Delirium in hospitalized COVID-19 patients is associated with dynamic changes in peripheral immune gene expression

Abstract Delirium is a neurologic syndrome characterized by inattention and cognitive impairment frequently encountered in medically ill older adults. As a hallmark of age-related brain vulnerability, delirium offers a clinical model to investigate how peripheral immune responses contribute to acute brain dysfunction. Peripheral inflammation is a key trigger of delirium, but the patient-specific immune responses that drive delirium onset and recovery remain poorly understood. This retrospective cohort study of prospectively collected biospecimens examines RNA sequencing from peripheral blood mononuclear cells of adults hospitalized for COVID-19 to better understand patient-specific factors associated with delirium ( n = 64). Longitudinal transcriptomic analyses highlight persistent immune dysregulation in delirium, marked by increasing expression trajectories of genes linked to innate immune pathways, including complement activation, cytokine production, and monocyte/macrophage recruitment. Genes involved adaptive immunity showed a declining trajectory over time in patients with delirium. Although corticosteroid treatment suppressed some aspects of immune hyperactivation, aberrant responses contributing to delirium were exacerbated. Delirium resolution was characterized by normalization of key transcripts such as CCL2 and innate immune markers. Novel associations with delirium included transcripts related to stress granule assembly and the T cell regulators DUSP2 and KLF10 . Delirium in COVID-19 is associated with distinct and dynamic peripheral immune trajectories that are modulated by corticosteroids. Further understanding these mechanisms has important implications for preventing delirium in older adults. These findings provide novel mechanistic insights with translational relevance for immunomodulatory strategies targeting maladaptive immune responses to prevent or treat delirium in medically ill populations.