New asthma guidelines emphasize control, regular monitoring
ABSTRACTUpdated asthma care guidelines have recently been released. This review will focus on several elements in the third Expert Panel Report (EPR3) guidelines that reflect substantial differences from recommendations of the second EPR (EPR2) guidelines, issued in 1997 and updated in 2002. A major difference is the emphasis on asthma control. Asthma control can be assessed serially by the use of validated instruments. The goal of asthma therapy is to achieve asthma control by reducing current impairment and future risk. Recommendations for asthma pharmacotherapy have also been revised since the release of the updated EPR2 guidelines. The revisions in asthma management proposed in these guidelines offer the potential for improved asthma care outcomes in the United States.
KEY POINTS
- The EPR3 recommends that management decisions be based initially on asthma severity, and subsequently on asthma control as assessed serially by validated tests.
- Omalizumab, a monoclonal antibody against immunoglobulin E, is the only adjunctive therapy to demonstrate efficacy when added to high-dose inhaled corticosteroids plus long-acting beta agonists in patients with severe, persistent, allergic asthma.
- The EPR3 guidelines recommend consideration of allergen immunotherapy for patients with mild or moderate persistent allergic asthma.
LABAs: Risks and benefits
Two studies21,22 have suggested that asthmatic patients who are homozygous for Arg/Arg at codon 16 of the beta-2 adrenergic receptor are predisposed to untoward asthma outcomes with regular exposure to LABAs. However, other data23–25 do not support the contention that B16 Arg/Arg patients experience adverse asthma outcomes with LABA exposure. In two recently published studies, no difference in rates of exacerbations, severe exacerbations, lung function, frequency of reliance on SABA, or nocturnal awakenings was observed in patients receiving formoterol combined with budesonide24 or salmeterol combined with fluticasone25 according to genotype. A prospective study26 also found no statistically significant difference in exacerbation rates according to beta adrenergic receptor genotype in individuals randomized to LABA monotherapy, or LABA combined with inhaled corticosteroids.
The updated EPR2 asthma guidelines,3 published in November 2002, stipulated that LABAs were the preferred controller agent to “add on” to low-dose inhaled corticosteroids for patients with moderate persistent asthma, and that the combination of low-dose inhaled corticosteroids and LABA was associated with superior outcomes: reduction of symptoms, including nocturnal awakening, increase in lung function, improvement in health-related quality of life, decreased use of “rescue” medication, and reduced rate of exacerbations and severe exacerbations, compared with higher-dose inhaled corticosteroid monotherapy. This management recommendation was categorized as level A, on the basis of data from multiple randomized, controlled, double-blinded trials.27–29 Additional evidence14,30 and data from two meta-analyses31,32 have provided further support for this recommendation, while no evidence linking LABA exposure to risk for fatal or near-fatal asthma has been found in cohort or case-control studies.33–38
Based on safety concerns, the EPR3 guidelines1 recommend that medium-dose inhaled corticosteroids be regarded as equivalent to adding LABAs to low-dose inhaled corticosteroids, and state: “the established, beneficial effects of LABA for the great majority of patients whose asthma is not well controlled with [inhaled corticosteroids] alone should be weighed against the increased risk for severe exacerbations, although uncommon, associated with daily use of LABA.”1
There is currently an honest difference of opinion39,40 among asthma specialists as to how this management recommendation for moderate persistent asthma—now depicted at “step 3” in the EPR3 guidelines (Table 4)—should be implemented. The LABA controversy was reviewed previously in the Cleveland Clinic Journal of Medicine.41
THE ROLE OF OMALIZUMAB: WEIGHING COST VS BENEFIT
The 2002 update to the EPR2 guidelines3 was issued before omalizumab (Xolair) was approved in June 2003.
Patients with severe persistent asthma are categorized in steps 5 or 6 in the EPR3 guidelines (Table 5).1 Preferred management for these patients includes inhaled corticosteroids in high doses combined with long-acting beta agonists and, for step 6 patients, oral corticosteroids.
Omalizumab was approved for management of patients with moderate or severe persistent asthma who are not achieving the goals of asthma management on inhaled corticosteroids, who exhibit a wheal-flare reaction to a perennial allergen, and whose immunoglobulin E (IgE) level is in the range of 30 to 700 IU/mL.42 Omalizumab dosing is based on the serum IgE level and on body weight.
Omalizumab, an anti-IgE monoclonal antibody
Omalizumab is a recombinant, humanized, monoclonal anti-IgE antibody that binds to IgE at the same Fc site as the high-affinity IgE receptor. Its primary mechanism of action is the binding of free IgE in the circulation, forming biologically inert, small complexes that do not activate complement and are cleared by the reticuloendothelial system.42 Its secondary mechanism of action entails a reduction in the number of high-affinity receptors on basophils, from approximately 220,000 to 8,300 receptors per cell. The latter effect was associated with a 90% reduction in histamine release from basophils in response to ex vivo challenge with dust mite allergen.43
Benefit in randomized trials
Omalizumab has been associated with statistically and clinically significant benefit in randomized, double-blind, placebo-controlled trials.44,45
Humbert et al46 randomized 419 patients whose asthma was not adequately controlled on high-dose inhaled corticosteroids and long-acting beta agonists, who were 12 to 75 years old, with reduced lung function and a history of recent asthma exacerbation, to treatment with omalizumab or placebo. Omalizumab was associated with a statistically significant reduction in the rate of asthma exacerbations and severe asthma exacerbations, as well as statistically significant improvements in asthma-related quality of life, morning peak expiratory flow rate, and asthma symptom scores.
These data support the recommendation in EPR3 to consider a trial of omalizumab in properly selected patients with severe, persistent allergic asthma.
