Pediatric Annals

A Step-Wise Approach to the Changing Drug Therapy of Asthma

Peter König, MD, PhD

Abstract

The last few years have seen a profound change in our concept of asthma. While previously it was considered to be a bronchospastic disease, now it is seen primarily as an inflammatory disease. A close connection has been found between airway hyperreactivity (the basic physiologic defect of asthma) and airway inflammation. Numerous factors that cause inflammation of the bronchial mucosa, such as late allergic reactions,1 viral infections,2 passive smoking,3 and pollutants,4 can cause an increase in bronchial hyperreactivity.

Another important fact is that despite improvements in the understanding and treatment of asthma, both mortality5 and morbidity6 of the disease have increased. Although the cause of this phenomenon is far from clear, one speculation is that overreliance on symptom suppression with bronchodilators and insufficient use of drugs that prevent (cromolyn sodium) or reverse (steroids) inflammation might have contributed to increased mortality.7

These new concepts have not yet produced any novel and exciting drugs, but they have resulted in a lively debate about the best way to use currently available agents. Perhaps the most hotly debated subject is whether inhaled corticosteroids, previously considered second-line drugs, should now be used as first-line drugs because of their anti- inflammatory effect.

Another controversial issue is the proper place of theophylline, considered by some to be the mainstay of asthma management8 while others consider it to be a third-line drug.9

This article addresses some of these controversies in the outpatient management of recurrent and chronic asthma and tries to reconcile the new "inflammatory disease" concept with a practical approach to clinical management.

ASSESSMENT OF SEVERITY AND MONITORING OF RESPONSE TO THERAPY

In order to establish a successful treatment regimen tailored to each individual patient's severity and disease pattern, it is vital to assess correctly the severity by both subjective and objective means. This process is made difficult by a number of factors:

1. Follow-up visits are usually separated by long intervals of time and memory is unreliable in such a rapidly changing disease.10

2. Both the patient's subjective feeling and the physician's physical examination tend to underestimate the severity of the airway obstruction.10,11

3. Pulmonary function tests performed at long intervals of time are not as reliable as twice daily measurements of peak expiratory flow rate (PEFR) for assessing the long-term severity of the disease.12

Therefore, it is important to use symptom diaries, frequent pulmonary function testing, and twice-daily measurements of PEFR at home especially in the initial stages of assessment, and continuously in severe patients. The process of initial assessment starts with a good history and a physical examination. However, a full assessment rarely ends in one visit and usually takes weeks or months. Asthma is a changing disease and regular follow-up is essential for continued good control.

Step 1

* Patients with intermittent mild-to-moderate symptoms, symptomatic for 3 or less days per week.

For these patients, the drug of choice is an inhaled adrenergic agent on an as-needed basis. Infants and young children unable to use a metered dose inhaler (MDI) can be treated with an oral preparation. However, spacer devices allow children as young as 2 to 5 years13 and perhaps even younger14 to use MDIs.

It is often forgotten that theophyuine is a relatively rapid-acting bronchodilator, that it can be used on an as-needed basis, and that it has an additive effect with inhaled adrenergic agents.15

For patients who cannot tolerate theophylline, inhaled ipratropium bromide can be a useful back-up for the adrenergic drugs (eg, albuterol and metaproterenol) and may even have an additive effect when taken concomitantly with theophylline plus an adrenergic agent.16

Some patients have intermittent but severe attacks. For…

The last few years have seen a profound change in our concept of asthma. While previously it was considered to be a bronchospastic disease, now it is seen primarily as an inflammatory disease. A close connection has been found between airway hyperreactivity (the basic physiologic defect of asthma) and airway inflammation. Numerous factors that cause inflammation of the bronchial mucosa, such as late allergic reactions,1 viral infections,2 passive smoking,3 and pollutants,4 can cause an increase in bronchial hyperreactivity.

Another important fact is that despite improvements in the understanding and treatment of asthma, both mortality5 and morbidity6 of the disease have increased. Although the cause of this phenomenon is far from clear, one speculation is that overreliance on symptom suppression with bronchodilators and insufficient use of drugs that prevent (cromolyn sodium) or reverse (steroids) inflammation might have contributed to increased mortality.7

These new concepts have not yet produced any novel and exciting drugs, but they have resulted in a lively debate about the best way to use currently available agents. Perhaps the most hotly debated subject is whether inhaled corticosteroids, previously considered second-line drugs, should now be used as first-line drugs because of their anti- inflammatory effect.

Another controversial issue is the proper place of theophylline, considered by some to be the mainstay of asthma management8 while others consider it to be a third-line drug.9

This article addresses some of these controversies in the outpatient management of recurrent and chronic asthma and tries to reconcile the new "inflammatory disease" concept with a practical approach to clinical management.

ASSESSMENT OF SEVERITY AND MONITORING OF RESPONSE TO THERAPY

In order to establish a successful treatment regimen tailored to each individual patient's severity and disease pattern, it is vital to assess correctly the severity by both subjective and objective means. This process is made difficult by a number of factors:

1. Follow-up visits are usually separated by long intervals of time and memory is unreliable in such a rapidly changing disease.10

2. Both the patient's subjective feeling and the physician's physical examination tend to underestimate the severity of the airway obstruction.10,11

3. Pulmonary function tests performed at long intervals of time are not as reliable as twice daily measurements of peak expiratory flow rate (PEFR) for assessing the long-term severity of the disease.12

Therefore, it is important to use symptom diaries, frequent pulmonary function testing, and twice-daily measurements of PEFR at home especially in the initial stages of assessment, and continuously in severe patients. The process of initial assessment starts with a good history and a physical examination. However, a full assessment rarely ends in one visit and usually takes weeks or months. Asthma is a changing disease and regular follow-up is essential for continued good control.

Step 1

* Patients with intermittent mild-to-moderate symptoms, symptomatic for 3 or less days per week.

For these patients, the drug of choice is an inhaled adrenergic agent on an as-needed basis. Infants and young children unable to use a metered dose inhaler (MDI) can be treated with an oral preparation. However, spacer devices allow children as young as 2 to 5 years13 and perhaps even younger14 to use MDIs.

It is often forgotten that theophyuine is a relatively rapid-acting bronchodilator, that it can be used on an as-needed basis, and that it has an additive effect with inhaled adrenergic agents.15

For patients who cannot tolerate theophylline, inhaled ipratropium bromide can be a useful back-up for the adrenergic drugs (eg, albuterol and metaproterenol) and may even have an additive effect when taken concomitantly with theophylline plus an adrenergic agent.16

Some patients have intermittent but severe attacks. For these, short courses of systemic steroids and nebulized adrenergic agents are helpful. In some, continuous drug prophylaxis with an agent such as cromolyn sodium may be justified.

Early intervention is an important principle, especially in those patients who tend to have severe attacks. In children who have attacks triggered by respiratory infections, giving short courses of prednisone with the first symptoms of an upper respiratory infection without waiting for the occurrence of wheezing has been recommended.17 Even though such treatment has been shown to be effective,17 more than four courses of prednisone per year can cause adrenal suppression.18 Therefore, this treatment cannot be recommended for every patient. In most cases, starting the bronchodilators and increasing the dosage of cromolyn (up to 5 to 6 doses/day) or inhaled corticosteroids (eg, beclomethasone up to 800 to 1000 µg/day) if already on these agents at the first symptoms of upper respiratory infection can prevent severe attacks of asthma from developing. Preventive administration of prednisone should be reserved for those patients not responding to these safer measures.

Step 2

* Patients symptomatic most of the time (more than 3 days per week, on average).

Patients who have symptoms more days of the week than not need continuous drug prophylaxis. THhe debate is mostly over which drugs should be considered first-line for maintenance use. In children, cromolyn sodium is widely considered the drug of choice in many countries.19 Audits of prescribing habits in Europe20 and the United States21 reflect that more pediatricians prefer cromolyn over inhaled corticosteroide as their initial agent. On the other hand, physicians treating adult patients tend to use inhaled corticosteroids more frequently.20-21

This is perhaps due to a long-held misconception that cromolyn is not effective in adult asthmatics. A previous review article analyzed differences in response to this agent between children and adults and came to the conclusion that there is a tendency for better results in children than in adults, but that the difference is not impressive and it usually does not reach statistical significance.22 Some recent studies strongly confirm the efficacy of cromolyn in adult asthmatics. Thus, Petty and associates found cromolyn sodium to be moderately to very effective in 61% of adult patients in a recent placebo-controlled double-blind trial.23

In an international multicenter study including children and adults (mean age: 30 years), cromolyn was considered successful in improving asthma symptoms and reducing concomitant medication in 65% of patients.24 Success rates in children tend to be around 65% to 89%,22 and therefore the difference in relative efficacy is not very large.

Another widely held misconception is that inhaled corticosteroids, the alternative anti-inflammatory agent, are totally devoid of systemic side effects until very large daily doses are reached. Most of the research has concentrated on suppression of the adrenal axis because of the fear of life-threatening adrenal insufficiency.25 When sensitive tests have been used, eg, sampling of plasma Cortisol every 20 to 30 minutes, significant reduction was found in children treated with 400 µg of beclomethasone dipropionate daily and in adults on 800 µg daily.26 In another study, integrate plasma cortisol was significantly lower in children receiving 200 to 600 µg of beclomethasone per day than in controls.27 However, these statistically significant changes are probably not very important clinically, and life- threatening adrenal insufficiency does not seem to be a problem even at higher doses of inhaled corticosteroids.25'28 Nevertheless, lower levels of cortisol late at night and early in the morning,29 at the same time that pulmonary function is at its nadir and asthma attacks and deaths are frequent, may contribute to the worsening of asthma and is of clinical concern. This nocturnal suppression also occurs at relatively low doses.26,29

While much effort has been dedicated to the study of adrenal axis function, few studies have been done on some other possible systemic side effects of aerosol steroids. Osteoporosis was only examined in one study using total body calcium assessments.30 Reid and associates found that inhaled corticosteroids (400 µg of beclomethasone dipropionate or 800 µg of betamethasone isovalerate daily) caused an 8.8% reduction in total body calcium.30 A dose of 1000 µg/day of beclomethasone in normal volunteers causes significantly elevated serum insulin levels, abnormal glucose levels after glucose challenge, and an increase of plasma cholesterol.31 Even though there was also a rise in high-density lipoprotein, which would mitigate the detrimental effect of an increased cholesterol level, it is possible that cardiovascular risk is enhanced. Thus, many of the possible systemic effects of inhaled corticosteroids have not been adequately explored.

In addition, inhaled corticosteroids can cause topical side effects such as oral candidiasis in 4% to 13% of cases and dysphonia in 5% to 50%.25 Less wellknown side effects are strider in children32 and angina bulosa hemorrhagica in adults taking inhaled steroids for more than 3 years.33

If one considers the systemic together with the topical side effects, it is clear that inhaled corticosteroids are not completely free of side effects. Tlieir use, like the use of any other drug, must be considered in the context of their risk/benefit ratio.

In those 60% to 89% of patients in whom cromolyn sodium is effective (children and adults), because of its greater safety and virtually total lack of systemic activity, cromolyn should be the preferred first-line drug. Both cromolyn sodium and beclomethasone have anti- infiamma tory effects and both can reduce nonspecific bronchial hyperreactivity over the long term.34'35 Although it is true that inhaled corticosteroids are more potent in reducing bronchial hyperreactivity,36 the clinical relevance of this difference remains to be established in long-term studies.

BRONCHODILATORS FOR CONTINUOUS USE

Theophylline has been widely used in the United States and in a few other countries. Its efficacy in terms of long-term asthma control is comparable to that of cromolyn.37 However, it has markedly more side effects, especially on the gastrointestinal and central nervous systems,38,39 and a very much poorer risk/benefit ratio. It has no effect on inflammatory processes, does not reduce bronchial hyperreactivity,35 and does not prevent allergen-induced increases in airway responsiveness (which is completely prevented by cromolyn sodium).40

Adrenergic agents have also been used on a continuous basis, especially in Europe. They have been proven to be less effective than cromolyn41 when used as maintenance agents and have a mixed record when compared with theophylline. Some investigators have found adrenergic agents to be as effective as theophylline in controlling symptoms,42'43 while others obtained better results with theophylline.44'45 Continuous use of adrenergic agents also results in tachyphylaxis16,46 and may cause a worsening of nonspecific bronchial hyperreactivity,47 a recent finding of some considerable concern.

The use of bronchodilators in general on a continuous basis also has the disadvantage of severely reducing the options for treating subsequent breakthrough attacks.

Step 3

* Patients not satisfactorily controlla1 by afirst-Une drug such as cromolyn sodium.

This group of patients can be approached in one of two ways. One is the so-called "add-on approach." Adding theophylline to cromolyn has been shown to be beneficial in some48 but not all studies.49 The efficacy of the combination of continuous theophylline plus adrenergic agents has also yielded controversial results.45,50

The clinician needs to remember that the "add-on approach" results in "poly-pharmacy," which is less than ideal because of increased cost, possibly increased side effects, and reduced compliance.

Therefore, in these patients, inhaled corticosteroids are the drug of choice, unless the patient is too young to use an MDI. For these more severe patients, the risk/benefit ratio of inhaled corticosteroids is acceptable and certainly preferable to systemic steroids or uncontrolled asthma.

In most cases, cromolyn sodium or theophylline can be discontinued after switching to inhaled steroids. If the patient is not satisfactorily controlled with small doses of inhaled steroids (such as 400 µ-g/day of beclomethasone), much larger doses up to 2000 µg/day can be given with a good dose response.51 A further improvement can be obtained by adding a spacer device to the MDI, probably due to better drug delivery to the peripheral airways.52 This has the additional advantage of minimizing local unwanted effects.

The combination of continuous theophylline53 or adrenergic agents5* with inhaled corticosteroids results in better control of asthma. Cromolyn sodium does not seem to be useful in patients already on inhaled corticosteroids.55 Perhaps this is because both agents exert an anti- inflammatory effect in the airways.

Using available drugs, it is possible to successfully treat the vast majority of asthmatics. A very small subgroup might need systemic steroids, which can be added to the inhaled route, preferably as an alternate day regimen.

The main problem confronting the clinician today is how to translate the new knowledge about the importance of inflammation in asthma into the day-to-day clinical management of the disease. In fact, in most cases the decision is not very difficult. In the most severe patients (Step 3), inhaled corticosteroids are clinically needed and they are also potent anti- inflammatory agents. In the moderately severe group who need continuous drug prophylaxis (Step 2), cromolyn is better than adrenergic agents41 and equally potent but safer than theophylline, therefore, the clinical criteria would point at cromolyn as the drug of choice. Cromolyn is also active in reducing inflammation and bronchial hyperreactivity, enabling both objectives (clinical and anti'inflammatory) to be met with the same drug.

The only group of patients in whom there is a real conflict of interest between the two objectives is the mild intermittent asthmatic (Step 1). In these patients, clinical judgment tends to favor bronchodilators on an "as-needed basis." On the other hand, Beasley and associates have demonstrated the presence of inflammation even in these mild patients.56 Long-term studies are needed to find out if the clinical outcome can be modified by continuous use of anti'inflammatory drugs (cromolyn or inhaled corticosteroids). Until the results of such trials become available, it seems premature to recommend continuous drug prophylaxis in these patients.

THE FUTURE

The future of asthma therapy looks very exciting. With better understanding of basic mechanisms such as inflammation and bronchial hyperreactivity, treatment can be aimed not only toward suppressing symptoms but, more importantly, toward modifying the basic defect. It will be interesting to see if such an approach can improve the long-term prognosis of asthma, both in terms of morbidity and mortality. Attempts to achieve these goals can be made by using new drugs and by better use of existing ones. One such new drug is nedocromil sodium, an agent that shares some properties with cromolyn sodium but appears to offer a broader spectrum of activity and to be effective over a wider range of asthma severity.57 Another interesting and novel drug is a ginkgolide mixture, a platelet-activating factor (PAF) antagonist, currently in the early stages of development.58

A number of ways need to be explored in which existing drugs can be used more effectively. One such approach is the wider and perhaps earlier use of drugs that affect the inflammatory process and bronchial hyperreactivity. Cromolyn sodium and inhaled corticosteroids are such presently available agents.

Another promising approach is that of "tight control" similar to that successfully followed in other chronic diseases such as diabetes and hypertension. Using a variety of drugs but mostly inhaled corticosteroids and cromolyn sodium, Woolcock and associates59 have achieved prolonged asymptomatic periods with much improved bronchial hyperreactivity by aggressive treatment of not only every asthma symptom but also any fall in the daily PEFR measurements taken at home. In this study, the tight control approach resulted in much better clinical results and significantly lower bronchial hyperreactivity than the traditional approach. More such studies are needed, but it seems a very promising avenue to explore.

Some changes in medical opinions are already being felt. Two recent international consensus meetings, one in London19 and the other in Toronto,60 agreed on a reduced role for theophylline and bronchodilators as maintenance drugs and a greater emphasis on true prophylactic drugs such as cromolyn sodium and inhaled corticosteroids. The experts on childhood asthma at both meetings agreed that eromolyn sodium is the preferred first-line drug for drug prophylaxis.

It seems that in the next few years we can look forward to promising new developments in the management of asthma.

Acknowledgments

The author thanks Mrs Shirley Haden and Mrs Joyce Schlemper for typing the manuscript.

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10.3928/0090-4481-19920901-07

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