Adding omalizumab therapy to guideline-directed care for inner-city children, adolescents, and young adults with allergic asthma resulted in a significant and clinically meaningful decrease in asthma-related symptoms of 0.48 days per 2-week period, as compared with placebo (from 1.96 to 1.48 days), a reduction in the number of participants with at least one exacerbation (30.3% in the omalizumab group vs. 48.8% in the placebo group), fewer hospitalizations (1.5% vs. 6.3%), and a reduced need for inhaled glucocorticoids to maintain this improved level of asthma control (budesonide-equivalent dose, 663 μg per day in the omalizumab group vs. 771 μg per day in the placebo group). No differences of concern regarding safety were noted between the two groups.
Omalizumab is already indicated for the treatment of moderate-to-severe asthma in patients older than 11 years of age and is recommended for step 5 or step 6 treatment in report 3 of the NAEPP guidelines.3
Our purpose in designing this study was to examine whether specifically targeting the allergic component in persistent asthma would offer a benefit beyond that provided by conventional treatment for asthma control, regardless of disease severity. Indeed, our study population represented all levels of asthma severity. After the 4-week run-in treatment period, during which conventional medications for asthma control were administered, 54% of the study population could be categorized as having severe asthma and 19% as having moderate asthma, according to report 3 of the NAEPP guidelines.3
Despite the use of guidelines-based management with scheduled opportunities to adjust the treatment, these levels of disease severity remained the same throughout the study in the placebo group. We chose to study children, adolescents, and young adults living in low- income urban areas because of the importance of allergy in the presentation of asthma in this group and the high associated morbidity.10,11
Even though we found omalizumab effective at all levels of asthma severity, we do not advocate its use outside of current recommendations27–29
given its cost and remaining questions regarding long-term safety in children.30,31
We do, however, believe that this study provides a strong proof of concept that the allergic component of asthma is crucial in this population. This postulate is further supported by our finding that omalizumab’s benefit was greatest in participants who were both sensitized and exposed to cockroach allergen and in those sensitized to dust mites, two major relevant indoor allergens.
A striking additional post hoc finding was the marked reduction in seasonal exacerbations seen with omalizumab (). Viral respiratory infections are a major cause of exacerbations, especially in the fall, with the start of school,24,25
but they were identified in less than 60% of the samples available for analysis, suggesting that other factors, such as allergen exposure, pollution, stress, or bacteria, also contribute to the risk of exacerbation.25,32
Omalizumab was equally effective in reducing exacerbations in the fall and the spring, with or without a viral infection, but it did not appear to prevent viral respiratory infections, since the rate of virus detection was similar in the omalizumab and placebo groups at a study visit not associated with an exacerbation.
The effect of omalizumab on exacerbations occurring during the fall and spring supports the notion of an interaction between allergy and viral infections in inducing asthma exacerbations, as previously suggested by epidemiologic research.33
Although the mechanisms of such an interaction have not been defined, a number of theories have been proposed. For example, both allergic inflammation and viral respiratory infections can injure airway epithelium, and one could speculate that they act synergistically to promote exacerbations.34
Furthermore, since human rhinovirus replication is increased in damaged epithelium, one could also speculate that underlying allergic inflammation serves to enhance viral growth, leading to more severe respiratory infection and thus increasing the chance of an exacerbation.35,36
Finally, it is possible that IgE-dependent mechanisms interfere with antiviral responses, leading to more severe and prolonged viral illnesses.37
Notably, neither guidelines-directed treatment nor omalizumab prevented all exacerbations (), suggesting that additional mechanisms underlie the residual risk of asthma exacerbations in this population.
Previous work to identify patients most likely to have a response to omalizumab has pointed toward IgE levels and asthma severity, but these criteria have limitations.19,38
Although the effectiveness of omalizumab was noted across many participant characteristics, participants who had been both sensitized and exposed to cockroach allergen had the greatest benefit (a 71.2% reduction in exacerbations); the combination of sensitization and exposure may therefore serve as a criterion to be applied in targeting its use for optimal effectiveness and cost benefits.27–29
Another potential approach to the same goal would be to focus the use of omalizumab on preventing seasonal peaks in asthma exacerbations; this would require studies examining a short, seasonal course of treatment in those at highest risk. The fact that the maximum effect of omalizumab occurred within 1 month, rather than 3 to 4 months, as previously reported,19,39–41
supports the potential benefit of this treatment approach.
In summary, omalizumab reduces symptoms and exacerbations in children, adolescents, and young adults with persistent allergic asthma, providing protection beyond that conferred with guidelines-directed care. Our findings may also help identify those patients most likely to have a response to omalizumab and provide insight into novel mechanisms of asthma exacerbations that could lead to improved treatment.