Delirium due to hip fracture is associated with activated immune-inflammatory pathways and a reduction in negative immunoregulatory mechanisms

Abstract

Background The objectives of this study were to delineate whether delirium in older adults is associated with activation of the immune-inflammatory response system (IRS) as indicated by activation of M1, T helper (Th)1, and Th17 profiles, and/or by reduced activities of the compensatory immunoregulatory system (CIRS), including Th2 and T regulatory profiles. Methods We recruited 65 older adult patients with a low energy impact hip fracture who underwent hip fracture operation. The CAM-ICU and the Delirium Rating Scale, Revised-98-Thai version (DRS-R-98) were assessed pre-operatively and 1, 2 and 3 days after surgery. Blood samples (day 1 and 2) post-surgery were assayed for cytokines/chemokines using a MultiPlex assay and the neutrophil/lymphocyte ratio. Results We found that delirium and/or the DRS-R-98 score were associated with IRS activation as indicated by activated M1, Th1, Th17 and T cell growth profiles and by attenuated CIRS functions. The most important IRS biomarkers were CXCL8, interleukin (IL)-6, and tumor necrosis factor-α, and the most important CIRS biomarkers were IL-4 and soluble IL-1 receptor antagonist. We found that 42.5% of the variance in the actual changes in the DRS-R-98 score (averaged from day 1 to day 3) was explained by T cell growth factors, baseline DRS-R-98 scores and age. An increase in the NLR reflects overall IRS, M1, Th1, Th17, and Th2 activation. Conclusions Post-hip surgery delirium is associated with activated IRS pathways and appears especially in patients with lowered CIRS functions.

Reactivity to neural tissue epitopes, aquaporin 4 and heat shock protein 60 is associated with activated immune-inflammatory pathways and the onset of delirium following hip fracture surgery

“…The intra-assay CV for all analytes was 11.0%. We used fluorescence intensities, blank analyte subtracted, in the data analysis because fluorescence intensities are a better option than concentrations, especially when using multiple plates [2]. Because more than 20% of the measured concentrations of IL-2, IL-10, IL-12, and IL-13 were below the detection limit, these cytokines/growth factors were excluded from the analyses of single cytokines/growth factors.…”

“…Delirium is a neuropsychiatric syndrome characterized by impairments in neurocognitive functions, awareness, psychomotor functions and circadian rhythms, and is common in hospitalized older adults following hip fracture surgery [1, 2]. The prevalence of this condition in the post-operative period is 16.9-24% [3, 4].…”

“…There is now evidence that delirium in older adults after surgery for hip fracture is associated with activation of immune-inflammatory pathways. Previous research has linked increases in peripheral C-reactive protein (CRP), interleukin-6 (IL-6), CXCL8 (IL-8), and tumor necrosis factor (TNF)-α to the onset of post-operative delirium [2]. These results indicate that activation of M1 macrophages and an acute phase (or inflammatory) response are associated with delirium.…”

“…Recently, we established that post-surgery delirium due to hip fracture is characterized by an increased activity of the immune-inflammatory response system (IRS) and a relative decrease in the activity of the compensatory immunoregulatory system (CIRS) as indicated by an increased IRS/CIRS ratio [2]. The IRS response comprises activation of the M1 phenotype (with increased levels of IL-6, CXCL8, and TNF-α), Th-1 phenotype (based on assays of IL-2, IL-12 ad interferon-γ (IFN-γ)), as well as the Th-17 phenotype (including IL-6 and IL-17) [2, 17]. The CIRS is the aggregate of different negative immunoregulatory factors, including Th-2 (e.g.…”

“…IL-4), T regulatory (Treg) (e.g. IL-10) and cytokine receptors, e.g., the IL-1 receptor antagonist (sIL-1RA) which have anti-inflammatory properties thereby preventing hyperinflammation [2, 17]. In delirium, the IRS/CIRS ratio is increased indicating that CIRS activities (particularly IL-4 and sIL-1RA) are insufficient to regulate and attenuate the IRS [2].…”