A central concept in the management of asthma is that a specific inflammatory response is present in the airway wall and the functional and structural changes in the airway that give rise to symptoms are considered secondary to this inflammation. This inflammatory response is usually glucocorticosteroid sensitive, regardless of the origin of the asthma.
Before initiating pharmacologic therapy I optimize non-pharmacologic aspects of management. These include allergen avoidance, as guided by skin prick testing, with emphasis on avoidance of indoor allergens (such as house dust mite and animal dander) occupational assessment, dietary advice, education about potentially harmful drugs (such as non-steroidal anti-inflammatory agents), advice on the value of weight control, physical fitness and stress management, and control of concomitant medical factors (such as gastroesophageal reflux and rhinosinusitis). Assuming all of these factors have been addressed, and intrusive symptoms persist, pharmacologic therapy is advisable, and glucocorticosteroids (GCSs) are key agents in current protocols.
Mechanism of action of glucocorticosteroids
Every cell has glucocorticoid receptors, and GCSs have a spectrum of actions. Their ability to reduce the synthesis of many different cytokines produced by multiple cell types is probably the most important effect of glucocorticosteroids on asthma. A network of cytokines (perhaps as many as 25) induce the production and influx of eosinophils and other cell types into the airway wall.
Secondary mediators released from these cells, and possibly resident cells (such as airway epithelial cells), are responsible for changes found in the asthmatic airway (epithelial desquamation, vascular leak, increased mucus production, increased muscle mass and contractility, and thickening of the wall including sub-basement membrane collagen and matrix deposition). The airway epithelial cell, the initial contact cell for inhaled glucocorticosteroid, could be a particularly important site of action for these agents.
Stepwise pharmacologic therapy
Successful use of pharmacologic therapy involves adequate explanation to the patient of the role of each medication and instruction in its use. Consensus guidelines on stepwise therapy for asthma have been developed in Canada, the United Kingdom, Australasia, and the United States. Guidelines need regular modification based on both new data and practical problems detected after implementation.
The most recently revised guidelines (Table 1) are from UK authorities, but all guidelines recommend anti-inflammatory treatment (step 2) when inhaled β2 adrenergic receptor agonist bronchodilators (β2-agonists) are needed more than once or twice daily (step 1). Some experts recommend anti-inflammatory agents as initial therapy.
|Table 1. Stepwise approach to pharmacologic therapy|
|Step 1: Occasional use of relief bronchodilators|
|Step 2: Regular inhaled anti-inflammatory medications|
|• Initial trial of sodium cromoglycate or nedocromil sodium|
|• If unsuccessful, budesonide or beclomethasone dipropionate, 200-800 µg/d|
|Step 3: High-dose inhaled glucocorticosteroids (eg, budesonide 1200-2600 µg/d)|
|Step 4: High-dose inhaled glucocorticosteroids and regular bronchodilators|
|• Oral slow-release theophylline|
|• Possible addition of inhaled ipratropium bromide or long-acting β2-agonist (salmeterol)|
|Step 5: Long-term alternate-day or daily oral prednisone*|
|Step 6: When stepping down, review treatment every 3 to 6 weeks|
|* Short courses of prednisone to stabilize asthma should initially be used.|
The only anti-inflammatory agents routinely available in Canada at present are glucocorticosteroids, cromoglycate, and nedocromil. Inhaled GCSs are efficacious for most patients. Cromoglycate and nedocromil are in general less efficacious, and individual responses are unpredictable. One may try cromoglycate or nedocromil for 1 month and, if control is not achieved, start inhaled glucocorticosteroid.
The median effective dose of GCS is 400 µg/d, and thus step 2 of all guidelines is 100 to 400 µg of inhaled GCS twice daily. Step 3 increases inhaled GCS to 1500 to 2000 µg/d, although not all trials have shown benefit from the increased dose. Ninety percent of all asthma patients will be adequately controlled by step 3 if drug-delivery techniques are optimized. Step 4 includes sequential therapeutic trials of sustained-release theophyllines, of anticholinergics, and of cromoglycate or nedocromil if these have not been tried previously. Long-acting inhaled β2-agonists (salmeterol) could have a valuable role as an alternative to step 3 or as an addition in step 4, but longer term safety trials are required. Step 5 is oral glucocorticosteroid.
When faced with a new patient who has poor symptom control, I initially maximize airway calibre and induce a systemic anti-inflammatory effect with a short course of prednisone at 0.6 g/kg/d as a single morning dose without tapering for 2 weeks.’ This often stabilizes patients sufficiently so that step 3 or 4 therapy is adequate. Oral glucocorticosteroids are sometimes needed because inhaled glucocorticosteroid might have only limited penetration to the airway adventitia, an important site of inflammation in severe asthma that can exaggerate airway narrowing,’ and because excessive airway secretions can also limit penetration of inhaled GCS.
Recent evidence suggests rapid control of nocturnal asthma is greater with a 3 pm dose schedule, and in this circumstance a twice daily regimen is sometimes useful for a few days. However, most of the course should be given as a single morning dose if effects on the adrenal axis are to be minimized. Only after repeated unsuccessful attempts at management with short courses of prednisone and high-dose inhaled GCS would I commit a patient to long-term daily prednisone therapy. Very few patients require such therapy because of the efficacy of inhaled glucocorticosteroid. A few asthma patients have GCS resistance, a poorly understood and rare disorder. It is likely that most patients labeled as GCS-resistant require higher doses for a time to overcome severe airway inflammation.
An important sixth step in managing patients with asthma is to review treatment regularly, eg, every 6 months; if control is achieved, a stepwise reduction in treatment could be possible. Reducing the dosage of these medications could be possible during one season or for more prolonged periods, and this is an area of active research. Remissions occur, and symptoms fluctuate in severity depending on exposure to viruses, allergens, and air pollutants.
A recent publication has documented that inhaled steroids, when introduced at initial diagnosis, were more effective than when introduced 2 years later (after monotherapy with β2-agonists). This is consistent with research from our laboratory and others suggesting that uncontrolled asthma leads to permanent structural changes in the airway, which in turn lead to persistent symptoms, even in the absence of active inflammation.’ It is important to remember that GCSs do not cure asthma and that tests of airway responsiveness, a surrogate of structural and functional changes, return to baseline values a few months after stopping inhaled glucocorticosteroid. Glucocorticosteroids also do not usually return airway responsiveness to “normal values”; indices of sensitivity to inhaled methacholine, such as the PC20, frequently shift only one doubling dose.