Neutrophil-lymphocyte ratio as a predictor of delirium in older hospitalized patients: a prospective cohort study

Background : Delirium is a common neuropsychiatric syndrome in older hospitalized patients. Previous studies have suggested that inflammation and oxidative stress contribute to the pathophysiology of delirium. However, it remains unclear whether neutrophil-lymphocyte ratio (NLR), an indicator of systematic inflammation, is associated with delirium. This study aimed to investigate the value of NLR as a predictor of delirium among older hospitalized patients. Methods : We conducted a prospective study of 740 hospitalized patients aged ≥ 70 years at the West China Hospital of Sichuan University. Neutrophil and lymphocyte counts were collected within 24 hours after hospital admission. Delirium was assessed on admission and every 48 hours thereafter. We used the Receiver operating characteristic analysis to assess the ability of the NLR for predicting delirium. The optimal cut-point value of the NLR was determined based on the highest Youden index (sensitivity + specificity - 1). Patients were categorized according to the cut-point value and quartiles of NLR, respectively. We then used logistic regression to identify the unadjusted and adjusted associations between NLR as a categorical variable and delirium. Results : The optimal cut-point value of NLR for predicting delirium was 3.626 (sensitivity: 75.2%; specificity: 63.4%; Youden index: 0.386). The incidence of delirium was significantly higher in patients with NLR >3.626 than NLR ≤ 3.626 (24.5% vs 5.8%; P <0.001). Significantly fewer patients in the first quartile of NLR experienced delirium than in the 3rd (4.3% vs 20.0%; P <0.001) and 4th quartiles of NLR (4.3% vs 24.9%; P <0.001). Multivariable logistic regression analysis showed that NLR was independently associated with delirium. Conclusions : NLR is a simple and practical marker that can predict the development of delirium in older hospitalized patients. In this study, we found that elevated NLR was significantly associated with increased odds of delirium in older hospitalized patients. The results suggest that NLR can serve as a convenient, inexpensive, and rapidly accessible marker to predict delirium. The findings of this study also underlines that systemic inflammation and oxidative stress play a key role in the pathophysiology of delirium. Thus, use of this marker in routine clinical research can help clinicians identify patients who at risk of delirium, and may help to prevent negative outcomes.


Background
Delirium is an acute neuropsychiatric syndrome characterized by disturbances in consciousness, cognition and attention [1]. Delirium is a common complication among hospitalized older patients and associated with a variety of adverse outcomes, including cognitive impairment, prolonged hospital stay, functional disability, and, mortality [2][3][4][5].
Diagnosis of delirium is primarily based on clinical observation and its underlying pathophysiology is not entirely understood [6]. Inflammation and oxidative stress have been reported to play a key role in the development of delirium [7,8]. Systemic inflammation could lead to neuro-inflammation and resultant delirium through activation of brain parenchymal cells and an expression of cytokines in the brain [9].
Hence, identification of simple inflammatory markers, easily available in every health care setting, is essential to improve delirium recognition and prediction among older patients.
The neutrophil-lymphocyte ratio (NLR), obtained easily from the circulation, is an indicator of inflammation and oxidative stress [15]. NLR has been applied to prognosis evaluation in various disciplines including malignancies, cardiovascular diseases, kidney diseases, and sepsis [16][17][18][19][20]. Additionally, several studies have reported a relationship between increased NLR and neurological or psychiatric conditions, such as Alzheimer's disease, schizophrenia, Parkinson's disease, ischemic stroke as well as memory disorders [15,21,22]. However, studies investigating the effect of NLR on delirium in older hospitalized patients are rare.
The present study aimed to explore the relationship between NLR and delirium among hospitalized older patients. We hypothesized that older hospitalized patients with an elevated level of NLR would be more likely to experience delirium.

Study population
We conducted a prospective cohort study at the Department of Geriatric, West China hospital of Sichuan from March of 2016 to July of 2017. Included patients were ≥70 years and had an anticipated length of stay of more than 2 days. Exclusion criteria were the presence of delirium on admission, severe hearing impairment, inability to communicate due to severe dementia or psychiatric illness, a terminal condition with life expectancy <6 months, and incomplete data. The study was performed in accordance with the Declaration of Helsinki and approved by the Institutional Review Boards of West China Hospital, Sichuan University. Written informed consent was obtained from all participants.

Data collection
All patients were assessed by trained research nurses within 24 h of admission.
Demographic and general clinical characteristics including age, gender, living situation, education level, marriage status, smoking, alcohol intake, and type of admission were recorded. Peripheral blood samples were collected from patients to measure neutrophil and lymphocyte counts. The NLR was calculated by dividing the neutrophil count by the lymphocyte count. Severity of comorbidities was evaluated using the Charlson Comorbidity Index (CCI), a score based on 19 chronic diseases [23]. Patients were divided into mild (CCI 1-2) , moderate (CCI 3-4) and severe (CCI ≥ 5) groups.
Cognitive level was assessed using the Short Portable Mental Status Questionnaire (SPMSQ) [24]. Baseline functional status was measured by the Barthel Index for activities of living (ADL) [25]. Visual acuity and hearing ability were assessed with the Snellen eye chart and the whispered voice test, respectively.  [26,27]. The CAM is a widely used diagnostic tool for delirium with a sensitivity of 94%, a specificity of 89%, and a Kappa's inter-rater reliability between 0.70 and 1.00 [28]. The CAM is based on the following four features: (i) acute onset and fluctuating course; (ii) inattention; (iii) disorganized thinking; and (iv) altered level of consciousness. Patients were considered delirious if they displayed features (i) and (ii), with either (iii) or (iv).

Statistical analysis
Descriptive data were expressed as number and percentage for categorical variables and as medians with the interquartile range (IQR) for continuous variables. Comparison between categorical variables was done using the chi-square test. Continuous variables were compared with the Mann-Whitney U-test or Kruskall-Wallis test. Receiver operating characteristic (ROC) curve analysis was performed and Youden index was calculated as "sensitivity + specificity -1". NLR that yielded the highest Youden index was determined as the optimal cut-point value for predicting delirium. Participants were grouped based on NLR quartiles and the optimal cut-point value of NLR. We then used logistic regression models to examine the unadjusted and adjusted associations between NLR as a categorial variable and delirium. The multivariate logistic regression model was adjusted for age, sex, alcohol use, smoking, vision impairment, hearing impairment, cognitive impairment, disability, and CCI.
All statistical analyses were performed using SPSS version 21.0 (IBM Crop., Armonk, NY). P-value ≤0.05 was considered significant.

Results
Of 740 patients included in the analysis, the median age was 84 years (IQR: 79-87 years) and the majority was male (71.2%). The median NLR value and length of hospital stay were 3.1 (IQR: 2.1-5.7) and 17 days (IQR: 12-26 days), respectively.
During hospital stay, 101 patients (13.6%) were diagnosed with delirium. Other baseline characteristics of all patients are presented in Table 1.
An ROC curve was performed to identify the predictive ability of NLR for delirium. The area under the ROC curve (AUC) of NLR was 0.714 (95% CI 0.66-0.77; P<0.001). The optimal cut-point value of NLR for predicting delirium was 3.636 determined by the highest Youden index (sensitivity, 75.2%; specificity, 63.4%) ( Figure   1).
Participants' characteristics by the cut-point value of NLR are shown in Table 1  Compared to those in the first quartile of NLR, patients in the 3rd and 4th quartiles of NLR had a greater proportion of delirium.

Discussion
This is the first prospective study conducted in older hospitalized patients investigating the association between NLR as a marker for systemic inflammation and delirium. We found that the median level of NLR was elevated in elderly patients with delirium. Individuals with high NLR were more likely to experience delirium than those with low NLR. These results suggest that NLR is an important risk factor for delirium among hospitalized older patients and maintaining a low level of an inflammation level may help prevent delirium.
Previous literature suggested that systemic inflammation and oxidative stress might be involved in the development of delirium [7,8]. Previous studies have reported that inflammatory markers and cytokines can be detected in serum and cerebrospinal fluid of elderly patients with delirium [11,[29][30][31]. In addition, there are studies showing that inflammatory condition could negatively affect frontotemporal cognitive abilities such as memory, attention and executive functions [32]. The initial immune response to stressful situations is characterized by systemic changes in leucocyte subtypes such as a increase in neutrophils and a decrease in lymphocytes [33], which can lead to an elevated levels of NLR. In fact, the relationship of leucocyte subtypes with delirium or cognitive decline have been investigated in previous studies. For example, the elevation of neutrophil count in elderly patients has been shown to be associated with delirium in previous studies [34]. There is other study indicating the significant association between increased neutrophils and cognitive impairment [35]. In a cohort study, lower levels of lymphocyte have been found to be an independent predictor of delirium [36].
Likewise, one recent study reported that patients with lower levels of lymphocyte were more likely to suffer from delirium [37].
NLR is emerging as a novel marker of systemic inflammation, which integrates information of neutrophils and lymphocytes. Moreover, NLR is different from traditional inflammatory markers (eg, CRP, PCT, IL-6, IL-8, or TNF). NLR is a simple, inexpensive, and readily available inflammatory marker that can be directly derived from white blood cell (WBC) count on admission. Furthermore, NLR is less likely to be influenced by fluid imbalance than the individual WBC subtypes [38]. Compared with conventional parameters such as CRP, the total WBC counts and the individual WBC subtypes, increased NLR has been identified as a more powerful predictor of adverse outcomes in many disciplines [39][40][41]. In particular, NLR has been reported to have higher predictive value in delirium than CRP, neutrophils and lymphocytes [42].
Therefore, NLR might be better at reflecting a association between systemic inflammation and delirium than neutrophil or lymphocyte alone.
Limited studies in recent years have investigated the possible association between NLR and delirium. Egberts et al [42] found that in a cohort of acutely ill elderly patients, a raised NLR was an independent predictor of delirium. Additionally, Kotfits et al [43] stated that an increased NLR is significantly associated with increased risk of delirium in patients with acute ischemic stroke. species released by neutrophils lead to disruption of the blood-brain barrier (BBB) and increase its permeability, cytokines then migrate across the BBB and activate microglia which will produce reactive oxygen species, the accumulation of cytokines and reactive oxygen species in brain may lead to the process of oxidization and inflammation and eventually result in neurodegeneration [7,46].
This study was conducted with a large sample of older hospitalized patients, which may reduce selection bias. However, our study had several limitations. First, this was a single-center study that might be insufficient to represent a general population of elderly patients with delirium. Second, a single measurement of NLR on admission does not allow for evaluating the stability of this marker over time and assessing the long-term effect of this marker on delirium. Third, other inflammatory markers (eg, CRP, IL-6, or IL-8), which may have influence on delirium, were not included in our study.

Conclusion
In this study, we found that elevated NLR was significantly associated with increased odds of delirium in older hospitalized patients. The results suggest that NLR can serve as a convenient, inexpensive, and rapidly accessible marker to predict delirium. The findings of this study also underlines that systemic inflammation and oxidative stress play a key role in the pathophysiology of delirium. Thus, use of this marker in routine clinical research can help clinicians identify patients who at risk of delirium, and may help to prevent negative outcomes.