Original article
Cytokines and acute phase response in delirium,☆☆

https://doi.org/10.1016/j.jpsychores.2006.11.013Get rights and content

Abstract

Objective

This study aimed to examine the expression patterns of pro- and anti-inflammatory cytokines in elderly patients with and without delirium who were acutely admitted to the hospital.

Methods

All consecutive patients aged 65 years and older, who were acutely admitted to the Department of Internal Medicine of the Academic Medical Center, Amsterdam, a tertiary university teaching hospital, were invited. Members of the geriatric consultation team completed a multidisciplinary evaluation for all study participants within 48 h after admission, including cognitive and functional examination by validated measures of delirium, memory, and executive function. C-reactive protein and cytokines (IL-1β, IL-6, TNF-α, IL-8, and IL-10) were determined within 3 days after admission.

Results

In total, 185 patients were included; mean age was 79 years; 42% were male; and 34.6% developed delirium within 48 h after admission. Compared to patients without delirium, patients with delirium were older and had experienced preexistent cognitive impairment more often. In patients with delirium, significantly more IL-6 levels (53% vs. 31%) and IL-8 levels (45% vs. 22%) were above the detection limit as compared with patients who did not have delirium. After adjusting for infection, age, and cognitive impairment, these differences were still significant.

Conclusions

Proinflammatory cytokines may contribute to the pathogenesis of delirium in acutely admitted elderly patients.

Introduction

Infections in humans are characterized by local, systemic, and central nervous system (CNS) effects. The effects of inflammation and infection on the aging brain are highly complex. The mechanisms, however, that mediate the behavioral effects of peripherally released cytokines on the brain, often described as sickness behavior, have partly been elucidated over the past decade [1], [2], [3], [4].

Cytokines, a diverse group of peptide molecules that regulate cell and tissue functions, are responsible for sickness behavior including malaise, fatigue, and reduced appetite. These cytokines, mainly interleukin-1 (IL-1α and IL-1β), IL-6, and tumor necrosis factor (TNF)-α, are supposed to act on the brain via a fast neural pathway and a slower humoral pathway [5]. The proinflammatory IL-1 is able to induce its own synthesis and the synthesis of other cytokines that potentiate (e.g., TNF-α, IL-6, and IL-8) or antagonize its effect (IL-10). Proinflammatory cytokines are involved in the production of IL-1 in the brain [4], [5], [6], and peripheral and central administration of IL-1β in animal studies induced all components of sickness behavior [7]. In humans, a high-serum IL-6 and other cytokines have been associated with neuropsychiatric illness like cognitive decline in dementia [8] and in depression [9] and cognitive impairment and fatigue in cancer [10], [11].

Delirium, an acute neuropsychiatric syndrome, characterized by deranged consciousness and by cognitive and attentional disturbances with a typical fluctuating course, is also hypothesized to be induced by circulating cytokines [12], [13]. Although a variety of factors are associated with delirium, such as psychiatric illness, older age, and cerebral vascular disease, the pathophysiology of delirium remains poorly understood. Interestingly, delirium has been recognized as a frequent manifestation of infections in the elderly [14]. Delirium usually disappears once the underlying illness that causes delirium has been resolved and is a fully reversible phenomenon [15] similar to cytokine-induced sickness behavior. Moreover, animal studies have demonstrated that cytokines can cause a reduction in the acetylcholinergic pathways [16], which are supposed to be impaired in delirium [17]. Based on this information, delirium may be considered as a distinct part of sickness behavior that can be seen as the outward expression of a potentially reversible episode of brain inflammation and is triggered by peripheral immune stimulation [12], [13], [18], [19]. These and other studies resulted in several hypotheses [13], [20], [21], suggesting that cytokines may be involved in the pathogenesis of delirium. There are, however, no data on the association between peripheral cytokine levels and delirium.

Section snippets

Aim

We performed a study among consecutive elderly patients who were acutely admitted to the hospital to compare the expression patterns of pro- and anti-inflammatory cytokines in patients with and without delirium.

Patients

All consecutive patients aged 65 years or older, who were acutely admitted to the Department of Medicine of the Academic Medical Center, Amsterdam, a 1024-bed university teaching hospital, were invited. Patients were excluded from the study if they were unable to speak or understand Dutch or English, if they or their relatives did not give permission to participate in the study, if they came from or were transferred to another ward, or if they left the ward within 48 h. Before enrolment,

Results

During the inclusion period, 576 patients aged 65 years and older were admitted. Of these patients, 88 came from another ward, resulting in 488 eligible patients. One hundred eighty-two patients were not included because no informed consent was provided, because the patients were unable to speak or understand Dutch or English, or because they were discharged within 48 h. In total, 306 patients were included; due to financial and time limitations of our experienced laboratory analyst, a random

Discussion

In this sample of consecutive, acutely hospitalized elderly patients, 34.6% met the criteria for delirium. Patients with delirium had significantly less often IL-6 and IL-8 levels below the DL. These differences remained after adjusting for age, preexisting cognitive impairment, and hospital admission due to infectious disease.

This is the first study that shows a relationship between peripherally measured cytokine levels and delirium as a symptom/exponent of sickness behavior in acutely

Acknowledgments

The authors thank Tom van der Poll, Jenny Pater, and Alex Vos for the determination of serum inflammatory marker levels and for their suggestions after reading the manuscript. The authors likewise express their gratitude to Caroline van Rijn, Marjolein van der Zwaan, and Arja Giesbers for interviewing all the patients and their relatives.

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    Funding source was our own hospital (it was an unrestricted grant).

    ☆☆

    S.R. is the principal investigator of the study; she designed the protocol, supervised its progress, and was involved in the acquisition of the data. B.M. was involved in the planning of the study and the acquisition of the data. J.K. was responsible for the statistical analysis. S.R., B.M., J.K., and M.L. drafted the manuscript. All authors contributed to the interpretation of the data and to the revisions of the paper; all read and approved the final manuscript.

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