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Aging and disease    2019, Vol. 10 Issue (3) : 544-556     DOI: 10.14336/AD.2018.0820
Orginal Article |
The Prognostic Value of Serum Cytokines in Patients with Acute Ischemic Stroke
Xianmei Li1, Siyang Lin2, Xiaoli Chen1, Wensi Huang3, Qian Li4, Hongxia Zhang5, Xudong Chen2, Shaohua Yang5, Kunlin Jin5, Bei Shao2,*
1Department of Rehabilitation, Wenzhou People’s Hospital, Wenzhou, China
2Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
3Department of Neurology, The People’s Hospital of Pingyang, Wenzhou, China
4Department of Neurology, Jinhua Municipal Central Hospital, Wenzhou, China
5Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, USA
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Abstract  

The inflammatory response is an unavoidable process and contributes to the destruction of cerebral tissue during the acute ischemic stroke (AIS) phase and has not been addressed fully to date. Insightful understanding of correlation of inflammatory mediators and stroke outcome may provide new biomarkers or therapeutic approaches for ischemic stroke. Here, we prospectively recruited 180 first-ever AIS patients within 72 hrs after stroke onset. We used the National Institutes of Health Stroke Scale (NIHSS) to quantify stroke severity and modified Rankin scale (mRS) to assess the 3-month outcome for AIS patients. Initially, we screened 35 cytokines, chemokines, and growth factors in sera from 75 AIS patients and control subjects. Cytokines that were of interest were further investigated in the 180 AIS patients and 14 heathy controls. We found that IL-1RA, IL-1β, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-13, IL-15, EGF, G-CSF, Flt-3L, GM-CSF and Fractalkine levels were significantly decreased in severe stroke patients. In particular, IL-1β, IL-4, IL-5, IL-7, IL-9, IL-10, IL-15, G-CSF and GM-CSF were significantly reduced in AIS patients with poor outcome, compared to those with good prognosis. IL-6 was notably higher in the poor outcome group. Only IL-9 level decreased in the large infarct volume group. After adjusting for confounders, we found that IL-5 was an independent protective factor for prognosis in AIS patients with an adjusted OR of 0.042 (P = 0.007), whereas IL-6 was an independent risk predictor for AIS patients with an adjusted OR of 1.293 (P = 0.003). Our study suggests the levels of serum cytokines are related to stroke severity, short-term prognosis and cerebral infarct volume in AIS patients.

Keywords acute ischemic stroke      cytokines      inflammation      prognosis      stroke severity     
Corresponding Authors: Shao Bei   
About author:

These authors contributed equally to this study.

Just Accepted Date: 14 September 2018   Issue Date: 28 May 2019
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Xianmei Li
Siyang Lin
Xiaoli Chen
Wensi Huang
Qian Li
Hongxia Zhang
Xudong Chen
Shaohua Yang
Kunlin Jin
Bei Shao
Cite this article:   
Xianmei Li,Siyang Lin,Xiaoli Chen, et al. The Prognostic Value of Serum Cytokines in Patients with Acute Ischemic Stroke[J]. Aging and disease, 2019, 10(3): 544-556.
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http://www.aginganddisease.org/EN/10.14336/AD.2018.0820     OR     http://www.aginganddisease.org/EN/Y2019/V10/I3/544
CharacteristicsTotal (N= 167)Prognosis at 3 months follow-up
P value
Favorable Outcome
(N= 113)
Poor Outcome
(N=54)
Age (years)63.02 ± 9.8462.08 ± 10.3565.00 ± 8.430.073
Males (%)100 (60.0)73 (64.6)27 (50.0)0.073
SBP (mmHg)162.34 ± 24.41160.18 ± 22.76166.87 ± 27.200.097
DBP (mmHg)85.43 ± 13.6885.48 ± 13.1385.31 ± 14.900.943
Hypertension (%)141 (84.4)93 (82.3)48 (88.9)0.273
Hyperlipidemia (%)32 (19.2)21 (18.6)11 (20.4)0.784
Diabetes (%)55 (32.9)33 (29.2)22 (40.7)0.139
Cardiac disease (%)19 (11.4)10 (8.8)9 (16.7)0.138
Smoking (%)57 (34.1)31 (27.4)24 (44.4)0.053
Alcohol drinking (%)43 (25.7)33 (29.2)9 (16.7)0.064
Stroke etiologic subtypes (%)0.982
 Large-artery atherosclerosis110 (65.7)76 (67.3)34 (62.3)-
 Cardioembolic13 (7.8)8 (7.1)5 (9.3)-
 Small-vessel disease38 (22.8)28 (24.8)10 (18.5)-
 Other or unknown cause6 (3.6)2 (1.8)4 (7.4)-
BMI (kg/m2)23.76 ± 3.1423.72 ± 3.1123.84 ± 3.230.808
Laboratory tests
 WBC (109/L)6.35 (5.57 - 7.79)6.29 (5.44 - 7.58)6.51 (5.82 - 8.60)0.081
 Neutrophils (109/L)3.88 (3.03 - 4.92)3.70 (2.89 - 4.82)4.22 (3.38 - 5.74)0.009
 Hs-CRP (mmol/L)1.86 (0.87 - 3.91)1.67 (0.60 - 3.30)2.64 (1.37 - 4.90)0.027
 IL-1RA (pg/mL)2.21 (0.68 - 8.66)2.30 (0.97 - 7.710)1.4 (0.27 - 5.56)0.165
 IL-1α (pg/mL)2.96 (0.32 - 17.69)2.96 (0.32 - 17.69)1.21 (0.08 - 27.21)0.365
 IL-1β (pg/mL)1.06 (0.73 - 1.60)1.11 (0.82 - 1.60)0.87 (0.60 - 1.56)0.007
 IL-4 (pg/mL)1.82 (0.54 - 6.47)3.10 (1.13 - 8.15)0.53 (0.28 - 1.32)< 0.001
 IL-5 (pg/mL)0.58 (0.35 - 0.82)0.63 (0.48 - 0.86)0.32 (0.24 - 0.66)< 0.001
 IL-6 (pg/mL)1.17 (0.65 - 1.95)1.17 (0.68 - 1.90)2.06 (0.49 - 2.13)0.021
 IL-7 (pg/mL)1.62 (0.86 - 2.5)1.78 (1.31 - 2.67)0.77 (0.45 - 1.95)< 0.001
 IL-8 (pg/mL)4.59 (3.03 - 9.17)4.59 (3.11 - 7.16)5.34 (2.86 - 14.43)0.262
 IL-9 (pg/mL)0.8 (0.36 - 1.15)0.95 (0.70 - 1.19)0.31 (0.24 - 0.73)< 0.001
 IL-10 (pg/mL)0.87 (0.60 - 1.80)0.96 (0.65 - 2.13)0.74 (0.49 - 1.22)0.027
 IL-13 (pg/mL)0.05 (0.02 - 0.17)0.06 (0.02 - 0.16)0.03 (0.01 - 0.15)0.071
 IL-15 (pg/mL)1.3 (0.77 - 1.77)1.37 (0.94 - 1.98)0.94 (0.54 - 1.65)0.002
 EGF (pg/mL)3.92 (0.84 - 20.06)5.96 (1.04 - 20.59)1.81 (0.26 - 17.69)0.084
 G-CSF (pg/mL)8.64 (4.27 - 17.69)10.77 (5.68 - 16.06)5.20 (0.20 - 18.61)0.017
 Flt-3 (pg/mL)0.4 (0.07 - 2.26)0.47 (0.08 - 2.53)0.25 (0.03 - 1.60)0.44
 GM-CSF (pg/mL)4.27 (1.19 - 20.61)7.71 (2.13 - 26.46)1.51 (0.83 - 6.47)< 0.001
 Fractalkine (pg/mL)19.57 (3.62 - 59.16)17.99 (7.06 - 56.99)21.75 (0.07 - 60.03)0.225
 IFN-γ (pg/mL)4.7 (2.06 - 9.17)4.54 (2.19 - 7.75)3.76 (1.43 - 13.67)0.897
 MDC (pg/mL)335.44 (248.06 - 471.03)337.56 (246.52 - 469.62)352.74 (251.20 - 540.90)0.365
 MIP-1α (pg/mL)2.03 (1.43 - 3.8)2.03 (1.45 - 3.08)2.39 (1.13 - 7.64)0.485
Infarct volume (cm3)1.26 (0.40 - 3.42)0.86 (0.29 - 2.06)3.07 (1.02 - 5.93)< 0.001
NIHSS score on admission, median (IQR)3.00 (2.00 - 5.00)3.00 (1.00 - 4.00)7.00 (4.00 - 10.00)< 0.001
NIHSS score on discharge, median (IQR)3.00 (1.00 - 5.00)2.00 (1.00 - 3.00)6.00 (4.75 - 9.00)< 0.001
Medication, (%)
 Statin135 (80.8)99 (87.6)36 (66.7)0.002
 Anticoagulation agents8 (4.8)6 (5.3)2 (3.7)0.448
 Antiplatelet agents132 (79.0)97 (85.8)35 (64.8)0.001
Table 1  Baseline characteristics of AIS patients with favorable or poor outcomes.
Figure 1.  The relationship between various inflammatory cytokines and stroke severity

The levels of IL-4, IL-5, IL-9, IL-13 and IL-15 were significantly decreased in the severe stroke group compared with the minor stroke group. Data are presented as mean ± SD, ***P < 0.001.

Median (IQR)
CytokinesMinor Stroke Group
(N=53)
Severe Stroke Group (N=94)P valueControl (N=14)
Hs-CRP (mmol/L)1.55 (0.59 - 3.50)2.56 (1.39 - 4.81)0.019
IL-1RA (pg/mL)2.56 (1.35 - 9.45)1.94 (0.48 - 8.15)0.0280.40(0.07-6.38)
IL-1α (pg/mL)3.2 (0.35 - 14.43)1.93 (0.19 - 24.28)0.2340.045 (0.02 - 28.49)
IL-1β (pg/mL)1.11 (0.92 - 1.68)0.93 (0.61 - 1.51)< 0.0010.73 (0.53 - 2.23)
IL-4 (pg/mL)3.62 (1.48 - 9.31)0.96 (0.32 - 3.10)< 0.0011.03 (0.44 - 5.45)
IL-5 (pg/mL)0.70 (0.51 - 0.90)0.40 (0.24 - 0.70)< 0.0010.23 (0.18 - 0.42)
IL-6 (pg/mL)1.34 (0.80 - 2.32)1.00 (0.49 - 1.76)< 0.0010.70 (0.33 - 1.36)
IL-7 (pg/mL)2.10 (1.45 - 2.84)1.09 (0.47 - 2.06)< 0.0010.82 (0.44 - 2.72)
IL-8 (pg/mL)4.76 (3.39 - 8.45)4.09 (2.38 - 11.73)0.23821.75 (2.05 - 82.14)
IL-9 (pg/mL)1.01 (0.77 - 1.29)0.37 (0.25 - 0.90)< 0.0010.33 (0.26 - 0.76)
IL-10 (pg/mL)1.12 (0.69 - 2.14)0.70 (0.49 - 1.27)< 0.0010.41 (0.23 - 1.16)
IL-13 (pg/mL)0.075 (0.03 - 0.22)0.03 (0.01 - 0.11)< 0.0010.02 (0.01 - 0.31)
IL-15 (pg/mL)1.42 (1.07 - 2.13)0.93 (0.59 - 1.65)< 0.0010.83 (0.55 - 1.38)
EGF (pg/mL)6.69 (1.35 - 22.78)2.14 (0.36 - 17.05)0.01617.83 (1.17 - 53.23)
G-CSF (pg/mL)12.24 (7.00 - 19.82)5.73 (0.22 - 14.05)< 0.0011.15 (0.27 - 9.91)
Flt-3 (pg/mL)0.52 (0.10 - 2.83)0.25 (0.04 - 1.60)0.0070.56 (0.10 - 23.93)
GM-CSF (pg/mL)11.56 (2.42 - 41.66)1.85 (0.91 - 9.17)< 0.0011.17 (0.86 - 5.27)
Fractalkine (pg/mL)23.93 (7.69 - 73.27)15.60 (0.20 - 50.88)< 0.0016.47 (0.20 - 23.93)
IFN-γ (pg/mL)5.14 (2.53 - 7.98)3.58 (1.53 - 11.00)0.0682.71 (1.39 - 11.44)
MDC (pg/mL)333.35 (246.52 - 462.26)352.74 (249.64 - 540.90)0.123731.67 (511.10 - 923.05)
MIP-1α (pg/mL)2.18 (1.54 - 3.36)1.75 (1.26 - 4.95)0.7545.23 (0.85 - 28.96)
Table 2  Levels of serum cytokines in different groups of stroke severity.
Figure 2.  The relationship between various inflammatory cytokines and stroke outcomes

The levels of IL-4 and IL-5 were significantly increased in the favorable outcome group compared with the poor outcome group. However, the concentration of IL-6 was significantly decreased in the favorable outcome group. Data are presented as mean ± SD, *P < 0.05, ***P < 0.001.

CharacteristicsUnadjusted OR (95% CI)P valueAdjusted OR (95% CI)P value
Age (years)1.032 (0.997 - 1.069)0.074
Male (%)0.548 (0.284 - 1.058)0.073
SBP (mmHg)1.012 (0.998 - 1.026)0.099
DBP (mmHg)0.999 (0.976 - 1.023)0.942
Hypertension (%)1.720 (0.648 - 4.568)0.276
Hyperlipidemia (%)1.121 (0.496 - 2.530)0.784
Diabetes (%)1.667 (0.846 - 3.282)0.139
Cardiac disease (%)2.060 (0.784 - 5.414)0.143
Smoking (%)1.939 (0.990 - 3.800)0.054
Alcohol drinking (%)0.465 (0.204 - 1.056)0.067
Stroke etiologic subtypes (%)1.010 (0.699 - 1.460)0.958
Large-artery atherosclerosis
Cardioembolic
Small-vessel disease
Other or unknown cause
BMI (kg/m2)1.013 (0.913 - 1.123)0.807
Laboratory tests
WBC (109 /L)1.192 (0.998 - 1.423)0.052
Neutrophils (109 /L)1.333 (1.075 - 1.654)0.009
Hs-CRP (mmol/L)1.008 (0.985 - 1.033)0.484
IL-1RA (pg/ml)1.004 (0.996 - 1.011)0.342
IL-1α (pg/ml)1.001 (0.998 - 1.004)0.593
IL-1β (pg/ml)0.992 (0.813 - 1.210)0.937
IL-4 (pg/ml)0.869 (0.788 - 0.960)0.005
IL-5 (pg/ml)0.244 (0.087 - 0.682)0.0070.039 (0.003 - 0.475)0.011
IL-6 (pg/ml)1.051(1.002 - 1.103)0.0411.329 (1.095 - 1.612)0.004
IL-7 (pg/ml)0.981 (0.909 - 1.059)0.630
IL-9 (pg/ml)0.768 (0.508 - 1.161)0.211
IL-10 (pg/ml)0.962 (0.845 - 1.094)0.554
IL-13 (pg/ml)1.052 (0.853 - 1.299)0.634
IL-15 (pg/ml)0.726 (0.514 - 1.025)0.069
EGF (pg/ml)1.003 (0.996 - 1.009)0.421
G-CSF (pg/ml)1.004 (0.998 - 1.009)0.165
GM-CSF (pg/ml)1.000 (0.994 - 1.007)0.916
Flt-3 (pg/ml)1.015 (0.992 - 1.038)0.200
Fractalkine (pg/ml)1.002 (0.999 - 1.005)0.244
IFN-γ (pg/ml)1.004 (0.996 - 1.013)0.324
MDC (pg/ml)1.001 (1.000 - 1.003)0.071
MIP-1α (pg/ml)1.069 (1.010 - 1.131)0.021
Infract volume (cm3)1.043 (0.997 - 1.090)0.065
NIHSS score on admission, median (IQR)2.148 (1.679 - 2.748)<0.001
NIHSS score on discharge, median (IQR)2.477 (1.855 - 3.307)<0.0012.494 (1.364 - 4.562)0.003
Medications, no. (%)
Statin0.283 (0.128 - 0.627)0.002
Anticoagulation agents2.135 (0.293 - 5.576)0.455
Antiplatelet agents0.304 (0.141 - 0.656)0.002
Table 3  Logistic regression model with predictors of poor outcome (N=167).
Figure 3.  ROC curve of IL-5 for predicting 3-months outcome of AIS patients

The optimal cutoff value was 0.385 pg/mL with a sensitivity of 86.6% and a specificity of 37.7% (AUC: 0.719, 95% CI (0.625 - 0.813; P < 0.001).

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