Guidelines for Using Anti-Inflammatory Agents in the Management of Asthma

Health care professionals must utilize every opportunity to reinforce the importance of continuing therapy for optimally controlling asthma.

Asthma is a significant health problem in the United States, affecting 5% to 10% of the population. The numbers of asthma patients and deaths have continued to rise over the past 20 years, in spite of increased medical knowledge and treatment options.¹

According to National Institutes of Health (NIH) estimates,2 asthma affected 14.9 million people in the United States in 1995, including nearly 5 million under the age of 18. Asthma accounted for approximately 1.5 million emergency department visits, 500,000 hospitalizations, and over 5,500 deaths in that year. The self-reported prevalence rate for asthma increased 75% from 1980 to 1994. Although the increase was evident across all races and age groups and both sexes, the largest increase (160%) was seen in children 0 to 4 years of age during this period.^1,2

The costs associated with these increases are staggering. In 1990, costs related to asthma were estimated at $6.2 billion. Asthma-related costs for 2000 are expected to exceed $14.5 billion. There are significant quality-of-life costs, as well. Asthma is the leading reason for school absences, with approximately 10 million days missed by US schoolchildren. In most cases, a parent must miss work to care for these children. In addition, asthma accounts for an estimated 3 million lost workdays for adults with asthma. Altogether, asthma is responsible for over 100 million days of restricted activity each year.³

DEVELOPMENT OF GUIDELINES
The reasons for these increases in asthma incidence are not completely clear. It appeared to leading experts in the field of asthma, however, that many of these hospitalizations and deaths were preventable.

Possible factors in the increases were identified by the National Heart, Lung, and Blood Institute (NHLBI).⁴ It noted that patients might have failed to avoid environmental triggers, recognize early warning signs of worsening asthma, appreciate the severity of an exacerbation, take appropriate medication, or get prompt medical help. Clinicians, in turn, might have failed to diagnose asthma, initiate appropriate therapy, monitor their patients’ condition adequately, recognize serious exacerbations, or educate their patients to prevent symptoms and develop a management plan.

In 1988, the NHLBI sponsored a workshop involving representatives of over 30 lay and professional organizations concerned with asthma; this group reached the consensus that a national center for asthma education for both patients and health professionals was needed. In 1989, the National Asthma Education and Prevention Program (NAEPP) was formed under the auspices of the NHLBI and NIH. The NAEPP defined a number of objectives for the organization; these included
• increasing knowledge and skills regarding signs, symptoms, and management strategies for asthma;
• encouraging objective measurement of lung function and ongoing monitoring of asthma patients;
• promoting active patient participation with physicians in asthma management;
• promoting research into the underlying causes, appropriate treatment, and management of asthma; and
• developing guidelines, resources, and materials for health professionals and patients in order to disseminate current and accurate information on diagnosis, pathogenesis, and the most effective treatment strategies for asthma.

The NAEPP convened its first expert panel in 1989. Its mission was to review the literature and scientific information then available on asthma and to develop guidelines for diagnosing and managing asthma based on current science. The result was a set of guidelines⁴ published in 1991 by the NIH. The expert panel’s recommendations identified four key components for effective asthma management. These were the use of objective measures of lung function to assess the severity of asthma and to monitor the course of therapy; the application of environmental control measures to avoid or eliminate factors that precipitate asthma symptoms or exacerbations; the employment of comprehensive pharmacologic therapy for long-term management designed to reverse and prevent the airway inflammation characteristic of asthma, as well as to manage asthma exacerbations; and patient education that fosters a partnership among patients, their families, and clinicians.

In 1995, another expert panel was convened by the NAEPP and charged with updating the guidelines. The NIH published the second expert panel report (EPR-2) in 1997.⁴ The new report was based on a review of 6,000 scientific articles by the expert panel. It built on advances in the understanding of the mechanisms of the disease and on new modes of treatment.

This expanded document clearly set forth the goals of asthma therapy:
• to prevent chronic and troublesome symptoms;
• to maintain normal or nearly normal pulmonary function;
• to maintain normal activity levels (including exercise and other physical activity);
• to prevent recurrent exacerbations of asthma and minimize the need for emergency department visits or hospitalizations;
• to provide optimal pharmacotherapy with minimal (or no) adverse effects; and
• to meet the expectations of patients and families and secure their satisfaction with asthma care.⁴

DEFINING ASTHMA
A key feature of the second expert panel report was the classification of asthma severity. This classification system defines four levels (or steps) of intermittent and persistent asthma based on daytime and nighttime symptoms such as cough, wheezing, chest tightness, shortness of breath, and activity limitation, as well as on objective measures of lung function. Expanding on themes first voiced in an international consensus report⁵ and the Global Initiatives on Asthma (GINA), guidelines were given for treating each level of the disease. A mechanism was also described that could be used to step up therapy during exacerbations and step down treatment as symptoms abated.⁶

The guidelines emphatically make the point that a patient’s severity level can change over time. Even a patient with mild, intermittent asthma “can experience severe and life-threatening exacerbations separated by long periods of normal lung function and no symptoms”⁴ (Figure 1).

INFLAMMATION IN ASTHMA
Central to the treatment guideline recommendations is the clear-cut identification of asthma as a chronic inflammatory disease of the airways, regardless of its severity level.⁴ Treatment should be aimed at trying to control the underlying process, in addition to relieving symptoms. This requires a change from earlier treatment paradigms that addressed relief of bronchospasm on an intermittent, as-needed basis.⁶

The EPR-2 guidelines put forth a working definition of asthma based on current knowledge. They state, “Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness and coughing, particularly at night or in the early morning.” The guidelines add, “These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli. Moreover, recent evidence indicates that sub-basement membrane fibrosis may occur in some patients with asthma and that these changes contribute to persistent abnormalities in lung function.”⁴

ASTHMA PHARMACOTHERAPY
This identification of asthma as a chronic inflammatory disorder has profound implications for physicians in formulating their treatment plans. Brian Tiep, MD, is medical director, Pulmonary Care Continuum, Upland, Calif. He says, “It is imperative to look at the pathophysiology of asthma. When a patient is identified as having asthma, it makes sense to start him or her on inhaled corticosteroids because of how the disease progresses. The physician needs to take this progression into account when formulating the treatment plan and look at where the patient might be in 10 to 15 years, rather than just addressing immediate symptoms.”

The risks associated with the undertreatment of asthma using anti-inflammatory medication were the subject of several presentations at a March 2000 meeting of the American Academy of Allergy, Asthma, and Immunology (AAAAI) in San Diego. Presentations emphasized the general belief that undertreatment using inhaled corticosteroids can lead to irreversible changes and loss of pulmonary function over time in some patients. Since many studies have demonstrated the efficacy of inhaled corticosteroids in controlling asthma symptoms and reducing the inflammatory response, the early, consistent use of these medications may help to prevent progression of the disease and the risk of irreversible changes.⁷

In order to address the importance of ongoing therapy with anti-inflammatory medications clearly, the guidelines divided available agents into two classifications: long-term control and quick relief.

Long-term-control medications are to be taken daily on an ongoing basis to achieve and maintain control of persistent asthma. Corticosteroids are considered to be the most potent and effective anti-inflammatory agents currently available.⁸

Inhaled corticosteroids should be the medications of choice for treating persistent asthma on a daily basis. Beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, triamcinolone acetonide, and mometasone furoate (for which approval by the US Food and Drug Administration is pending, but expected in 2000) are examples of today’s inhaled corticosteroids.

Oral or systemic corticosteroids are reserved for gaining control of severe asthma exacerbations, and attempts are made to wean patients from these medications as soon as tolerated. Prednisone, methyl prednisolone, and prednisolone are currently in use in the United States. Cromolyn sodium and nedocromil are mildly-to-moderately anti-inflammatory medications used most frequently for initial therapy in children. They are also used preventatively before exercise.

Examples of long-acting bronchodilators are salmeterol, sustained-release albuterol tablets, and theophylline. These medications may be used as adjuncts to anti-inflammatory therapy and can be useful in controlling nocturnal asthma symptoms. Newer guidelines caution against using these medications in place of anti-inflammatory therapy.⁹

Leukotrienes are biochemical mediators that contract airway smooth muscle, increase mucus secretion, and attract and activate inflammatory cells in the airways, along with increasing vascular permeability. Leukotriene modifiers interfere with these actions by acting either as leukotriene receptor agonists (zafirlukast) or as 5-lipoxygenase inhibitors (zileuton). The second guidelines report classifies them as useful in mild, persistent asthma or as adjuncts to therapy.⁴

Quick-relief medications are used to provide immediate reversal of acute airflow obstruction and the accompanying bronchospasm of asthma. All asthma patients should receive a prescription for a short-acting inhaled b2-agonist for use during exacerbations.⁸ Short-acting b2-agonists are the therapy of choice for relief of acute symptoms and prevention of exercise-induced bronchospasm. Examples include albuterol, bitolterol, levalbuterol, pirbuterol, and terbutaline. These medications are available in the form of metered-dose inhalers, dry-powder inhalers, nebulizer solutions, and oral tablets.

Ipratropium bromide may lend some added benefit to the use of short-acting b2-agonists in some patients, especially patients with concomitant chronic obstructive pulmonary disease. It may also be used as an alternative for patients who do not tolerate other drugs. Oral corticosteroids may be used in short bursts to establish control in severe asthma exacerbations or when initiating therapy, but are best used as a short-term solution because of systemic adverse effects.

It is important to note that increasing use of quick-relief medications generally indicates inadequate asthma control and that increased use of medications intended for long-term control may be required. ⁹

Using the stepwise approach to asthma management, the therapy is tailored to the condition of the patient upon initial examination. Treatment decisions factor in the results of physical examination, pulmonary function testing, symptom history, and health care utilization history, along with quality-of-life issues. Current guidelines are summarized in Figure 2.

One must be aware of the correct therapeutic dosages of the various medications that are available. The inhaled corticosteroids vary greatly in potency and topical efficacy. The clinician should consult available guidelines directly to be sure that the correct dose is being prescribed (Figure 3).

INHALED CORTICOSTEROIDS
Inhaled corticosteroids are widely acknowledged to be the most nearly ideal asthma drugs available today. According to Gary S. Rachelefsky, MD, past president of the AAAAI, the ideal corticosteroid is “one that is efficiently delivered to the airways, one that is highly potent with good retention within the lung, one that has rapid systemic elimination so that you reduce systemic side effects, and one that has low retention elsewhere—in other words it does its work in the lungs and goes away very quickly.”¹⁰ Some of the important factors that influence efficacy and systemic exposure are potency, lipophilicity (which affects the ability of a drug to cross cell membranes and enter the nucleus), dissolution rate, receptor-binding affinity, receptor-binding half-life, plasma elimination half-life, particle size within the respirable fraction of an aerosol, and systemic bioavailability. A good tool to use in comparing medications is the therapeutic index. In this case, one should look at the ratio of topical effects to systemic effects. In inhaled corticosteroids, the medications showing the highest therapeutic index are those that demonstrate high lipophilicity, high receptor binding, long receptor binding, and short serum half-life. Beclomethasone, fluticasone, and mometasone have demonstrated the highest therapeutic ratios in studies10-12 to date.

Clinical efficacy, in asthma medications, is assessed by noting improvements in pulmonary function and quality of life; it is promoted by convenient dosing to promote patient compliance, reliable and simple-to-use delivery systems, and safety. In this regard, some of the newer medications that are available (or due to be released soon) appear to be clinically desirable. Budesonide and mometasone are both dry-powder inhalers that are easy for the patient to use; good results are achieved with once-daily or twice-daily dosing, which can lead to increased compliance.^12-14

One of the most important concerns in the use of inhaled corticosteroid drugs is their potential for creating systemic adverse effects. There has been some evidence that inhaled corticosteroid use at moderate-to-high doses over a long period of time may result in cataract formation, wide-angle glaucoma, adrenal suppression, osteo-porosis, and some slowing of the growth rate in children (in certain individuals).

Cumming et al¹⁵ found a dose-response relationship for posterior subcapsular cataracts in a group of subjects (aged 49 to 97 years) who used inhaled corticosteroids for the treatment of asthma. The clinical significance of this finding is not yet clear. Many of these subjects had severe asthma, and whether they had previously used oral corticosteroids (which have been strongly linked to cataracts) was noted. The point is strongly made for continual assessment with step-down therapy and environmental control to reduce risk.

Several studies have investigated decreased growth in children receiving inhaled corticosteroid therapy. One such study, conducted in Scotland by McGowan,¹⁶ indicated that children receiving high doses of inhaled corticosteroids demonstrated lower height and weight than their contemporaries. This correlated with high hospital and clinic care utilization as well.¹⁶

An encouraging study was published by Silverstein et al.¹⁷ It looked at attained adult height in 153 patients who had been treated using inhaled corticosteroids since childhood. This study demonstrated only a very small average decrease of 1.25 cm in the height of asthma patients, compared with the adult height of studied children who were not treated with these medications.

Pedersen¹⁸ conducted a 15-year follow-up study of more than 300 children in Sweden. The majority of these children did show a lag in growth during the first year of steroid treatment. When their actual heights were compared with expected heights 15 years later, however, no effects were seen. The decline in growth rates in the first year was not indicative of final height. The only indicator seemed to be height before beginning steroid treatment. Those children who had the most poorly controlled asthma had the shortest stature prior to beginning inhaled corticosteroid treatment. Therefore, it was concluded that uncontrolled asthma, not inhaled corticosteroid therapy, was responsible for the growth deficits.

According to Rachelefsky, “Many of the studies out there have problems. Some of them mix prepubescent and postpubescent children together, and most of them don’t have pretreatment and posttreatment growth rates. The dosing is different and the delivery devices are different. I don’t think, at this present time, that we really have enough information to make a definitive statement about the adverse effect of inhaled corticosteroids on growth, especially in the doses that we use in the vast majority of our patients.”¹⁰ Pediatric Asthma: Promoting Best Practice, published by the AAAAI¹⁹ in 1999, concluded that poorly controlled asthma may, in itself, delay growth.

The consensus appears to be that the benefit-to-risk ratio still dictates that inhaled corticosteroids be the drug of choice in persistent asthma.^4,8,9,19 Considerable attention is being focused on reducing any systemic risks. The promotion of step-down therapy is one example of this focus. Many studies are being conducted to look at the use of other long-term control drugs, such as salmeterol and the leukotriene modifiers, to see if they can either replace inhaled corticosteroids or reduce the corticosteroid dose through combination therapy with these alternative medicines. Studies by Simons et al²⁰ and Verberne et al²¹ both demonstrated a clinically important additive effect for these agents with the potential to improve control of chronic asthma using lower doses of inhaled corticosteroids. No study, however, has yet shown that these medications can replace the anti-inflammatory effectiveness of the inhaled corticosteroids completely in moderate-to-severe persistent asthma.^20,21

Early studies of leukotriene modifiers indicate promise for their use as well, especially in mild, persistent asthma. They have been shown to be effective only for 40% to 60% of patients, however, and their efficacy is not as great as that of inhaled corticosteroids. Again, they may serve, in combination therapy, to allow the use of reduced doses of steroidal medications.^22-24 Newer investigations of asthma treatment with monoclonal anti-immunoglobulin E treatments also show promise.^24,25

CURRENT STATUS
Even 3 years after publication of the second expert panel report, it is apparent that the recommendations of the guidelines have not yet been universally put into practice. Copies of the guidelines were sent to every physician in the United States. There have been several subsequent publications of streamlined guidelines aimed at primary care practitioners; these have also been widely distributed.^8,9,19 Nonetheless, there are several studies that show that inhaled corticosteroids are not being prescribed as indicated for persistent asthma. Mamlok et al²⁶ compared prescribed maintenance medications for patients treated by either specialists (allergists or pulmonologists) or primary care practitioners. They found that specialists prescribed controller medications 62% of the time and short-acting bronchodilators 38% of the time. The primary care provider group, in contrast, prescribed short-acting agents 68% of the time and controller medications 32% of the time. Another study²⁷ of asthma patients in a large HMO in the Northwest compared the patients of both allergists and generalists in the organization. The investigators found that the patients treated by the allergists were more likely to be using daily medication to control their asthma (specifically, inhaled corticosteroids); were more likely to receive treatment in the clinic, rather than the emergency department; and reported better quality of life, as measured by the Short Form-36 scale.

There is a great deal of evidence that the message of the second expert panel is not reaching patients and their families, either. Some studies^28,29 have shown that less than 50% of prescribed asthma medications are ever used. In one large multicenter trial,³⁰ renewal rates for inhaled corticosteroids have been shown to be as low as one prescription per year.

One member of the NAEPP Coordinating Committee believes that the key to successful use of inhaled corticosteroids in asthma management is patient acceptance. Susan Clark, RN, coordinator of pulmonary rehabilitation, Cedars-Sinai Medical Center, Los Angeles, says, “I work in a geographic area where inhaled corticosteroids are commonly prescribed, but the patients I see do not adequately perceive the importance of maintaining consistent use of these medications.” She continues, “Because these patients do not have an immediate perception of relief from these inhalers, they often discard them. It is critical for the health professional to give clear guidelines for use, including a time line for efficacy, in order to achieve patient commitment. The message should be supplemented by written handouts briefly summarizing the important points and reinforced in all subsequent patient contacts.” Tiep says, “As health professionals, we all acknowledge the importance of continuing education so that we may keep learning, and have our knowledge reinforced, yet we are expecting our patients to be smarter than we are: that we can show them what they need to know one time, and that they will understand and adhere to their treatment plan.”

The message is clear. All health professionals involved in the care of asthma patients should use every opportunity to reinforce the importance of continuing therapy for optimal control of their asthma. Using handouts, clinic visits, respiratory treatments, and time in the emergency department to enhance patients’ understanding of their treatment plans is critical. Asthma education programs and follow-up sessions provided through clinic visits, telephone contact, and electronic monitoring are all opportunities to improve the quality of life and disease management for asthma patients.

Peggy Walker, RRT, RCP, is a clinician at Asthma & Allergy Support Center, Redondo Beach, Calif.

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