Using network analysis to examine links between individual depressive symptoms, inflammatory markers, and covariates.
Fried E I,von Stockert S,Haslbeck J M B,Lamers F,Schoevers R A,Penninx B W J H
Psychological medicine
BACKGROUND:Studies investigating the link between depressive symptoms and inflammation have yielded inconsistent results, which may be due to two factors. First, studies differed regarding the specific inflammatory markers studied and covariates accounted for. Second, specific depressive symptoms may be differentially related to inflammation. We address both challenges using network psychometrics. METHODS:We estimated seven regularized Mixed Graphical Models in the Netherlands Study of Depression and Anxiety (NESDA) data (N = 2321) to explore shared variances among (1) depression severity, modeled via depression sum-score, nine DSM-5 symptoms, or 28 individual depressive symptoms; (2) inflammatory markers C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α); (3) before and after adjusting for sex, age, body mass index (BMI), exercise, smoking, alcohol, and chronic diseases. RESULTS:The depression sum-score was related to both IL-6 and CRP before, and only to IL-6 after covariate adjustment. When modeling the DSM-5 symptoms and CRP in a conceptual replication of Jokela et al., CRP was associated with 'sleep problems', 'energy level', and 'weight/appetite changes'; only the first two links survived covariate adjustment. In a conservative model with all 38 variables, symptoms and markers were unrelated. Following recent psychometric work, we re-estimated the full model without regularization: the depressive symptoms 'insomnia', 'hypersomnia', and 'aches and pain' showed unique positive relations to all inflammatory markers. CONCLUSIONS:We found evidence for differential relations between markers, depressive symptoms, and covariates. Associations between symptoms and markers were attenuated after covariate adjustment; BMI and sex consistently showed strong relations with inflammatory markers.
10.1017/S0033291719002770
Exploratory Investigation of Early Biomarkers for Chronic Fatigue in Prostate Cancer Patients Following Radiation Therapy.
Feng Li Rebekah,Wolff Brian S,Lukkahatai Nada,Espina Alexandra,Saligan Leorey N
Cancer nursing
BACKGROUND:Fatigue is one of the most debilitating adverse effects of cancer therapy. Identifying biomarkers early during cancer therapy may help us understand the biologic underpinnings of the persistence of fatigue following therapy. OBJECTIVE:We aimed to identify early biomarkers of fatigue by examining correlations of levels of cytokines during external beam radiation therapy (EBRT) with persistence of fatigue 1 year following treatment completion in men with nonmetastatic prostate cancer (NM-PC). METHODS:A sample of 34 men with nonmetastatic prostate cancer scheduled to receive EBRT were followed up at baseline (T1), midpoint of EBRT (T2), and 1 year following EBRT (T3). Demographic and clinical data were obtained by chart review. The Functional Assessment of Cancer Therapy-Fatigue was administered to measure fatigue levels. Plasma cytokine levels were determined at T1 and T2 using the Bio-Rad Bio-Plex Cytokine Assay Kits. RESULTS:Significant correlations were observed between levels of interleukin 2 (IL-3), IL-8, IL-9, IL-10, IL-16, interferon γ-induced protein 10, interferon α2, interferon γ, and stromal cell-derived factor 1α at T2 with worsening of fatigue from T1 to T3. CONCLUSIONS:Immunological changes prior to chronic fatigue development may reflect the long-term response to radiation therapy-induced damage. IMPLICATIONS FOR PRACTICE:Early biomarkers for chronic fatigue related to cancer therapy will help advance our understanding of the etiology of this distressing symptom and will help nurses identify patients at risk of developing chronic fatigue after cancer treatment. This information will also aid in patient education, as well as symptom management.
10.1097/NCC.0000000000000381
[Sepsis masquerading as delirium].
Seifert A,Hartog C S,Zweigner J,Schummer W,Reinhart K
Der Anaesthesist
A previously healthy 60-year-old patient presented to the emergency department with severe headache, altered personality and fever. He was treated for bacterial meningitis with delirium of unknown cause but presumed to be due to alcohol withdrawal. Despite receiving the antibiotic therapy regimen recommended for bacterial meningitis the patient's condition rapidly deteriorated with profound delirium and tachypnea. The intensivist who was consulted immediately suspected sepsis-associated organ failure and admitted the patient to the intensive care unit (ICU). The blood culture was positive for Listeria. After 10 days the patient could be discharged from the ICU and ultimately recovered completely. In patients presenting with unexplained delirium or altered personality the suspicion of septic encephalopathy should always be considered. They should be admitted to the ICU and sepsis treatment should be initiated without delay.
10.1007/s00101-017-0361-x
Bispectral EEG (BSEEG) quantifying neuro-inflammation in mice induced by systemic inflammation: A potential mouse model of delirium.
Yamanashi Takehiko,Malicoat Johnny R,Steffen Kalvon T,Zarei Kasra,Li Rui,Purnell Benton S,Najafi Annice,Saito Kenji,Singh Uday,Toth Brandon A,Lee Shelley,Dailey Michael E,Cui Huxing,Kaneko Koichi,Cho Hyunkeun Ryan,Iwata Masaaki,Buchanan Gordon F,Shinozaki Gen
Journal of psychiatric research
Most of the animal studies using inflammation-induced cognitive change have relied on behavioral testing without objective and biologically solid methods to quantify the severity of cognitive disturbances. We have developed a bispectral EEG (BSEEG) method using a novel algorithm in clinical study. This method effectively differentiates between patients with and without delirium, and predict long-term mortality. In the present study, we aimed to apply our bispectral EEG (BSEEG) method, which can detect patients with delirium, to a mouse model of delirium with systemic inflammation induced by lipopolysaccharides (LPS) injection. We recorded EEG after LPS injection using wildtype early adulthood mice (2~3-month-old) and aged mice (18-19-month-old). Animal EEG recordings were converted for power spectral density to calculate BSEEG score using the similar BSEEG algorithm previously developed for our human study. The BSEEG score was relatively stable and slightly high during the day. Alternatively, the BSEEG score was erratic and low in average during the night. LPS injection increased the BSEEG score dose-dependently and diminished the diurnal changes. The mean BSEEG score increased much more in the aged mice group as dosage increased. Our results suggest that BSEEG method can objectively "quantify" level of neuro-Inflammation induced by systemic inflammation (LPS), and that this BSEEG method can be useful as a model of delirium in mice.
10.1016/j.jpsychires.2020.12.036
Biomarkers of Delirium in a Low-Risk Community-Acquired Pneumonia-Induced Sepsis.
Tomasi Cristiane Damiani,Vuolo Francieli,Generoso Jaqueline,Soares Márcio,Barichello Tatiana,Quevedo João,Ritter Cristiane,Dal-Pizzol Felipe
Molecular neurobiology
There are different theories about the pathophysiology of sepsis-associated encephalopathy (SAE), and the majority of our knowledge was derived from critically ill patients. 7In less severe sepsis, it is probable that neuroinflammation can be a major aspect of SAE development. We hypothesized that in non-severe septic patients, blood biomarkers of inflammation, endothelial activation, coagulation, and brain function would be different when compared to patients with and without brain dysfunction. A total of 30 patients presenting with community-acquired pneumonia (CAP)-induced sepsis were included of which 10 (33 %) developed SAE. Eight medical patients admitted to the general ward, except due to sepsis or infection, which developed delirium were included as delirium, non-sepsis group. From all measured biomarkers, only brain-derived neurotrophic factor (BDNF), regulated upon activation normal T cell expressed, and presumably secreted (RANTES), and interleukin (IL)-10 where significantly different when compared to SAE and sepsis groups. In addition, SAE patients presented higher levels of BDNF, vascular cellular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), platelet-derived growth factor (PDGF)-AB/BB and RANTES when compared to delirium patients. In conclusion, the profile of biomarkers differs between SAE, sepsis, and delirium patients, suggesting that pathways related to SAE are different from delirium and from sepsis itself.
10.1007/s12035-016-9708-6
Biomarkers of Delirium Duration and Delirium Severity in the ICU.
Critical care medicine
OBJECTIVES:Both delirium duration and delirium severity are associated with adverse patient outcomes. Serum biomarkers associated with delirium duration and delirium severity in ICU patients have not been reliably identified. We conducted our study to identify peripheral biomarkers representing systemic inflammation, impaired neuroprotection, and astrocyte activation associated with delirium duration, delirium severity, and in-hospital mortality. DESIGN:Observational study. SETTING:Three Indianapolis hospitals. PATIENTS:Three-hundred twenty-one critically ill delirious patients. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:We analyzed the associations between biomarkers collected at delirium onset and delirium-/coma-free days assessed through Richmond Agitation-Sedation Scale/Confusion Assessment Method for the ICU, delirium severity assessed through Confusion Assessment Method for the ICU-7, and in-hospital mortality. After adjusting for age, gender, Acute Physiology and Chronic Health Evaluation II score, Charlson comorbidity score, sepsis diagnosis and study intervention group, interleukin-6, -8, and -10, tumor necrosis factor-α, C-reactive protein, and S-100β levels in quartile 4 were negatively associated with delirium-/coma-free days by 1 week and 30 days post enrollment. Insulin-like growth factor-1 levels in quartile 4 were not associated with delirium-/coma-free days at both time points. Interleukin-6, -8, and -10, tumor necrosis factor-α, C-reactive protein, and S-100β levels in quartile 4 were also associated with delirium severity by 1 week. At hospital discharge, interleukin-6, -8, and -10 retained the association but tumor necrosis factor-α, C-reactive protein, and S-100β lost their associations with delirium severity. Insulin-like growth factor-1 levels in quartile 4 were not associated with delirium severity at both time points. Interleukin-8 and S-100β levels in quartile 4 were also associated with higher in-hospital mortality. Interleukin-6 and -10, tumor necrosis factor-α, and insulin-like growth factor-1 were not found to be associated with in-hospital mortality. CONCLUSIONS:Biomarkers of systemic inflammation and those for astrocyte and glial activation were associated with longer delirium duration, higher delirium severity, and in-hospital mortality. Utility of these biomarkers early in delirium onset to identify patients at a higher risk of severe and prolonged delirium, and delirium related complications during hospitalization needs to be explored in future studies.
10.1097/CCM.0000000000004139
Delirium in patients with acute ischemic stroke admitted to the non-intensive stroke unit: Incidence and association between clinical features and inflammatory markers.
Kozak Hasan Hüseyin,Uğuz Faruk,Kılınç İbrahim,Uca Ali Ulvi,Serhat Tokgöz Osman,Akpınar Zehra,Özer Nejla
Neurologia i neurochirurgia polska
BACKGROUND:Stroke patients with development of delirium have unfavorable outcomes, higher mortality, longer hospitalizations, and a greater degree of dependence after discharge. Studies suggest that delirium is associated with abnormal immunological responses and a resultant increase in inflammatory markers. OBJECTIVE:Our aim was to determine whether there is an entity relationship between delirium, inflammation and acute ischemic stroke (AIS). METHODS:Sixty AIS patients admitted to the hospital were consecutively recruited. Delirium was diagnosed with the clinical assessment according to the Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum levels of Interleukin-1 beta (IL-1 beta), Interleukin 18 (IL-18), Tumor Necrosis Factor-alpha (TNF-alpha), Brain-Derived Neurotrophic Factor (BDNF), and Neuron Specific Enolase (NSE) at admission. RESULTS:Eleven (18.3%) of 60 patients were diagnosed with delirium, and the majority (n=8, 72.7%) was the hypoactive type. Delirious and non-delirious patients had similar demographic and clinical features. Delirious patients had significantly higher lengths of hospital stay, National Institutes of Health Stroke Scale (NIHSS) at admission and discharge compared to non-delirious patients. In addition, there was no significant statistical difference between delirious and non-delirious patients with AIS in respect of levels of TNF-alpha, IL-1 beta, IL-18, BDNF and NSE. This study suggests that delirium is not scarce in patients with AIS admitted to the non-intensive stroke unit, and that delirium developing after AIS seems not to be associated with serum TNF-alpha, IL-1 beta, IL-18, BDNF and NSE but is associated with length of hospital stay and stroke severity.
10.1016/j.pjnns.2016.10.004
C-reactive protein for risk prediction of post-operative delirium and post-operative neurocognitive disorder.
Knaak Cornelia,Vorderwülbecke Gerald,Spies Claudia,Piper Sophie K,Hadzidiakos Daniel,Borchers Friedrich,Brockhaus Wolf-Rüdiger,Radtke Finn M,Lachmann Gunnar
Acta anaesthesiologica Scandinavica
BACKGROUND:Post-operative delirium (POD) and post-operative neurocognitive disorder (NCD) are frequently seen in the elderly. Development of biomarkers for pre-operative risk prediction is of major relevance. As inflammation present before surgery might predispose to POD and post-operative NCD development, we aim to determine associations between pre-operative C-reactive protein (CRP) and the incidence of POD and post-operative NCD. METHODS:In this observational study, we analyzed 314 patients enrolled in the SuDoCo trial, who had a pre-operative CRP measurement the day before surgery. Primary outcomes were POD assessed according DSM-4 from day 1 until day 7 after surgery and post-operative NCD assessed 3 months after surgery. We conducted multivariable logistic regression analysis adjusted for age, sex, randomization, body mass index, MMSE, ASA status, infection/autoimmune disease/malignoma and types of surgery to determine associations between CRP with POD and post-operative NCD, respectively. RESULTS:Pre-operative CRP was independently associated with POD [OR 1.158 (95% CI 1.040, 1.291); P = .008]. Patients with CRP values ≥5 mg/dL had a 4.8-fold increased POD risk [OR 4.771 (95% CI 1.765, 12.899; P = .002)] compared to patients with lower CRP values. However, no association was seen between pre-operative CRP and post-operative NCD [OR 0.552 (95% CI 0.193, 1.581); P = .269]. CONCLUSIONS:Pre-operative CRP levels were independently associated with POD but not post-operative NCD after three months. Moreover, higher pre-operative CRP levels showed higher risk for POD. This strengthens the role of inflammation in the development of POD. Assessment of CRP before surgery might allow risk stratification of POD. TRIAL REGISTRATION:This study was registered with ISRCTN Register 36437985 on 02 March 2009.
10.1111/aas.13441
Increased neutrophil-lymphocyte ratio in delirium: a pilot study.
Egberts Angelique,Mattace-Raso Francesco Us
Clinical interventions in aging
AIM:Delirium is a common and severe complication among older hospitalized patients. The pathophysiology is poorly understood, but it has been suggested that inflammation and oxidative stress may play a role. The aim of this pilot study was to investigate levels of the neutrophil-lymphocyte ratio (NLR) - a marker of systemic inflammation and oxidative stress - in patients with and without delirium. METHODS:This pilot study was performed within a retrospective chart review study that included acutely ill patients, 65 years and older, who were admitted to the ward of geriatrics of the Erasmus University Medical Center. All patients in whom the differential white blood cell (WBC) counts as well as the C-reactive protein (CRP) level were determined within 24 h after admission were included in the present study. Differences in NLR between patients with and without delirium were investigated using univariate analysis of variance, with adjustments for age, sex, comorbidities, CRP level, and total WBC count. RESULTS:Eighty-six patients were included. Thirteen patients were diagnosed with delirium. In adjusted models, higher mean NLR values were found in patients with, than in those without, delirium (9.10 vs 5.18, =0.003). CONCLUSION:In this pilot study, we found increased NLR levels in patients with delirium. This finding might suggest that an inadequate response of the immune system and oxidative stress may play a role in the pathogenesis of delirium. Further studies are needed to confirm the association between NLR and delirium.
10.2147/CIA.S137182
Platelet-to-lymphocyte ratio as a predictive index for delirium in critically ill patients: A retrospective observational study.
Medicine
Delirium is a neuropsychiatric syndrome commonly encountered in critically ill patients, and systemic inflammation has been strongly implicated to underlie its pathophysiology. This study aimed to investigate the predictive value of the platelet-to-lymphocyte ratio (PLR) for delirium in the intensive care unit (ICU).In this retrospective observational study, we analyzed the clinical and laboratory data of 319 ICU patients from October 2016 to December 2017. Using the Locally Weighted Scatterplot Smoothing technique, a PLR knot was detected at a value of approximately 100. Logistic regression was used to investigate the association between the PLR and delirium.Of the 319 patients included in this study, 29 (9.1%) were diagnosed with delirium. In the delirium group, the duration of mechanical ventilation was significantly longer than that in the no-delirium group (40.2 ± 65.5 vs. 19.9 ± 26.5 hours, respectively; P < .001). A multiple logistic regression analysis showed that PLR > 100 (odds ratio [OR]: 1.003, 95% confidence interval [CI]: 1.001-1.005), age (OR: 2.76, 95% CI: 1.110-6.861), and the ratio of arterial oxygen partial pressure to the inspired oxygen fraction (OR: 0.996, 95% CI: 0.992-0.999) were independent predictors of delirium.In our study, a high PLR value on ICU admission was associated with a higher incidence of delirium. Owing to easy calculability, the PLR could be a useful delirium predictive index in ICUs, thereby enabling early interventions to be implemented.
10.1097/MD.0000000000022884
Long-Term Self-Reported Cognitive Problems After Delirium in the Intensive Care Unit and the Effect of Systemic Inflammation.
Wolters Annemiek E,Peelen Linda M,Veldhuijzen Dieuwke S,Zaal Irene J,de Lange Dylan W,Pasma Wietze,van Dijk Diederik,Cremer Olaf L,Slooter Arjen J C
Journal of the American Geriatrics Society
OBJECTIVES:To describe the association between intensive care unit (ICU) delirium and self-reported cognitive problems in 1-year ICU survivors, and investigate whether this association was altered by exposure to systemic inflammation during ICU stay. DESIGN:Prospective cohort study. SETTING:Dutch medical-surgical ICU. PARTICIPANTS:One-year ICU survivors, admitted to the ICU ≥48 hours. MEASUREMENTS:Self-reported cognitive problems were measured with the Cognitive Failures Questionnaire (CFQ). Cumulative exposure to systemic inflammation was based on all daily C-reactive protein (CRP) measurements during ICU stay, expressed as the area under the curve (AUC). Multivariable linear regression was conducted to evaluate the association between delirium and the CFQ. The effect of inflammation on the association between delirium and CFQ was assessed, comparing the effect estimate (B) of delirium and CFQ between models with and without inclusion of the AUC of CRP. RESULTS:Among 567 1-year ICU survivors, the CFQ was completed by 363 subjects. Subjects with multiple days of delirium during ICU stay reported more self-reported cognitive problems (Badj = 5.10, 95% CI 1.01-9.20), whereas a single day delirium was not associated with higher CFQ scores (Badj = -0.72, 95% CI -5.75 to 4.31). Including the AUC of CRP did not change the association between delirium and the CFQ (ratio for a single and multiple days were respectively: 1.00, 95%CI 0.59-1.44 and 0.86, 95% CI 0.47-1.16). CONCLUSION:Multiple days of delirium was associated with long-term self-reported cognitive problems. The cumulative exposure to systemic inflammation did not alter this association, suggesting that delirium in the context of little inflammation is also detrimental.
10.1111/jgs.14660
Pathophysiological and behavioral effects of systemic inflammation in aged and diseased rodents with relevance to delirium: A systematic review.
Schreuder Leroy,Eggen B J,Biber Knut,Schoemaker Regien G,Laman Jon D,de Rooij Sophia E
Brain, behavior, and immunity
Delirium is a frequent outcome for aged and demented patients that suffer a systemic inflammatory insult. Animal models that reconstruct these etiological processes have potential to provide a better understanding of the pathophysiology of delirium. Therefore, we systematically reviewed animal studies in which systemic inflammation was superimposed on aged or diseased animal models. In total, 77 studies were identified. Aged animals were challenged with a bacterial endotoxin in 29 studies, 25 studies superimposed surgery on aged animals, and in 6 studies a bacterial infection, Escherichia coli (E. coli), was used. Diseased animals were challenged with a bacterial endotoxin in 15 studies, two studies examined effects of the cytokine IL-1β, and one study used polyinosinic:polycytidilic acid (poly I:C). This systematic review analyzed the impact of systemic inflammation on the production of inflammatory and neurotoxic mediators in peripheral blood, cerebrospinal fluid (CSF), and on the central nervous system (CNS). Moreover, concomitant behavioral and cognitive symptoms were also evaluated. Finally, outcomes of behavioral and cognitive tests from animal studies were compared to features and symptoms present in delirious patients.
10.1016/j.bbi.2017.01.010