Emergency Medicine

Neutrophil to lymphocyte ratio is associated with in-hospital mortality in older adults admitted to the emergency department

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 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 prob- lem. We excluded patients with hematologic malignancy. Baseline NLR values were measured at the time of ad- mission 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.

(C) 2020

  1. Background

The elderly population is steadily increasing, which is one of the major causes of increased health care burden in the emergency depart- ment (ED) [1-3]. Elderly individuals are admitted to the ED more fre- quently 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 indi- viduals are at high risk for ED revisit, hospital admission, intensive care unit admission, and death [2-6]. Several Screening tools have been de- veloped to recognize the increased risk of adverse outcomes, but these Risk assessment tools are considered to lack sufficient prognostic accu- racy [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 is a simple marker that in- dicates 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 dis- eases, such as sepsis, bacteremia and appendicitis [9-12]. In addition, the NLR has also been associated with the outcome of noninfectious dis- eases, such as acute myocardial infarction, stroke and several types of cancers [13-17]. The exact mechanism is not fully elucidated, but in- creased neutrophils exhibit systemic inflammation, which affects ath- erosclerosis and tumor progression, and lymphocytes play an opposite role [18,19]. Thus, the NLR is a systemic inflammatory marker and a po- tential 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 mor- bidity and mortality in older adults [19-22]. However, there are few studies on the association between elevated NLR and mortality in el- derly 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/(C) 2020

assessed the association between the NLR at admission to the ED and all-cause in-hospital mortality.

  1. Methods
    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.

    1. 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 in- jury; had a hematologic disease, such as leukemia, myelodysplastic syn- dromes, myeloproliferative disease or myelofibrosis; or did not have a complete blood count .

    1. 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 , hy- pertension (HBP), coronary artery disease (CAD), heart failure , liver cirrhosis (LC), chronic kidney disease (CKD), chronic pulmonary disease and malignancies. Initial laboratory findings such as white blood cell count with NLR, Blood urea nitrogen , creatinine (Cr), hemoglobin (Hb), platelets, glucose, sodium, potassium and chlo- ride 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

N = 2637

N = 140

Age, years

75(70, 81)

79(71, 84)

b0.001

Sex (male)

1272(48.2)

87(62.1)

0.001

DM

773(29.3)

58(41.4)

0.002

HTN

1458(55.3)

78(55.7)

0.922

CAD

436(16.5)

23(16.4)

0.974

LC

61(2.3)

6(4.3)

0.138

CKD

167(6.3)

15(10.7)

0.041

ESRD on HD

83(3.1)

7(5.0)

0.228

Chronic pulmonary disease

456(17.3)

47(33.6)

b0.001

CHF

58(2.2)

5(3.6)

0.288

Malignancy

596(22.6)

65(46.4)

b0.001

SOFA

1(0, 2)

5(3, 7)

b0.001

MAP, mm Hg

98.7(86.7, 110.3)

90.0(77.7, 101.1)

b0.001

HR

85(74, 98)

96(84, 112)

b0.001

Temp, ?C

36.8(36.4, 37.2)

36.8(36.3, 37.4)

0.843

GCS

15(15, 15)

15(14, 15)

b0.001

WBC, 109/L

7.7(6.0, 10.7)

10.3(7.2, 14.5)

b0.001

Hb, mg/dl

12.5(11.0, 13.7)

10.9(9.6, 12.7)

b0.001

PLT, 109/L

208(167, 262)

187(131, 261)

0.008

Glucose, mg/dl

123(102, 157)

138(98, 208)

0.001

BUN, mg/dl

18.8(14.2, 26.6)

36.9(21.4, 63.3)

b0.001

Creatinine, mg/dl

0.93(0.74, 1.23)

1.51(0.89, 2.64)

b0.001

Na, mEq/L

140(137, 142)

140(135, 145)

0.001

K, mEq/L

4.3(4.0, 4.7)

4.6(4.0, 5.4)

b0.001

Cl, mEq/L

103(99, 106)

100(98, 108)

0.503

APACHE II

12 (8, 16)

22 (16, 27)

b0.001

NLR

3.69 (2.1, 6.92)

8.08 (4.29, 15.25)

b0.001

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 consid- ered statistically significant. The Youden Index was used to determine the optimal cut off point for mortality.

  1. Results
    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 myelofi- brosis). 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 charac- teristics 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 sur- vivors (median, 3.69, IQR 2.1-6.92, P b 0.001) [Fig. 1].

    1. Logistic regression analysis

In the univariate analysis, age, male gender, DM, CKD, chronic pulmo- nary disease, malignancy, SOFA score, MAP, HR, GCS, WBC, Hb, PLT, glu- cose, 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.

Chronic Health Evaluation II (APACHE II) were calculated at the time of ED admission.

    1. Outcomes

The primary outcome of this study was the association of NLR with all-cause in-hospital mortality. Survival to hospital discharge was de- fined if the patient was discharged from the hospital alive to home or to another health care facility.

    1. Analysis

Normality tests were performed for continuous variables, and con- tinuous variables are presented as the means with the standard devia- tion 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. Uni- variate 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 all- cause in-hospital mortality, multivariate logistic regression analyses

Survivors

Non-survivors p

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 per- formed on each model to evaluate the association between NLR and all-

Abbreviations: DM = diabetes mellitus; HTN = hypertension; CAD = coronary artery dis- ease; 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.

Image of Fig. 1

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 all- cause in-hospital mortality. When treating the NLR as a continuous var- iable, 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 ad- justed 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].

    1. Prognostic value of NLR

The sensitivity, specificity, positive likelihood ratio (PLR) and nega- tive likelihood ratio (NLR) of NLR for different cutoff points are pre- sented 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].

  1. Discussion

The main finding of this study was that NLR at admission was an in- dependent 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

0.315 (0.111-0.894)

CKD

0.51 (0.259-1.005)

Malignancy

1.956 (1.27-3.011)

Glucose

1.002 (1-1.004)

SOFA

1.519 (1.392-1.656)

APACHE II

1.091 (1.054-1.129)

NLR >= 6

2.49 (1.664-3.727)

NLR as continuous variable OR (95% CI)

LC

0.322 (0.122-0.928)

CKD

0.582 (0.3-1.13)

Chronic pulmonary disease

1.488 (0.936-2.364)

Malignancy

2.057 (1.328-3.187)

Glucose

1.003 (1.001-1.004)

SOFA

1.545 (1.413-1.689)

APACHE II

1.077 (1.037-1.118)

NLR

1.03 (1.014-1.046)

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 dis- tribution width (RDW) of b14.5, then the risk of survival hospital dis- charge 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. Sa- maras 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, lym- phocytes regulate the inflammatory response. Therefore, a high NLR in- dicates an imbalance of the inflammatory response and may be a surrogate marker of disease severity in infectious diseases, such as sep- sis and bacteremia.

The NLR is also associated with the outcome after cardiovascular dis- ease, 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 pa- tients 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 imbal- ance of the inflammatory response due to acute illness, as in sepsis, bac- teremia 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 inflamma- tion. Thus, an increased NLR may indicate the level of chronic inflamma- tion 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 unmea- sured 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 asso- ciation between serial NLR and mortality, then this association could

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 bio- markers such as blood lactate may be useful, but further data are needed.

  1. Conclusions

In conclusion, the NLR at admission to the ED is associated with all- cause 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 neutrophil to lymphocyte ratio ED emergency department

SD standard deviation CBC complete blood count MAP mean arterial pressure HR heart rate

GCS Glasgow Coma Scale DM diabetes mellitus

HBP hypertension

CAD coronary artery disease HF heart failure

LC 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 82.14 (74.8-88.1) 52.86 (50.9-54.8) 1.72 (1.6-1.9) 0.36 (0.3-0.5)

N6 62.86 (54.3-70.9) 69.93 (68.1-71.7) 2.09 (1.8-2.4) 0.53 (0.4-0.7)

Abbreviations: PLR = positive likelihood ratio; NLR = negative likelihood ratio.

CKD chronic kidney disease BUN blood urea nitrogen

Cr creatinine

Hb hemoglobin

SOFA sequential organ failure assessment OR odds ratio

AUC area under the curve RDW red cell distribution width

Image of Fig. 3

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).

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 avail- able 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 depart- ment: a review. Ann Emerg Med 2010;56:261-9.
  4. Strange GR, Chen EH, Sanders AB. Use of emergency departments by elderly pa- tients: projections from a multicenter data base. Ann Emerg Med 1992;21:819-24.
  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 emer- gency department: comparison between the Identification of Seniors at Risk and Tri- age Risk screening tool. Rejuvenation Res 2012;15:288-94.
  9. Xuan Liu, Yong Shen, Hairong Wang, et al. Prognostic significance of neutrophil-to- lymphocyte ratio in patients with sepsis: a prospective observational study. Media- tors 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 co- hort 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. Ayca B, Akin 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-to- lymphocyte 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 nar- rative 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-of- hospital cardiac arrest based on automated blood cell count and neutrophil lympho- cyte 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 ST- elevated myocardial infarction undergoing primary coronary intervention. Athero- sclerosis 2013;228:203-10.

Leave a Reply

Your email address will not be published. Required fields are marked *