A103-01 The Sepsis Response Signature Identifies Patients With Treatable Immune Traits in COVID-19

Rationale Immunomodulatory agents have been applied to sepsis with mixed results but were beneficial in hypoxemic COVID-19 patients; hypoxemia may be a surrogate for immune dysregulation, but more precise predictors are needed. The sepsis-response signature (SRS) leveraged bulk RNA sequencing to identify two reproducible sepsis endotypes associated with prognosis and a differential response to corticosteroids. We hypothesized the SRS-1 endotype may identify patients with treatable immune traits. Methods We enrolled 351 patients presenting to the emergency room at a tertiary care hospital with febrile respiratory illness of which 302 patients had SARS-CoV-2 infection by nasal PCR, and 4 patients from a trial evaluating anti-IL6R therapy in severe COVID-19. Clinical features and peripheral blood were collected at enrollment and longitudinally. Samples were characterized with single-cell RNA sequencing and Olink proteomics. Cellular subsets were annotated and gene programs were derived with consensus non-negative matrix factorization. We applied the SepstratifR classifier to classify patients as SRS-1, and modeled the association between cellular subsets, gene expression, gene programs and serum protein with SRS-1 over time and after treatment with anti-IL6R. All linear models were adjusted for demographic factors, presence of SARS-CoV-2 infection, and severity. Results Within the observational cohort, 106 (30.2%) patients were classified as SRS-1 on presentation. All anti-IL6R treated patients were classified as SRS-1 at enrollment. SRS-1 patients at presentation had more significant respiratory failure (OR = 2.2, p = 0.001), and staying or transitioning to SRS-1 was associated with maximum severity (OR = 2.5, p = 0.006). SRS-1 patients enriched for CD14+CLU+ myeloid-derived suppressor cells (MDSCs) (L2FC=0.64, p = 4.9E-6), CD14+ hematopoietic stem cells (L2FC= 0.13, p = 5E-4), and NK cells (L2FC=0.26, p = 0.004), but demonstrated broad reductions in T lymphocyte subsets. There was repression of gene expression across subsets excepting CD14+ monocytes. These subsets expressed the sepsis-associated monocyte program (MS1) to varying degrees and expression associated with SRS-1 (p = 5.4E-17). Serum IL-6 levels were associated with SRS-1 (p = 5.4E-8) and MS1 expression (p = 8.2E-53). Three of the four patients treated with IL6R blockade transitioned from SRS-1 within 3 days of administration with concomitant obliteration of the MS1 program and rescue of antigen presentation. Conclusion The SRS-1 endotype associates with COVID-19 severity and is characterized by enrichment for MDSCs expressing the MS1 signature and repression of antigen expression and T lymphocyte function independent of severity. The MS1 program is obliterated by IL6R blockade with a consequent transition from the SRS-1 endotype. The SRS-1 endotype may identify patients with treatable traits responsive to immunomodulatory therapy.