Peripheral blood mononuclear cell transcriptomic trajectories reveal dynamic regulation of inflammatory actors in delirium.
Sara C LaHue, Naoki Takegami, Rubinee Simmasalam, Abiya Baqai, Elena Munoz, Anya Sikri, Thibault du Buisson de Courson, Nilika S Singhal, Walter Eckalbar, Charles R Langelier, Carolyn M Hendrickson, Carolyn S Calfee, David J Erle, Matthew F Krummel, Prescott G Woodruff, Tomiko Oskotsky, Marina Sirota, Adam Ferguson, Vanja C Douglas, John C Newman, Samuel J Pleasure, Michael R Wilson, COMET consortium, Neel S Singhal
Author Information
Sara C LaHue: Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA.
Naoki Takegami: Weill Institute for Neurosciences, UCSF.
Rubinee Simmasalam: Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA.
Abiya Baqai: Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA.
Elena Munoz: Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA.
Anya Sikri: Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA.
Thibault du Buisson de Courson: Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA.
Nilika S Singhal: Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA.
Walter Eckalbar: Department of Medicine, UCSF.
Charles R Langelier: Division of Infectious Diseases, UCSF.
Carolyn M Hendrickson: Department of Medicine, UCSF.
Carolyn S Calfee: Department of Medicine, UCSF.
David J Erle: Department of Medicine, UCSF.
Matthew F Krummel: UCSF CoLabs, UCSF.
Prescott G Woodruff: Department of Medicine, UCSF.
Tomiko Oskotsky: Bakar Computational Health Sciences Institute, UCSF. ORCID
Marina Sirota: Bakar Computational Health Sciences Institute, UCSF.
Adam Ferguson: Weill Institute for Neurosciences, UCSF.
Vanja C Douglas: Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA.
John C Newman: Buck Institute for Research on Aging, Novato, USA. ORCID
Samuel J Pleasure: Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA.
Michael R Wilson: Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA. ORCID
Neel S Singhal: Department of Neurology, School of Medicine, University of California-San Francisco (UCSF), USA. ORCID
Delirium is a neurologic syndrome characterized by inattention and cognitive impairment frequently encountered in the medically ill. Peripheral inflammation is a key trigger of delirium, but the patient-specific immune responses associated with delirium development and resolution are unknown. 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 and innate immune markers. Novel associations with delirium were found in genes related to stress granule assembly and and , which mediate T-cell responses. These findings provide insights into the peripheral immune responses accompanying delirium and their modulation by corticosteroids. Future trials targeting aberrant inflammatory responses may mitigate the severe outcomes associated with delirium due to COVID19.
