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Abstract
Introduction and objectives Epidemiologic studies have implicated aeroallergens and respiratory infections as triggers underlying seasonal increases in asthma exacerbations in spring and autumn months. These seasonal factors may trigger or amplify airway inflammation in atopic, Type 2 high asthma patients that precipitates acute worsening of symptoms. Biologic therapies targeting Type 2 cytokine pathways have demonstrated efficacy in reducing the rate of severe asthma exacerbations, particularly in patients selected on the basis of Type 2 biomarkers. In children with asthma, increased inhaled corticosteroid or anti-IgE therapy has been found to reduce the rate of seasonal exacerbations. We hypothesised that lebrikizumab (anti-IL-13) therapy would likewise be effective in reducing seasonal exacerbations in adults with asthma.
Methods We conducted post-hoc analyses of the Phase III LAVOLTA studies (NCT01867125 and NCT01868061) to assess the seasonal dependence of exacerbations and efficacy of lebrikizumab in 2,148 adults with moderate to severe asthma. We employed Poisson regression utilising linear mixed models to estimate the per-month (normalised by hemisphere) annualised exacerbation rate and treatment effect of lebrikizumab in reducing exacerbations (percent rate reduction).
Results Per-month exacerbation rates in placebo treated eosinophil-low (<300/µL) patients were lower and less variable (0.34 to 0.72 per year) than in eosinophil-high (≥300/µL) patients; (0.63/year in August to 1.43/year in September). The 95% confidence intervals for the per-month lebrikizumab treatment effect overlapped with zero in eosinophil-low patients for all calendar months. The maximum per-month treatment effects for eosinophil-high patients were observed during the autumn and spring months (62.7 [10.1, 84.5]% for September and 65.1 [8.6,86.7]% for May). The minimum per-month treatment effects were observed in the summer months (11.3[−148.7, 68.4]% for July and 6.6[−166.0, 67.2]% for August).
Conclusions We conclude that seasonal spikes in exacerbations may be primarily dependent on Type 2 inflammatory processes. The molecular pathways underlying asthma exacerbations are heterogeneous and therapeutic strategies targeting Type 2 biology alone may have the greatest efficacy in limiting seasonal spikes in exacerbation rates. Overall, these data highlight that a significant proportion of asthma exacerbations may be independent of seasonal influences and/or Type 2 biology and that increased therapeutic efficacy may require targeting multiple distinct pathways in asthma.
Seasonal analysis of exacerbations in subjects defines by baseline blood eosinophil counts. Unadjusted exacerbation rates are plotted as a function monthe normalised by hemisphere. The month for corresponding hemispheric season are annotated in plot margins. Analyses for subject with baseline blood eosinophils < 300/μL or > 300/μL are plotted on left and right panels respectively.