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Neutrophil to lymphocyte ratio is associated with in-hospital mortality in older adults admitted to the emergency department
YAJEM-158730; No of Pages 5 American Journal of Emergency Medicine xxx (xxxx) xxx
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Neutrophil to lymphocyte ratio is associated with in-hospital mortality in older adults admitted to the emergency department Hwan Song, M.D, Hyo Joon Kim, M.D, Kyu Nam Park, M.D, Soo Hyun Kim, M.D, Sang Hoon Oh, M.D, Chun Song Youn, M.D ⁎ Department of Emergency Medicine, Seoul St. Mary Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea
a r t i c l e
i n f o
Article history: Received 16 August 2019 Received in revised form 19 December 2019 Accepted 24 January 2020 Available online xxxx Keywords: Neutrophil to lymphocyte ratio Mortality Older adults
a b s t r a c t Background: The objective of this study was to test the hypothesis that an elevated neutrophil to lymphocyte ratio (NLR) at admission is associated with and increased risk of mortality in older patients admitted to the emergency department (ED). Methods: We performed a retrospective analysis of patients admitted to the ED between November 2016 and February 2017. We included patients who were older than 65 years who visited the ED with any medical problem. We excluded patients with hematologic malignancy. Baseline NLR values were measured at the time of admission to the ED. The primary outcome was all-cause in-hospital mortality. A multivariate logistic analysis was performed. Results: A total of 2777 patients were included in this study. The median age was 75 years (IQR 70–81), and 1359 (48.9%) patients were male. The in-hospital mortality rate was 5.0% (140 patients). The NLR value was higher in nonsurvivors (median, 8.08, IQR 4.29–15.25) than in survivors (median, 3.69, IQR 2.1–6.92, P b 0.001). In the multivariate logistic regression analysis, the NLR was associated with all cause in-hospital mortality after adjusting for confounding factors (OR = 1.03, 95% CI = 1.014–1.046). Conclusions: These results show that the NLR at admission is associated with in-hospital mortality among patients older than 65 years without hematologic malignancy. Thus, NLR at admission may represent a surrogate marker of disease severity. © 2020 Elsevier Inc. All rights reserved.
1. Background The elderly population is steadily increasing, which is one of the major causes of increased health care burden in the emergency department (ED) [1-3]. Elderly individuals are admitted to the ED more frequently than are younger adults [2]. Elderly patients may be delayed in diagnosis and treatment due to atypical signs and symptoms, many comorbid diseases, and several medications [2,3]. Moreover, these individuals are at high risk for ED revisit, hospital admission, intensive care unit admission, and death [2-6]. Several screening tools have been developed to recognize the increased risk of adverse outcomes, but these risk assessment tools are considered to lack sufficient prognostic accuracy [7,8].
⁎ Corresponding author at: Department of Emergency Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-Gu, Seoul 06591, Republic of Korea. E-mail address: [email protected] (C.S. Youn).
The neutrophil to lymphocyte ratio (NLR) is a simple marker that indicates the inflammatory status of a subject and has the advantage of being an inexpensive, reproducible, rapid and easily accessible marker. The NLR has been associated with the prognosis of infection-related diseases, such as sepsis, bacteremia and appendicitis [9-12]. In addition, the NLR has also been associated with the outcome of noninfectious diseases, such as acute myocardial infarction, stroke and several types of cancers [13-17]. The exact mechanism is not fully elucidated, but increased neutrophils exhibit systemic inflammation, which affects atherosclerosis and tumor progression, and lymphocytes play an opposite role [18,19]. Thus, the NLR is a systemic inflammatory marker and a potential predictor of risk and outcome in many diseases. Moreover, the NLR has been thought as a better predictive factor than total WBC count or neutrophil count [20]. Recent evidence suggests that chronic inflammation associated with aging is a significant risk factor for morbidity and mortality in older adults [19-22]. However, there are few studies on the association between elevated NLR and mortality in elderly patients. We tested the hypothesis that an elevated NLR at admission to the ED increases the risk of in-hospital mortality in older adults. We
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Please cite this article as: H. Song, H.J. Kim, K.N. Park, et al., Neutrophil to lymphocyte ratio is associated with in-hospital mortality in older adults admitted to ..., American Journal of Emergency Medicine, https://doi.org/10.1016/j.ajem.2020.01.044
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assessed the association between the NLR at admission to the ED and all-cause in-hospital mortality. 2. Methods
cause in-hospital mortality. Statistical analyses were performed using SPSS version 24.0 (SPSS, Chicago, IL, USA) and MedCalc version 15.2.2 (MedCalc Software, Mariakerke, Belgium). P-values ≤ 0.05 were considered statistically significant. The Youden Index was used to determine the optimal cut off point for mortality.
2.1. Study design and setting We performed a retrospective observational study of a consecutive cohort admitted to an ED in Seoul, Korea, between November 2016 and February 2017. Our institutional review board approved this study, and a waiver of consent was allowed because of its retrospective nature. 2.2. Selection of participants We included patients older than 65 years who visited the ED with any medical problem. Patients were excluded if they had a trauma-related injury; had a hematologic disease, such as leukemia, myelodysplastic syndromes, myeloproliferative disease or myelofibrosis; or did not have a complete blood count (CBC). 2.3. Methods of measurement We collected the following demographics and clinical findings from the medical records of the study participants: age, sex, mean arterial pressure (MAP), heart rate (HR), body temperature, Glasgow Coma Scale (GCS) and comorbidities, including diabetes mellitus (DM), hypertension (HBP), coronary artery disease (CAD), heart failure (HF), liver cirrhosis (LC), chronic kidney disease (CKD), chronic pulmonary disease and malignancies. Initial laboratory findings such as white blood cell (WBC) count with NLR, blood urea nitrogen (BUN), creatinine (Cr), hemoglobin (Hb), platelets, glucose, sodium, potassium and chloride were also collected. The CBC was measured using an automated blood cell counter (Sysmex XE-2100, Sysmex Corp., Kobe, Japan). The NLR was calculated as the neutrophil count divided by the lymphocyte count in the same blood sample at admission to the ED. A sequential organ failure assessment (SOFA) score and Acute Physiology And Chronic Health Evaluation II (APACHE II) were calculated at the time of ED admission. 2.4. Outcomes The primary outcome of this study was the association of NLR with all-cause in-hospital mortality. Survival to hospital discharge was defined if the patient was discharged from the hospital alive to home or to another health care facility. 2.5. Analysis Normality tests were performed for continuous variables, and continuous variables are presented as the means with the standard deviation or as median values with interquartile ranges, as appropriate. Categorical variables are presented as frequencies and percentages. For patient characteristics and comparisons between groups, we used Student's t-test of Mann-Whitney U test for continuous variables and Fisher's exact test and the chi-square test for categorical variables. Univariate analysis was performed to determine the covariates for all-cause in-hospital mortality. Variables with a P-value ≥ 0.157 on univariate analysis were excluded from the multivariate logistic regression model. In order to examine the association between the NLR and allcause in-hospital mortality, multivariate logistic regression analyses with backward elimination were performed. We evaluated the association not only as a continuous variable for NLR and all-cause in-hospital mortality but also as a categorical variable. The cutoff value for the NLR as a categorical variable was set to 6, with reference to a previous study [23]. Multiple logistic regression was performed on each model to evaluate the association between NLR and all-
3. Results 3.1. Characteristics of study subjects During the study period, a total of 3302 patients older than 65 years were admitted to our ED with a medical problem. A total of 525 patients were excluded from the final analysis because they did not have a CBC (N = 389) or had hematologic malignancies (N = 136; leukemia, myelodysplastic syndromes, myeloproliferative disease, and myelofibrosis). Finally, 2777 patients were included in this study. The median age was 75 years (IQR 70–81), and 1359 (48.9%) patients were male. The in-hospital mortality rate was 5.0% (N = 140). The baseline characteristics of the study groups are presented in Table 1. The median value of NLR was 3.81 (IQR 2.15–7.19). The NLR value was higher in nonsurvivors (median, 8.08, IQR 4.29–15.25) than in survivors (median, 3.69, IQR 2.1–6.92, P b 0.001) [Fig. 1]. 3.2. Logistic regression analysis In the univariate analysis, age, male gender, DM, CKD, chronic pulmonary disease, malignancy, SOFA score, MAP, HR, GCS, WBC, Hb, PLT, glucose, BUN, Cr, sodium, potassium and APACHE II score were associated with all-cause in-hospital mortality. Variables with a P-value b 0.157 on univariate analysis were selected for multivariate logistic regression models. Table 1 Demographic and laboratory findings in patients with or without in-hospital mortality.
Age, years Sex (male) DM HTN CAD LC CKD ESRD on HD Chronic pulmonary disease CHF Malignancy SOFA MAP, mm Hg HR Temp, °C GCS WBC, 109/L Hb, mg/dl PLT, 109/L Glucose, mg/dl BUN, mg/dl Creatinine, mg/dl Na, mEq/L K, mEq/L Cl, mEq/L APACHE II NLR
Survivors N = 2637
Non-survivors N = 140
p
75(70, 81) 1272(48.2) 773(29.3) 1458(55.3) 436(16.5) 61(2.3) 167(6.3) 83(3.1) 456(17.3) 58(2.2) 596(22.6) 1(0, 2) 98.7(86.7, 110.3) 85(74, 98) 36.8(36.4, 37.2) 15(15, 15) 7.7(6.0, 10.7) 12.5(11.0, 13.7) 208(167, 262) 123(102, 157) 18.8(14.2, 26.6) 0.93(0.74, 1.23) 140(137, 142) 4.3(4.0, 4.7) 103(99, 106) 12 (8, 16) 3.69 (2.1, 6.92)
79(71, 84) 87(62.1) 58(41.4) 78(55.7) 23(16.4) 6(4.3) 15(10.7) 7(5.0) 47(33.6) 5(3.6) 65(46.4) 5(3, 7) 90.0(77.7, 101.1) 96(84, 112) 36.8(36.3, 37.4) 15(14, 15) 10.3(7.2, 14.5) 10.9(9.6, 12.7) 187(131, 261) 138(98, 208) 36.9(21.4, 63.3) 1.51(0.89, 2.64) 140(135, 145) 4.6(4.0, 5.4) 100(98, 108) 22 (16, 27) 8.08 (4.29, 15.25)
b0.001 0.001 0.002 0.922 0.974 0.138 0.041 0.228 b0.001 0.288 b0.001 b0.001 b0.001 b0.001 0.843 b0.001 b0.001 b0.001 0.008 0.001 b0.001 b0.001 0.001 b0.001 0.503 b0.001 b0.001
Abbreviations: DM = diabetes mellitus; HTN = hypertension; CAD = coronary artery disease; LC = liver cirrhosis; CKD = chronic kidney disease; ESRD = end-stage renal disease; HD = hemodialysis; CHF = congestive heart failure; SOFA = sequential organ failure score; MAP = mean arterial pressure; HR = heart rate; GCS = Glasgow Coma Scale; WBC = white blood cell; Hb = hemoglobin; PLT = platelet; BUN = blood urea nitrogen; APACHE II = Acute Physiology And Chronic Health Evaluation II; NLR = neutrophil to lymphocyte ratio.
Please cite this article as: H. Song, H.J. Kim, K.N. Park, et al., Neutrophil to lymphocyte ratio is associated with in-hospital mortality in older adults admitted to ..., American Journal of Emergency Medicine, https://doi.org/10.1016/j.ajem.2020.01.044
H. Song et al. / American Journal of Emergency Medicine xxx (xxxx) xxx
Fig. 1. The NLR at admission according to discharge status.
The NLR was examined as a continuous variable and a categorical variable. Table 2 shows the association between the variables and allcause in-hospital mortality. When treating the NLR as a continuous variable, the adjusted odds ratio (OR) was 1.03 (95% CI, 1.014–1.046), and when treating the NLR as a categorical variable (cutoff value ≥6), the adjusted OR was 2.49 (95% CI, 1.664–3.727). The association between the NLR and all-cause in-hospital mortality was consistently significant across subgroups, except for the subgroup with a history of CKD, no history of chronic pulmonary disease and no history of malignancy [Fig. 2]. 3.3. Prognostic value of NLR The sensitivity, specificity, positive likelihood ratio (PLR) and negative likelihood ratio (NLR) of NLR for different cutoff points are presented in Table 3. The best cutoff value of NLR was 3.88, with 82.14% sensitivity and 52.86% specificity. Mortality rate of NLR above 3.88 was 8.5% (N = 115) and below 3.88 was 1.8% (N = 25). The area under the curve (AUC) for the NLR for predicting in-hospital mortality was 0.714 (95% CI 0.669–0.759) [Fig. 3]. 4. Discussion The main finding of this study was that NLR at admission was an independent predictor of all-cause in-hospital mortality among patients older than 65 years. After adjustment for age; male gender; history of DM, CKD, chronic pulmonary disease and malignancy; and SOFA scores, the all-cause in-hospital mortality rate increased by 3.5% for each 1%
Table 2 Logistic regression analysis for predicting all-cause in-hospital mortality. NLR as categorical variable OR (95% CI) LC CKD Malignancy Glucose SOFA APACHE II NLR ≥ 6
0.315 (0.111–0.894) 0.51 (0.259–1.005) 1.956 (1.27–3.011) 1.002 (1–1.004) 1.519 (1.392–1.656) 1.091 (1.054–1.129) 2.49 (1.664–3.727)
NLR as continuous variable OR (95% CI) LC CKD Chronic pulmonary disease Malignancy Glucose SOFA APACHE II NLR
0.322 (0.122–0.928) 0.582 (0.3–1.13) 1.488 (0.936–2.364) 2.057 (1.328–3.187) 1.003 (1.001–1.004) 1.545 (1.413–1.689) 1.077 (1.037–1.118) 1.03 (1.014–1.046)
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increase in the NLR as a continuous variable. After adjusting for MAP, HR, WBC, Hb, platelet, glucose, BUN, Cr, sodium, potassium and SOFA scores, the all-cause in-hospital mortality rate increased by 2.3% for each 1% increase in the NLR as a continuous variable. When using the best cutoff value of NLR, the PPV and NPV were 8.5% (95% CI 7.8–9.2) and 98.2% (95% CI 97.5–98.8), respectively. If a patient has an NLR of N6, then the risk of in-hospital death is 9.9%. If a patient has a red cell distribution width (RDW) of b14.5, then the risk of survival hospital discharge is 97.2%. Although the number of elderly patients in the ED is increasing, there are few studies on the mortality rate of elderly patients. Elderly patients often present atypical signs and symptoms and have multiple comorbid conditions with multiple medications, which often leads to delayed diagnosis and treatment. Indeed, these patients are at higher risk of ED revisit, hospital admission, intensive care unit admission, and death than are young adults [2]. Emergency physicians may find it time consuming and difficult to completely assess older patients. Samaras et al. proposed a targeted approach for high-risk patients [3]. Our results may also help in the identification of older patients at higher risk. The NLR is associated with the outcome after sepsis and bacteremia [9-11]. The NLR is a marker of systemic inflammation and indicates the balance between innate and adaptive immune responses. Hwang et al. stated that the NLR at ED admission was independently associated with 28-day mortality in patients with severe sepsis and septic shock [10]. The theoretical basis is not yet clear. However, neutrophils play crucial roles in the innate immune response, resulting in multiple organ failure and even death when severely activated. In contrast, lymphocytes regulate the inflammatory response. Therefore, a high NLR indicates an imbalance of the inflammatory response and may be a surrogate marker of disease severity in infectious diseases, such as sepsis and bacteremia. The NLR is also associated with the outcome after cardiovascular disease, such as CAD, acute coronary syndrome and stroke [13-15,24]. Sen et al. demonstrated that an elevated NLR upon admission was correlated with both the no-reflow phenomenon and long-term prognosis in patients with ST-elevation myocardial infarction who underwent primary percutaneous intervention [18]. Moreover, the NLR is also associated with stroke severity, functional outcome and recurrent ischemic stroke in patients with acute ischemic stroke [15]. One possible mechanism is that inflammatory mediators from neutrophils could cause vascular wall degeneration, while lymphocytes play an anti-atherosclerotic role. The exact mechanism underlying the association between NLR and mortality in elderly patients admitted to the ED is unclear. One possible explanation is systemic inflammation due to acute illness. It is possible that the NLR is associated with mortality because it represents an imbalance of the inflammatory response due to acute illness, as in sepsis, bacteremia or cardiovascular disease. In other words, the NLR may be a surrogate marker indicating disease severity in elderly patients. Another possible explanation is chronic inflammation, which is the cause of aging in elderly patients [21]. The NLR is a marker of chronic inflammation. Thus, an increased NLR may indicate the level of chronic inflammation in that patient. The exact mechanism underlying the association between NLR and mortality should be further investigated. This study has some important limitations to consider. Our study is a single center, retrospective study, needs to be replicated with larger prospective studies. Consistent with other retrospective studies, this study is limited by an inability to control for all measured and unmeasured confounders. Our primary outcome was all-cause in-hospital mortality, so we could not analyze the cause of specific mortalities. The exact mechanisms underlying the association between NLR and mortalities in elderly individuals are not certain. Systemic inflammation may cause mortality, but further studies are needed to identify the exact mechanisms. We only checked the NLR at admission; however, there may be a specific pattern in serial NLR examination. If there is an association between serial NLR and mortality, then this association could
Please cite this article as: H. Song, H.J. Kim, K.N. Park, et al., Neutrophil to lymphocyte ratio is associated with in-hospital mortality in older adults admitted to ..., American Journal of Emergency Medicine, https://doi.org/10.1016/j.ajem.2020.01.044
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Fig. 2. Subgroup analysis for the association between the NLR at admission and all-cause in-hospital mortality.
have more specificity in predicting mortality. As previously discussed, our study only shows an association, so there is a limitation of the clinical implications. Thus, more studies are needed to identify the associations between the NLR and cause-specific mortality in elderly individuals. NLR used with other known prognostic tools such as APACHE II or biomarkers such as blood lactate may be useful, but further data are needed. 5. Conclusions
CKD BUN Cr Hb SOFA OR AUC RDW
chronic kidney disease blood urea nitrogen creatinine hemoglobin sequential organ failure assessment odds ratio area under the curve red cell distribution width
In conclusion, the NLR at admission to the ED is associated with allcause in-hospital mortality among patients older than 65 years without hematologic malignancies. Thus, the NLR at admission may represent a surrogate marker of disease severity. However, we need more external validation to use the NLR in the clinical decision-making process. Abbreviations NLR ED SD CBC MAP HR GCS DM HBP CAD HF LC
neutrophil to lymphocyte ratio emergency department standard deviation complete blood count mean arterial pressure heart rate Glasgow Coma Scale diabetes mellitus hypertension coronary artery disease heart failure liver cirrhosis
Table 3 Sensitivity, specificity, positive likelihood ratio and negative likelihood ratio for different cutoff point. NLR
Sensitivity (95% CI)
Specificity (95% CI)
PLR (95% CI)
NLR (95% CI)
N3.88 N6
82.14 (74.8–88.1) 62.86 (54.3–70.9)
52.86 (50.9–54.8) 69.93 (68.1–71.7)
1.72 (1.6–1.9) 2.09 (1.8–2.4)
0.36 (0.3–0.5) 0.53 (0.4–0.7)
Abbreviations: PLR = positive likelihood ratio; NLR = negative likelihood ratio.
Fig. 3. Prognostic value of the NLR for the prediction of all-cause in-hospital mortality. The AUC is 0.714 (95% CI 0.669–0.759).
Please cite this article as: H. Song, H.J. Kim, K.N. Park, et al., Neutrophil to lymphocyte ratio is associated with in-hospital mortality in older adults admitted to ..., American Journal of Emergency Medicine, https://doi.org/10.1016/j.ajem.2020.01.044
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Ethics approval and consent to participate This study was approved by the Institutional Review Board of Seoul St. Mary's Hospital (file number: XC17REDI0071); waiver of consent was allowed because of the retrospective nature of the study. Consent for publication Not applicable. Availability of data and materials The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Funding There were no funding sources in this study. Authors' contributions CSY and KNP conceived the project. Data collection and analyses were performed by HS, HJK, SHK and SHO. The manuscript was written by HS and SM, and revised by CSY. All authors read and approved the final manuscript. Declaration of competing interest The authors declare that they have no competing interests. References [1] American College of Emergency Physicians, American Geriatrics Society, Emergency Nurses Association, Society for Academic Emergency Medicine, Geriatric Emergency Department Guidelines Task Force. Geriatric emergency department guidelines. Ann Emerg Med 2014;63:e7-25. [2] Aminzadeh F, Dalziel WB. Older adults in the emergency department: a systematic review of patterns of use, adverse outcomes, and effectiveness of interventions. Ann Emerg Med 2002;39:238–47. [3] Samaras N, Chevalley T, Samaras D, Gold G. Older patients in the emergency department: a review. Ann Emerg Med 2010;56:261–9. [4] Strange GR, Chen EH, Sanders AB. Use of emergency departments by elderly patients: projections from a multicenter data base. Ann Emerg Med 1992;21:819–24.
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[5] Baum SA, Rubenstein LZ. Old people in the emergency room: age-related differences in emergency department use and care. J Am Geriatr Soc 1987;35:398–404. [6] Strange GR, Chen EH. Use of emergency departments by elder patients: a five-year follow-up study. Acad Emerg Med 1998;5:1157–62. [7] Moons P, De Ridder K, Geyskens K, et al. Screening for risk of readmission of patients aged 65 years and above after discharge from the emergency department: predictive value of four instruments. Eur J Emerg Med 2007;14:315–23. [8] Salvi F, Morichi V, Lorenzetti B, et al. Risk stratification of older patients in the emergency department: comparison between the Identification of Seniors at Risk and Triage Risk screening tool. Rejuvenation Res 2012;15:288–94. [9] Xuan Liu, Yong Shen, Hairong Wang, et al. Prognostic significance of neutrophil-tolymphocyte ratio in patients with sepsis: a prospective observational study. Mediators Inflamm 2016. [10] Hwang SY, Shin TG, Jo IJ, et al. Neutrophil-to-lymphocyte ratio as a prognostic marker in critically-ill septic patients. Am J Emerg Med 2017;35:234–9. [11] Terradas R, Grau S, Blanch J, et al. Eosinophil count and neutrophil-lymphocyte count ratio as prognostic markers in patients with bacteremia: a retrospective cohort study. PLoS One 2012;7:e42860. [12] Jung SK, Rhee DY, Lee WJ, et al. Neutrophil-to-lymphocyte count ratio is associated with perforated appendicitis in elderly patients of emergency department. Aging Clin Exp Res 2017;29:529–36. [13] Ayça B, Akın F, Celik O, et al. Neutrophil to lymphocyte ratio is related to stent thrombosis and high mortality in patients with acute myocardial infarction. Angiology 2015;66:545–52. [14] Zuin M, Rigatelli G, Picariello C, et al. Correlation and prognostic role of neutrophil to lymphocyte ratio and SYNTAX score in patients with acute myocardial infarction treated with percutaneous coronary intervention: a six-year experience. Cardiovasc Revasc Med 2017;18:565–71. [15] Xue J, Huang W, Chen X, et al. Neutrophil-to-lymphocyte ratio is a prognostic marker in acute ischemic stroke. J Stroke Cerebrovasc Dis 2017;26:650–7. [16] Ethier JL, Desautels D, Templeton A, et al. Prognostic role of neutrophil-tolymphocyte ratio in breast cancer: a systematic review and meta-analysis. Breast Cancer Res 2017;5(19):2. [17] Yin Y, Wang J, Wang X, et al. Prognostic value of the neutrophil to lymphocyte ratio in lung cancer: a meta-analysis. Clinics (Sao Paulo) 2015;70:524–30. [18] Angkananard T, Anothaisintawee T, McEvoy M, et al. Neutrophil lymphocyte ratio and cardiovascular disease risk: a systematic review and meta-analysis. Biomed Res Int 2018. [19] Faria SS, Fernandes Jr PC, Silva MJ, et al. The neutrophil-to-lymphocyte ratio: a narrative review. Ecancermedicalscience 2016;10:702. [20] Bhat T, Teli S, Rijal J, Bhat H, Raza M, Khoueiry G, et al. Neutrophil to lymphocyte ratio and cardiovascular diseases: a review. Expert Rev Cardiovasc Ther 2013;11(1):55–9 Jan. [21] Bandeen-Roche K, Walston JD, Huang Y, et al. Measuring systemic inflammatory regulation in older adults: evidence and utility. Rejuvenation Res 2009;12:403–10. [22] Sanada F, Taniyama Y, Muratsu J, et al. Source of chronic inflammation in aging. Front Cardiovasc Med 2018;5:12. [23] Weiser C, Schwameis M, Sterz F, et al. Mortality in patients resuscitated from out-ofhospital cardiac arrest based on automated blood cell count and neutrophil lymphocyte ratio at admission. Resuscitation 2017;116:49–55. [24] Sen N, Afsar B, Ozcan F, et al. The neutrophil to lymphocyte ratio was associated with impaired myocardial perfusion and long term adverse outcome in patients with STelevated myocardial infarction undergoing primary coronary intervention. Atherosclerosis 2013;228:203–10.
Please cite this article as: H. Song, H.J. Kim, K.N. Park, et al., Neutrophil to lymphocyte ratio is associated with in-hospital mortality in older adults admitted to ..., American Journal of Emergency Medicine, https://doi.org/10.1016/j.ajem.2020.01.044
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Neutrophil to lymphocyte ratio is associated with in-hospital mortality in older adults admitted to the emergency department Hwan Song, M.D, Hyo Joon Kim, M.D, Kyu Nam Park, M.D, Soo Hyun Kim, M.D, Sang Hoon Oh, M.D, Chun Song Youn, M.D ⁎ Department of Emergency Medicine, Seoul St. Mary Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea
a r t i c l e
i n f o
Article history: Received 16 August 2019 Received in revised form 19 December 2019 Accepted 24 January 2020 Available online xxxx Keywords: Neutrophil to lymphocyte ratio Mortality Older adults
a b s t r a c t Background: The objective of this study was to test the hypothesis that an elevated neutrophil to lymphocyte ratio (NLR) at admission is associated with and increased risk of mortality in older patients admitted to the emergency department (ED). Methods: We performed a retrospective analysis of patients admitted to the ED between November 2016 and February 2017. We included patients who were older than 65 years who visited the ED with any medical problem. We excluded patients with hematologic malignancy. Baseline NLR values were measured at the time of admission to the ED. The primary outcome was all-cause in-hospital mortality. A multivariate logistic analysis was performed. Results: A total of 2777 patients were included in this study. The median age was 75 years (IQR 70–81), and 1359 (48.9%) patients were male. The in-hospital mortality rate was 5.0% (140 patients). The NLR value was higher in nonsurvivors (median, 8.08, IQR 4.29–15.25) than in survivors (median, 3.69, IQR 2.1–6.92, P b 0.001). In the multivariate logistic regression analysis, the NLR was associated with all cause in-hospital mortality after adjusting for confounding factors (OR = 1.03, 95% CI = 1.014–1.046). Conclusions: These results show that the NLR at admission is associated with in-hospital mortality among patients older than 65 years without hematologic malignancy. Thus, NLR at admission may represent a surrogate marker of disease severity. © 2020 Elsevier Inc. All rights reserved.
1. Background The elderly population is steadily increasing, which is one of the major causes of increased health care burden in the emergency department (ED) [1-3]. Elderly individuals are admitted to the ED more frequently than are younger adults [2]. Elderly patients may be delayed in diagnosis and treatment due to atypical signs and symptoms, many comorbid diseases, and several medications [2,3]. Moreover, these individuals are at high risk for ED revisit, hospital admission, intensive care unit admission, and death [2-6]. Several screening tools have been developed to recognize the increased risk of adverse outcomes, but these risk assessment tools are considered to lack sufficient prognostic accuracy [7,8].
⁎ Corresponding author at: Department of Emergency Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-Gu, Seoul 06591, Republic of Korea. E-mail address: [email protected] (C.S. Youn).
The neutrophil to lymphocyte ratio (NLR) is a simple marker that indicates the inflammatory status of a subject and has the advantage of being an inexpensive, reproducible, rapid and easily accessible marker. The NLR has been associated with the prognosis of infection-related diseases, such as sepsis, bacteremia and appendicitis [9-12]. In addition, the NLR has also been associated with the outcome of noninfectious diseases, such as acute myocardial infarction, stroke and several types of cancers [13-17]. The exact mechanism is not fully elucidated, but increased neutrophils exhibit systemic inflammation, which affects atherosclerosis and tumor progression, and lymphocytes play an opposite role [18,19]. Thus, the NLR is a systemic inflammatory marker and a potential predictor of risk and outcome in many diseases. Moreover, the NLR has been thought as a better predictive factor than total WBC count or neutrophil count [20]. Recent evidence suggests that chronic inflammation associated with aging is a significant risk factor for morbidity and mortality in older adults [19-22]. However, there are few studies on the association between elevated NLR and mortality in elderly patients. We tested the hypothesis that an elevated NLR at admission to the ED increases the risk of in-hospital mortality in older adults. We
https://doi.org/10.1016/j.ajem.2020.01.044 0735-6757/© 2020 Elsevier Inc. All rights reserved.
Please cite this article as: H. Song, H.J. Kim, K.N. Park, et al., Neutrophil to lymphocyte ratio is associated with in-hospital mortality in older adults admitted to ..., American Journal of Emergency Medicine, https://doi.org/10.1016/j.ajem.2020.01.044
2
H. Song et al. / American Journal of Emergency Medicine xxx (xxxx) xxx
assessed the association between the NLR at admission to the ED and all-cause in-hospital mortality. 2. Methods
cause in-hospital mortality. Statistical analyses were performed using SPSS version 24.0 (SPSS, Chicago, IL, USA) and MedCalc version 15.2.2 (MedCalc Software, Mariakerke, Belgium). P-values ≤ 0.05 were considered statistically significant. The Youden Index was used to determine the optimal cut off point for mortality.
2.1. Study design and setting We performed a retrospective observational study of a consecutive cohort admitted to an ED in Seoul, Korea, between November 2016 and February 2017. Our institutional review board approved this study, and a waiver of consent was allowed because of its retrospective nature. 2.2. Selection of participants We included patients older than 65 years who visited the ED with any medical problem. Patients were excluded if they had a trauma-related injury; had a hematologic disease, such as leukemia, myelodysplastic syndromes, myeloproliferative disease or myelofibrosis; or did not have a complete blood count (CBC). 2.3. Methods of measurement We collected the following demographics and clinical findings from the medical records of the study participants: age, sex, mean arterial pressure (MAP), heart rate (HR), body temperature, Glasgow Coma Scale (GCS) and comorbidities, including diabetes mellitus (DM), hypertension (HBP), coronary artery disease (CAD), heart failure (HF), liver cirrhosis (LC), chronic kidney disease (CKD), chronic pulmonary disease and malignancies. Initial laboratory findings such as white blood cell (WBC) count with NLR, blood urea nitrogen (BUN), creatinine (Cr), hemoglobin (Hb), platelets, glucose, sodium, potassium and chloride were also collected. The CBC was measured using an automated blood cell counter (Sysmex XE-2100, Sysmex Corp., Kobe, Japan). The NLR was calculated as the neutrophil count divided by the lymphocyte count in the same blood sample at admission to the ED. A sequential organ failure assessment (SOFA) score and Acute Physiology And Chronic Health Evaluation II (APACHE II) were calculated at the time of ED admission. 2.4. Outcomes The primary outcome of this study was the association of NLR with all-cause in-hospital mortality. Survival to hospital discharge was defined if the patient was discharged from the hospital alive to home or to another health care facility. 2.5. Analysis Normality tests were performed for continuous variables, and continuous variables are presented as the means with the standard deviation or as median values with interquartile ranges, as appropriate. Categorical variables are presented as frequencies and percentages. For patient characteristics and comparisons between groups, we used Student's t-test of Mann-Whitney U test for continuous variables and Fisher's exact test and the chi-square test for categorical variables. Univariate analysis was performed to determine the covariates for all-cause in-hospital mortality. Variables with a P-value ≥ 0.157 on univariate analysis were excluded from the multivariate logistic regression model. In order to examine the association between the NLR and allcause in-hospital mortality, multivariate logistic regression analyses with backward elimination were performed. We evaluated the association not only as a continuous variable for NLR and all-cause in-hospital mortality but also as a categorical variable. The cutoff value for the NLR as a categorical variable was set to 6, with reference to a previous study [23]. Multiple logistic regression was performed on each model to evaluate the association between NLR and all-
3. Results 3.1. Characteristics of study subjects During the study period, a total of 3302 patients older than 65 years were admitted to our ED with a medical problem. A total of 525 patients were excluded from the final analysis because they did not have a CBC (N = 389) or had hematologic malignancies (N = 136; leukemia, myelodysplastic syndromes, myeloproliferative disease, and myelofibrosis). Finally, 2777 patients were included in this study. The median age was 75 years (IQR 70–81), and 1359 (48.9%) patients were male. The in-hospital mortality rate was 5.0% (N = 140). The baseline characteristics of the study groups are presented in Table 1. The median value of NLR was 3.81 (IQR 2.15–7.19). The NLR value was higher in nonsurvivors (median, 8.08, IQR 4.29–15.25) than in survivors (median, 3.69, IQR 2.1–6.92, P b 0.001) [Fig. 1]. 3.2. Logistic regression analysis In the univariate analysis, age, male gender, DM, CKD, chronic pulmonary disease, malignancy, SOFA score, MAP, HR, GCS, WBC, Hb, PLT, glucose, BUN, Cr, sodium, potassium and APACHE II score were associated with all-cause in-hospital mortality. Variables with a P-value b 0.157 on univariate analysis were selected for multivariate logistic regression models. Table 1 Demographic and laboratory findings in patients with or without in-hospital mortality.
Age, years Sex (male) DM HTN CAD LC CKD ESRD on HD Chronic pulmonary disease CHF Malignancy SOFA MAP, mm Hg HR Temp, °C GCS WBC, 109/L Hb, mg/dl PLT, 109/L Glucose, mg/dl BUN, mg/dl Creatinine, mg/dl Na, mEq/L K, mEq/L Cl, mEq/L APACHE II NLR
Survivors N = 2637
Non-survivors N = 140
p
75(70, 81) 1272(48.2) 773(29.3) 1458(55.3) 436(16.5) 61(2.3) 167(6.3) 83(3.1) 456(17.3) 58(2.2) 596(22.6) 1(0, 2) 98.7(86.7, 110.3) 85(74, 98) 36.8(36.4, 37.2) 15(15, 15) 7.7(6.0, 10.7) 12.5(11.0, 13.7) 208(167, 262) 123(102, 157) 18.8(14.2, 26.6) 0.93(0.74, 1.23) 140(137, 142) 4.3(4.0, 4.7) 103(99, 106) 12 (8, 16) 3.69 (2.1, 6.92)
79(71, 84) 87(62.1) 58(41.4) 78(55.7) 23(16.4) 6(4.3) 15(10.7) 7(5.0) 47(33.6) 5(3.6) 65(46.4) 5(3, 7) 90.0(77.7, 101.1) 96(84, 112) 36.8(36.3, 37.4) 15(14, 15) 10.3(7.2, 14.5) 10.9(9.6, 12.7) 187(131, 261) 138(98, 208) 36.9(21.4, 63.3) 1.51(0.89, 2.64) 140(135, 145) 4.6(4.0, 5.4) 100(98, 108) 22 (16, 27) 8.08 (4.29, 15.25)
b0.001 0.001 0.002 0.922 0.974 0.138 0.041 0.228 b0.001 0.288 b0.001 b0.001 b0.001 b0.001 0.843 b0.001 b0.001 b0.001 0.008 0.001 b0.001 b0.001 0.001 b0.001 0.503 b0.001 b0.001
Abbreviations: DM = diabetes mellitus; HTN = hypertension; CAD = coronary artery disease; LC = liver cirrhosis; CKD = chronic kidney disease; ESRD = end-stage renal disease; HD = hemodialysis; CHF = congestive heart failure; SOFA = sequential organ failure score; MAP = mean arterial pressure; HR = heart rate; GCS = Glasgow Coma Scale; WBC = white blood cell; Hb = hemoglobin; PLT = platelet; BUN = blood urea nitrogen; APACHE II = Acute Physiology And Chronic Health Evaluation II; NLR = neutrophil to lymphocyte ratio.
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Fig. 1. The NLR at admission according to discharge status.
The NLR was examined as a continuous variable and a categorical variable. Table 2 shows the association between the variables and allcause in-hospital mortality. When treating the NLR as a continuous variable, the adjusted odds ratio (OR) was 1.03 (95% CI, 1.014–1.046), and when treating the NLR as a categorical variable (cutoff value ≥6), the adjusted OR was 2.49 (95% CI, 1.664–3.727). The association between the NLR and all-cause in-hospital mortality was consistently significant across subgroups, except for the subgroup with a history of CKD, no history of chronic pulmonary disease and no history of malignancy [Fig. 2]. 3.3. Prognostic value of NLR The sensitivity, specificity, positive likelihood ratio (PLR) and negative likelihood ratio (NLR) of NLR for different cutoff points are presented in Table 3. The best cutoff value of NLR was 3.88, with 82.14% sensitivity and 52.86% specificity. Mortality rate of NLR above 3.88 was 8.5% (N = 115) and below 3.88 was 1.8% (N = 25). The area under the curve (AUC) for the NLR for predicting in-hospital mortality was 0.714 (95% CI 0.669–0.759) [Fig. 3]. 4. Discussion The main finding of this study was that NLR at admission was an independent predictor of all-cause in-hospital mortality among patients older than 65 years. After adjustment for age; male gender; history of DM, CKD, chronic pulmonary disease and malignancy; and SOFA scores, the all-cause in-hospital mortality rate increased by 3.5% for each 1%
Table 2 Logistic regression analysis for predicting all-cause in-hospital mortality. NLR as categorical variable OR (95% CI) LC CKD Malignancy Glucose SOFA APACHE II NLR ≥ 6
0.315 (0.111–0.894) 0.51 (0.259–1.005) 1.956 (1.27–3.011) 1.002 (1–1.004) 1.519 (1.392–1.656) 1.091 (1.054–1.129) 2.49 (1.664–3.727)
NLR as continuous variable OR (95% CI) LC CKD Chronic pulmonary disease Malignancy Glucose SOFA APACHE II NLR
0.322 (0.122–0.928) 0.582 (0.3–1.13) 1.488 (0.936–2.364) 2.057 (1.328–3.187) 1.003 (1.001–1.004) 1.545 (1.413–1.689) 1.077 (1.037–1.118) 1.03 (1.014–1.046)
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increase in the NLR as a continuous variable. After adjusting for MAP, HR, WBC, Hb, platelet, glucose, BUN, Cr, sodium, potassium and SOFA scores, the all-cause in-hospital mortality rate increased by 2.3% for each 1% increase in the NLR as a continuous variable. When using the best cutoff value of NLR, the PPV and NPV were 8.5% (95% CI 7.8–9.2) and 98.2% (95% CI 97.5–98.8), respectively. If a patient has an NLR of N6, then the risk of in-hospital death is 9.9%. If a patient has a red cell distribution width (RDW) of b14.5, then the risk of survival hospital discharge is 97.2%. Although the number of elderly patients in the ED is increasing, there are few studies on the mortality rate of elderly patients. Elderly patients often present atypical signs and symptoms and have multiple comorbid conditions with multiple medications, which often leads to delayed diagnosis and treatment. Indeed, these patients are at higher risk of ED revisit, hospital admission, intensive care unit admission, and death than are young adults [2]. Emergency physicians may find it time consuming and difficult to completely assess older patients. Samaras et al. proposed a targeted approach for high-risk patients [3]. Our results may also help in the identification of older patients at higher risk. The NLR is associated with the outcome after sepsis and bacteremia [9-11]. The NLR is a marker of systemic inflammation and indicates the balance between innate and adaptive immune responses. Hwang et al. stated that the NLR at ED admission was independently associated with 28-day mortality in patients with severe sepsis and septic shock [10]. The theoretical basis is not yet clear. However, neutrophils play crucial roles in the innate immune response, resulting in multiple organ failure and even death when severely activated. In contrast, lymphocytes regulate the inflammatory response. Therefore, a high NLR indicates an imbalance of the inflammatory response and may be a surrogate marker of disease severity in infectious diseases, such as sepsis and bacteremia. The NLR is also associated with the outcome after cardiovascular disease, such as CAD, acute coronary syndrome and stroke [13-15,24]. Sen et al. demonstrated that an elevated NLR upon admission was correlated with both the no-reflow phenomenon and long-term prognosis in patients with ST-elevation myocardial infarction who underwent primary percutaneous intervention [18]. Moreover, the NLR is also associated with stroke severity, functional outcome and recurrent ischemic stroke in patients with acute ischemic stroke [15]. One possible mechanism is that inflammatory mediators from neutrophils could cause vascular wall degeneration, while lymphocytes play an anti-atherosclerotic role. The exact mechanism underlying the association between NLR and mortality in elderly patients admitted to the ED is unclear. One possible explanation is systemic inflammation due to acute illness. It is possible that the NLR is associated with mortality because it represents an imbalance of the inflammatory response due to acute illness, as in sepsis, bacteremia or cardiovascular disease. In other words, the NLR may be a surrogate marker indicating disease severity in elderly patients. Another possible explanation is chronic inflammation, which is the cause of aging in elderly patients [21]. The NLR is a marker of chronic inflammation. Thus, an increased NLR may indicate the level of chronic inflammation in that patient. The exact mechanism underlying the association between NLR and mortality should be further investigated. This study has some important limitations to consider. Our study is a single center, retrospective study, needs to be replicated with larger prospective studies. Consistent with other retrospective studies, this study is limited by an inability to control for all measured and unmeasured confounders. Our primary outcome was all-cause in-hospital mortality, so we could not analyze the cause of specific mortalities. The exact mechanisms underlying the association between NLR and mortalities in elderly individuals are not certain. Systemic inflammation may cause mortality, but further studies are needed to identify the exact mechanisms. We only checked the NLR at admission; however, there may be a specific pattern in serial NLR examination. If there is an association between serial NLR and mortality, then this association could
Please cite this article as: H. Song, H.J. Kim, K.N. Park, et al., Neutrophil to lymphocyte ratio is associated with in-hospital mortality in older adults admitted to ..., American Journal of Emergency Medicine, https://doi.org/10.1016/j.ajem.2020.01.044
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Fig. 2. Subgroup analysis for the association between the NLR at admission and all-cause in-hospital mortality.
have more specificity in predicting mortality. As previously discussed, our study only shows an association, so there is a limitation of the clinical implications. Thus, more studies are needed to identify the associations between the NLR and cause-specific mortality in elderly individuals. NLR used with other known prognostic tools such as APACHE II or biomarkers such as blood lactate may be useful, but further data are needed. 5. Conclusions
CKD BUN Cr Hb SOFA OR AUC RDW
chronic kidney disease blood urea nitrogen creatinine hemoglobin sequential organ failure assessment odds ratio area under the curve red cell distribution width
In conclusion, the NLR at admission to the ED is associated with allcause in-hospital mortality among patients older than 65 years without hematologic malignancies. Thus, the NLR at admission may represent a surrogate marker of disease severity. However, we need more external validation to use the NLR in the clinical decision-making process. Abbreviations NLR ED SD CBC MAP HR GCS DM HBP CAD HF LC
neutrophil to lymphocyte ratio emergency department standard deviation complete blood count mean arterial pressure heart rate Glasgow Coma Scale diabetes mellitus hypertension coronary artery disease heart failure liver cirrhosis
Table 3 Sensitivity, specificity, positive likelihood ratio and negative likelihood ratio for different cutoff point. NLR
Sensitivity (95% CI)
Specificity (95% CI)
PLR (95% CI)
NLR (95% CI)
N3.88 N6
82.14 (74.8–88.1) 62.86 (54.3–70.9)
52.86 (50.9–54.8) 69.93 (68.1–71.7)
1.72 (1.6–1.9) 2.09 (1.8–2.4)
0.36 (0.3–0.5) 0.53 (0.4–0.7)
Abbreviations: PLR = positive likelihood ratio; NLR = negative likelihood ratio.
Fig. 3. Prognostic value of the NLR for the prediction of all-cause in-hospital mortality. The AUC is 0.714 (95% CI 0.669–0.759).
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Ethics approval and consent to participate This study was approved by the Institutional Review Board of Seoul St. Mary's Hospital (file number: XC17REDI0071); waiver of consent was allowed because of the retrospective nature of the study. Consent for publication Not applicable. Availability of data and materials The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Funding There were no funding sources in this study. Authors' contributions CSY and KNP conceived the project. Data collection and analyses were performed by HS, HJK, SHK and SHO. The manuscript was written by HS and SM, and revised by CSY. All authors read and approved the final manuscript. Declaration of competing interest The authors declare that they have no competing interests. References [1] American College of Emergency Physicians, American Geriatrics Society, Emergency Nurses Association, Society for Academic Emergency Medicine, Geriatric Emergency Department Guidelines Task Force. Geriatric emergency department guidelines. Ann Emerg Med 2014;63:e7-25. [2] Aminzadeh F, Dalziel WB. Older adults in the emergency department: a systematic review of patterns of use, adverse outcomes, and effectiveness of interventions. Ann Emerg Med 2002;39:238–47. [3] Samaras N, Chevalley T, Samaras D, Gold G. Older patients in the emergency department: a review. Ann Emerg Med 2010;56:261–9. [4] Strange GR, Chen EH, Sanders AB. Use of emergency departments by elderly patients: projections from a multicenter data base. Ann Emerg Med 1992;21:819–24.
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Please cite this article as: H. Song, H.J. Kim, K.N. Park, et al., Neutrophil to lymphocyte ratio is associated with in-hospital mortality in older adults admitted to ..., American Journal of Emergency Medicine, https://doi.org/10.1016/j.ajem.2020.01.044