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Controller Therapy for Asthma

Appropriate Use of Controller Therapy in Mild-to-Moderate Asthma

“Even though it has been demonstrated that lack of adherence to National Institutes of Health guidelines for the management of asthma is associated with increased morbidity and cost, we are currently not doing a very good job of following them,” said Myron Zitt, MD, clinical associate professor of medicine, State University of New York, Stony Brook. 

The first step in treating patients according to established guidelines is to classify the severity of their disease. Mild intermittent asthma can be distinguished from mild persistent asthma by symptoms less than twice weekly, nocturnal symptoms less than twice monthly, and completely normal lung function. Mild persistent asthma is diagnosed if symptoms occur more than two times per week, nocturnal symptoms occur more than two times per month, and there is peak expiratory flow variability of more than 20%. Moderate persistent asthma should be diagnosed in anyone with abnormal lung function, daily symptoms requiring short-acting beta-agonists, and nocturnal symptoms more than once weekly. In reality, studies indicate that most patients who have been classified as having mild persistent asthma, particularly by primary care practitioners, actually have abnormal lung function and should therefore be classified as having moderate asthma. 

Recommended therapy for mild persistent asthma is a low-dose inhaled corticosteroid, although sodium cromolyn, theophylline, or anti-leukotrienes are alternatives. For moderate persistent asthma, a medium-dose inhaled corticosteroid or low to medium dose inhaled corticosteroid plus a long-acting bronchodilator are recommended. Leukotriene antagonists or theophylline are alternatives for add-on therapy.

“There are several weaknesses of the guidelines that may explain why they are not optimally adhered to,” said Dr. Zitt. One weakness is that some patients with mild intermittent asthma have severe, sometimes life-threatening exacerbations. Treating these patients with PRN beta-agonists alone as recommended for patients with mild intermittent asthma is probably insufficient. In addition, the current recommended treatment for mild persistent asthma is controller monotherapy. Nonetheless, in practice, a fixed dose inhaled corticosteroid/long-acting beta-agonist combination is often employed for this asthma category. Whether fixed combination therapy is indicated for mild persistent asthma or, for that matter, where it fits in overall asthma management, is not addressed in current guidelines. 

The most commonly used therapies for mild persistent asthma in the United States are inhaled corticosteroids and leukotriene modifiers. Studies indicate that both therapies are effective in improving lung function and reducing asthma symptoms, incidence of exacerbations, and use of rescue medication. “Improvements in FEV-1 are significantly greater with inhaled corticosteroids than leukotriene modifiers,” said Dr. Zitt. 

In patients who are not controlled with inhaled corticosteroids alone, there are several choices for therapy. Although studies that consider only improvement in lung function as an outcome indicate that there is a flat dose-response curve with inhaled corticosteroids, studies that consider markers of inflammation, such as airway hyperresponsiveness and sputum eosinophilia, indicate that there is a greater response at higher doses. Thus, increasing the steroid dose may be helpful; however a meta-analysis of trials of adding a long-acting beta-agonist to an inhaled corticosteroid indicates that this results in more improvement in symptoms and lung function than doubling the dose of inhaled corticosteroids. Alternatively, adding a leukotriene modifier has been shown to have an additive anti-inflammatory effect; however, this is not as effective as adding a beta-agonist. 

“Several questions regarding the treatment of asthma remain to be answered, and the guidelines need to be updated,” said Dr. Zitt. Treatment directed at symptom scores and lung function alone without addressing inflammation may lead to suboptimal therapy. 
 

Long-Term Safety of Controller Therapy for Persistent Asthma in Adults


Michael Schatz, MD, chief, Department of Allergy, Kaiser Permanente Medical Center, San Diego, CA, discussed issues related to the safety of various controller therapies for asthma. “There have been a lot of published studies about the safety of inhaled steroids, some of which are contradictory and confusing,” said Dr. Schatz.

The dose-response curves for inhaled corticosteroids differ with respect to safety and efficacy. Dose response for therapeutic effects rises early and plateaus early, whereas there is a threshold below which adverse effects do not occur, and above which there is a dose-dependent rise. Most of the literature on adverse events refers to the effect on hypothalamic-pituitary-adrenal (HPA) axis suppression; however, this effect may be the least clinically relevant. Chemical suppression is usually reported at doses of 800 µg/day or greater. Important clinical consequences have rarely been reported. Comparative data indicate that at therapeutically equivalent doses, beclomethasone causes greater systemic effects than fluticasone or budesonide.

“The issue of whether bone density is affected by inhaled corticosteroid use is clinically more important than HPA axis suppression,” said Dr. Schatz. A dose-response relationship has been reported, with a 0.5 SD decrease in bone density for every 1000 µg increase in daily dose of beclomethasone or budesonide. The threshold is not known, but it may be 1000 µg per day. Studies of bone markers suggest that beclomethasone has a greater effect on bone density than fluticasone at therapeutically equivalent doses. Calcium supplements, or hormone replacement therapy in postmenopausal women, may help prevent bone loss.

Ophthalmologic effects of inhaled corticosteroids have become apparent in the last 5 years. The increase in risk of cataracts probably occurs only in patients over the age of 40 years. A threshold of 1000 µg daily for at least 2 years has been suggested. Incidence increases with current daily dose and cumulative dose. The threshold for increased risk of glaucoma is even greater, probably occurring at approximately 1500 µg per day.

Skin changes also occur with inhaled corticosteroids. Both atrophy and bruising increase with daily dose and age, and are more common in women. Bruising occurs at a lower threshold than atrophy. Large studies of women who initiated therapy with budesonide or beclomethasone during pregnancy revealed no increased incidence of congenital malformations.

Side effects of other controller therapies are rare overall. Montelukast and zafirlukast have been demonstrated in long-term studies to have side effects no greater than placebo. Zileuton has been associated with hepatotoxicity in 3% of patients. No human data are available on use of these agents during pregnancy, although animal studies of montelukast and zafirlukast are reassuring. Side effects of salmeterol are headache and palpitations, which may necessitate discontinuation of therapy in a very small proportion of patients.

“In conclusion, inhaled corticosteroids have an excellent therapeutic index at doses less than 1000 µg daily,” said Dr. Schatz. “In patients who require higher doses, it appears that adverse effects can be reduced by surveillance and therapy.”

Considerations in Choosing Controller Therapy in Infants and Young Children

“The treatment of young children with asthma or recurrent wheezing is a challenging area of clinical medicine,” said Michael Mellon, MD, staff pediatric allergist, Southern California Permanente Medical Group, San Diego. While some young children later develop chronic asthma, at least 60% of those who wheeze during viral infections have a transient condition that will subside by the early school years. Unfortunately, it is not currently possible to predict clinically which of these children need long-term controller therapy for chronic asthma. Children with parental asthma, allergic rhinitis, eosinophilia, eczema, or wheezing without infection are more likely to go on to develop chronic asthma.

Young children do not fit easily into the mild, moderate, and severe classification system used in older children and adults. Indications for controller therapy in young children include not only those with persistent asthma according to the guidelines, but also children who have 2 to 4 or more episodes requiring oral steroids per year. Another group for which controller therapy should be considered is those with exercise-induced asthma that is not controlled by pre-exercise beta-agonists. 

“Clearly, the best controller therapy we have is an inhaled corticosteroid,” said Dr. Mellon. In young children, a current area of focus is the benefit of early treatment. Studies have indicated that children who begin inhaled corticosteroid therapy within two years of diagnosis have fewer hospitalizations, less decline in FEV-1, and less requirement for steroids than those who begin inhaled corticosteroids later in the course of the illness. Other studies indicate that the benefit of inhaled steroids is inversely proportional to the length of time the patient had asthma before initiation of therapy. 

Inhaled corticosteroids may also be beneficial in the treatment of episodic viral-induced wheezing. A recent meta-analysis of studies concluded that in children with mild episodic viral-induced wheeze, administration of high-dose (1.6 to 2.25 mg/day) budesonide at the onset of an upper respiratory infection reduces the severity of exacerbations but not of hospital admissions or bronchodilator use. Use of daily low-dose inhaled corticosteroids is not beneficial in these children. “While this approach applies to children with mild symptoms, the best preventive strategy for moderate or severe viral-induced wheezing remains to be determined,” said Dr. Mellon.

“Choosing the type of delivery device that is best suited to a particular child and caregiver is important in young children,” said Dr. Mellon. Jet nebulizers are inefficient. Continuous output nebulizers are used in the United States, whereas breath-actuated nebulizers are available in other countries. Although these are inefficient, nebulizers are necessary in most children under the age of 2 years, who have rapid respiratory rates and low tidal volume. Children should be switched to a mouthpiece with nebulizer and compressor combination when they’re able, and then to a metered dose inhaler with holding chamber and mask. Metered dose inhalers for inhaled corticosteroids are not approved for use under the age of 6 years, but are frequently used off label. Caution must be taken to ensure that the mask fits tightly so that air is not sucked in around the mask. Dry powdered inhalers are an efficient way to deliver the maximum desired amount of drug to the lungs; this form can be used in school-age children. 

The first nebulizable corticosteroid, budesonide inhalation suspension, became available in the United States in August 2000. It is indicated for children age 1 to 8 years, and is the first inhaled corticosteroid approved for ages 1 to 4 years. In clinical trials, children ages 6 months to 8 years with mild-to-moderate asthma were treated with budesonide at doses ranging from 0.25 mg daily to 1 mg BID for 3 months with a 52-week safety extension. Symptom scores, bronchodilator use, and lung function improved significantly compared to placebo. The safety profile was similar to placebo. Improvement in lung function was greater in children treated with 0.5 mg than 0.25 mg per day. Once-daily dosing was also effective in some patients.

Fluticasone propionate has also been studied in young children, although not as extensively as budesonide. A study of young children with mean age 28 months with moderate asthma were treated with fluticasone 50 mg or 100 mg twice daily using a metered dose inhaler and spacer device. Symptom scores improved significantly in both treatment groups compared with placebo. Exacerbation rates improved in a dose-dependent fashion. There was a similar low incidence of adverse effects in all groups over the 12-week study. 

Other controller therapies include cromolyn and leukotriene receptor antagonists. Although cromolyn is recommended for initial controller therapy in infants and young children, clinical trials examining benefit are contradictory. 

The observation of increased levels of cysteinyl leukotrienes in the respiratory tract of children with respiratory syncytial virus-induced bronchiolitis suggests a role for these pro-inflammatory mediators in the development of asthma. A study of montelukast, which is approved for use in children as young as 2 years, indicates improvement in symptom-free days, rescue beta-agonist use, and peripheral eosinophilia. No difference was demonstrated in caregiver global evaluations and asthma attacks over placebo. While symptomatic control of asthma can be achieved with leukotriene receptor antagonists, its role in long-term use in preschool age children remains to be defined by further studies.

“Early intervention appears increasingly to be important, and good safety data underscores our decision to treat infants with frequent wheezing,” said Dr. Mellon. “There are now good choices of controller agents and delivery devices that can be used to treat young children.” 

 

Controversial Issues in Inhaled Corticosteroid Therapy for Asthma

Soren Pedersen, MD, PhD, professor of pediatric respiratory medicine at the University of Southern Denmark and McMaster University, Toronto, Ontario, Canada; and consulting pediatric chest physician and allergist, Department of Pediatrics, Kolding Hospital, Kolding, Denmark, discussed current controversies related to treatment of asthma with inhaled corticosteroids.

Prior to the early 1990s, asthma was treated primarily with beta-agonists, theophylline, or sodium cromolyn. The inclusion of inhaled corticosteroids in treatment regimens has provided information supporting aggressive introduction of these agents in both adults and children; however, it has also increased the complexity of treatment and raised several controversial issues. 

Among these issues are questions about the aims of asthma management and the outcomes used in measuring treatment success. The aims of therapy are to produce the maximum achievable effect on all outcome measures and to prevent adverse effects of both long-term disease and long-term therapy. In recent years, additional outcomes have been recognized in addition to symptoms and peak expiratory flow rate, including reduction in acute exacerbations, normalization of physical activity, improvement in quality of life, control of airway hyper-responsiveness, normalization of chronic airway inflammation, preservation of normal lung growth, and avoidance of adverse effects of therapy. Further research is needed to define the outcome or combination of outcome measures that most accurately ensures achievement of the aims of asthma management. “It is clear that we have to distinguish between which outcomes are important for research, and which are most clinically relevant to follow in day-to-day management,” said Dr. Pedersen.

Clinical and research experience indicate that the aims of freedom from symptoms and maintenance of normal lung function are not fulfilled in many patients, and patients are commonly undertreated. This is due to variations in perception and definitions of symptoms, inability to accurately assess daily physical activity and degree of lifestyle restriction, and patient understanding of the disease. 

Another issue in asthma therapy is whether patients who are maintained on inhaled corticosteroids need special monitoring. Although patients on any form of anti-asthma therapy should be questioned about side effects, as no controlled studies have reported any clinically relevant systemic side effects with inhaled corticosteroids at doses of 100 µg to 200 µg, patients taking these doses do not require additional special monitoring for adverse events. “Whether patients who receive long-term treatment with higher doses of inhaled corticosteroids require special monitoring is more controversial,” said Dr. Pedersen.

Most studies of the effects of inhaled corticosteroids on growth have been conducted in children with mild asthma at doses greater than needed for optimal control. It is unclear whether the findings of transient growth retardation in the first 1 to 2 years of treatment can be extrapolated to patients with more severe disease. To increase clinical relevance, growth studies should be several years long and use doses tailored to disease severity. Recent studies indicate that growth retardation reported during the first year of treatment with inhaled corticosteroids does not adversely affect final adult height. Further studies are needed to determine what degree of growth retardation should suggest consideration of a change in therapy.

“The best way to assess if both the immediate aims and the long-term aims of asthma therapy are achieved may be to give aggressive, effective treatment at an initial period, and to use this period as a reference for assessing further therapy,” said Dr. Pedersen. Assessments of immediate outcome parameters, which may serve as surrogate markers for long-term outcomes, should be performed at regular intervals, and data should be plotted longitudinally to reveal trends over time. Further research may be needed to assess the role of inflammatory markers in patient management. 

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