Bachman, Kay A

Objective To evaluate the effects of mepolizumab therapy on the blood transcriptome in patients with severe eosinophilic asthma (SEA) and to determine whether changes in gene expression predict responsiveness to mepolizumab treatment. Methods Fourteen consecutive patients diagnosed with SEA were prospectively enrolled. Each patient had sequential blood samples obtained pre-initiation and at 4, 8, and 12 weeks post-initiation of mepolizumab. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples for bulk RNA sequencing. Paired differential expression (DE) gene analysis was performed comparing baseline gene expression versus all timepoints. Changes in gene expression were also compared between responders versus nonresponders to mepolizumab treatment. Finally, gene set enrichment analysis was evaluated across timepoints and its interaction with the response to mepolizumab treatment. Results Principal component analysis of all genes demonstrated a homogeneous distribution, which did not separate into distinct groups based on either timepoint or therapeutic response. At week 12, 149 genes had significant DE (FDR < 0.05) compared to baseline. When performing all-way timepoint comparisons, 74 genes (63 protein-coding) were found to be downregulated at weeks 4, 8 and 12 compared to baseline, but no differences were observed between post baseline timepoints. Twenty-eight genes (16 protein-coding) did change with progression of time and were associated with response to therapy, and 56 protein-coding genes distinguished responders and nonresponders. At week 12, nonresponders had a high enrichment of genes involved with signaling pathways, including cytokines, growth factors, cell differentiation markers, and protein kinases. Conclusion In this exploratory study, mepolizumab use was associated with limited global transcriptomic separation with some preliminary differential-expression and enrichment findings. No definitive mechanistic or predictive response signatures were identified due to the study limitations. Future studies, including larger cohorts followed for longer durations with interrogation of specific immune subsets, may offer additional insight into the pathophysiology of severe eosinophilic asthma and into predicting response to mepolizumab treatment.

Abstract Rationale Difficulty of asthma ascertainment and its associated methodologic heterogeneity have created significant barriers to asthma care and research. Objectives We evaluated the validity of an existing natural language processing (NLP) algorithm for asthma criteria to enable an automated chart review using electronic medical records (EMRs). Methods The study was designed as a retrospective birth cohort study using a random sample of 500 subjects from the 1997–2007 Mayo Birth Cohort who were born at Mayo Clinic and enrolled in primary pediatric care at Mayo Clinic Rochester. Performance of NLP-based asthma ascertainment using predetermined asthma criteria was assessed by determining both criterion validity (chart review of EMRs by abstractor as a gold standard) and construct validity (association with known risk factors for asthma, such as allergic rhinitis). Measurements and Main Results After excluding three subjects whose respiratory symptoms could be attributed to other conditions (e.g., tracheomalacia), among the remaining eligible 497 subjects, 51% were male, 77% white persons, and the median age at last follow-up date was 11.5 years. The asthma prevalence was 31% in the study cohort. Sensitivity, specificity, positive predictive value, and negative predictive value for NLP algorithm in predicting asthma status were 97%, 95%, 90%, and 98%, respectively. The risk factors for asthma (e.g., allergic rhinitis) that were identified either by NLP or the abstractor were the same. Conclusions Asthma ascertainment through NLP should be considered in the era of EMRs because it can enable large-scale clinical studies in a more time-efficient manner and improve the recognition and care of childhood asthma in practice.