Short-Acting β2-Agonist Use Could Be a Confounding Factor for Interpreting Increased IL-6.

To the Editor:

The proinflammatory cytokine IL-6 is upregulated approximately threefold during naturally occurring asthmatic attacks (1). Importantly, in relation to overuse of β2-agonists in the context of asthma exacerbations, IL-6 induction by rhinovirus was further augmented by β2-agonists (2). In vitro studies on bronchial epithelial cells demonstrated that IL-6 is upregulated by β2-agonists (3).

SARP (Severe Asthma Research Program) enrollment procedures determined that participants maintained medications for asthma as prescribed by their care provider (4). I could not find details on the asthma medications use in the SARP III trials (4, 5). Peters and colleagues (5) did not address the possibility that β2-agonist use might be confounding the association between plasma IL-6 and higher asthma exacerbation rates. Knowledge about the asthma medication and ideally about the blood levels of β2-agonists is needed to exclude any influence of β2-agonists on the increment of IL-6 increase before adopting it as an exacerbation-prone biomarker.

Jevnikar and colleagues (6) recently described a subset of patients with asthma and high IL-6TS. This subset constitutes a novel asthma phenotype associated with frequent exacerbations, eosinophilia, airway inflammation, remodeling, and impaired epithelial integrity. It was noted that 86% of the patients of U-BIOPRED (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes) cohorts used short-acting β2-agonists and that 98% of the patients used long-acting β2-agonists (7), but the authors did not take into account this probable confounding factor.

I would like to alert the authors of both studies that IL-6 could be upregulated by overuse of β2-agonists.