Association of Soluble ST2 With Functional Outcome, Perihematomal Edema, and Immune Response After Intraparenchymal Hemorrhage

Abstract

Background and Objectives:Perihematomal edema (PHE) contributes to poor outcome after deep intraparenchymal hemorrhage (IPH), which is characterized by neuroinflammation and an influx of peripherally derived innate immune cells. We previously identified soluble ST2 (sST2) as a candidate for immune-mediated secondary brain injury. Leveraging prospectively collected cohorts from two centers, we sought to determine if sST2 was associated with functional outcome, PHE and the immune response following IPH.Methods:Patients with deep IPH were enrolled within 36 hours of ictus and blood was collected for sST2 and immune cell measurement. Hematoma volume and PHE were measured on serial CT scans. Good outcome was defined as modified Rankin Scale 0-3 at 90 days. Linear mixed effects models were used to analyze the relationship between sST2 and PHE over time. Flow cytometry was used to identify shifts in immune cell populations associated with sST2. Immunohistochemistry of human brain tissue was used to identify ST2-expressing cells in the perihematomal region.Results:The 55 included patients had median admission GCS of 14 [IQR 9-15], ICH score of 1 [IQR 1-2], and hematoma volume of 8.6mL [IQR 3.4-13.8]. Receiver operating curve analysis found sST2 level to be predictive of poor outcome with an area under the curve of 0.763 (95% CI 0.632 – 0.894) and Youden’s optimum cut point of 61.8ng/mL (p< 0.001). sST2 remained an independent predictor after adjustment for ICH score (adjusted OR 2.53 [95% CI 1.03-6.19],p= 0.042). Measurement of PHE found those patients with high sST2 to have greater edema volume over time (β = 1.07 [95% CI 0.51-1.63],p< 0.001). High sST2 was associated with a shift towards an innate peripheral immune response (monocytes and NK cells; 68.6±5.1% vs. 47.5±4.0%;p= 0.003).Discussion:Our findings demonstrate that elevated sST2 links the peripheral innate immune response to PHE volume and outcome after IPH. This knowledge is relevant to future studies that seek to identify IPH patients at highest risk for immune-mediated injury or limit injury through targeted interventions.

Updates in Management of Large Hemispheric Infarct

“…Optic nerve sheath diameter is another noninvasive bedside tool used to detect elevations in intracranial pressure (ICP), although there are issues with interrater variability 55 and differences in normative values between men and women. 56 Serum markers including endothelin-1, 57 matrix metalloproteinase-9 (MMP-9), 58 and soluble serum stimulation-2 59 have been associated with edema but are not available for routine clinical use. ICP monitoring is not recommended on the basis that clinical deterioration and outcomes cannot be reliably predicted.…”

Is Soluble ST2 a Novel Biomarker of Intracerebral Hemorrhage?

“…In this issue of Neurology ®, Bevers et al 5 publish a study that looks at the association of serum soluble suppression in tumorigenicity-2 (sST2) with PHE, peripheral blood immune response, and functional outcome of patients with ICH. Interleukin 33 (IL-33) and ST2 ligand-receptor system represents interleukin signaling pathway, and the interaction between sST2 receptor with IL-33 blocks the IL-33/ST2L system leading to proinflammatory response.…”