Deciphering Immune Endotypes Within Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) Syndrome

ABSTRACT Background Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a rare, severe delayed‐type drug hypersensitivity reaction. It can range from mild reactions with little or no organ involvement to severe, potentially life‐threatening forms. It is unclear whether these distinct clinical phenotypes are associated with different immune signatures and, ultimately, distinct pathomechanisms. Aims The aim of this study was to explore systemic immune profiles of DRESS patients. Our hypothesis was that different grades of DRESS severity would be associated with distinct inflammatory profiles. Methods In this multicentric study, we included a total of 26 DRESS patients from Switzerland and South Africa. Serum samples were obtained at the time of diagnosis. 6 healthy controls (HC) were included. Serum levels of inflammation–/immune response‐associated proteins were measured by two panels [180 proteins] of a targeted high‐throughput proteomics assay (OLINK). Results Our targeted proteomics findings from serum show immune activation in DRESS. Type 2‐/eosinophil‐axis associated cytokines (e.g., IL4, IL5 and IL13) were increased in all DRESS patients compared to HC. In addition, we saw an upregulation of proinflammatory mediators like IL6, IL10, CXCL9, and IFN‐gamma and of immune regulatory proteins such as PSIP1, ADA, and SH2D1A. Regarding disease severity, all grades showed overlap in inflammation‐related upregulated proteins, including chemokines (CXCL9, CXCL10), interferon signaling (IFN‐gamma), and immune checkpoint molecules (LAG3, PD‐L1). Strikingly, there was a heterogeneous expression of immune proteins in DRESS patients regardless of the severity grade. We identified three immune clusters based on unsupervised clustering. Group 1 was characterized by the upregulation of IL7 and milder immune activation. Group 1 patients were older, had shorter drug latency, and longer hospitalizations. Group 2 displayed features of a pronounced type 3 immune response. This was marked by increased levels of Th17‐related cytokines and proteins involved in Toll‐like receptor signaling, contributing to a more inflammatory profile. There was a significantly higher rate of HIV‐positive patients in this group 2. Group 3 was defined by high eosinophil counts and elevated eosinophil‐associated mediator expression, namely elevated levels of like, for example, MCP‐4 (CCL13), which is highly effective at recruiting eosinophils, along with a predominant type 2 cytokine response. Conclusion Our targeted serum proteomics findings suggest a systemic immune activation, particularly of the type 2−/eosinophil axis. Our findings of different DRESS immune profiles could, if further validated, pave the way for patient stratification and more targeted treatment approaches.