Single cell RNA-seq discovery of blood biomarkers predicting treatment outcome in severe asthma patients

Biologic monoclonal antibody therapies for severe asthma target the Type 2 endotype through blockade of the IgE, IL-5/eosinophil, or IL-4/13 pathways, which represents at least two-thirds of patients, and have led to significant clinical benefits in severe asthma management. However, studies show that 10-20% of patients may be non-responders and require a change in therapy. There is also the emerging concept that a significant percentage of patients may enter clinical remission, with a very high level of disease control and virtually symptom-free. These clinical scenarios and heterogeneity increase the need to develop blood-based biomarkers that can predict outcome. Identifying markers of clinical remission may also have potential for expanding access to other severe asthma patients not currently identified through serum IgE, blood eosinophils, or FeNO. In this study, blood was taken prior to therapy from severe asthma patients (n=31) with a Type 2 endotype, high serum IgE, atopy, and blood eosinophilia who qualified for both Omalizumab (anti-IgE) and Mepolizumab (anti-IL-5) and were randomised to receive either treatment. White blood cells underwent single cell RNA-sequencing and patients were assessed for clinical outcomes over a 6-month period. Non-response to either Omalizumab or Mepolizumab was predicted by a gene signature expressed in antiviral plasmacytoid dendritic cells. Clinical remission was predicted by a common gene signature in rarer CD34+ blood progenitors and circulating MAIT cells with a ROC Curve AUC of 0.91 and 0.88, respectively. This discovery study identifies novel blood biomarkers that predict clinical outcome to multiple biologic therapies in severe asthma.