Pathophysiology

Asthma is a chronic inflammatory disease of the lower respiratory tract (1) which is triggered by exposure to allergens or other airway irritants. This inflammation results in airway hyper-responsiveness (2), bronchial muscle spasm, mucous gland hypersecretion, and mucosal edema, which combine to increase the work of breathing, and to create symptoms such as cough, wheezing, chest pain or tightness, and respiratory distress. The obstruction to air flow which occurs during asthmatic inflammation is potentially reversible, a factor which usually distinguishes asthma from chronic obstructive pulmonary disease (COPD) (3). The inflammatory process is highly variable, both from time to time in any individual, and from person to person, so that asthma is a disorder with many possible presentations, and with drastic differences in severity. Wheezing asthma, or asthma requiring hospital treatment, is usually obvious, whereas asthma masquerading as COPD, easy fatigueability, intermittent asthma, exercise induced asthma, or cough variant asthma may proceed for years without clinical recognition.

Prevalence

Asthma is the most common serious chronic disease in most industrialized nations (4). Estimates of the current asthma prevalence in the United States range up to 12 million persons (5). The incidence of asthma in children appears to be increasing, and since long term studies have shown persistence of symptomatic asthma as children age, it is likely that the future prevalence of asthma will be even greater (5). Since the 1970s, the overall mortality due to asthma has also been steadily increasing worldwide, growing by 40% in the United States between 1982 and the end of 1991 (6). Presently, about 4 to 5 thousand asthmatics die each year in the United States (7). The self reported prevalence of asthma during the same time period increased by 42%, to almost five persons per hundred. Asthma morbidity and hospitalization rates are also increasing. Making such data imprecise are the practical difficulties in identifying all affected patients and in classifying pulmonary disorders as asthmatic or not (3).

Variability of Asthma Expression

The phenotypic expression of asthma appears to be controlled by multiple genes (8), which may help to explain the variable nature of this disease. The great majority of asthmatics, perhaps all, are now known to be allergic (9,10), so that the old distinction between intrinsic and extrinsic asthma no longer pertains. However, the reverse is not true, since obvious asthma is only present in a fraction of allergic persons, for example, in up to 11% of people with allergic rhinitis (11). How the various genetic and environmental factors that are active in asthma interact to produce clinical illness in any individual remains largely unknown. For example, only 26% of the children in families with one asthmatic parent develop asthma during childhood (8). However, there is no question that environmental triggers are of major importance. For example, about two thirds of asthmatics in the United States live in areas with significant smog (6), and it is known that the oxidant chemical pollutants in both indoor and outdoor air cause lung inflammation and act as priming agents for subsequent allergen exposure (12,13). Many other non-allergic environmental factors are known to trigger or exacerbate asthma, including viral infections (14), bacterial infections (15, 16), exercise (17), stress (18), cold air, gastroesophageal reflux, sinusitis, exposure to certain drugs and chemicals, and endocrine dysfunction (7). Allergic asthma triggers include the full range of inhalant (19, 20), food (21), and chemical (22, 23) allergens. Finally, nutrition, especially anti-oxidant status, may significantly influence allergic lung disease severity (24). The clinical variability of asthma thus may depend on how many of these factors are simultaneously or sequentially interacting with the unique genetic setting of each individual asthmatic.

Clinical Diagnosis

Asthma is diagnosed primarily by clinical suspicion, by noting typical episodic symptoms and typical triggering patterns in the patient¹s history. Any person with unexplained wheezing, frequent cough, or dyspnea, especially when associated with recognized asthma triggers, should elicit the clinical suspicion that asthma could be at fault. Confirmation of asthma depends on the combined use of physical examination, pulmonary function testing, and, when indicated, radiologic examination, and by a successful response to asthma management.

During the physical examination, chest auscultation may detect typical expiratory wheezes or decreased breath sounds, but often, cough is the only audible symptom. Asthmatic sputum, when produced, is clear and tenacious, and colored or bloody mucus should raise suspicion of infection or malignancy. Discovery of a past personal or family history of allergy, especially of asthma, hay fever, serous otitis, eczema, or migraine suggests that atopy may be present, and increases the likelyhood of asthma. Current evidence for allergy should be sought, particularly during examination of the skin and the head and neck. For example, eczema, old tympanic membrane scars, enlarged or inflamed turbinates, pharyngeal bands, or allergic eyelid edema and discoloration may be found. Evaluation of the larynx can help to include or exclude consideration of gastroesophageal reflux.

Assessment of Severity

Once asthma is seriously suspected, an assessment of the severity of disease should be made. Episodes of prior emergency room or hospital care for respiratory problems, including multiple episodes of croup as a child, or multiple episodes of systemic corticosteroid therapy, are significant indicators of possibly severe asthma. On the other hand, infrequent symptoms associated primarily with infections or exercise normally identifies mild asthma. The frequency and severity of symptoms have particular value in classifying patients. For example, daily to weekly wheezing, nighttime awakening or arising more than once a week with symptoms, or daily to weekly limitation of home or sporting activities usually indicates severe asthma (25). This clinical evaluation should yield a rough risk assessment, and this will, in turn, dictate the speed and depth of subsequent evaluation.

Pulmonary Function Testing

In most cases, pulmonary function tests (PFTs) will be the next step (3). PFTs, done before and after bronchodilator use, give objective data to establish the diagnosis of reversible obstructive lung disease. PFTs also allow the objective assessment of disease severity. This should match the clinical severity assessment, and if it does not, special care in the subsequent evaluation is warrented. PFTs may also be used to measure the response to therapy, and can be used as a guide to the need for aggressive anti-inflammatory treatment. The one second forced expiratory volume (FEV1) is the measurement most often used. Less than a 20% decrease from normal indicates mild asthma, a drop of 20% to 40% is moderate asthma, and a greater than 40% decline is severe asthma (26). In some cases of asthma, initial PFTs may be normal, or there may be no bronchodilator effect, and yet, provocative PFTs, using a graded methacholine inhalational challenge, will be positive. Finally, PFTs may sometimes detect other lung diseases, such as pneumonitis, COPD, or a fixed airway obstruction. In these cases, PFTs may have to be supplemented with carbon monoxide diffusion or other tests (27).

Graphing spirometric flow-volume curves gives a visually distinctive pattern to different pulmonary diseases, and makes office use of PFTs both easy and clinically valuable. Rate of airflow in liters/sec is graphed on the vertical axis, and volume of exhaled or inhaled air in liters is graphed on the horizontal axis. Asthma is usually easily recognized because the exhaled flow-volume curve is reduced compared to age, sex, and height adjusted normal data, the downslope becomes concave in shape, and, use of a bronchodilator partially or completely reverses the curve to normal. However, lack of rapid reversibility does not exclude asthma, since long standing inflammation may require months of treatment before improvement is measureable (27). Methacholine challenge maybe helpful in these cases of irreversible obstruction. If the FEV1 is greater than 60% of predicted, a methacholine challenge may be done, and if it shows a further drop in FEV1 , then asthma, rather than COPD, is the probable diagnosis (28). If PFTs of an asthmatic are done when there are no symptoms, the flow-volume curve may be normal. In this situation, provocation with methacholine will usually produce a greater than 20% drop in FEV1, which is considered diagnostic of asthma (28). For diagnostic accuracy, office spirometers need regular calibration, and spirometric technicians need to carefully coach patients so that reliable PFTs are recorded (29).

Other Examinations

In many cases of asthma, history, exam, and PFTs are sufficient information on which to base clinical management. However, when there is a history of tobacco use, exposure to tuberculosis or environmental risk factors, unusual symptoms, or failure to respond to treatment, radiologic studies and bronchoscopy may be needed. Even in incontestable cases of asthma, lung cancer, tuberculosis, asbestosis, and other diseases may also be present, and timely consultations with pulmonologists and other specialists can be important. Pulmonology consultations are also helpful for sharing the management of moderately severe and severe asthmatics.

Strategy for Asthma Management

Guidelines for asthma diagnosis and management were developed by the National Heart, Lung, and Blood Institute and published in 1991 (30). These guidelines emphasize three basic components in an integrated strategy for asthma control: environmental control, anti-inflammatory therapy, and education. Furthermore, since asthma is now recognized as a chronic inflammatory disease, maintenance anti-inflammatory treatment is indicated in all but the most mild asthmatics. This is a significant change in therapeutic emphasis, with symptomatic bronchodilator treatment no longer considered to be adequate for more than occasional use.

Environmental control can be very effective, because the elimination of incitants prevents lung inflammation from ocurring, but it is often difficult to fully implement (30). However, any achievable measures that will reduce exposure to allergens or pollutants are very beneficial. For example, simple enclosure of the mattress with a zippered encasing can reduce dust mite exposure by 99% (31). Air cleaners remain controversial because controlled studies have generally failed to show significant effects (32), yet, many patients report clear benefit from their use. In cases of extreme sensitivity, even the control of sources of indoor combustion may be required (33). In general, the more severely affected the individual, the greater the potential benefits that can accrue from thorough investigation of incitants and institution of effective environmental controls (34).

Anti-inflammatory treatment of two general types is available, pharmacologic and immunotherapeutic. Some form of anti-inflammatory therapy is indicated for all moderate or severe asthmatics, and also is useful for mild asthmatics (26). This anti-inflammatory treatment imperative has evolved during the past decade, during which it became evident that the irreversability of chronic asthma is due to uncontrolled chronic inflammation, and that bronchodilator treatment does not affect the underlying pathology (30). Three anti-inflammatory inhaled drugs are currently available: cromolyn, nedocromil, and several varieties of glucocorticoids. Mild to moderate asthma can be managed with inhaled cromolyn or nedocromil, whereas moderate and severe asthma usually requires inhaled steroid use. Severe cases may also require systemic steroid treatment, either intermittent during attacks, or as continuous therapy. Immunotherapy can be employed as the sole anti-inflammatory therapy in mild asthma, but is more commonly used as adjunctive therapy along with pharmacotherapy. In more severe asthma cases, immunotherapy is used as a steroid sparing treatment, and may be able to reduce or eliminate the need for systemic steroid treatment. Properly administered anti-inflammatory treatment can effectively control asthma in almost all patients.

Education is the third crucial component in asthma control. Without enlisting the patient and their family in their own therapy, and educating them adequately, asthma control is neither easily achieved nor maintained. For example, at least half of patients do not follow physician instructions (26), but a family education program can improve compliance enough to significantly decrease emergency room visits and hospitalizations (35). Education can also improve the use of inhalers, increase environmental controls, increase activity, decrease symptoms, and help patients and families adjust to their illness. In some cases, education reduces treatment costs (36). Education can be especially effective in teaching patients how to monitor and respond to their asthma, for example, by initiating a regular program of home peak flow monitoring (37). Ongoing physician education and review of these home monitoring records is a very effective way to improve asthma control in motivated patients

Pharmacotherapy

Pharmacotherapy is an important part of asthma treatment, but if used without patient education, environmental control measures, and regular physician contact, it¹s results will seldom be satisfactory. Asthma currently can be effectively treated, singly, or in combination, by either systemic or topical use of seven classes of drugs: mucolytics, anticholinergic agents, antihistamines, theophylline, beta agonists, mast cell stabilizers, and corticosteroids. A variety of other treatments including antioxidant vitamins (24), magnesium (38), other nutrients, and various immunosuppressants (39, 40), have been reported to have activity. Drugs capable of blocking leucotrienes, either during synthesis (41) or at receptor sites (42), are about to be released for general clinical use, and also have useful anti-asthma activity (43). Farther in the future, there is potential for other antiinflammatory agents based on selective antagonists for cytokines, adhesion molecules, platelet activating factor, bradykinin, and other inflammatory mediators

Mucolytics

Mucolytic, expectorant, or mucokinetic agents are useful as adjunctive agents to thin the excessively viscid mucus component of asthma. Some agents can be applied topically, as in steam inhalation, or by inhalation of the substituted amino acid N-acetylcysteine (Mucomyst), which has long been used by inhalation (44), but is also effective orally. Related, parenterally administered mercaptans have also been postulated to have a direct antiallergic effect via the in vivo denaturation of IgE molecules (45). Finally, two other agents, iodides and guiafenesin, are available only in oral form. Iodides, such as potassium iodide, calcium iodide, and iodinated glycerol, have been shown to be effective in asthma treatment (46), but are normally indicated only for short term use. Guiafenesin is often used for long term therapy, but there is no convincing evidence of efficacy (46).

Anticholinergic Agents

Anticholinergic agents have been found to be effective treatment, but administration via oral and transdermal routes often produces unacceptable cardiac, central nervous system, opthalmic (47), and antisecretory side effects. Glycopyrrolate (Robinul), and ipratropium (Atrovent) are more effective than atropine (48). Direct inhalation via nebulizer or inhaler decreases secretions and bronchodilates, with few side effects (48). These drugs are poorly absorbed, producing blood levels that are usually too low to cause anticholinergic side effects (49). The degree of response to anticholinergics is variable, so these drugs should be considered to be secondary agents, for use in either acute or chronic asthma when other drugs are not well tolerated or not fully effective (48).

Antihistamines

Although H1, H2, and H3 histamine receptors are present in the lung, only H1 antihistamines appear to have any significant clinical effect on bronchial hyperreactivity or asthma symptoms (50). Antihistamines are generally useful to reduce all allergic symptoms, but were not officially recommended for asthma treatment until 1993 because of concerns for causing overdrying and formation of mucus plugs (51). Although effective for both prophylactic and symptomatic therapy, classical H1 antihistamines administered via the oral route often produce unacceptable anticholinergic or central nervous system side effects. In addition, constant use of these drugs frequently leads to tolerance and loss of efficacy.

The recent development of second generation, nonsedating, antihistamines that have little central nervous system penetration (52) or anticholinergic activity has been a significant therapeutic advance. These new drugs have high affinity binding to histamine receptors, producing both potent clinical effects and eliminating drug tolerance (53,54). Further, the lack of secretion-drying anticholinergic activity allows these drugs to also be used in asthma treatment without any concern that mucus plugs will form. Nonsedating antihistamines do differ significantly from each other in speed of onset and in duration of action. For example, astemizole, loratadine, mequitazine, and noberastine have long enough elimination half lives to allow the convenience of once daily dosing (55,56, 57). Since there is a noticible diurnal variation in asthma symptoms, with increased severity during the night and on awakening (56), nighttime use of these long-acting drugs may be especially helpful. Many of these new drugs also have additional antiallergic and anti-inflammatory actions which may extend the drug's activity beyond blockade of the immediate allergic reaction to also ameliorate the late phase reaction (58,59). For example, cetirizine inhibits monocyte and T-lymphocyte chemotaxis (60), and has been shown to improve pulmonary function (61). Because of these added properties, the second generation antihistamines also are not necessarily equivalent in their therapeutic effects, either to classic antihistamines or to each other. They are also not necessarily equivalent in their side effects, as shown by two recent studies. Loratadine, in contrast to terfenadine and astemizole, has been shown to not alter cardiac conduction at clinically achievable concentrations (62,63). Cetirizine and doxylamine, in contrast to loratadine, astemizole, and hydroxyzine, do not promote tumor growth in mice (64,65). Finally, antihistamines vary by more than tenfold in their purchase price, but the more expensive agents are generally those with better side effect profiles (66).

In addition to the four already approved, terfenadine, astemizole, loratidine, and acrivastine (67-71), several other new antihistamines are nearing FDA approval in the US, including cetirizine (72-73). Ketotifen is significantly sedating, but also has useful antiinflammatory activity (74). Finally, extended age indications are being sought, and some second generation drugs will probably soon be available in liquid form for pediatric and geriatric use. Like anticholinergic drugs and mucolytics, antihistamines currently are considered as secondary anti-asthma drugs, useful in certain patients, especially when other drugs are not satisfactory (58). Because of low toxicity and possible benefit, a trial of several antihistamines is warrented in all severe asthmatics.

Theophylline

Since 1937, intravenous theophylline has been used for emergency asthma treatment, and oral therapy has been used for chronic asthma (75). However, several recent controlled trials have shown little efficacy of theophylline in the emergency treatment of bronchospasm, and greater toxicity than competing therapies (48,76, 77, 78). Despite these reports, theophylline does decrease asthma symptoms, especially nocturnal dyspnea (75), and may also decrease corticosteroid needs (79). Theophylline has multiple modes of action, and has recently been found to have significant anti-inflammatory activity at lower serum levels where toxicity is minimal (80, 81). Because theophylline clearance is variable, and maintaining an appropriate serum level is important in preventing side effects (79), monitoring of theophylline levels is recommended (48). The exact place of theophylline in asthma treatment is currently in flux. Formerly a first line agent, it has recently been de-emphasized, but is still useful, especially in difficult to control asthma, or when nocturnal symptoms are prominent. A trial of theophylline should be considered as a possible means to decrease systemic steroid use.

Beta Agonists

Ephedrine has been used since ancient times, and chemically similar, inhaled, beta adrenergic agonists are still the drugs of choice for rapid control of bronchoconstriction that is mediated by smooth muscle contraction. Acting by stimulating beta-2 receptors (48), they have a rapid, predictable onset, are more potent than anticholinergic drugs or theophylline, and are usually well tolerated (48, 82). The primary side effects which may limit beta agonist use are tremor and cardiac excitability. Older beta agonists, such as epinephrine, isoproterenol, and metaproterenol are less beta-2 selective, and thus more likely to cause side effects (79). Available beta-2 selective beta agonists include albuterol, bitolterol, pirbuterol, and terbutaline. In order to maximally decrease systemic side effects, these drugs are usually inhaled, but oral use may be beneficial in children who have not been able to learn to use metered dose inhalers (82). Recently, a slow onset, long duration, selective beta agonist, salmeterol (Serevent) has been introduced in the U.S. (83). Unlike other beta agonists, salmeterol is not useful for relief of acute asthma symptoms, but it is useful for prolonged symptom suppression, especially for nocturnal asthma. Many experts recommend salmeterol only for patients who are regularly using inhaled corticosteroids (79).

Whether beta agonists should be used on a regular schedule, or only on an as needed basis is controversial (79, 82). In numerous studies, increased use of beta agonists has been correlated with increased risk of death from asthma. In the province of Saskatchewan, use of more than 1.4 canisters of beta agonist per month was the threshold for increased risk, and the higher the use above that point, the higher the risk (82). The central issue is whether the correlation actually reflects adverse physiologic effects from the drug, or whether increased drug use is a marker for more severe asthma, which naturally has a higher death rate. This issue has recently been reviewed, and the answer is still unclear (79,84, 85). In New Zealand, changes in asthma deaths appear to have been correlated with use of fenoterol, a very long duration non-selective beta agonist that is not available in the U.S.. In this particular case, it is suspected that the excess mortality was due to direct effects the drug, and not to insufficient use of anti-inflammatory agents, or to poor education and medical supervision (79,86). Because of this unresolved controversy, the most conservative practice is to institute anti-inflammatory therapy if beta agonist use is greater than three times weekly (26), or greater than one canister per month (48). Furthermore, patients who are using a long duration drug, such as salmeterol, should be warned to use one of the rapid acting beta agonists, rather than salmeterol, for relief of acute symptoms (79).

Beta Antagonists (Beta Blockers)

Drug Interactions may complicate treatment of asthma, especially during beta agonist treatment of status asthmaticus or anaphylaxis. Beta-adrenergic antagonists (87) are the class of interfering drug most likely to be encountered, but other drugs may also be of concern, especially in elderly patients (87.5). Beta-blockade has three major types of adverse effects during asthma treatment. First, beta-blockade is proallergic since it both blocks smooth muscle relaxation and amplifies the production of anaphylactic mediators (87), thus increasing the severity of asthma, or any allergic reaction (88). Second, beta-blockade increases the dose of a beta agonist required to overcome the block and produce bronchodilation. Third, beta-blockade may cause hypertensive crisis due to unopposed alpha adrenergic effects which will occur if epinephrine is used to treat the asthma (88). Beta-1 selective beta-blockers have relatively less bronchoconstricting effect than their desireable cardiac effects (mediated by beta-1 receptors), and theoretically should be less likely to cause harm when used in allergic persons. However, the effects of beta-blockers on mediator production are nonselective, and thus even beta-1 selective drugs are proallergic (87). Consequently, use of beta antagonists in asthma is not recommended, unless there is no good alternate treatment.

Mast Cell Stabilizers

There are only two clinically useful drugs that are primarily mast cell stabilizers, although both corticosteroids and some of the antihistamines may also produce some of their antiallergic activity by cell stabilization. The first drug in this class, cromolyn, or sodium cromoglycate, was introduced about twenty years ago, almost simultaneously with the introduction of inhaled corticosteroids (89). Cromolyn has been found to be effective and very safe for allergic therapy, but is limited by being essentially nonabsorbed, and thus restricted to topical treatment. Cromolyn is available in an inhaled form, Intal, that acts directly on the bronchial mucosa, and an oral form, Gastrocrom, that blocks the effects of allergic foods which can cause asthma, although it is not yet approved in the U.S. for this indication (90). In treatment of allergic rhinitis, cromolyn has been found to be comparable in efficacy to oral doses of nonsedating antihistamines (91), and the combination of cromolyn and an antihistamine is more effective than either drug used alone (92). However, cromolyn is less effective than intranasal corticosteroids in control of most rhinitis symptoms (93,94). The experience with mast cell stabilizers in asthma therapy parallels their use in rhinitis. Cromolyn is an effective anti-inflammatory agent for exercise-induced asthma or mild chronic asthma (26, 79). When used to treat exercise-induced asthma, the combination of cromolyn with a beta agonist is superior to either drug alone (95).

Recently, a second drug which is chemically unrelated to cromolyn, but has a similar pharmacologic activity profile and similar receptor sites, was found. This drug, nedocromil, differs from cromolyn in having slightly greater oral absorption, but is available only in an inhaled formulation. In in vitro tests, nedocromil is about tenfold more potent on a molar basis than cromolyn, while in animal studies, the two drugs are equally effective when applied topically, but nedocromil has longer duration of action (96). Nedocromil, like cromolyn, is an effective anti-inflammatory agent for exercise-induced asthma or mild chronic asthma. It is as effective as beclomethasone in mild asthma (97), but is less effective than corticosteroids in moderate or severe asthma (79). Research is still being done on nedocromil¹s mechanisms of action, but it appears that it both prevents granulocyte mediator release and reduces local irritative axon reflexes by blocking membrane chloride channels (97).

Both mast cell stabilizers inhibit both the immediate and late phase allergic reactions if they are administered prior to allergen challenge. However, neither drug can prevent the late phase reaction if given after the immediate reaction has ocurred (98). The action of mast cell stabilizers differs from that of corticosteroids in two ways. First, mast cell stabilizers effectively prevent the immediate reaction, whereas corticosteroids, even when used for prolonged periods, have only a weak effect on the immediate reaction (99). Secondly, unlike mast cell stabilizers, corticosteroids significantly attenuate the late phase reaction if given during or after the immediate reaction (98). Both mast cell stabilizers and corticosteroids are most effective when used prior to allergen challenge (98, 100). Mast cell stabilizers are most useful as an alternative to corticosteroids in mild or moderate asthma, and are also used as adjunctive therapy in difficult to control asthma. Both cromolyn and nedocromil have been shown to significantly improve daytime symptom control when added to a regimen of inhaled bronchodilators and corticosteroids (101). Furthermore, adding nedocromil also improves nighttime symptom control and allows the dose of inhaled steroid to be reduced (97,100.5).

Corticosteroids

Corticosteroids are the most effective class of drugs for control of asthmatic inflammation. In addition to gradually decreasing inflammatory airway edema, corticosteroids potentiate the effect of beta agonists on smooth muscle relaxation, decrease beta agonist tachyphylaxis, and decrease mucus production (48). In treatment of acute asthma attacks, use of corticosteroids decreases immediate mortality, hospital admissions, and risk of relapse within ten days of treatment (48). Corticosteroids are thought to be effective primarily by blocking late phase reactions, and although their effects begin immediately, they do not become maximally effective for several days after treatment begins. This gradual effect on late phase inflammation appears to be due to inhibition of interleukin-4 expression (100) as well as suppression of the conversion of arachidonic acid into prostaglandins and leucotrienes (26). Other studies suggest that there may be additional corticosteroid effects, including even some mild effects on early phase reactions (99).

The use of inhaled corticosteroids to treat the inflammatory component of allergies dates from the introduction of beclomethasone in 1974, and has been viewed as the most important advance in allergy treatment since the discovery of antihistamines (102). Prior to use of topical steroids, glucocorticoids could only be administered systemically, with significant long-term risks (102, 103). Possible steroid side effects are protean: osteoporosis with fractures, glucose intolerance, infections, gastric ulcers and gastrointestinal bleeding, cataracts, glaucoma, and accelerated arteriosclerosis, among many (103). There is a direct dose-risk relationship with long term oral steroid use, with detectable increases in risk even for very low doses, such as 5 mg per day of prednisone (103). Because of this, since the earliest days of corticosteroid use In the 1950s, there have been attempts to utilize these drugs topically, rather than systemically. Early attempts at topical treatment failed due to insufficient drug potency, or from high systemic absorption and adrenal suppression, or because of poor delivery methods, problems that were overcome by Brostoff and Czarny¹s work in 1968 (104). Fortuitously, beclomethasone and other highly potent corticosteroids appear to be even more effective when administered topically, rather than orally (104,105).

Although physician acceptance was initially slow, inhaled corticosteroids have gradually become accepted as primary treatment for serious asthma. Topical steroids are now being advocated for treatment of mild asthma, although this remains contentious because the risk-benefit analysis has not been established in mild asthma. Since mild asthma is diagnosed in about two-thirds of all asthmatics, the long term safety, potential benefits, and treatment cost of using inhaled corticosteroids in these cases is of major importance (106). Particularly critical to resolving this issue is the current lack of knowledge regarding whether untreated mild asthmatics have any natural progression of their disease or ever develop irreversible obstruction. However, there is no question that inhaled corticosteroids are both safe and effective for moderate or severe asthma, and that they do ameliorate the natural progression of the disease (106). In fact, physician reluctance to use adequate doses of corticosteroids currently causes significant preventable disability and decrease in quality of life, while steroid-induced side effects are rarely observed (107).

Five different strategies for using corticosteroids in asthma can currently be formulated (26,107). First, for outpatient treatment of acute asthma exacerbations, short term oral corticosteroids for up to ten days are appropriate (79), and simultaneously, consideration should be given to adding or increasing inhaled corticosteroids. Second, for emergency room or inpatient treatment of acute severe asthma, short term intravenous corticosteroids are used (108), followed by tapering outpatient oral treatment and maintenance inhaled therapy. Third, inhaled corticosteroids, at standard doses, are appropriate maintenance therapy for moderate or severe asthma. Fourth, if asthma control is not achieved, inhaled corticosteroid doses should be increased to a high dose regimen. Finally, in difficult cases, long term maintenance oral corticosteroid therapy, using a short duration drug such as prednisone or prednisolone, can be added to inhaled corticosteroids. When regular use of oral steroids is necessary, the use of alternate day morning dosing can significantly decrease the incidence of corticosteroid side effects (79, 107).

With over twenty years of clinical use in the U.S., topical glucocorticoids have shown few major side effects. Problems with throat irritation, hoarseness, and cough have been decreased by developing improved dispensers, and by providing more patient education. Occasionally, inhaled steroids may trigger contact allergy (109). Local fungal infections of the oral cavity or larynx (107), which usually clear with cessation of therapy, may also occur. Available drugs differ mainly in degree of absorption into the systemic circulation, speed of metabolic inactivation, inhaler design, and in frequency of dosing required to maintain efficacy. Of currently available drugs, and at recommended doses, only dexamethasone regularly causes significant hypothalamic-pituitary-adrenal suppression (110,105,93). Although it does not ordinarily cause systemic effects at normal doses (111), flunisolide has a narrow safety margin. The more recently released topical corticosteroids have been designed to be both highly lipophilic, and consequently poorly absorbed, and to undergo rapid metabolism (112). When used in recommended doses for either intranasal use or for normal pulmonary inhaled doses, significant systemic absorption and steroid side effects have seldom been observed with the newer agents (107, 113, 114). However, even with low dose intranasal steroid use (115), a few cases of posterior subcapsular cataracts have been noted, and measurable growth retardation may occur in children (116). There are also single case reports of detectable adrenal suppression from intranasal beclomethasone (117,118), and fluticasone (119), and measureable changes in daily serum and urinary cortisol levels with both fluticasone and budesonide (120). Furthermore, in circulating lymphocytes, specific glucocorticoid receptor regulated genes show measureable changes in levels of messenger RNA transcription during intranasal treatment with fluticasone or budesonide (120). Pulmonary doses of inhaled corticosteroids are higher than nasal doses, but clinically apparent, steroid-induced side effects are still very uncommon (107), although dose related mild suppression of bone metabolism, of unknown clinical relevance, may be detected (26, 121). Occasionally some growth retardation is seen in children, but final adult height appears unaffected (79). Whether or not these changes may eventually increase osteoporosis is not known (121), although a recent ten year study suggests not (122). Rarely, significant adrenal suppression can occur with usual pulmonary doses, and with progressively higher dose pulmonary treatment, toxicity may ultimately approach that of chronic oral steroid use (121).

Recommendations for Use of Inhaled Corticosteroids

Unfortunately, little objective data on relative drug potencies and risks in humans is available to allow detailed comparison of the available topical corticosteroids (121). Also of concern is the fact that significant differences in patient susceptibility to steroid-induced side effects have been observed (121). Finally, the potential for complications from very long periods of topical corticosteroid use is not known. Taken together, all of these observations indicate the need for thoughtful use of corticosteroids. There are four aspects to this intelligent use of topical steroids. First, adhere to proper indications and doses, using published guidelines for asthma treatment (30,123,124). Second, use the lowest possible dose of steroids that can control the asthma, in topical form whenever possible (125, 126). Third, use all possible measures to reduce unwanted corticosteroid absorption, for example, by use of spacers and mouth rinsing to minimize swallowing of inhaled steroids (127). Fourth, periodically re-evaluate each patient's condition to see if their corticosteroids might be decreased or eliminated. After prolonged corticosteroid therapy, in some cases it is possible to simply discontinue treatment with no clinical worsening (128). In other cases, the corticosteroids may be replaced with a mast cell stabilizer, or the corticosteroid dose may be reduced by addition of a mast cell stabilizer (97, 129), theophylline, antihistamine, or immunotherapy, or by successful efforts at environmental control measures and nutritional management.

Immunotherapy

Use of immunotherapy for asthma has recently been controversial. Prior to the introduction of corticosteroids, immunotherapy was the only available anti-inflammatory treatment for asthma, and was widely practiced. Since the advent of effective drug treatments, the risk-benefit analysis for immunotherapy has been re-evaluated, and in some areas, particularly in Scandinavia and the United Kingdom, concern over possible anaphylaxis risk has led to a marked decrease in immunotherapy, while in the rest of the world and the U.S., immunotherapy use continues (130). Available data do suggest that asthmatics are at increased risk of undergoing anaphylaxis, as compared to other allergy patients treated with immunotherapy (131). On the other hand, a recent meta-analysis (132) has reviewed twenty placebo-controlled, randomized, double-blind studies of immunotherapy for asthma, and finds that there is significant improvement with immunotherapy. Positive effects are found for symptomatic improvement, reduced medication use, reduced bronchial hyper-reactivity, and improvement in FEV1 . Immunotherapy should therefore be considered for use in asthmatics, especially as a means of reducing the need for corticosteroid therapy.

Summary

Asthma is an increasingly common disease worldwide, and is frequently seen in the Otolaryngology patient population. Because unrecognized asthma is an important source of patient morbidity and is a potential risk during medical and surgical treatment of head and neck patients, Otolaryngologists should be familiar with this disease. Diagnosis of asthma relies primarily on clinical suspicion in patients with wheezing, dyspnea, chest discomfort, or cough. Appropriate use of pulmonary function tests, environmental control measures, anti-inflammatory therapy, nutritional management, and patient education is critical to successful intervention. Rational use of pharmacotherapy and immunotherapy entails knowledge of indications, side effects, limitations, and useful combinations of treatments. Finally, utilization of timely consultations with other knowledegable physicians may be essential in developing an effective, individualized treatment plan for each patient.

Acknowledgement:

The author thanks Nancy E. Frazier, Beverly J. Flynn, and Sally C. Schumann, Cape Cod Hospital Medical Library, for their expertise in literature search strategies and procurement of rare source materials

References

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