Abstract
Interleukin (IL)-31/IL-33 axis has been proved to play an important role in the regulation of inflammation, and serum IL-33 was found to be a novel serum prognostic marker of intracerebral hemorrhage (ICH), while the value of serum IL-31 levels on prognosis in patients with ICH remains unknown. The present study was designed to study the value of serum IL-31 levels on prognosis in ICH patients. A total of 200 ICH patients and 50 healthy people were included in this study. We collected clinical data such as demographic data, laboratory data, admission disease scores and medical histories of these participants. We measured serum IL-31 levels using enzyme-linked immunosorbent assay, and assessed the prognosis of ICH patients 3 months after onset by mRS scale, and mRS > 2 was defined as a 3-month poor outcome. The level of IL-31 in ICH patients were significantly higher than that in healthy control people (211.91 ± 61.61 vs 167.64 ± 27.45 pg/mL, P < .001), and levels of IL-31 in ICH patients with 3-month good outcome were significantly lower than that in ICH patients with 3-month poor outcome (196.09 ± 50.84 vs 248.05 ± 41.41 pg/mL, P < .001). Results of correlation analysis suggested that the level of serum IL-31 was positively related to admission NIHSS score (r = 0.627, P < .001), hematoma volume (r = 0.352, P < .001), mRS score (r = 0.515, P < .001), high-density lipoprotein-cholesterol (r = 0.177, P = .012), serum C-reactive protein levels (r = 0.483, P < .001), and serum tumor necrosis factor α levels (r = 0.389, P < .001) in ICH patients, while the level of serum IL-31 was negatively related to the admission GCS score (r = −0.518, P < .001) and triglycerides (r = −0.147, P = .038). Results of multivariate regression analysis shows that serum IL-31 levels are an independent risk factor affecting NIHSS scores (OR = 1.023, 95% CI = 1.010–2.036) and 3-month prognosis (OR = 1.023, 95% CI = 0.982–1.747) in ICH patients. The receiver operating characteristic curve analysis showed that the sensitivity and specificity of serum IL-31 level in evaluating the prognosis of ICH were 85.2% and 76.7%, respectively. A cutoff value of serum IL-31 level > 185.30 pg/mL may indicate a poor prognosis for ICH. Serum IL-31 levels on admission in ICH patients are associated with patient prognosis, and higher serum IL-31 levels are associated with a higher risk of poor prognosis in ICH patients.
Keywords: biomarkers, Interleukin-31, intracerebral hemorrhage, prognosis
1. Introduction
Intracerebral hemorrhage (ICH) is the most common subtype of stroke, with high disability, fatality, and morbidity as distinct clinical features, and it is a disease that brings a serious burden to society.[1,2] Globally, the incidence of ICH is generally lower in developed countries than in cerebral infarction, but it accounts for far more of all strokes in many Asian and low-income countries than in developed countries,[3] and China faces a greater burden of ICH than other countries.[4,5] In China, the case fatality rate of cerebrovascular diseases is 14.49 per 100,000, accounting for 22% of the total mortality rate of Chinese residents.[4,5] ICH patients accounted for 14.9% of all stroke patients, and ICH patients died in hospital/unordered hospital accounted for 19.5%, 30% to 50% of ICH patients with in-hospital hemorrhage died within 6 months of onset, and only 12% to 39% of ICH patients survived independently for a long time.[6,7] A study based on Chinese population shows that the prevalence of stroke in China and most provinces has continued to rise in the past years (2013–2019).[8] Clinical research data show that standardized treatment and specialized care can significantly reduce the mortality of patients with ICH and improve the clinical outcomes of patients with ICH.[9,10] However, early identification of patients with ICH with different clinical outcomes remains difficult, mainly due to the lack of biomarkers that predict the prognosis of patients with ICH.
Interleukin 31 (IL-31) is a newly discovered cytokine, belonging to the IL-6 family, mainly expressed in activated Th2 cells, and its functional receptor is IL-31 receptor.[11,12] In the past, research on IL-31 has focused on the area of skin pruritus, mainly because mice overexpressing IL-31 have been found to experience severe itching, hair removal, and skin inflammatory cell infiltration.[13,14] At present, more and more researches focus on the role of IL-31 in the field of immunity and inflammation, mainly involving the IL-33/IL-31 axis. The IL-33/IL-31 axis has not only been shown to play an important role in immune-mediated and allergic diseases,[15,16] but has also been found to be involved in regulating inflammatory progression by regulating downstream pathways, including PI3K/AKT, JAK/STAT, and MAPK pathways.[17] Importantly, data from a recent single-center study in patients with ICH suggested that IL-33 was found in lower serum levels in patients with ICH with a poor prognosis, and serum IL-33 level on admission may be a prognostic indicator of ICH.[18]
IL-31, as an important role in IL-31/IL-33 axis, has not been studied in ICH patients. In the present study, we first determined the level of serum IL-31 in heathy people and ICH patients, and designed to analysis the value of serum IL-31 levels on prognosis in ICH patients.
2. Material and Methods
2.1. Patients and ethical statement
From January 2021 to June 2022, we prospectively recruited 200 ICH patients into this study in Beijing Hepingli Hospital, and all ICH patients must meet the following criteria. Inclusion criteria: age > 18 years old; within 12 hours of cerebral ischemia symptoms; within 12 hours of blood collection; patients with ICH are diagnosed by computed tomography (CT) on admission. Exclusion criteria: ICH caused by trauma, aneurysm and arterial malformation; complicated with malignant tumor, chronic infectious diseases (HIV, HCV, HBV, Mycobacterium tuberculosis, etc.), heart disease, autoimmune disease and past history of cerebral hemorrhage; severe liver and kidney dysfunction; mental disorders, dementia and mental disorders; and pregnancy, lactation, menstruation and coagulation dysfunction. At the same time, 50 healthy people for physical examination as healthy control group. In addition, this study was reviewed and approved by the ethics committee of Beijing Hepingli Hospital (no. 2020-2-2241).
2.2. Collection of baseline clinical data
All volunteers were recruited to collect their baseline data, such as gender, age, body mass index (BMI), hypertension, systematic blood pressure, diastolic blood pressure, total cholesterol, triglycerides, high-density lipoprotein (HDL)-cholesterol and low-density lipoprotein (LDL)-cholesterol. In addition, ICH patients were also collected with the following data, including admission time (the time from ICH symptoms to admission), blood collection time (the time from ICH symptoms to blood collection), atrial fibrillation, lobar hemorrhage, infrastructural hemorrhage and intravascular hemorrhage.
2.3. Admission assessment
All ICH participants were assessed for the extent of nerve damage using the National Institutes of Health Stroke Scale (NIHSS) at admission, and were assessed for consciousness by the Glasgow Coma Scale (GCS). The NIHSS scale evaluates the degree of nerve damage from 11 aspects, and the higher the score, the higher the degree of nerve damage.[19] The GCS scale assesses patient awareness from eyes, language, and movement, with scores inversely proportional to the level of awareness.[20]
2.4. Hematoma volume measurement by CT
All patients with ICH were examined by head CT at admission, and the volume of ICH hematoma was calculated by referring to the volume of sphere, that is, hematoma volume = hematoma length (cm) × hematoma width (cm) × height (cm).
2.5. Serum IL-31, C-reactive protein and tumor necrosis factor α (TNF-α) level determination
Fifty participants in the control group were drawn fasting peripheral blood in the morning, while 200 ICH participants were drawn peripheral blood at admission. All peripheral blood was centrifuged at room temperature to collect serum, and the serum was frozen in liquid nitrogen for testing. Serum IL-31, C-reactive protein (CRP), and TNF-α were detected using human IL-31 (SEKH-0040, Solarbio), CRP (EH0099, FineTest), and TNF-α (SEKH-0047, Solarbio) enzyme-linked immunoassay kits, respectively.
2.6. Prognosis assessment
All patients were asked to return to the hospital after 3 months of treatment for evaluation by modified Rankin scale (mRS). The prognosis of ICH patients was divided into 7 categories by the mRS scale, and the corresponding scores ranged from 0 to 6. The mRS scores from 0 to 6 were correspond to complete asymptomatic, no obvious dysfunction, mild disability, moderate disability, severe disability, severe disability and death, respectively. In the present study, mRS score > 2 was defined as 3-months poor out-come, and mRS ≤ 2 was defined as 3-months good out-come.[18]
2.7. Statistical analysis
Data was recorded in an Excel table and being analyzed by SPSS25.0 (IBM, Almond, NY). Counting data is expressed as a percentage, while metering data is expressed as (mean ± standard deviation). We use chi square test to compare the difference of counting data between the 2 groups, and use Student t test to compare the difference of measuring data between the 2 groups. Pearson correlation coefficient was used to analyze the correlation between 2 kinds of measurement data. Receiver operating characteristic (ROC) curves were constructed and the area under the curve was calculated to assess the performance of serum IL-31 levels in distinguishing between ICH patients with 3 months good and poor outcome. P < .05 indicated significant difference.
3. Results
3.1. Serum IL-31 elevation in ICH patients
A total of 250 volunteers were recruited for this study, 50 healthy people in control group and 200 ICH patients in ICH group (Figure S1, Supplemental Digital Content, http://links.lww.com/MD/K513). There was no significantly different on gender, age, BMI and rate of hypertension between control and ICH groups, while the level of systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol and serum IL-31 in ICH patients of ICH group were all significantly higher than those in healthy people of control group (Table 1).
Table 1.
Baseline data and serum IL-31 levels in controls and ICH patients.
| Variables | Control (n = 50) | ICH (n = 200) | t/χ2 | P value |
|---|---|---|---|---|
| Gender (male/female) | 35/15 | 123/77 | 1.043 | .307 |
| Age (yr) | 64.10 ± 6.19 | 64.21 ± 6.99 | 0.097 | .923 |
| BMI (kg/m2) | 24.04 ± 1.56 | 24.28 ± 1.55 | 0.992 | .322 |
| Hypertension, n (%) | 14 (28.00) | 69 (34.50) | 0.762 | .383 |
| Systolic blood pressure (mm Hg) | 115.88 ± 16.86 | 160.97 ± 24.25 | 12.411 | <.001 |
| Diastolic blood pressure (mm Hg) | 79.30 ± 9.85 | 92.51 ± 11.34 | 7.553 | <.001 |
| Total cholesterol (mmol/L) | 4.08 ± 0.75 | 5.08 ± 0.43 | 12.383 | <.001 |
| Triglycerides (mmol/L) | 1.51 ± 0.42 | 1.83 0 0.16± | 8.622 | <.001 |
| LDL-cholesterol (mmol/L) | 2.17 ± 0.52 | 2.71 ± 0.36 | 8.506 | <.001 |
| HDL-cholesterol (mmol/L) | 1.10 ± 0.33 | 1.30 ± 0.74 | 8.034 | <.001 |
| Serum IL-31 (pg/mL) | 167.64 ± 27.45 | 211.91 ± 61.61 | 4.954 | <.001 |
BMI = body mass index, HDL = high-density lipoprotein, ICH = intracerebral hemorrhage, IL = interleukin, LDL = low-density lipoprotein.
3.2. Serum IL-31 was related to severity of ICH
The relationship between elevated IL-31 in serum in ICH patients and disease in ICH patients remains unknown and not reported, so we firstly analyzed the relationship between serum IL-31 and the indicator of severity of ICH, such as the admission NIHSS score, hematoma volume and the admission GCS score. And results showed that the level of serum IL-31 was positively related to admission NIHSS score (r = 0.627, P < .001) and hematoma volume (r = 0.352, P < .001) in ICH patients of ICH group, while the level of serum IL-31 was negatively related to the admission GCS score (r = −0.518, P < .001) (Fig. 1).
Figure 1.
Correlation between serum IL-31 and NIHSS score (A), hematoma volume (B), and GCS score (C) in patients with ICH. GCS = Glasgow Coma Scale, ICH = intracerebral hemorrhage, NIHSS = National Institutes of Health Stroke Scale.
In addition, we divided ICH patients into Mild group (NIHSS < 15) and Severe group (NIHSS ≥ 15) based on the NIHSS score. We used the severity of ICH as the dependent variable, and age, BMI, male (yes = 1, no = 0), hypertension (yes = 1, no = 0), Systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides, LDL-cholesterol, HDL-cholesterol, admission time, blood collection time, atrial fibrillation (yes = 1, no = 0), lobar hemorrhage (yes = 1, no = 0), infratentorial hemorrhage (yes = 1, no = 0), Intraventricular hemorrhage (yes = 1, no = 0), hematoma volume, GCS score and serum levels of CRP, TNF-α, IL-31 as the independent variable. Results of multivariate logistic regression analysis showed that hypertension, intravenous hemorrage, hematoma volume, GCS score, and serum IL-31 are influencing factors on the severity condition of ICH patients (Table 2).
Table 2.
Multivariate logistic regression analysis on the severity of nerve injury in ICH patients.
| Variables | β | SE | Wals | P | OR | 95% CI | |
|---|---|---|---|---|---|---|---|
| Lower | Upper | ||||||
| Age | −0.019 | 0.035 | 0.312 | .576 | .981 | 0.916 | 1.050 |
| BMI | 0.050 | 0.145 | 0.118 | .731 | 1.051 | 0.791 | 1.395 |
| Male | −0.104 | 0.431 | 0.058 | .809 | 0.901 | 0.388 | 2.095 |
| Hypertension | 0.380 | 0.465 | 0.667 | .041 | 1.462 | 0.588 | 3.638 |
| Systolic blood pressure | 0.016 | 0.010 | 2.692 | .101 | 1.016 | 0.997 | 1.035 |
| Diastolic blood pressure | −0.006 | 0.020 | 0.082 | .775 | 0.994 | 0.957 | 1.033 |
| Total cholesterol | −0.753 | 0.545 | 1.911 | .167 | 0.471 | 0.162 | 1.370 |
| Triglycerides | −0.180 | 1.674 | 0.012 | .914 | 0.835 | 0.031 | 22.223 |
| LDL-cholesterol | 0.470 | 0.738 | 0.406 | .524 | 1.600 | 0.377 | 6.794 |
| HDL-cholesterol | −5.042 | 3.144 | 2.572 | .109 | 0.006 | 0.000 | 3.065 |
| Admission time | 0.112 | 0.353 | 0.100 | .752 | 1.118 | 0.560 | 2.233 |
| Blood collection time | −0.033 | 0.349 | 0.009 | .925 | 0.968 | 0.489 | 1.917 |
| Atrial fibrillation | −0.141 | 0.480 | 0.086 | .770 | 0.869 | 0.339 | 2.227 |
| Lobar hemorrhage | −0.482 | 0.473 | 1.040 | .308 | 0.617 | 0.244 | 1.560 |
| Infratentorial hemorrhage | −0.127 | 0.530 | 0.057 | .811 | 0.881 | 0.312 | 2.488 |
| Intraventricular hemorrhage | 0.251 | 0.453 | 0.306 | .028 | 0.778 | 0.320 | 1.892 |
| Hematoma volume | 2.312 | 1.137 | 4.399 | .033 | 3.179 | 1.052 | 6.055 |
| GCS | −0.474 | 0.092 | 26.334 | .000 | 0.623 | 0.519 | 0.746 |
| CRP | −0.017 | 0.031 | 0.303 | .582 | 0.983 | 0.924 | 1.045 |
| TNF-α | −0.008 | 0.013 | 0.332 | .564 | 0.992 | 0.966 | 1.019 |
| IL-31 | 1.231 | 0.006 | 12.052 | .001 | 1.023 | 1.010 | 2.036 |
BMI = body mass index, CRP = c-reactive protein, GCS = Glasgow coma scale, HDL = high-density lipoprotein, ICH = intracerebral hemorrhage, LDL = low-density lipoprotein, NIHSS = National institute of health stroke scale.
3.3. Association between serum IL-31 levels and clinical characteristics
Further, we compared serum IL-31 levels in patients with different subtypes of ICH patients, and we found that there was no significantly different between male ICH patients and female ICH patients (Fig. 2A), ICH patients with hypertension and without hypertension (Fig. 2B), ICH patients with atrial fibrillation and without trial fibrillation (Fig. 2C), ICH patients with lobar hemorrhage and without lobar hemorrhage (Fig. 2D), ICH patients with and without infratentorial hemorrhage (Fig. 2E), and ICH patients with and without intraventricular hemorrhage (Fig. 2F). In addition, we also analyzed the correlation between levels of serum IL-31 and clinical characteristics of continuous variable, and found that levels of serum IL-31 and age (r = 0.005, P = .945), BMI (r = 0.023, P = .750), systolic blood pressure (r = 0.029, P = .684), diastolic blood pressure (r = 0.042, P = .552), total cholesterol (r = −0.037, P = .405), LDL-cholesterol (r = 0.112, P = .116), admission time (r = 0.115, P = .104) and blood collection time (r = 0.128, P = .070) do not have a significant correlation, while levels of serum IL-31 has a negative relationship to triglycerides (r = −0.147, P = .038), and has a positive relationship to HDL-cholesterol (r = 0.177, P = .012), serum CRP (r = 0.483, P < .001), and serum TNF-α (r = 0.389, P < .001) in ICH patients (Table 3).
Figure 2.
Comparison of serum IL-31 levels in patients with different subtypes of ICH. (A) Gender; (B) hypertension; (C) atrial fibrillation; (D) lobar hemorrhage; (E) infratentorial hemorrhage; and (F) intraventricular hemorrhage. ICH = intracerebral hemorrhage.
Table 3.
Association between serum IL-31 levels and clinical characteristics of continuous variable in ICH patients (n = 200).
| Variables | r | P value |
|---|---|---|
| Age (yr) | 0.005 | .945 |
| BMI (kg/m2) | 0.023 | .750 |
| Systolic blood pressure (mm Hg) | 0.029 | .684 |
| Diastolic blood pressure (mm Hg) | 0.042 | .552 |
| Total cholesterol (mmol/L) | −0.037 | .605 |
| Triglycerides (mmol/L) | −0.147 | .038 |
| LDL-cholesterol (mmol/L) | 0.112 | .116 |
| HDL-cholesterol (mmol/L) | 0.177 | .012 |
| Admission time (h) | 0.115 | .104 |
| Blood collection time (h) | 0.128 | .070 |
| Serum CRP (mg/L) | 0.483 | <.001 |
| Serum TNF-α (pg/mL) | 0.389 | <.001 |
BMI = body mass index, CRP = c-reactive protein, HDL = high-density lipoprotein, ICH = intracerebral hemorrhage, IL = interleukin, LDL = low-density lipoprotein.
3.4. Serum IL-31 was related to 3-months poor out-come
Three months after ICH, we used the mRS score to assess the prognosis of ICH patient, and 23, 46, 28, 27, 35, 51 and 18 patients had mRS score 0, 1, 2, 3, 4, 5 and 6, respectively. The value of mRS score > 2 was defined as poor prognosis, so there were 131 ICH patients with 3-months poor out-come and 69 ICH patients with 3-months good out-come. The level of serum IL-31 in ICH patients with 3-months good out-come was (196.09 ± 50.84) pg/mL, which was significantly lower than that in ICH patients with 3-months poor out-come (248.05 ± 41.41) pg/mL (P < .001) (Fig. 3). And there was a positive correlation between levels of serum IL-31 and mRS score in ICH patients (Fig. 4). Furthermore, we also analyzed differences in clinical features in ICH patients with different 3-month outcomes, and found that there was no significantly different on gender, age, BMI, rate of hypertension, systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, admission time, blood collection time, rate of atrial fibrillation, rate of lobar hemorrhage, rate of infratentorial hemorrhage and rate of intraventricular hemorrhage between ICH patients with 3-months poor out-come and ICH patients with 3-months good out-come, while there was significantly different on the admission NIHSS score, hematoma volume, the admission GCS score, serum CRP and serum TNF-α between ICH patients with 3-months poor out-come and ICH patients with 3-months good out-come (Table 4).
Figure 3.
Comparison of serum IL-31 levels in ICH patients with different 3-mo outcome. ICH = intracerebral hemorrhage. IL = interleukin.
Figure 4.
Scatter plot showing the correlation of serum IL-12 levels with mRS scores. IL = interleukin, mRS = modified Rankin scale.
Table 4.
Factors associated with 3-mo poor out-comes in patients with ICH.
| Variables | 3-mo out-comes | t/χ2 | P value | |
|---|---|---|---|---|
| Good (n = 69) | Poor (n = 131) | |||
| Gender (male/female) | 44/25 | 79/52 | 0.226 | .632 |
| Age (yr) | 64.19 ± 6.78 | 64.21 ± 7.13 | 0.024 | .981 |
| BMI (kg/m2) | 24.27 ± 1.59 | 24.30 ± 1.54 | 0.150 | .881 |
| Hypertension (n) | 23 (33.33) | 46 (35.11) | 0.063 | .801 |
| Systolic blood pressure (mm Hg) | 158.00 ± 26.54 | 162.53 ± 22.90 | 1.257 | .210 |
| Diastolic blood pressure (mm Hg) | 90.68 ± 11.17 | 93.48 ± 11.36 | 1.667 | .097 |
| Total cholesterol (mmol/L) | 5.12 ± 0.51 | 5.06 ± 0.37 | 1.011 | .313 |
| Triglycerides (mmol/L) | 1.85 ± 0.12 | 1.82 ± 0.17 | 1.227 | .221 |
| LDL-cholesterol (mmol/L) | 2.69 ± 0.23 | 2.71 ± 0.41 | 0.340 | .734 |
| HDL-cholesterol (mmol/L) | 1.30 ± 0.52 | 1.30 ± 0.84 | 0.433 | .666 |
| Admission time (h) | 5.43 ± 2.02 | 5.88 ± 2.12 | 1.427 | .155 |
| Blood collection time (h) | 6.07 ± 1.98 | 6.54 ± 2.17 | 1.500 | .135 |
| Atrial fibrillation, n (%) | 20 (28.99) | 40 (30.53) | 0.052 | .820 |
| Lobar hemorrhage, n (%) | 17 (24.64) | 37 (28.24) | 0.298 | .585 |
| Infratentorial hemorrhage, n (%) | 14 (20.29) | 29 (22.14) | 0.091 | .762 |
| Intraventricular hemorrhage, n (%) | 18 (26.09) | 38 (29.01) | 0.191 | .662 |
| Admission NIHSS | 10.38 ± 5.76 | 13.76 ± 4.74 | 4.447 | <.001 |
| Hematoma volume (mL) | 19.08 ± 8.20 | 22.12 ± 10.92 | 2.034 | .043 |
| Admission GCS | 9.26 ± 3.38 | 8.21 ± 2.97 | 2.255 | .025 |
| Serum CRP (mg/L) | 20.34 ± 8.56 | 29.36 ± 6.58 | 8.284 | <.001 |
| Serum TNF-α (pg/mL) | 72.54 ± 14.59 | 77.76 ± 20.05 | 2.104 | .037 |
BMI = body mass index, CRP = c-reactive protein, GCS = Glasgow coma scale, HDL = high-density lipoprotein, ICH = intracerebral hemorrhage, LDL = low-density lipoprotein, NIHSS = National institute of health stroke scale.
At the same time, We used the 3-months poor out-comes as the dependent variable, and age, BMI, male (yes = 1, no = 0), hypertension (yes = 1, no = 0), Systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides, LDL-cholesterol, HDL-cholesterol, admission time, blood collection time, atrial fibrillation (yes = 1, no = 0), lobar hemorrhage (yes = 1, no = 0), infratentorial hemorrhage (yes = 1, no = 0), Intraventricular hemorrhage (yes = 1, no = 0), hematoma volume, GCS score and serum levels of CRP, TNF-α, IL-31 as the independent variable. Results of multivariate logistic regression analysis showed that NIHSS score, GCS score, and serum levels of CRP and IL-31 are influencing factors on 3-months poor out-comes of ICH patients (Table 5).
Table 5.
Multivariate logistic regression analysis on the 3-mo poor out-comes in ICH patients.
| Variables | β | SE | Wals | P | OR | 95% CI | |
|---|---|---|---|---|---|---|---|
| Lower | Upper | ||||||
| Age | −0.018 | 0.035 | 0.282 | .596 | 0.982 | 0.918 | 1.051 |
| BMI | −0.100 | 0.139 | 0.522 | .470 | 0.905 | 0.689 | 1.187 |
| Male | 0.394 | 0.428 | 0.847 | .358 | 1.483 | 0.641 | 3.433 |
| Hypertension | −0.001 | 0.468 | 0.000 | .999 | 0.999 | 0.399 | 2.502 |
| Systolic blood pressure | −0.002 | 0.010 | 0.040 | .842 | 0.998 | 0.979 | 1.017 |
| Diastolic blood pressure | 0.051 | 0.021 | 5.735 | .017 | 1.052 | 1.009 | 1.097 |
| Total cholesterol | −0.384 | 0.502 | 0.586 | .444 | 0.681 | 0.255 | 1.820 |
| Triglycerides | −0.528 | 1.474 | 0.128 | .720 | 0.590 | 0.033 | 10.606 |
| LDL-cholesterol | −0.437 | 0.729 | 0.361 | .548 | 0.646 | 0.155 | 2.693 |
| HDL-cholesterol | 1.028 | 3.231 | 0.101 | .750 | 2.796 | 0.005 | 3.895 |
| Admission time | −0.083 | 0.265 | 0.099 | .752 | 0.920 | 0.548 | 1.545 |
| Blood collection time | 0.215 | 0.275 | 0.610 | .435 | 1.240 | 0.723 | 2.125 |
| Atrial fibrillation | −0.307 | 0.496 | 0.383 | .536 | 0.736 | 0.279 | 1.944 |
| Lobar hemorrhage | −0.680 | 0.495 | 1.883 | .170 | 0.507 | 0.192 | 1.338 |
| Infratentorial hemorrhage | −0.759 | 0.579 | 1.718 | .190 | 0.468 | 0.151 | 1.456 |
| Intraventricular hemorrhage | 0.037 | 0.440 | 0.007 | .934 | 1.037 | 0.438 | 2.458 |
| Hematoma volume | 0.017 | 0.026 | 0.443 | .506 | 1.017 | 0.967 | 1.070 |
| NIHSS | 0.251 | 0.062 | 0.230 | .023 | 0.971 | 0.860 | 2.096 |
| GCS | −0.199 | 0.093 | 4.606 | .032 | 1.220 | 1.017 | 1.463 |
| CRP | 0.147 | 0.033 | 20.149 | .000 | 1.158 | 1.086 | 1.235 |
| TNF-α | −0.015 | 0.014 | 1.249 | .264 | 0.985 | 0.959 | 1.012 |
| IL-31 | 0.130 | 0.008 | 13.029 | .000 | 1.030 | 0.982 | 1.747 |
BMI = body mass index, CRP = c-reactive protein, GCS = Glasgow coma scale, HDL = high-density lipoprotein, ICH = intracerebral hemorrhage, LDL = low-density lipoprotein, NIHSS = National institute of health stroke scale.
3.5. Predictive analysis of serum IL-31 on 3-month poor outcome
In addition, the results of ROC curve analysis showed that serum IL-31 levels could be used to differentiate patients at risk for suffering from an unfavorable outcome with an area under the curve of 0.774 (95% CI: 0.700–0.847) (Fig. 5). When the serum IL-31 level of 185.30 pg/mL was used as the cutoff value to distinguish the 3-month poor outcome after hemorrhage, and the sensitivity of serum IL-31 in the diagnosis of the 3-month poor outcome after hemorrhage in patients with ICH is 85.20% and the specificity is 76.70% (Fig. 5).
Figure 5.
ROC curve regarding predictive value of serum IL-31 levels for 3-mo poor outcome. IL = interleukin, ROC = receiver operating characteristic curve.
4. Discussion
The IL-6 cytokine family includes IL-6, IL-11, IL-27, IL-31, ciliary neurotrophic factor, leukemia inhibitory factor, cardiac trophic factor 1, cardiac trophic factor-like factor, and mortostatin M, all with common glycoprotein 130 (gp130, IL6ST) receptor signaling subunits. Previous studies have found that IL-6,[21] IL-11,[22] IL-27,[23] ciliary neurotrophic factor,[24] and leukemia inhibitory factor[25] were all related to ICH. In the present study, we found that the level of IL-31 in ICH patients were significantly higher than that in healthy control people, and the level of serum IL-31 was positively related to admission NIHSS score and hematoma volume, while the level of serum IL-31 was negatively related to the admission GCS score in ICH patients, which suggesting that serum IL-31 may be related ICH.
IL-31 was first identified in 2004 as a cytokine mainly secreted by Th2 cells and mast cells, and it was found that its secretion depended on the induction of IL-4. Previous studies found that IL-31 was found to regulate the transmission of a large number of cell biological function signals, including inducing the secretion of proinflammatory cytokines, regulating cell proliferation and participating in tissue remodeling. As we all know, inflammatory response plays an important role in the whole period of ICH-induced brain injury, including primary brain injury and secondary brain injury.[26,27] Inflammatory cells, including leukocytes, glial cells/macrophages, astrocytes, and their released various cytokines, chemokines, enzymes, and immunologically active small-molecule polypeptides secreted, are involved in inflammatory cascade post-ICH.[28,29] And they all play an important role in the inflammatory cascade and are also considered to be important biomarkers for predicting the prognosis of patients after ICH.[28,29] Therefore, we have reason to suspect that IL-31 is related to the prognosis of ICH patients, mainly because IL-31 is not only an inflammatory regulator, but also an increase in serum levels in ICH patients and is related to early neurological injury in ICH patients.
Further analysis showed that levels of serum IL-31 has a negative relationship to triglycerides, and has a positive relationship to HDL-cholesterol, serum CRP and serum TNF-α in ICH patients, which suggesting serum IL-31 levels are associated with peripheral blood inflammation in patients with ICH. The gene encoding human IL-31 is located on chromosome 12q24.31, and the mouse orthologous is located in the common region of chromosome 5. IL-31 is a short-chain cytokine, including 164 amino acids, which regulate the conduction of downstream pathways by binding to its receptor, and then participate in the regulation of a variety of cell biological functions.[30] IL-33 has long been thought to synergize with IL-31 to regulate the progression of inflammation in the body, and the mechanism is that IL-31 is induced by IL-4, while IL-33 increases IL-31 secretion induced by IL-4.[17] Previous researches have found that IL-31 protein induction was mediated by IL-4/STAT6 and IL-33/NF-κB signaling and is downregulated by suppressor of cytokine signaling 3 in Th2 cells.[31,32] Interestingly, a recent study has found that levels of serum IL-33 in ICH patients with 3-months poor out-come was significantly higher than that in ICH patients with 3-months good out-come, and was related to admission NIHSS score, admission GCS score and hematoma volume in ICH patients, suggesting serum IL-33 maybe related the prognosis of ICH patients.[18] In addition, the 12 month mortality and recurrence rate of stroke patients were 8.6% and 5.7% respectively. Early prediction can help reduce the mortality and recurrence rate of stroke patients after discharge.[33] Similarly, IL-31 maybe related to the prognosis of ICH patients via regulating inflammation, but its specific role needs further research and verification.
Fortunately, our data also showed that the level of serum IL-31 in ICH patients with 3-months good out-come was significantly lower than that in ICH patients with 3-months poor out-come, and there was a positive correlation between levels of serum IL-31 and mRS score in ICH patients. In addition, ROC analysis showed that the sensitivity and specificity of serum IL-31 level in evaluating the prognosis of ICH were 85.2% and 76.7%, respectively, and a cutoff value of serum IL-31 level > 185.30 pg/mL may indicate a poor prognosis for ICH. In a conclusion, our data indicated that elevated serum levels of IL-31 in patients with ICH are associated with early neurological impairment, hematoma volume, and 3-month prognosis in patients with ICH. Inflammation may be a key point in the involvement of IL-31 in early damage and long-term prognosis of ICH, but evidence is lacking in this study.
Some of the limitations of our study should be noted. First, as a single center study, this study included a low sample size and had regional restrictions. Second, although we collect blood from patients after admission to detect the level of IL-31 and limited the time, the time of collecting blood from different patients varied greatly, and this study did not dynamically monitor the level of IL-31. Third, some factors that may affect the serum IL-31 level have not been considered, such as smoking, alcohol abuse, drug treatment, etc. At last, we did not follow up ICH patients for a long time.
5. Conclusion
This study is the first to quantify serum IL-31 levels in ICH patients, and analyze its relationship with early neurological injury and prognosis after 3 months. In the present study, we firstly reported that serum IL-31 levels in ICH patients were higher than in healthy controls, and elevated serum IL-31 were associated with poor prognosis after 3 months in ICH.
Author contributions
Conceptualization: Xing Li.
Data curation: Jingfeng Liu.
Formal analysis: Jingfeng Liu.
Investigation: Jingfeng Liu, Ji Qu.
Methodology: Ji Qu.
Writing – original draft: Xing Li.
Writing – review & editing: Xing Li.
Supplementary Material
Abbreviations:
- BMI
- body mass index
- CRP
- C-reactive protein
- GCS
- Glasgow Coma Scale
- HDL
- high-density lipoprotein
- ICH
- intracerebral hemorrhage
- IL
- interleukin
- LDL
- low-density lipoprotein
- NIHSS
- National Institutes of Health Stroke Scale
- ROC
- receiver operating characteristic
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.
Supplemental Digital Content is available for this article.
How to cite this article: Liu J, Li X, Qu J. Serum IL-31 is related to the severity and 3-month prognosis of patients with Intracerebral hemorrhage. Medicine 2024;103:5(e35760).
Contributor Information
Xing Li, Email: lixhplh@sina.com.
Ji Qu, Email: qji1984@163.com.
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