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To the Editor:
Omalizumab is an anti-IgE monoclonal antibody that reduces both baseline disease activity and the risk of allergen-triggered acute exacerbations among patients with allergic asthma. The effect of omalizumab on asthma exacerbation caused by rhinovirus, the dominant trigger for acute exacerbation among children, is less well understood (1, 2). Furthermore, whether IgE-targeted therapy moderates the actual severity of acute asthma exacerbation has not been addressed.
In this observational prospective cohort study, 265 subjects aged 6 to 17 years with physician-diagnosed asthma were enrolled at the time of acute asthma exacerbation and followed until they had returned to symptomatic baseline. The Boston Children’s Hospital institutional review board approved this study, and consent was obtained before participation. Study methods are published elsewhere (3). Here we present data on the subset of patients (n = 161) who were single positive only for rhinovirus (out of a panel of 12 common respiratory viruses) at the time of presentation to the emergency department with acute asthma exacerbation. Study cohort characteristics are shown in Table 1. Time to every-2-hours albuterol refers to the hours over which β-agonist therapy was weaned. A standard clinical assessment and management plan, which matched treatments to clinical symptom scores, dictated the albuterol weaning schedule. The Modified Pulmonary Index Score is a validated indicator of acute asthma exacerbation severity (4).
Comparisons were made between subjects treated with omalizumab (n = 28) and those managed primarily with inhaled corticosteroids (ICS; n = 133). Individuals in the omalizumab group had all received treatment within the 4 weeks before study enrollment. Accounting for body weight and total IgE levels, each subject was current with their anti-IgE therapy according to a revised omalizumab dosing table (5). Multivariate linear and logistic regression analyses were used to investigate associations between predictor variables and continuous and binary outcome variables, respectively. Covariates for multivariable models were chosen based on a purposeful selection algorithm, with a significance threshold of 0.25 and a change in coefficient threshold of 20%. The following covariates were included in the multivariable models: age, sex, race, baseline FEV1 percent predicted, composite asthma severity index (6), lapsed prescriptions (>60 d since filling controller medication), high-dose daily ICS, symptom duration before presentation, total number of immunoCAP positives (out of a panel of nine antigens), annual income, and season. A two-sided P value<0.05 was considered significant.
Examining multiple outcome measures, we found that the acute severity of rhinovirus-triggered asthma exacerbation among omalizumab-treated patients was significantly lower than patients treated primarily with ICS therapy (Table 2), even though the omalizumab group had worse baseline disease activity (Table 1). These outcome measures included assessment of initial clinical severity (Modified Pulmonary Index Score, exacerbation peak expiratory flow), risk of hospital admission, intensity of therapeutic interventions (risk of using supplemental oxygen, noninvasive positive pressure ventilation, and intensive care unit admission), and duration of treatment (time to albuterol every 2 h and hospital length of stay). The association between omalizumab and reduced acute severity remains significant even after adjusting for the following confounders: age, sex, race, baseline lung function, baseline disease activity (6), medication adherence, controller regimen, symptoms duration, total number of immunoCAP positives (a measure of allergen-specific IgE), annual income, and season (Table 2). Omalizumab therapy was associated with a 62% reduction in the time to every-2-hours albuterol (omalizumab positive, 15 h; omalizumab negative, 30.8 h; P<0.001) and also with a 42% reduction in hospital length of stay (omalizumab positive, 34.5 h; omalizumab negative, 58.5 h, P<0.001). Finally, to verify that omalizumab treatment effectively interfered with binding of IgE to the cognate Fc receptor, we measured free IgE using well-established methods (7) and found that treated patients often had near undetectable free IgE levels (omalizumab positive, mean 66±76.4 units/ml; omalizumab negative, 383±335 units/ml; P<0.001).
Rhinovirus is the dominant trigger for acute exacerbation among children with asthma and is associated with the actual severity of acute exacerbation (3). Here we report a strong association between omalizumab treatment and reduced severity of acute asthma exacerbation triggered by rhinovirus, one that is robust to the outcome measure used and encompasses several different facets of acute severity. Although previous studies have found that omalizumab reduces the risk of seasonal asthma exacerbation, to our knowledge this is the first study to offer evidence that IgE-targeted therapy might directly modify the phenotype of asthma exacerbation caused by an infectious trigger. A role for omalizumab in mitigating the severity of rhinovirus-triggered asthma exacerbation is biologically plausible, as rhinovirus has been shown to interact with allergic status to regulate asthma phenotypes (3).
Several lines of evidence suggest that the factors that contribute to the risk of asthma exacerbation may be distinct from those that regulate the actual severity of acute exacerbation in children (e.g., References 4, 8, and 9). Even in adults, the factors related to baseline disease activity demonstrate poor overall sensitivity and specificity for predicting future severe exacerbations (10). Indeed, the factors that contribute to interindividual variation in acute severity of asthma exacerbation are poorly understood and represent a considerable knowledge gap. The distinction between factors that contribute to the risk of asthma exacerbation and those that influence asthma exacerbation severity are important to understand because health care costs, morbidity, and mortality each have a strong relationship to the severity of asthma exacerbation (12).
This study has several limitations. First, this is an observational study in which patients were not randomized to receive omalizumab, so our results may be confounded by unmeasured covariates. However, it is notable that patients treated with omalizumab had significantly worse baseline disease activity than patients treated primarily with ICS (Table 1). Second, this study was not adequately powered to determine whether omalizumab mitigates the severity of acute asthma exacerbation triggered by other viruses. However, there is robust clinical and biological evidence demonstrating an interaction between rhinovirus and allergic sensitization (Reference 3 and references therein), which raises the possibility that omalizumab may specifically alter the clinical course of rhinovirus infection in pediatric patients with asthma. Last, the associations that we identified in this cohort of children presenting to the emergency department may not be generally applicable to other populations of children with asthma.
Our results suggest that therapies targeting IgE-initiated signaling events, which have been shown to modify baseline disease activity and reduce the frequency of exacerbation (2), may also be effective in reducing the actual severity of rhinovirus-triggered acute asthma exacerbation. Given the lack of antiviral therapies against rhinovirus, IgE-targeted therapies may offer a promising avenue to explore for prevention and treatment of rhinovirus-triggered severe acute asthma exacerbation in children.
Supported by National Institutes of Health grants T32 HD040128 (D.B.K.), K12 HD047349 (D.B.K.), U01 AI110397 (W.P.), U01 AI126614 (W.P.), R01 AI073964 (W.P.), K24 AI106822 (W.P.), and U10 HL098102 (W.P.); the American Medical Association Seed Grant (D.B.K.); and the American Asthma Foundation (J.N.H.). This work was conducted with support from Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102), and financial contributions from Harvard University and its affiliated academic healthcare centers.
Author Contributions: D.B.K., W.P., and J.N.H.: study conceptualization, design, and implementation; data acquisition, statistical analysis, and interpretation; and manuscript preparation and critical revision. M.C.M., N.S., B.J.S., and C.D.S.: data acquisition and manuscript revision. K.A.N.: study conceptualization, design, and implementation; data acquisition; and manuscript revision. All authors agree to the final version of the manuscript and to be held accountable for all aspects of the work.