Corticosteroids have been used to treat asthma since 1950 and are presumed to act by their broad anti-inflammatory efficacy, medi-ated in part by inhibition of production of inflammatory cyto-kines . They do not relax airway smooth muscle directly but reduce bronchial reactivity and reduce the frequency of asthma exacerbations if taken regularly. Their effect on airway obstruction may be due in part to their contraction of engorged vessels in the bronchial mucosa and their potentiation of the effects of β-receptor agonists, but their most important action is inhibition of the infiltration of asthmatic airways by lymphocytes, eosinophils, and mast cells.
Clinical studies of corticosteroids consistently show them to be effective in improving all indices of asthma control—severity of symptoms, tests of airway caliber and bronchial reactivity, fre-quency of exacerbations, and quality of life. Because of severe adverse effects when given chronically, oral and parenteral corti-costeroids are reserved for patients who require urgent treatment, ie, those who have not improved adequately with bronchodilators or who experience worsening symptoms despite maintenance therapy. Regular or “controller” therapy is maintained with aerosol corticosteroids.
Urgent treatment is often begun with an oral dose of 30–60 mg prednisone per day or an intravenous dose of 1 mg/kg methyl-prednisolone every 6–12 hours; the daily dose is decreased after airway obstruction has improved. In most patients, systemic cor-ticosteroid therapy can be discontinued in 7–10 days, but in other patients symptoms may worsen as the dose is decreased to lower levels. Because adrenal suppression by corticosteroids is related to dose and because secretion of endogenous corticosteroids has a diurnal variation, it is customary to administer corticosteroids early in the morning after endogenous adrenocorticotropic hor-mone secretion has peaked. For prevention of nocturnal asthma, however, oral or inhaled corticosteroids are most effective when given in the late afternoon.
Aerosol treatment is the most effective way to avoid the sys-temic adverse effects of corticosteroid therapy. The introduction of corticosteroids such as beclomethasone, budesonide, cicle-sonide, flunisolide, fluticasone, mometasone, and triamcino-lone has made it possible to deliver corticosteroids to the airwayswith minimal systemic absorption. An average daily dose of four puffs twice daily of beclomethasone (400 mcg/d) is equivalent to about 10–15 mg/d of oral prednisone for the control of asthma, with far fewer systemic effects. Indeed, one of the cautions in switching patients from oral to inhaled corticosteroid therapy is to taper oral therapy slowly to avoid precipitation of adrenal insuffi-ciency. In patients requiring continued prednisone treatment despite inhalation of standard doses of an aerosol corticosteroid, higher doses appear to be more effective; inhalation of high doses of both fluticasone and ciclesonide, for example, have been shown to be effective in weaning patients from chronic prednisone ther-apy. Although these high doses of inhaled steroids may cause adrenal suppression, the risks of systemic toxicity from chronic use appear negligible compared with those of the oral corticosteroid therapy they replace.
A special problem caused by inhaled topical corticosteroids is the occurrence of oropharyngeal candidiasis. The risk of this complication can be reduced by having patients gargle water and spit after each inhaled treatment. Hoarseness can also result from a direct local effect of inhaled corticosteroids on the vocal cords. These agents are remarkably free of other short-term complications in adults but may increase the risks of osteoporosis and cataracts over the long term. In children, inhaled corticosteroid therapy has been shown to slow the rate of growth by about 1 cm over the first year of treatment, but not the rate of growth thereafter, so that the effect on adult height is minimal.
A novel approach to minimizing the risk of toxicity from sys-temic absorption of an inhaled corticosteroid underlay the devel-opment of ciclesonide. This recently approved corticosteroid is inhaled as a prodrug activated by cleavage by esterases in bronchial epithelial cells. When absorbed into the circulation, the active product is tightly bound to serum proteins, and so has little access to glucocorticoid receptors in skin, eye, and bone, minimizing its risk of causing cutaneous thinning, cataracts, osteoporosis, or temporary slowing of growth. Ciclesonide has been shown to be effective in improving asthma control in clinical trials, but studies have not yet proven that its use is associated with the significant reduction in systemic toxicity predicted from its design as a pro-drug with low corticosteroid activity, activated to a much more potent corticosteroid agonist by esterases at its site of deposition in the airways.
Chronic use of inhaled corticosteroids effectively reduces symptoms and improves pulmonary function in patients with mild asthma. Such use also reduces or eliminates the need for oral corticosteroids in patients with more severe disease. In con-trast to β-stimulant agents and theophylline, chronic use of inhaled corticosteroids reduces bronchial reactivity. Because of the efficacy and safety of inhaled corticosteroids, national and international guidelines for asthma management recommend their prescription for patients who require more than occasional inhalations of a β agonist for relief of symptoms. This therapy is continued for 10–12 weeks and then withdrawn to determine whether more prolonged therapy is needed. Inhaled corticoster-oids are not curative. In most patients, the manifestations of asthma return within a few weeks after stopping therapy even if they have been taken in high doses for 2 years or longer. A prospective, placebo-controlled study of the early, sustained use of an inhaled corticosteroids in young children with asthma showed significantly greater improvement in asthma symptoms,pulmonary function, and frequency of asthma exacerbations over the 2 years of treatment, but no difference in overall asthma control 3 months after the end of the trial. Inhaled corticoster-oids are thus properly labeled as “controllers.” They are effective only so long as they are taken.
Another approach to reducing the risk of long-term, twice-daily use of inhaled corticosteroids is to administer them only intermittently, when symptoms of asthma flare. Taking a single inhalation of an inhaled corticosteroid with each inhalation of a short-acting β-agonist reliever (eg, an inhalation of beclometha-sone for each inhalation of albuterol) or taking a 5–10 day course of twice-daily high-dose budesonide or beclomethasone when asthma symptoms worsen has been found to be as effective as regular daily therapy in adults and children with mild to moderate asthma, although these approaches to treatment are neither endorsed by guidelines for asthma management nor approved by the FDA.