Cytokines of the Interleukin-1 superfamily and Interleukin-6 are associated with neuroinflammation and brain injury in Herpes Simplex Virus Encephalitis

Early adjunctive anti-inflammatory therapy could modulate the immune response and improve clinical outcomes in Herpes Simplex Virus encephalitis (HSE). However, data on the array of inflammatory mediators to target and the immunomodulatory drugs to use are limited. This study aimed to determine key cytokines associated with HSV-induced neuroinflammation, brain injury, and clinical outcomes, and the effect of dexamethasone on their blood levels. We profiled the levels of forty-eight cytokines and four brain injury biomarkers (GFAP, NfL, Tau and UCHL-1) in CSF and serum samples collected from HSE adult patients; recruited in a randomised clinical trial to receive either adjunctive dexamethasone plus intravenous aciclovir or aciclovir alone. We found that cytokines of the IL-1 superfamily (IL-1, IL-18, IL-1RA) and IL-6 were most consistently associated with neuroinflammation, brain injury and poor clinical outcomes. Spearman correlation analysis revealed positive associations between CSF concentrations of IL-1RA, IL-18, and IL-10 and serum concentrations of IL-1RA and IL-6 with the astrocytic marker, Glial fibrillary acidic protein (GFAP). Levels of CSF IL-1RA and IL-18 were associated with increased volume of cerebral oedema on MRI and were significantly raised (p < 0.05) in both patients with abnormal GCS scores (< 15) and worse outcomes (LoS <3). Moreover, the blood levels of these key mediators were unaffected by adjunctive dexamethasone treatment. Taken together, this work identified key targets for direct, targeted adjunctive anti-inflammatory and neuroprotective therapy to be taken forward in clinical trials, aiming to improve outcomes following HSE.