Variability of Type 2 inflammatory markers guiding biologic therapy of severe asthma: A 5-year retrospective study from a single tertiary hospital

Abstract

Background Currently, biotherapy is mainly administered to treat patients with severe asthma with the Type 2 (T2) inflammation phenotype. The variability of T2 inflammatory markers remains poorly understood. Objective We aimed to describe the individual distributions of different biomarkers at varying thresholds and their variation patterns in participants with severe asthma. Methods We retrospectively reviewed the data of participants who had completed 2 or more fraction of exhaled nitric oxide (FeNO) and peripheral blood eosinophil counts in our centre within 5 years. The individual distribution of biomarkers (blood or sputum eosinophils, FeNO, and serum total IgE) with repeated measurements at different thresholds was analysed. The varied patterns of biomarkers were analysed by cluster analysis. Results A total of 241 eligible participants were screened. Through long-term longitudinal multiple measurements, we found that approximately 50% of severe asthmatics had blood eosinophil levels fluctuating around the threshold defined by biological agents. FeNO persisted at levels >19.5 ppb or 25 ppb in more than half of patients; about 30% of participants crossed this threshold. In our centre, 47.4% of participants consistently exceeded sputum eosinophils >3%, and 47.4% of patients crossed this threshold. Approximately 66.7% of participants had more than 50% alterations of serum total IgE, and 98.1% of participants continued to have IgE levels greater than 30 IU/mL. We used cluster analysis to classify variability and levels of FeNO and blood eosinophils and identified 4 patient clusters. Cluster 1 can be summarised as T2 severe asthma with low blood eosinophil levels and stability. Cluster 2 can be summarised as asthma with continuous increase and small fluctuations in various T2 inflammatory markers. Cluster 3 can be summarised as a non/low-T2 inflammatory phenotype. Cluster 4 can be summarised as a stable, moderate T2 inflammatory phenotype. Conclusion We identified the distributions and variable patterns of the T2 inflammatory markers currently used to guide asthma biotherapy in clinical practice. The longitudinal comprehensive multiple assessments of T2 inflammatory markers provide support for initiating biologic therapy patients with severe asthma whose biomarker levels vary.

Corticosteroid Responsiveness Following Mepolizumab in Severe Eosinophilic Asthma—A Randomized, Placebo-Controlled Crossover Trial (MAPLE)

“…This suggests that the increase in percentage of sputum eosinophils is more likely from natural variations in sputum eosinophil count over time. 49 Lastly, a major limitation is that prednisolone was given during stable rather than exacerbation state. As such, patients had wellcontrolled asthma symptoms, which may not be amenable to further improvements.…”

Critical evaluation of asthma biomarkers in clinical practice

“…. 300 cells/mL threshold was chosen only 22% of the participants continued to exceed the cut-off value over time (34).…”

“…Moderately better results were demonstrated in a more restricted population of 75 uncontrolled asthmatic patients, yielding a significant positive relationship between the percentage of S-EOS and B-EOS ( r = 0.3647), yet limited by the use of the cut-off point of B-EOS of 1.5% of WBC ( 33 ). Higher sensitivity and specificity and AUC as a biomarker of S-EOS (≥3%) in a population of uncontrolled asthmatics were reported to increase the peripheral B-EOS cut-off percentage to 2.7% ( 34 ). A systematic review and meta-analysis including 14 studies investigating B-EOS as a predictor marker for airway eosinophilia in patients with asthma yielded overall a modest capacity to distinguish between patients with or without airway eosinophilia (AUC of 0.78) and either eosinophil ≥2 or >3% did not affect the accuracy of the test ( 35 ).…”

“…Repeated B-EOS measurements during a five-year follow-up of severe asthmatics showed a high probability to cross the count above or below the thresholds of 150, 300, 400, and 500 cells/μL. When the 300 cells/mL threshold was chosen only 22% of the participants continued to exceed the cut-off value over time ( 34 ).…”

“…Interestingly the phenotype change was not influenced either by the dose of inhaled corticosteroids or orally used either in phenotypes or by the number of exacerbations reported during this time ( 72 ). Repeated measurements at different thresholds of S-EOS were retrospectively analyzed in a group of severe asthmatics: 47.4% of participants ( n = 87) consistently exceeded S-EOS > 3%, while other 47.4% ( N = 82) were crossing the threshold along the time of observation ( 34 ). Generally, reports assessing longitudinal stability of sputum airway inflammation show a very wide range of longitudinal persistence of elevated eosinophils in both moderate and severe asthma (7 to 76%).…”