Urinary Bromotyrosine Measures Asthma Control and Predicts Asthma Exacerbations in Children

Current guidelines for asthma treatment from the National Institutes of Health (NIH) emphasize not only the need for asthma control, but also a reduction of airway inflammation. This is because of the wealth of data indicating airway inflammation directly contributes to airway hyperresponsiveness and obstruction, giving rise to clinical symptoms at baseline and, worse yet, during exacerbations.1,2 Mechanism-based noninvasive markers that concomitantly track with the extent of underlying airway inflammation, the degree of asthma control, and the risk of future exacerbations, could prove to be of tremendous clinical utility in achieving the goals set forth by NIH guidelines. Sputum eosinophils have shown some promise in this regard. They serve as an indirect metric of the extent of eosinophilic airway inflammation that, according to early studies, tracks with indexes of asthma control and maybe even predicts exacerbations in children with asthma.3,4 Unfortunately, samples for sputum eosinophils are relatively difficult to collect, especially in children, because the hypertonic saline solution induction protocols are not well tolerated; moreover, the cytologic examination required is both relatively expensive and time-consuming.5 An alternative and perhaps better tolerated noninvasive diagnostic test for monitoring airway inflammation is exhaled nitric oxide (NO). Some studies have demonstrated a correlation between exhaled NO levels and eosinophilic airway inflammation. NO is produced abundantly in asthmatic airways as a result of the up-regulation of inducible NO synthase by proinflammatory mediators.7 However, exhaled NO, too, has its limitations, including an unclear relationship to risk for asthma exacerbation.8,9 Beyond NO, the inflammatory milieu of asthmatic airways gives rise to a diverse array of oxidant species.10 Although these oxidants are generally too labile to measure directly, the molecular footprints they leave behind can serve as quantitative indexes of the precise inflammatory processes at play. For example, we have shown that eosinophils generate potent brominating oxidants, such as hypobromous acid, when recruited to asthmatic airways and activated by proinflammatory mediators.11,12 On activation, eosinophils generate a respiratory burst and secrete granule proteins, including eosinophil peroxidase. We have shown that eosinophil peroxidase uses respiratory burst–generated hydrogen peroxide to form reactive brominating species such as hypobromous acid, a highly potent antimicrobial oxidant that can preferentially brominate protein tyrosine residues to form 3-bromotyrosine (BrTyr), a stable post-translational modification of proteins.11,12 BrTyr can be measured noninvasively in urine as a relatively specific molecular marker of eosinophil activation (respiratory burst and degranulation). After oxidative modification (eg, bromination) of proteins, as airway remodeling occurs and the modified proteins are digested/degraded, the oxidized amino acids are efficiently removed by excretion in urine. In fact, in a recent clinical study of patients with asthma and healthy control subjects, we showed that urinary BrTyr serves as a noninvasive marker that is higher in patients with asthma and associated with multiple spirometric parameters of airway obstruction.13 In this study, we sought to investigate the potential clinical utility of urinary BrTyr as a sensitive noninvasive marker for both assessing the degree of asthma control and the risk of subsequent acute decompensation of chronic asthma control in pediatric participants. In parallel, the ability of exhaled NO, a distinct noninvasive marker of airway inflammation, along with traditional blood and spirometric measures of asthma control, were examined for their ability to predict asthma exacerbations over a near term (6-week) follow-up period.