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Journal of the Neurological Sciences 387 (2018) 115–118

Contents lists available at ScienceDirect

Journal of the Neurological Sciences


journal homepage: www.elsevier.com/locate/jns

Neutrophil to lymphocyte ratio and early clinical outcomes in patients with T


acute ischemic stroke
Sungwook Yua,b,c, Hisatomi Arimab, Carin Bertmarc, Stephen Clarkec, Geoffrey Herkesc,

Martin Krausec,
a
Department of Neurology, Korea University College of Medicine, Seoul, Republic of Korea
b
The George Institute for Global Health, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia
c
Department of Neurology, Royal North Shore Hospital, St Leonards and University of Sydney, Sydney, Australia

A R T I C L E I N F O A B S T R A C T

Keywords: Background: The neutrophil to lymphocyte ratio (NLR) is closely linked to mortality in patients with cardio-
Neutrophil vascular disease. We investigated whether NLR is associated with early clinical outcomes in patients with acute
Lymphocyte ischemic stroke.
Leukocyte Methods: We collated data from a tertiary hospital's stroke registry including admitted patients with a first-ever
Outcomes
acute ischemic stroke within 72 h of onset. White blood cell counts and peripheral differential counts were
Ischemic stroke
measured on admission. Early clinical outcomes were in-hospital mortality and disability at discharge assessed
by the modified Rankin scale (mRS).
Results: Among 1131 stroke patients, 454 patients were included and classified into tertile groups based on NLR
on admission. Patients in higher tertiles of NLR were likely to have severe neurologic deficit at discharge. Higher
NLR tertiles were associated with an unfavourable shift of mRS score (p < .0001). This association remained
significant after adjustment for clinical and laboratory variables including age, sex, hypertension, hypercho-
lesterolemia, atrial fibrillation, stroke severity, and glucose level (p = .032 for trend). However, risk of death or
major disability (score of 3–6 on mRS) and in-hospital mortality were not significantly different across NLR
tertile groups.
Conclusions: In patients with acute ischemic stroke, NLR was predictive of short-term functional outcome.

1. Introduction stroke patients also proposed the prognostic value of NLR for prediction
of mortality [12,14–17]. Furthermore, higher NLR has been shown to
Inflammation after stroke contributes to brain injury [1–3] and a be independently associated with worse outcome at 3 months in is-
number of inflammatory biomarkers have been investigated in stroke chemic stroke patients treated with thrombolytic therapy [18,19].
patients [4]. Elevated peripheral leukocyte count has been shown to be However, this relationship has been investigated in a relatively narrow
associated with mortality or poor clinical outcome in patients with range of stroke patients and the literature on the association between
acute ischemic stroke [5–8] or with higher risks of stroke in patients NLR and functional outcomes is limited.
with symptomatic intracranial atherosclerotic disease [9]. However, We undertook this study to evaluate whether NLR was associated
post-stroke immunologic response is a complex process inducing acti- with short-term clinical outcome in patients with acute ischemic stroke.
vation of diverse inflammatory cells and immunodepression [2,3].
Neutrophils and lymphocytes among subtypes of leukocytes might have 2. Materials and methods
different effects on clinical outcomes since a prior study suggested an
inverse association between lymphocyte counts within three days of 2.1. Study design
stroke onset and functional outcome at three months [10].
Recently, neutrophil to lymphocyte ratio (NLR) has emerged as a We included consecutive patients with stroke or transient ischemic
strong predictor of mortality in patients with cardiovascular disease attack who were admitted to Royal North Shore Hospital (RNSH), a
[11,12] or peripheral arterial occlusive disease [13]. Previous studies in tertiary hospital in Sydney, Australia, and registered in the hospital's


Corresponding author at: Department of Neurology, Royal North Shore Hospital, University of Sydney, Sydney, New South Wales, Australia.
E-mail address: martin.krause@sydney.edu.au (M. Krause).

https://doi.org/10.1016/j.jns.2018.02.002
Received 17 June 2017; Received in revised form 28 January 2018; Accepted 1 February 2018
Available online 02 February 2018
0022-510X/ © 2018 Published by Elsevier B.V.
S. Yu et al. Journal of the Neurological Sciences 387 (2018) 115–118

stroke registry database from January 2009 to March 2013. Patients (44–56). Median duration of hospitalization was 5.5 days (3.3–9.0).
who were older than 18 years and were admitted to the hospital within Dyslipidemia was more frequently observed in patients with the highest
72 h of onset due to a first-ever acute ischemic stroke were selected. NLR tertile. Other stroke risk factors were not different across NLR
Patients were excluded if they had a transient ischemic attack, throm- tertile groups. Patients in higher tertiles of NLR were more likely to
bolysis therapy, an in-hospital stroke, a history of steroids or im- have severe neurologic deficit. (Table 1) Median SSS scores from the
munosuppressive agents, an infection history within one week before lowest to the highest tertiles of NLR were 56 (50–58), 55 (46–56), and
admission, and the occurrence of infection during hospitalization. 50 (32–56), respectively. Moreover, patients in higher NLR tertiles
Infection including pneumonia and urinary tract infection was defined stayed longer at hospital. Duration of hospitalization was significantly
by typical symptoms with supported evidence from physical examina- correlated to the severity of neurologic deficit assessed by SSS
tion, blood or urinary tests, imaging etc. This study was approved by (r = −0.40, p < .0001). Time intervals from stroke onset to admission
the Institutional Review Board with a waiver of patients' informed or to blood sampling were not different among the tertile groups. WBC
consent due to the retrospective study design. and neutrophils counts increased in higher NLR tertile groups. How-
Ischemic stroke was diagnosed by the World Health Organization's ever, lymphocytes and eosinophils counts decreased as the NLR in-
definition [20] and confirmed by computerized tomography or mag- creased. Elevated levels of glucose were found in the higher tertile
netic resonance imaging. Baseline demographics were collated from the groups.
stroke registry database including vascular risk factors, e.g. hyperten-
sion, diabetes, hypercholesterolemia, atrial fibrillation, ischemic heart 3.2. Clinical outcomes
diseases, smoking status and alcohol consumption. Information on
previous medication was obtained including antiplatelet agents, antic- During hospitalization, 98 (21.6%) patients had unfavourable out-
oagulants, and lipid lowering agents. comes: 78 patients with major disability (mRs 3–5) and 20 patients who
Stroke severity was assessed by the Scandinavian Stroke Scale (SSS) died in hospital (4.4%). Higher tertiles of NLR were significantly as-
on admission and categorised into four groups with very severe (score sociated with unfavourable shift of mRS scores in multinomial logistic
of 0 to 14 points), severe (15 to 29 points), moderate (30 to 44 points), regression analysis (p < .0001) (Table 2). The highest tertile group
and mild (45 to 58 points) deficit [21]. We assessed disability at dis- had 2.68 fold-increased risks of unfavourable shift of mRS compared to
charge by the modified Rankin scale (mRS) and in-hospital mortality as the lowest tertile group of NLR. [95% confidence interval (CI)
clinical outcomes. 1.77–4.06]. In univariable analysis, age, sex, hypertension, smoking,
hypercholesterolemia, atrial fibrillation, glucose level, and SSS score
2.2. Neutrophil to lymphocyte ratio were confounding variables significantly associated with unfavourable
shift of mRS. After adjustments for clinical and laboratory variables that
Blood samples were collected on admission and white blood cell had significant association with outcomes, the association between
counts and peripheral differential counts were measured. NLR was tertiles of NLR and unfavourable shift of mRS remained significant
calculated by neutrophil count divided by lymphocyte count. All pa- (p < .032).
tients were grouped into tertiles according to their NLR on admission. Risk of death or major disability (mRS 3–6) significantly increased
in higher tertiles of NLR (p = .0002 for trend). However, the associa-
2.3. Statistical analysis tion was no longer significant after adjustment of confounding variables
as outlined above. There was a trend towards increased in-hospital
Data were presented as number (%), mean (standard deviation) or mortality in the higher NLR, but this association did not reach statistical
median (interquartile range [IQR]) as appropriate. Baseline demo- significance.
graphic and laboratory data were compared across NLR tertile groups
using Fisher's exact test for categorical variables and Kruskal-Wallis test 4. Discussion
for continuous variables. Correlation between two variables was as-
sessed by Pearson or Spearman correlation test. Clinical Outcomes were In patients with acute first-ever ischemic stroke, higher NLR within
mRS distribution at discharge, in-hospital mortality and death or major 3 days after the stroke onset was an independent predictor for un-
disability (mRS 3–6) at discharge. We used binomial and multinomial favourable functional outcomes at discharge. NLR on admission, how-
logistic regression to investigate the association between NLR and ever, was not significantly associated with increased in-hospital mor-
clinical outcomes. To adjust for other potential confounding variables, tality after adjustment for other potential predictors. These results
multivariable analyses including age, sex, and other variables, that suggest that NLR on admission after acute ischemic stroke is a simple
were significant in univariable analyses with P < .05, were performed. and useful hematologic biomarker to estimate short-term functional
P value < .05 for two-sided hypothesis testing was considered as sta- outcomes.
tistically significant. Statistical analyses were conducted using SAS Post-stroke inflammation causes a deleterious effect on brain injury
version 9.3 (SAS Institute, Cary, North Carolina, USA). while it might play a different role in tissue repair and regeneration in a
time-dependent way [2]. Neutrophils are a major subtype of leukocytes
3. Results to respond early after stroke and represent active inflammatory reaction
[2,22]. Subsets of lymphocyte, specific T cell lymphocytes, might have
3.1. Baseline characteristics a regulatory function in inflammation inducing neuroprotection [1–3].
It has been well known that stroke-induced systemic immunosuppres-
Among 1131 consecutive stroke patients, 626 had the first ever is- sion, e.g. lymphopenia, could increase susceptibility to infection in-
chemic stroke. Of 626 patients, 172 were excluded due to age under cluding pneumonia and urinary tract infections [3,23], which cause a
18 years (n = 3), thrombolysis treatment (n = 38), onset to admission harmful effect on clinical outcomes. In acute ischemic stroke patients,
time over 72 h (n = 49), unknown onset time (n = 16), and occurrence total WBC and neutrophil counts within three days after symptom onset
of infection during hospitalization (n = 66). Finally, 454 patients were had a positive correlation with stroke severity and infarct volume,
included in this study. Number of patients who were admitted within while higher lymphocyte counts was associated with early improve-
24 h after stroke onset was 376 (82.8%). ment during the first week after admission and good functional out-
Baseline clinical characteristics are presented in Table 1. Median come at three months [10,24]. Therefore, higher NLR could be a more
(IQR) age of included patients was 72.4 years (62.1–82.6) and 201 sensitive marker indicating higher level of post-stroke inflammation
(44.3%) were male. Median (IQR) score of SSS on admission was 54 [25].

116
S. Yu et al. Journal of the Neurological Sciences 387 (2018) 115–118

Table 1
Baseline characteristics according to tertiles of neutrophil to lymphocyte ratio.

Neutrophil to lymphocyte ratio

1st 2nd 3rd

All ≤2.36 2.37–4.10 4.12≤

(n = 454) (n = 151) (n = 152) (n = 151) P value

Demographic
Age (years) 70.0 ± 16.0 68.1 ± 17.1 69.8 ± 15.2 72.0 ± 15.6 0.084
Male 253 (55.7) 80 (53.0) 89 (58.6) 84 (55.6) 0.621

Medical history
Hypertension 256 (56.4) 82 (54.3) 88 (57.9) 86 (57.0) 0.808
Diabetes mellitus 90 (19.8) 27 (17.9) 32 (21.1) 31 (20.5) 0.759
Smoking 54 (11.9) 17 (11.3) 18 (11.8) 19 (12.6) 0.939
Hypercholesterolemia 257 (25.6) 103 (68.2) 83 (54.6) 71 (47.0) 0.0008
Atrial fibrillation 137 (30.2) 40 (26.5) 42 (27.6) 55 (36.4) 0.120
Ischemic heart diseases 75 (16.5) 21 (13.9) 23 (15.1) 31 (20.5) 0.257

Medication history
Anticoagulation agent 51 (11.2) 9 (6.0) 17 (11.2) 25 (16.6) 0.014
Antiplatelet agent 137 (30.2) 43 (28.5) 54 (35.5) 40 (26.5) 0.197
Lipid lowering agent 147 (32.4) 48 (31.8) 48 (31.6) 51 (33.8) 0.904

Clinical features
Fever 123 (26.4) 38 (25.2) 43 (28.3) 39 (25.8) 0.810

Laboratory findings
Hemoglobin (g/dL) 13.8 ± 1.6 14.1 ± 1.5 13.8 ± 1.5 13.7 ± 1.8 0.144
Platelet count (×109/L) 226.0 ± 84.1 219.0 ± 69.8 235.1 ± 107.1 223.8 ± 69.5 0.387
White blood cell count (×109/L) 8.3 ± 2.6 7.3 ± 2.0 7.9 ± 2.2 9.7 ± 2.9 < 0.0001
Neutrophils 5.7 ± 2.5 4.1 ± 1.1 5.3 ± 1.6 7.8 ± 2.8 < 0.0001
Lymphocytes 1.7 ± 0.9 2.4 ± 1.0 1.7 ± 0.5 1.1 ± 0.4 < 0.0001
Monocytes 0.6 ± 0.2 0.6 ± 0.2 0.6 ± 0.2 0.6 ± 0.2 0.661
Eosinophils 0.1 ± 0.2 0.2 ± 0.2 0.2 ± 0.2 0.1 ± 0.1 < 0.0001
Glucose (mmol/L) 7.0 ± 3.1 6.7 ± 3.0 6.9 ± 2.6 7.3 ± 3.7 0.016
Creatinine (μmol/L) 87.8 ± 30.0 87.3 ± 24.5 86.5 ± 24.9 89.6 ± 38.6 0.810
SSS score 54 (44–56) 56 (50–58) 55 (46–56) 50 (32–56) < 0.0001
SSS score category
Mild (45–58) 337 (74.2) 125 (82.8) 121 (79.6) 91 (60.3) 0.0004
Moderate (30–44) 54 (11.9) 11(7.3) 16 (10.5) 27 (17.9)
Severe (15–29) 32 (7.1) 9 (6.0) 6 (4.0) 17 (11.3)
Very severe (0–14) 31 (6.8) 6 (4.0) 9 (5.9) 16 (10.6)
Onset to admission time (hours) 14.3 ± 20.8 14.4 ± 21.4 16.7 ± 23.2 11.8 ± 17.3 0.315
Onset to sampling time (hours) 19.0 ± 25.1 19.4 ± 24.2 22.3 ± 29.5 15.4 ± 20.3 0.599
Hospitalization (days) 5.5 (3.3–9.0) 4.7 (2.6–6.5) 5.3 (3.3–9.3) 7.3 (3.6–10.6) < 0.0001

Number is expressed as number (%) or mean (standard deviation) or median (interquartile range) as appropriate. Scandinavian Stroke Scale (SSS).

Previous reports have demonstrated that NLR was related to infarct There were limitations in this study. This was a retrospective study
volume and stroke severity [14,15]. Moreover, NLR has been reported in a single university hospital with a relatively small sample size.
to have a predictive value associated with mortality or functional out- Information on post-stroke complications including cerebral edema and
comes in patients with acute stroke. Higher NLR on admission was hemorrhagic transformation was not collected, which might be poten-
consistently found to be related to mortality within 60 days after acute tial imaging parameters to affect functional outcomes. We included
ischemic stroke [14–17]. Recently, increased NLR was identified as an patients within 72 h after stroke onset. Although most of the study
independent factor for symptomatic intracerebral hemorrhage or poor population (82.8%) had the time from stroke onset to admission < 24
outcome at 3 months in acute ischemic patients who were treated with h, a relatively longer inclusion time window might have affected the
IV recombinant tissue plasminogen activator or endovascular therapy findings of this study. Variation in length of hospital stay may also have
[18,19]. In line with previous studies, this study demonstrated the affected the results of this study despite the short-term clinical out-
predictive value of NLR in association with unfavourable outcome at comes and adjustment of the severity of stroke. In addition, the statis-
discharge. However, we did not find the association of higher NLR with tical power of the present analysis may have been somewhat limited
mortality. This might be due to a low mortality rate (< 5%) in this because of low mortality rate. We did not measure the change of NLR
study in contrast to the higher mortality rate of 13% to 28% [14–17] in during hospitalization. Change of NLR over time may provide valuable
the previous studies. This difference is likely to be caused by the large information for understanding the underlying mechanism of post-stroke
proportion of patients (over 70%) with mild stroke in our study and immunologic response and its clinical implications.
specific target groups with atherothrombotic stroke [16] or supra- The strength of NLR is the fact that it is easy and simple to be
tentorial ischemic stroke [14,15] in the previous studies. The popula- evaluated on admission. NLR might reflect post-stroke immunologic
tion in the present study including consecutive ischemic patients had a imbalance after stroke more accurately than total WBC or neutrophil
wide range of stroke patients. Thus, the results of this study may be counts. Our results suggest that, in patients with acute ischemic stroke,
clinically more relevant and provide an evidence to extend predictive NLR on admission could be useful in prediction of short-term clinical
value of NLR for clinical outcomes in patients with acute ischemic outcomes.
stroke.

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S. Yu et al. Journal of the Neurological Sciences 387 (2018) 115–118

Table 2
Risks of clinical outcomes according to tertiles of neutrophil to lymphocyte ratio.

Neutrophil/lymphocyte ratio

1st 2nd 3rd

≤2.36 2.37–4.10 4.12≤

(n = 151) (n = 152) (n = 151) P trend


Score on the modified Rankin scale (mRS)
n (%)
0: No symptoms at all 74 (49.0) 71 (46.7) 38 (25.2)
1: No substantive disability despite symptoms 35 (23.2) 35 (23.0) 40 (26.5)
2: Slight disability 21 (13.9) 17 (11.2) 25 (16.6)
3: Moderate disability requiring some help 9 (6.0) 15 (9.9) 18 (11.9)
4: Moderate–severe disability requiring assistance with daily living 5 (3.3) 3 (2.0) 7 (4.6)
5: Severe disability, bedbound and incontinent 3 (2.0) 5 (3.3) 13 (8.6)
6: Death 4 (2.7) 6 (4.0) 10 (6.6)
Crude OR (95%CI) 1 (reference) 1.14 (0.75–1.74) 2.68 (1.77–4.06) < 0.0001
Adjusted OR (95%CI) 1 (reference) 1.23 (0.69–2.20) 1.87 (1.05–3.34) 0.032

Death or major disability (mRS 3–6)


n (%) 21 (13.9) 29 (19.1) 48 (31.8)
Crude OR (95%CI) 1 (reference) 1.46 (0.79–2.70) 2.89 (1.62–5.12) 0.0002
Adjusted OR (95%CI) 1 (reference) 1.56 (0.55–4.48) 1.26 (0.44–3.60) 0.701

Death
n (%) 4 (2.7) 6 (4.0) 10 (6.6)
Crude OR (95%CI) 1 (reference) 1.51 (0.42–5.46) 2.61 (0.80–8.50) 0.098
Adjusted OR (95%CI) 1 (reference) 1.71 (0.10–28.67) 0.87 (0.06–12.72) 0.740

OR, odds ratio; 95%CI, 95% confidence interval.


Adjustments were made for age, sex, hypertension, smoking, hypercholesterolemia, atrial fibrillation, glucose level, and Scandinavian Stroke Scale score.

The difference in the modified Rankin scale scores was determined using ordinal logistic regression models.

Conflict of interest 26–34.


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