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See Section 1, "Overall Methods Used To Develop This Report," for the literature search strategies and tallies of results used to update each class of medication discussed in this section. Evidence Tables were prepared for: 11, Inhaled Corticosteroids: Combination Therapy; 12, Inhaled Corticosteroids: Dosing Strategies; 13, Immunomodulators: Anti-IgE; 14, Leukotriene Receptor Antagonists: Monotherapy/Effectiveness Studies; 15, Bronchodilators: Safety of Long-Acting Beta 2 -Agonists; 16, Bronchodilators: Levalbuterol.

Pharmacologic therapy is used to prevent and control asthma symptoms, improve quality of life, reduce the frequency and severity of asthma exacerbations, and reverse airflow obstruction. Recommendations in this "Component 4: Medications," reflect the scientific concepts that asthma is a chronic disorder with recurrent episodes of airflow limitation, mucus production, and cough and that the severity of the underlying asthma may vary over time. Asthma medications are categorized into two general classes: long-term control medications taken daily on a long-term basis to achieve and maintain control of persistent asthma (these medications are also known as long-term preventive, controller, or maintenance medications) and quick-relief medications taken to provide prompt reversal of acute airflow obstruction and relief of accompanying bronchoconstriction (these medications are also known as reliever or rescue medications). Patients who have persistent asthma require both classes of medication. and present summaries of the indications, mechanisms, potential adverse effects, and therapeutic issues for currently available long-term control and quick-relief medications. The discussion in this component includes the following: an overview of asthma medications—both long-term control and quick-relief—and an overview of complementary alternative medicine strategies.

The Expert Panel recommends that long-term control medications be taken daily on a long-term basis to achieve and maintain control of persistent asthma. The most effective long-term-control medications are those that attenuate the underlying inflammation characteristic of asthma (Evidence A).

Long-term control medications include ICSs, inhaled long-acting bronchodilators, leukotriene modifiers, cromolyn, theophylline, and immunomodulators. Because eosinophilic and lymphocytic inflammation is a constant feature of the mucosa of the airways in asthma, the most effective long-term control medications are those that attenuate inflammation (; ; ). The Expert Panel defines anti-inflammatory medications as those that cause a reduction in the markers of airway inflammation in airway tissue or airway secretions (e.g., eosinophils, mast cells, activated lymphocytes, macrophages, and cytokines; or ECP and tryptase; or extravascular leakage of albumin, fibrinogen, or other vascular protein) and thus decrease the intensity of airway hyperresponsiveness. Because many factors contribute to the inflammatory response in asthma, many drugs may be considered anti-inflammatory. It is not yet established, however, which anti-inflammatory actions are responsible for therapeutic effects, such as reduction in symptoms, improvement in expiratory flow, reduction in airway hyperresponsiveness, prevention of exacerbations, or prevention of airway wall remodeling.

The Expert Panel concludes that ICSs are the most potent and consistently effective long-term control medication for asthma (Evidence A). The broad action of ICSs on the inflammatory process may account for their efficacy as preventive therapy. Their clinical effects include reduction in severity of symptoms; improvement in asthma control and quality of life; improvement in PEF and spirometry; diminished airway hyperresponsiveness; prevention of exacerbations; reduction in systemic corticosteroid courses, ED care, hospitalizations, and deaths due to asthma; and possibly the attenuation of loss of lung function in adults (; ; ; ; ; ; ; ; ; ; ; ). Which of these clinical effects depend on specific anti-inflammatory actions of corticosteroids is not yet clear. Corticosteroids suppress the generation of cytokines, recruitment of airway eosinophils, and release of inflammatory mediators. These anti-inflammatory actions of corticosteroids have been noted in clinical trials and analyses of airway histology (; ; ; ; , ; ; ). The anti-inflammatory effects of corticosteroids are mediated through receptors that modulate inflammatory gene expression. ICSs do not have the same bioavailability as oral systemic corticosteroids; hence, the risk of potential side effects is substantially reduced with ICSs.

The Expert Panel concludes that sensitivity and consequently clinical response to ICS can vary among patients (Evidence B). Variation in sensitivity to ICS therapy may be related to high levels of inflammation, corticosteroid-insensitive pathways, or structural changes refractory to corticosteroid therapy (). Corticosteroid responsiveness is decreased in smokers (; ) and persons who have asthma with predominantly neutrophilic inflammation (; ). Also, African American children who have poor control of their asthma appear to have an increased risk for corticosteroid insensitivity; this could be related to diminished glucocorticoid responsiveness at the cellular level, specifically T lymphocytes (; ). Efficacy of Inhaled Corticosteroids as Compared to Other Long-Term Control Medications as Monotherapy The Expert Panel concludes that studies demonstrate that ICSs improve asthma control more effectively in both children and adults than LTRAs or any other single long-term control medication (Evidence A).

For the EPR—3: Full Report 2007, the evidence of the efficacy of ICS therapy compared to other single daily long-term control medications in patients ≥5 years of age was obtained from nine randomized trials, most of which compared ICS to LTRA; five of these trials had placebo control groups (; ; , ; ). These studies confirm findings discussed in . Patients who have mild or moderate persistent asthma and are treated with ICS, compared to other single long-term control medications, demonstrate greater improvements in prebronchodilator FEV 1 ; reduced airway hyperresponsiveness, symptom scores, exacerbation rates, and symptom frequency; as well as less use of supplemental SABA, fewer courses of oral systemic corticosteroids, and less use of hospitalization. The evidence does not suggest, however, that ICS use is associated with improved long-term postbronchodilator FEV 1 (). Studies comparing ICS to cromolyn or theophylline are limited, but available evidence shows that neither of these long-term control medications appears to be as effective as ICS in improving asthma outcomes. Efficacy of Inhaled Corticosteroid and Adjunctive Therapy (Combination Therapy)

The Expert Panel recommends that when patients ≥ 12 years of age require more than low-dose ICS alone to control asthma (i.e., step 3 care or higher), a therapeutic option is to add LABA to ICS (Evidence A). Alternative, but not preferred adjunctive therapies include LTRA (Evidence B), theophylline (Evidence B), or, in adults, zileuton (Evidence D). (See Evidence Table 11, Inhaled Corticosteroids: Combination Therapy.) For children 0–11 years of age, LABA, LTRA, and, in children 5–11 years of age, theophylline may be considered as adjunctive therapies in combination with ICS (Evidence B, based on extrapolation from studies in older children and adults; see also section 4, "Managing Asthma Long Term" for recommendations on adjunctive therapies at different steps of care for different age groups in children).

Although numerous studies have examined adjunctive therapy in adults, adjunctive therapy has not been studied adequately in children 5–11 years of age, and it has not been evaluated at all in children less than 4 years of age. An extensive review of the literature on this topic, conducted for the , concluded that strong evidence in adults and older children indicates that the combination of ICS and LABA leads to improvements in lung function and symptoms and reduced need for quick-relief SABA. Adding an LTRA or theophylline to ICS or doubling the dose of ICS also was shown to improve outcomes, but the evidence was not as substantial as with the addition of LABA ().

The current review of the evidence supports this conclusion. The 2006 evidence review included studies comparing the combination of ICS and LABA to either baseline dose of ICS (two articles) or increasing doses of ICS (eight articles); comparing the combination of ICS and LTRA to baseline doses of ICS (three articles) or increasing doses of ICS (one article); comparing the combination of ICS and LABA to ICS and LTRA (seven articles); and comparing the combination of ICS and one LABA to another LABA (two articles), as well as three Cochrane Review meta-analyses (See Evidence Table 11, Inhaled Corticosteroids: Combination Therapy for complete citations.). The weight of the evidence reviewed continues to demonstrate that the addition of LABA to ICS leads to greater improvement in lung function, symptoms, and less use of SABA than increasing the dose of ICS or using LTRA as adjunctive therapy. Studies on the addition of LTRA to ICS have limitations that preclude conclusions, although the studies reveal a trend showing that LTRA improved lung function and some but not all trials report improvements in some measures of asthma control (See also the section below on "Leukotriene Modifiers."). Recent data indicate potential risks that need to be considered for uncommon but life-threatening exacerbations associated with the daily use of LABAs (See the section below on "Safety of Inhaled Long-Acting Beta 2 -Agonists."). See also section 4 on "Managing Asthma Long Term" for a discussion of issues to consider regarding combination therapy compared to increasing the dose of ICS.

The Expert Panel concludes that dosages for ICSs vary, depending upon the specific product and delivery devices. (See for issues on delivery devices; see figures 4-4b, and 4-8b in section 4, "Managing Asthma Long Term," for comparative ICS dosages.) For all ICS preparations, the dose-response relationship appears to flatten in patients who have mild or moderate asthma for most clinical parameters and lung function in the low- to medium-dose range (Evidence C).

Although most of the benefits of treatment are achieved with a low dose, the dose-response to ICS may vary, based on the response measured (e.g., improvement in lung function, prevention of exacerbations, or improvement in bronchial hyperresponsiveness, individual variability in response to ICS, and disease severity). Several studies show that for patients who have mild or moderate persistent asthma, use of higher doses improves asthma control modestly if at all (; ; ; ; ; ; ). However, the dose-response continued to improve at a higher dose for patients who have severe asthma (). This efficacy of low-dose ICS therapy may account for the success of once-per-day treatment of patients who have mild or moderate persistent asthma, using several ICS preparations—both ICS alone (; ; ; ; ) and in combination with LABA (). This efficacy may also account for the finding that mild and moderate asthma are as well controlled by starting treatment with a low, standard dose of an ICS as by starting with a high dose (; ). These generalizations may not apply to patients who have more severe, uncontrolled asthma or to patients who have frequent, severe exacerbations. In these patients, twice-daily therapy with a higher dose may be necessary (; ), although control is achieved in a higher proportion of patients, and at a lower ICS dose, when it is given in combination with a LABA (, ).

The Expert Panel recommends that, given the variations over time in the severity of the pathophysiologic processes underlying asthma, it may be useful to adjust anti-inflammatory therapy accordingly (Evidence B). (See Evidence Table 12, Inhaled Corticosteroids: Dosing Strategies.) Several studies have shown that, for most patients whose asthma has been well controlled for at least 2 months by a high dose of an ICS alone, a 50 percent reduction in dose does not lead to loss of control (; ; ; ). This finding does not mean, however, that treatment with an ICS can be stopped altogether, for studies show that asthma control in most patients can worsen within a few weeks when treatment is discontinued (; ). Trials are now focusing on clinical features or "biomarkers" to distinguish between those patients who need continued treatment and those in whom it can be reduced or discontinued (; ).

Whether ICS treatment should be increased temporarily in response to some index of worsening asthma is also being examined. The effectiveness of this adjustable dose approach may be a function of timing or of dose. When asthma symptoms have worsened to the point of qualifying as an asthma exacerbation (See section 5 on "Managing Exacerbations of Asthma" for definition.), simply doubling the regular maintenance dose of ICS treatment does not appear to be effective (; ). Studies that have shown benefit to patients from treatment with an adjustable dose regimen have employed greater increase in the dose of ICS (e.g., fourfold) and/or have made this adjustment earlier, at the first appearance of worsening symptoms (; ; ; ; ; ; ; ). An interesting application of this approach was made possible by the development of an inhaler containing both budesonide (an ICS) and formoterol (a LABA with a rapid onset of action). Although this product does not have approved labeling for use as an acute quick-relief medication, one study has shown that use of a low dose of budesonide from this combination inhaler twice daily (maintenance therapy) plus additional use for relief of symptoms (adjustable therapy) was associated with a lower rate of asthma exacerbations and a lower cumulative dose of budesonide than was twice daily treatment with a fourfold greater dose of budesonide alone (; ; ).

Another approach to adjustable therapy with an ICS is to link the dose adjustments to measurement of a biomarker of airway inflammation. Three biomarkers have been examined: bronchial reactivity to methacholine (), sputum eosinophils (), and the concentration of nitric oxide in exhaled air (FeNO) (). In these studies, biomarker-adjusted therapy reduced the rate of asthma exacerbations. In two of the studies (; ), the cumulative dose of ICS was reduced as well as in comparison to standard maintenance therapy alone.

The Expert Panel concludes that ICSs are the most effective long-term therapy available for patients who have persistent asthma and, in general, ICSs are well tolerated and safe at the recommended dosages (Evidence A). Systemic activity has been identified, particularly at high doses (See figures 4-4b and 4-8b.), for a definition of high-, medium-, and low-dose ICSs), but their clinical significance remains unclear (). Furthermore, there may be interindividual variations in dose-response effects; thus, some patients may experience effects at lower doses. See Key Points, above, for a summary of recommendations to minimize the potential for adverse effects. In general, the potential for adverse effects must be weighed against the risk of uncontrolled asthma; to date, evidence supports the use of ICS, especially at low and medium doses (; ; ; ; ; ). The Expert Panel recommends the following actions to minimize potential adverse effects of ICS. Specific recommendations and evidence rank are presented under "Prevention and Treatment."

Oral candidiasis (thrush) is one of the most common adverse effects of ICSs. Positive throat cultures of Candida can be identified in about 45–58 percent of patients, whereas clinical thrush is diagnosed in only 0–34 percent of patients (; ; ). With lower dosages of ICS, candidiasis is uncommon (5 percent) (), although it is more frequent in adults than in children. Prevention and Treatment: Use a spacer or VHC with a non-breath-activated MDI to reduce the incidence of colonization and clinical thrush; rinse mouth with water after inhalation (). No data are available on the use of spacers or VHCs with ultrafine-particle-generated HFA MDIs. Administer ICS less frequently (bid versus qid). Topical or oral antifungal agents should be used to treat active infections (). Dysphonia is reported in 5–50 percent of patients who use an ICS and is associated with vocal stress and increasing dosages of ICS (). Prevention and Treatment: Use a spacer or VHC with a non-breath-activated MDI, temporarily reduce dosage, or rest for vocal stress ().

Reflex cough and bronchospasm. Prevention and Treatment: These effects can be reduced by slower rates of inspiration and/or use of a spacer or valved holding chamber or by pretreatment with SABA. There is no convincing evidence that the routine use of a SABA before each dose of ICS increases intrapulmonary delivery of the ICS or reduces dosage requirement ().

A reduction in growth velocity may occur in children or adolescents as a result of inadequate control of chronic diseases such as asthma or from the use of corticosteroids for treatment. Overall, however, the available cumulative data about children suggest that, although low or medium doses of ICS may have the potential of decreasing growth velocity, the effects are small, nonprogressive, and may be reversible (; ; ). Furthermore, studies of early intervention with low- or medium-dose ICS showed significantly improved asthma outcomes, despite a small reduction in growth velocity (; ).

The long-term prospective studies on growth involved budesonide, the retrospective analyses included studies on beclomethasone, and several shorter term studies have been performed on a variety of moieties, but the results have been generalized to include all ICS preparations. Although different preparations and delivery devices may have a systemic effect at different doses, all short-term studies on numerous preparations suggest that the effect of ICS on growth is a drug-class effect. When high doses of ICS are necessary to achieve satisfactory asthma control, the use of adjunctive long-term control therapy should be initiated to reduce the dose of ICS and thus minimize possible dose-related long-term effects on growth. Prevention and Treatment: Physicians should monitor the growth of children and adolescents who are taking corticosteroids by any route and should weigh the benefits of corticosteroid therapy and asthma control against the possibility of growth suppression or delay if a child's or an adolescent's growth appears slowed (Evidence D).

Low and medium doses of ICS appear to have no serious adverse effects on BMD in children (; ). A small, dose-dependent reduction in BMD may be associated with ICS use in patients older than 18 years of age (; ), but the clinical significance of these findings is not clear. A large observational study of older patients (>65 years of age) with prolonged use of ICS showed that, at <2,000 mcg/day of beclomethasone or equivalent, there was no increase in the risk of fractures (). Data in adults suggest a cumulative dose relationship to the effects of ICS on BMD (). Prevention and Treatment: In patients who have risk factors for osteoporosis or low BMD scores, consideration can be given to bone-protecting therapies (e.g., bisphosphonates), although data are mixed in supporting the use of these therapies specifically in asthma patients who are taking ICS (; ) (Evidence C). Measuring BMD may be considered every 1–2 years, depending on duration and dose of ICS and oral corticosteroid treatment as well as previous BMD scores (Evidence D).

Although high doses of ICS theoretically present risks similar to those of systemic corticosteroid treatment, the reports of disseminated varicella in patients receiving only ICS are rare, causality is not clear, and there is no evidence that recommended doses of the ICSs are immunosuppressive. Cases have been reported of children who have severe persistent asthma, and are taking immunosuppressive doses of systemic corticosteroids, developing fatal disseminated disease from varicella infection (; ). Other case reports indicate complications for patients who have Strongyloides or tuberculosis and who take high doses of systemic corticosteroids. Prevention and Treatment of Varicella: Children who require episodic therapy with systemic corticosteroids and who have not had clinical varicella should receive the varicella vaccine (). The vaccine should not be administered to patients who are receiving immunosuppressive doses of systemic corticosteroids (2 mg/kg or more of prednisone equivalent or 20 mg/day of prednisone for more than 1 month), unless this dosage is discontinued for at least 1 month. Children who have completed a short prednisone course may receive varicella vaccine without delay (; ). Children and adults on treatment with immunosuppressive doses of corticosteroids who have not been immunized against varicella and are exposed to varicella infection are candidates for oral antiviral therapy (e.g., valacyclovir). If they develop clinical varicella, intravenous antiviral therapy should be given ().

In children, low- and medium-dose ICS therapy appears to have no significant effects on the incidence of subcapsular cataracts or glaucoma (). In adults, high cumulative lifetime exposure (greater than 2,000 mg of beclomethasone dipropionate or equivalent) to ICS may increase the prevalence of cataracts, as suggested in three retrospective studies of adult and elderly patients (Evidence C) (; ; ). A retrospective, case-control study showed an association between long-term ICS use and the development of glaucoma (). A subsequent cross-sectional, retrospective study in adults reported an association between elevated intraocular pressure and glaucoma in patients who had a family history of glaucoma and used ICS, particularly at higher doses (defined in this study as more than 4 puffs per day). There was no increase in risk in ICS users who did not have a family history of glaucoma (). Prevention and Treatment: These data suggest the advisability of periodic assessments and treatments, if indicated, for increased intraocular pressures in asthma patients who use ICS, particularly at higher doses, and have a family history of glaucoma (Evidence C).

The available evidence indicates that, on average, children may experience only clinically insignificant, if any, effects of low- or medium-dose ICS on the hypothalamic-pituitary-adrenal (HPA) axis (). Rarely, however, some individuals may be more susceptible to the effects of ICS even at conventional doses.

In a study of children, ICS at dosages from 400 to 1,000 mcg/day (budesonide) did not affect fasting glucose or glycosolated hemoglobin. At 1,000 mcg/day, a significantly greater rise in fasting serum insulin levels and glucose during a glucose tolerance test was noted, but results remained within normal limits ().

The Expert Panel recommends that chronic administration of oral systemic corticosteroids as a long-term-control medication be used only for the most severe, difficult-to-control asthma because of well-documented risk for side effects (). The Expert Panel recommends that, because the magnitude of adverse effects is often related to the dose, frequency of administration, and the duration of corticosteroid use (Evidence A), every consideration should be given to minimize systemic corticosteroid doses and maximize other modes of therapy (Evidence D). It is necessary, therefore, to monitor for the development and progression of adverse effects and to take appropriate steps to minimize the risk and impact of adverse corticosteroid effects (Evidence D). Oral systemic corticosteroids suppress, control, and reverse airway inflammation. However, side effects with chronic administration include adrenal suppression, growth suppression, dermal thinning, hypertension, Cushing's syndrome, cataracts, and muscle weakness. Chronic corticosteroid use can also result in immunologic attenuation with loss of delayed-type hypersensitivity, diminished immunoglobulin G (IgG) levels without change in functional antibody response, potential for reactivation of latent tuberculosis infection, and possible increased risk for infection, especially the development of severe varicella ().

Cromolyn and nedocromil are alternative, not preferred, medications for the treatment of mild persistent asthma (Evidence A). They can also be used as preventive treatment before exercise or unavoidable exposure to known allergens (). Although cromolyn and nedocromil have distinct properties (), they have similar anti-inflammatory actions. The mechanism of cromolyn and nedocromil appears to involve the blockade of chloride channels () and modulate mast cell mediator release and eosinophil recruitment (). The two compounds are equally effective against allergen challenge (), although nedocromil appears to be more potent than cromolyn in inhibiting bronchospasm provoked by exercise (; ), by cold dry air (), and by bradykinin aerosol (). Dosing recommendations for both nedocromil and cromolyn are for administration four times a day, although nedocromil has been shown to be clinically effective with twice-daily dosing (; ).

Cromolyn sodium and nedocromil have been shown to provide symptom control greater than placebo in some but not all clinical trials (; ; ) and to confer protection against exacerbations of asthma leading to hospitalization, particularly in children (), and ED visits (). These results, along with the excellent safety profile, justify consideration of cromolyn and nedocromil as treatment options. However, a systematic review () concluded that insufficient evidence existed to conclude that cromolyn had a beneficial effect on maintenance treatment of childhood asthma. Compared to placebo, nedocromil reduces both urgent care visits as well as the need for prednisone, which are meaningful clinical outcomes. However, nedocromil is no different than placebo on all other outcome measures (). Overall, nedocromil is significantly less effective than ICS in improving outcomes measures (). Nedocromil has not been studied adequately in children younger than 5 years of age. As a result of these disparate findings (i.e., some, but limited, effectiveness and strong safety profile), the Expert Panel's opinion is that cromolyn for children of all ages and nedocromil for children ≥5 years of age could be considered in the treatment of persistent asthma for children of all ages, but they are not preferred therapies. The Expert Panel's review of the literature in 2006 found that no new studies have been published that would change these conclusions.

Many different pharmaceutical agents have been tested for their ability to provide long-term control and/or steroid-sparing effects. These agents are loosely defined as immunomodulators. New information is available and discussed here on methotrexate, soluble interleukin-4 (IL-4) receptor, anti-IL-5, recombinant IL-12, cyclosporin A, intravenous immunoglobulin (IVIG), clarithromycin, omalizumab (anti-IgE), and others. For discussion of immunotherapy as an asthma management strategy, see "Component 3: Control of Environmental Factors and Comorbid Conditions That Affect Asthma."

The Expert Panel recommends that omalizumab may be considered as adjunctive therapy in step 5 or 6 care for patients who have allergies and severe persistent asthma that is inadequately controlled with the combination of high-dose ICS and LABA (Evidence B). (See Evidence Table 13, Immunomodulators: Anti-IgE.)