(1049) Severe or Mild Transcriptomic Score Is Conserved in Infectious and Noninfectious Critical Illness

Introduction: We previously described the Severe-or-Mild (SoM) transcriptomic host response signature in pan-viral infections, which quantifies the detrimental and protective host response. Given its broad conservation across viral etiologies, we hypothesized that this immune signature would be conserved across infectious and non-infectious critical illness and would carry therapeutic relevance.

Methods: To evaluate the conservation of the SoM signature across infectious and non-infectious illness, we integrated 1,922 peripheral blood bulk transcriptome profiles from 18 publicly available datasets from patients with bacterial infections, trauma, and healthy controls using COCONUT co-normalization. We then evaluated the association of SoM signature with severity using Jonkheere-Terpstra test and Fisher’s Exact Test.

To evaluate the association of host response scores with differential response to immunomodulation, we used datasets that treated patients with septic shock (E-MTAB-7851) or trauma (GLUE Grant) with steroids. Patients were divided into high and low protective immune responses based on the median protective score at baseline. Association with outcomes was assessed using Fisher’s Exact Test.

Results: The SoM score was associated with severity across both infectious (JT test p < 2.2e-16) and traumatic (JT test p = 9.4e-8) critical illness. SoM signature predicted ICU admission or mortality in bacterial infections with an AUROC of 0.8 (0.77-0.83). In the Glue grant, a high SoM signature was associated with increased risk of multi-system organ failure or 30-day mortality (OR=2, 95% CI 1.4-2.8, p< 0.001). High protective module score at baseline was associated with an increased risk of mortality when treated with steroids in septic shock patients (OR 4.8, 1.6-15.6, p = 0.002) and trauma patients (OR 9.0, 2.7 – 28.6, p = 0.001).

Conclusions: The SoM signature is conserved across infectious and non-infectious critical illness and is associated with differential treatment response to steroids. This has broad implications to the risk stratification and treatment of systemic immune dysregulation in critical care.