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Objectives: Given the strong association between systemic inflammation and cognitive decline, we aimed to determine whether nonneurologic infections are associated with accelerated cognitive decline and structural changes in the brain using pre- and post-infection neuropsychologic assessments and repeated brain MR images., Design: Additional analysis of the prospective observational Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort study., Setting: Single-center study at the Radboud university medical center, Nijmegen, The Netherlands, between January 2006 and September 2015., Patients: Five-hundred three participants (50-85 yr old) with cerebral small vessel disease were included and followed for 9 years., Measurements and Main Results: Participants underwent repeated cognitive measurements and brain MRI. Infectious events were collected. Sepsis episodes were analyzed, and additionally, patients were stratified in three groups: having had a severe infectious episode (e.g., sepsis or hospitalization for infection), a mild, or no infectious episode. Development of dementia, trajectories of cognition, and structural brain changes on MRI in the subsequent follow-up periods were compared between the groups. Complete infectious data were available from 331 patients (mean age 64 ± 8 yr, 57% males). Twenty-nine participants (9%) suffered from a sepsis episode, 69 (21%) from a severe, 201 (61%) from a mild, and 61 (18%) had no infectious episode during follow-up. After correction for age, baseline cognition, and brain volume, each sepsis episode remained associated with an 82% increased risk to develop dementia within the follow-up period (hazard ratio, 1.82; 95% CI, 1.07-3.10; p = 0.027). Infections had no effect on the trajectory of structural changes to the brain after correction for baseline differences., Conclusions: In this 9-year observational follow-up study, sepsis episodes were associated with subsequent development of dementia. Nonneurologic infections had no effect on the trajectory of structural cerebral changes., Competing Interests: Drs. Meijer-van Leijsen and de Leeuw disclosed work for hire. Dr. de Leeuw received funding from a clinical established investigator grant from the Dutch Heart Foundation (2014T060) and by a Vidi innovational grant from The Netherlands ZonMw (grant number 016126351). Dr. Tuladhar received funding from the Dutch Heart Foundation (grant number 2016T044). Dr. Abdo received funding from a research grant from the Netherlands Organization for Health Research and Development (ZonMw Clinical Fellowship Grant 90715610). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Decades of sepsis research into a specific immune system-targeting adjunctive therapy have not resulted in the discovery of an effective compound. Apart from antibiotics, source control, resuscitation and organ support, not a single adjunctive treatment is used in current clinical practice. The inability to determine the prevailing immunological phenotype of patients and the related large heterogeneity of study populations are regarded by many as the most important factors behind the disappointing results of past clinical trials. While the therapeutic focus has long been on immunosuppressive strategies, increased appreciation of the importance of sepsis-induced immunoparalysis in causing morbidity and mortality in sepsis patients has resulted in a paradigm shift in the sepsis research field towards strategies aimed at enhancing the immune response. However, similar to immunosuppressive therapies, precision medicine is imperative for future trials with immunostimulatory compounds to succeed. As such, identifying those patients with a severely suppressed or hyperactive immune system who will most likely benefit from either immunostimulatory or immunosuppressive therapy, and accurate monitoring of both the immune and treatment response is crucial. This review provides an overview of the challenges lying ahead on the path towards precision immunotherapy for patients suffering from sepsis.