaline alone compared with placebo treatment and on combined treatment compared with budesonide alone (mean fold decrease of 0.57 [95% CI = 0.36, 0.90] and 0.65 [95% CI = 0.43, 0.97], respectively). PD(20) methacholine was not affected by the use of terbutaline either alone or in combination with budesonide. The percentage of eosinophils in induced sputum increased during terbutaline treatment alone compared with placebo (median 8.3% versus 4.4%, p = 0.049). The addition of terbutaline to budesonide did not affect the percentage of eosinophils compared with budesonide treatment alone. These findings support the hypothesis that short-acting beta-agonists have a permissive effect on airway inflammation and that when used in high dose there may be an unfavorable interaction with inhaled corticosteroids.     

Combination Therapy: Appropriate for Everyone?

The severity of asthma often varies throughout the course of the disease. At times the symptoms and underlying inflammation that are characteristic of asthma can worsen. Thus during an episode of viral-induced asthma or during a seasonal increase in asthma severity, a patient may be directed to increase his or her dosage of asthma controllers (i.e., inhaled corticosteroid) or add a long-acting bronchodilator (or other controller medications such as antileukotrienes) to manage symptoms, as recommended in guidelines published by the National Institutes of Health (NIH). Similarly, when symptoms are stable, decreasing dosages or discontinuing certain medications may be appropriate. The recent introduction of a combination product, of a long-acting bronchodilator formulated in the same dry powder device with an inhaled corticosteroid raises new challenges for the step care approach to asthma management recommended by the NIH in 1997. Although unquestionably more convenient for the patient, a combination formulation has the potential to decrease the flexibility required to successfully manage asthma over long periods. In addition, controversy exists regarding long-acting beta-agonists alone because their regular use may mask inflammation in the lung and decrease responsiveness to the bronchodilating effects of rescue medications (i.e., short-acting beta-agonists). The purpose of this article is to help physicians make informed therapeutic decisions for their patients with asthma. It focuses on the advantages and potential disadvantages of using combination products, which contain both an inhaled corticosteroid and a long-acting beta-agonist in the context of the NIH step care approach. Recent publications outlining the use of other add-on controller medications are also discussed.     

Combination Therapy: Appropriate for Everyone?

The severity of asthma often varies throughout the course of the disease. At times the symptoms and underlying inflammation that are characteristic of asthma can worsen. Thus during an episode of viral-induced asthma or during a seasonal increase in asthma severity, a patient may be directed to increase his or her dosage of asthma controllers (i.e., inhaled corticosteroid) or add a long-acting bronchodilator (or other controller medications such as antileukotrienes) to manage symptoms, as recommended in guidelines published by the National Institutes of Health (NIH). Similarly, when symptoms are stable, decreasing dosages or discontinuing certain medications may be appropriate. The recent introduction of a combination product, of a long-acting bronchodilator formulated in the same dry powder device with an inhaled corticosteroid raises new challenges for the step care approach to asthma management recommended by the NIH in 1997. Although unquestionably more convenient for the patient, a combination formulation has the potential to decrease the flexibility required to successfully manage asthma over long periods. In addition, controversy exists regarding long-acting beta-agonists alone because their regular use may mask inflammation in the lung and decrease responsiveness to the bronchodilating effects of rescue medications (i.e., short-acting beta-agonists). The purpose of this article is to help physicians make informed therapeutic decisions for their patients with asthma. It focuses on the advantages and potential disadvantages of using combination products, which contain both an inhaled corticosteroid and a long-acting beta-agonist in the context of the NIH step care approach. Recent publications outlining the use of other add-on controller medications are also discussed.     

The use of inhaled corticosteroids in asthma.

Inhaled corticosteroids are the most important therapeutic agents for the pharmacological control of pulmonary inflammation in asthma. There is concern, however, about the occurrence of side effects with the long-term use of inhaled corticosteroids. Because of the potential seriousness of some of these side effects, patients should be monitored carefully and preventively treated for the side effects. Various noncorticosteroid medications have been recommended in guidelines as substitutes for inhaled corticosteroids for daily use as long-term controllers in asthma, e.g., sustained-release theophylline, long-acting beta-agonists, leukotriene modifiers, cromolyn, and nedocromil. However, of the long-term controller medications recommended in the guidelines, only inhaled corticosteroids have to date, been shown clinically to reduce asthma fatalities and to prevent asthma induced lung remodeling.     

Long-acting beta2-agonists: comparative pharmacology and clinical outcomes

Salmeterol and formoterol are both long-acting beta(2)-adrenoceptor agonists (beta(2)-agonists). They both provide excellent bronchodilating and bronchoprotective effects in patients with asthma but their are some differences between these two long-acting beta(2)-agonists in vitro and in vivo. Formoterol has a greater potency and intrinsic activity than salmeterol, which can become especially apparent at higher doses than that clinically recommended, and in contracted bronchi. Long-term use of long-acting beta(2)-agonists can induce tolerance, which can be partially reversed with corticosteroids. Long-acting beta(2)-agonists have some anti-inflammatory effects in vitro, but data in vivo are less convincing. Compared with doubling the dose of inhaled corticosteroids, the addition of inhaled long-acting beta(2)-agonists to inhaled corticosteroids improves symptom control in patients with asthma and reduces both the exacerbation rate of asthma and hospital admission rate. No enhanced airway responsiveness or loss of perception of dyspnea has been observed with the use of inhaled long-acting beta(2)-agonists. Monotherapy with long-acting beta(2)-agonists is not recommended.     

Formoterol, montelukast, and budesonide in asthmatic children: effect on lung function and exhaled nitric oxide

BACKGROUND: It has been proposed that asthma control may be achieved in part by minimizing airway inflammation. The simultaneous effects of inhaled steroids associated with long-acting beta-agonists and leukotriene antagonists on pulmonary function and airway inflammation are still largely unexplored in children with moderate persistent asthma. OBJECTIVES: The aim of this study was to investigate the effects of add-on therapy with long-acting beta-agonists and leukotriene antagonists on FEV1 and exhaled nitric oxide levels (FENO) in children. METHODS: Forty-eight steroid-na?ve atopic asthmatic children, 7-11 years of age, were randomly treated in four groups for two consecutive one-month periods, as follows: (1) first month: budesonide 200 microg twice daily; second month: budesonide 400 microg twice daily; (2) first month: budesonide 200 microg twice daily+formoterol 9 microg twice daily; second month: budesonide 200 microg twice daily+montelukast 5mg once daily; (3) first month: budesonide 200 microg twice daily+montelukast 5mg once daily; second month budesonide 200 microg+formoterol 9 microg twice daily; (4) first and second month: budesonide 400 microg twice daily. RESULTS: All treatments resulted in a significant increase in lung function and a decrease in FENO compared with values at baseline. Budesonide+montelukast in combination was the most effective treatment for reducing FENO levels. CONCLUSION: This study demonstrates that add-on therapy with montelukast plus low-dose budesonide is more effective than the addition of long-acting beta-agonists or doubling the dose of budesonide for controlling FENO in asthmatic children.     

Effets synergiques et additifs entre les différentes classes d'anti-inflammatoires de l'asthme

Persistent asthma is a chronic airway inflammatory disease that requires treatment with anti-inflammatory drugs. Inhaled corticosteroids are the cornerstone of the treatment of airway inflammation. Clinical studies have shown that asthmatic patients treated with long-acting β₂-agonists and inhaled corticosteroids have more reduced exacerbations than those given higher doses of corticosteroids suggesting synergistic effects on the inflammatory process. The understanding of the molecular modes of action of these two classes of drugs explained part of the enhanced anti-inflammatory activity of the combination therapy. However, the production of cysteinyl-leukotrienes is not well controlled by corticosteroids. Antileukotrienes, by the blockade of the effects of cysteinyl-leukotrienes, exert therefore a complementary antiinflammatory action. In addition, the efficacy of antileukotrienes for the symptomatic treatment of allergic seasonal rhinitis can improve both the quality of life and asthma control in mild to moderate persistent asthmatic patients, with seasonal allergic rhinitis, who are already treated with an antileukotriene as maintenance treatment for their asthma.     

Do chronic inhaled steroids alone or in combination with a bronchodilator prolong life in chronic obstructive pulmonary disease patients?

PURPOSE OF REVIEW: Inhaled corticosteroids with or without long-acting beta2 adrenergic agonists are commonly used to treat patients with chronic obstructive pulmonary disease to attenuate symptoms and to prevent exacerbations. Whether these medications prolong survival is uncertain. RECENT FINDINGS: Inhaled corticosteroids attenuate airway and systemic inflammation, reduce airway hyperreactivity, improve patient symptoms and prevent exacerbations in chronic obstructive pulmonary disease patients. The data on mortality are mixed. A pooled analysis of published randomized controlled trials indicated that inhaled corticosteroids reduced mortality by around 25%; however other studies have failed to show a beneficial effect on mortality. The addition of long-acting beta2 adrenergic agonists to inhaled corticosteroids enhances the clinical effectiveness of these medications and confers incremental mortality benefits to patients. Interestingly, these medications appear to be especially beneficial in reducing cardiovascular morbidity and mortality, though large randomized controlled trials powered specifically on these endpoints are needed to confirm these early findings. SUMMARY: Inhaled corticosteroids, especially with long-acting beta2 adrenergic agonists, reduce airway inflammation and appear to prolong survival in chronic obstructive pulmonary disease patients. They may be particularly effective in reducing cardiovascular morbidity and mortality of patients, pending confirmation by additional clinical studies powered specifically on these endpoints.     

Effect of procaterol, a beta(2) selective adrenergic receptor agonist, on airway inflammation and hyperresponsiveness.

BACKGROUND: beta-agonists are frequently used as bronchodilators for asthma as not only a reliever but also a controller, and their utility has increased with the development of long-acting beta(2) selective drugs. Although anti-inflammatory effects of beta(2) selective-agonists have been reported in vitro, side effects on augmentation of airway hyperresponsiveness by chronic use of beta(2) selective-agonists have been described in several reports. In this study, we investigated the effects of procaterol, a second-generation beta(2)-agonist, on airway inflammation in vivo using an antigen-specific murine model of asthma. METHODS: Mice immunized with ovalbumin (OVA) + alum and challenged with inhaled ovalbumin were orally administered procaterol during the challenge. After inhalation, the mice were tracheostomized and placed in a body box under controlled ventilation to measure airway resistance before and after acetylcholine inhalation. RESULTS: Administration of procaterol at a clinical dose equivalent did not augment airway hyperresponsiveness, inflammation of the airway wall, or subsequent airway wall thickening induced by OVA inhalation. BALF cell analysis revealed that the eosinophil number in the BALF was significantly reduced in procaterol-treated mice compared to untreated mice. CONCLUSIONS: Oral administration of procaterol at a clinical dose did not augment airway responsiveness, but did reduce eosinophil inflammation.     

Fracture risk in patients with chronic lung diseases treated with bronchodilator drugs and inhaled and oral corticosteroids

BACKGROUND: Chronic lung diseases and drugs used to treat patients with chronic lung diseases may be associated with an increased fracture risk. METHODS: The design was a case-control study of all patients with a fracture (n=124,655) in the year 2000 in Denmark as case subjects. For each case subject, three age- and gender-matched control subjects were randomly drawn from the general population (n=373,962). RESULTS: Chronic lung diseases such as COPD (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.13 to 1.25), emphysema (OR, 1.31; 95% CI, 1.16 to 1.48), and other chronic lung diseases (OR, 1.20; 95% CI, 1.00 to 1.44) were associated with a higher relative risk of any fracture than asthma (OR, 1.06; 95% CI, 1.01 to 1.12). Oral corticosteroids were associated with a dose-dependent increased risk of fractures. Inhaled short-acting beta-agonists were associated with an increase in fracture risk that was not dose dependent and was seen already at low doses. Oral beta-agonists were associated with an increase in fracture risk at low doses but not at higher doses. Other bronchodilators (inhaled long-acting beta-agonists, inhaled beta-agonists plus inhaled corticosteroids, inhaled beta-agonists plus antimuscarinic substances, inhaled antimuscarinic substances, inhaled cromoglycate and cromoglycate-like substances, oral theophylline, and oral leukotriene receptor antagonists), and inhaled corticosteroids were not associated with fracture risk. CONCLUSIONS: The increase in fracture risk seen with inhaled short-acting beta-agonists may be linked to the severity of the underlying lung disease rather than with the beta-agonists, per se, as other types of beta-agonists were not associated with fractures.     

Role of long-acting beta2-adrenergic agonists in asthma management based on updated asthma guidelines

PURPOSE OF REVIEW: This review examines the role of long-acting beta2-adrenergic agonists in the management of asthma, particularly focusing on recommendations in the newly revised Global Initiative for Asthma (GINA) and National Heart, Lung, and Blood Institute (NHLBI) asthma guidelines. RECENT FINDINGS: GINA guidelines recommend increasing inhaled corticosteroid doses in all children with asthma not controlled on low-dose inhaled corticosteroids before adding a long-acting beta2-adrenergic agonist, whereas NHLBI guidelines have different age-based recommendations for children. In patients younger than 5 years, NHLBI guidelines recommend increasing the inhaled corticosteroid dose before adding a long-acting beta2-adrenergic agonist; in children aged 5-11 years, equal weight is given to increasing the inhaled corticosteroid dose or including add-on therapy to low-dose inhaled corticosteroids. In adults and adolescents aged 12 years and older, GINA recommends adding long-acting beta2-adrenergic agonists to low-dose inhaled corticosteroids over increasing the inhaled corticosteroid dose. NHLBI guidelines give equal weight to these choices, with alternative, although not preferred, therapies including the addition of theophylline, zileuton, or leukotriene receptor antagonists to low-dose inhaled corticosteroids. SUMMARY: In the recently updated GINA and NHLBI asthma guidelines, long-acting beta2-adrenergic agonists are an important class of agents for the management of persistent asthma in patients whose asthma is not well controlled with inhaled corticosteroid monotherapy.     

Adverse effects of beta-agonists: are they clinically relevant?

Inhaled beta(2)-adrenoceptor agonists (beta(2)-agonists) are the most commonly used asthma medications in many Western countries. Minor adverse effects such as palpitations, tremor, headache and metabolic effects are predictable and dose related. Time series studies suggested an association between the relatively nonselective beta-agonist fenoterol and asthma deaths. Three case-control studies confirmed that among patients prescribed fenoterol, the risk of death was significantly elevated even after controlling for the severity of asthma. The Saskatchewan study not only found an increased risk of death among patients dispensed fenoterol, but also suggested this might be a class effect of beta(2)-agonists. However, in subsequent studies, the long-acting beta(2)-agonist salmeterol was not associated with increased asthma mortality. In a case-control study blood albuterol (salbutamol) concentrations were found to be 2.5 times higher among patients who died of asthma compared with controls. It is speculated that such toxic concentrations could cause tachyarrhythmias under conditions of hypoxia and hypokalemia. The risk of asthma exacerbations and near-fatal attacks may also be increased among patients dispensed fenoterol, but this association may be largely due to confounding by severity. Although salmeterol does not appear to increase the risk of near-fatal attacks, there is a consistent association with the use of nebulized beta(2)-agonists. Nebulized and oral beta(2)-agonists are also associated with an increased risk of cardiovascular death, ischemic heart disease and cardiac failure. Caution should be exercised when first prescribing a beta-agonist for patients with cardiovascular disease. A potential mechanism for adverse effects with regular use of beta(2)-agonists is tachyphylaxis. Tachyphylaxis to the bronchodilator effects of long-acting beta(2)-agonists can occur, but has been consistently demonstrated only for formoterol (eformoterol) a full agonist, rather than salmeterol, a partial agonist. Tachyphylaxis to protection against induced bronchospasm occurs with both full and partial beta(2)-agonists, and probably within a matter of days at most. Underlying airway responsiveness to directly acting bronchoconstricting agents is not increased when the bronchodilator effect of the regular beta(2)-agonist has been allowed to wear off, although there may be an increase in responsiveness to indirectly acting agents. While there has been speculation that underlying airway inflammation in asthma may be made worse by regular use of short-acting beta(2)-agonists, in contradistinction, a number of studies have shown that long-acting beta(2)-agonists have positive anti-inflammatory effects. An Australian Cochrane Airways Group systematic review of the randomized, controlled trials of short-acting beta-agonists found only minimal and clinically unimportant differences between regular use and use as needed. Regular short-acting treatment was better than placebo. However, a subsequent systematic review has found that regular use of long-acting beta-agonists had significant advantages over regular use of short-acting beta-agonists. More studies and data are needed on the regular use of beta(2)-agonists in patients not taking inhaled corticosteroids, and in potentially vulnerable groups, such as the elderly and those with particular genotypes for the beta-receptor, who might be more prone to adverse effects.     

Treating asthma: is there a place for leukotriene receptor antagonists?

Asthma is a chronic disorder, characterized by airway hyperresponsiveness (AHR), airway inflammation and airway remodelling. Evidence has been provided for a relationship between pathophysiology, airway inflammation and remodelling. Moreover, these asthma features have been shown to respond to anti-inflammatory therapy. According to current guidelines, monitoring of asthma is predominantly based on symptoms and lung function data. However, these parameters appeared as poor indices for asthma control. Alternatively, asthma control relates well to exacerbations and (anamnestic) surrogate biomarkers of airway inflammation. Hence, appropriate treatment of asthma should primarily target the airway inflammation. According to current guidelines for asthma management, anti-inflammatory therapy with inhaled corticosteroids (ICS) is the cornerstone in the treatment of persistent asthma. To further optimize asthma control, add-on therapy with long-acting beta2-agonists (LABA) or leukotriene receptor antagonists (LTRA) should be combined with low to high doses of ICS. While the first combination focuses on optimal control of symptoms and lung function, the second provides a more complete suppression of the airway inflammation. In this paper we discuss treatment of asthma according to current guidelines versus new insights, addressing practical issues.     

Asthma exacerbations: pharmacological prevention

Asthma exacerbations are responsible for many emergency medical interventions and account for a significant proportion of the health costs of the disease. Increased airway inflammation is a key feature of exacerbations in asthma and therefore inhaled corticosteroids (ICS) are considered as first-line therapy for long-term asthma control. ICS have been demonstrated to reduce the risk of asthma exacerbations, as well as improving lung function. Oral leukotriene receptor antagonists also reduce the incidence of asthma exacerbations but are less effective than ICS. In patients with inadequately controlled persistent asthma despite low-dose ICS, the addition of a long-acting inhaled beta-agonist (LABA) should be considered. LABA should not be given alone and should always be associated with ICS in asthma. The anti-immunoglobulin E antibody, omalizumab, reduces severe exacerbations and emergency visits in patients with severe allergic asthma. In clinical trials measurement of the inflammatory response in induced sputum could provide information concerning appropriate drug therapy. Asthma-associated comorbidities should be investigated and treated, particularly in severe asthma. Despite a high prevalence of both gastro-oesophageal reflux and allergic rhinitis among patients with asthma, treatment with proton-pump inhibitors or nasal corticosteroids does not reduce the rate of asthma exacerbations.