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Serum periostin concentrations and outcomes after severe traumatic brain injury
Clinica Chimica Acta 471 (2017) 298–303
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Serum periostin concentrations and outcomes after severe traumatic brain injury
MARK
Xiao-Qiao Dong, Wen-Hua Yu⁎, Quan Du, Hao Wang, Qiang Zhu, Ding-Bo Yang, Zhi-Hao Che, Yong-Feng Shen, Li Jiang Department of Neurosurgery, The Hangzhou First People's Hospital, Nanjing Medical University, 261 Huansha Road, Hangzhou 310006, China
A R T I C L E I N F O
A B S T R A C T
Keywords: Traumatic brain injury Periostin Severity Mortality Outcome Prognosis Biomarker
Background: Periostin, a neurite outgrowth-promoting factor, is increasingly expressed in rat brain tissues after cerebral ischemia or subarachnoid hemorrhage. However, periostin concentrations are undetermined in peripheral blood from patients with traumatic brain injury (TBI). Methods: In this prospective, observational study, serum periostin concentrations were measured in 130 controls and 130 severe TBI patients. We investigated its association with trauma severity reflected by Glasgow Coma Scale (GCS) score and prognosis (i.e., 30-day mortality and 30-day overall survival). Results: As compared with the controls, serum periostin concentrations were significantly increased in the patients [(median, 246.5 ng/ml; interquartile range, 164.5–328.6 ng/ml) vs. (median, 61.8 ng/ml; interquartile range, 37.9–77.9 ng/ml), P < 0.001]. Periostin concentrations independently correlated with GCS scores (t = −6.199, P < 0.001). Serum periostin concentrations higher than 308.2 ng/ml predicted 30-day mortality with a sensitivity of 72.4% and a specificity of 78.2% [area under curve, 815; 95% confidence interval (CI), 0.737–0.878]. Periostin concentrations higher than 246.5 ng/ml were independently related to 30-day mortality and 30-day overall survival with odds ratio value of 3.829 (95% CI, 1.104–13.281) and hazard ratio value of 5.667 (95% CI, 1.953–16.443) respectively. Conclusions: Increased serum periostin concentrations clearly reflect trauma severity and mortality following TBI.
1. Introduction Traumatic brain injury (TBI) is a set of secondary pathological and/ or functional alteration within brain because of a sudden external force and represents a problem of enormous public health importance [1–3]. An early risk assessment with estimate of the severity of disease and prognosis is crucial for optimized care and allocation of healthcare resources to improve outcome [4–6]. To date, Glasgow Coma Scale (GCS) has been the most accepted clinical system to assess trauma severity and to predict the TBI outcome [7–9]. However, recently, the interests of clinicians have focused on the potential role of circulating markers in TBI [10–13]. Periostin is a 90-kD extracellular matrix protein, containing an amino-terminal cysteine-rich EMI domain in its N-terminal portion, four tandemly lined fasciclin I domains in the middle, and an alternative splicing domain in its C-terminal portion [14,15]. Accumulating evidence has shown that periostin plays pivotal roles in cell survival
under hypoxic conditions, migration of cancer cells and proliferation of cardiomyocytes after acute myocardial infarction [16–18]. Moreover, periostin concentrations in peripheral blood are markedly enhanced in asthma, chronic obstructive pulmonary diseases, cancers, idiopathic pulmonary fibrosis, atopic dermatitis and acute myocardial infarction [19–24]. Interestingly, periostin has been identified as a neurite outgrowth-promoting factor, which significantly enhances neural stem cell proliferation and differentiation after hypoxia-ischemia [25,26]. Recently, it is verified that periostin expression is up-regulated in brain tissues after ischemic stroke or subarachnoid hemorrhage [27,28]. 2. Materials and methods 2.1. Study population In this prospective and observational study, we consecutively recruited all severe TBI patients at the Hangzhou First People's Hospital
Abbreviations: CT, computerized tomography; GCS, Glasgow Coma Scale; TBI, traumatic brain injury ⁎ Corresponding author. E-mail address: [email protected] (W.-H. Yu). http://dx.doi.org/10.1016/j.cca.2017.06.020 Received 12 June 2017; Received in revised form 23 June 2017; Accepted 27 June 2017 Available online 28 June 2017 0009-8981/ © 2017 Elsevier B.V. All rights reserved.
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samples with a quantitative sandwich enzyme-linked immunosorbent assay kit (Wuhan USCN Science Co., Ltd.) according to the manufactures' instructions. Intra-assay CV revealed a coefficient of variation of 9.8%, with an accuracy of 99%. The inter-assay CV was 11.5%, with an accuracy of 97%. Recovery was 94%.
from August 2011 to September 2015. Severe TBI was defined as GCS < 9 points. Exclusion criteria included Injury Severity Score in non-cranial aspects > 9 points, time from trauma to admission > 6 h, < 18 years, surgery or trauma during the preceding 2 months, neurological disease including ischemic or hemorrhagic stroke, use of antiplatelet or anticoagulant medication, immunosuppressive therapy, acute and chronic infections at study enrollment (based on history report and physical examination), and presence of other prior systemic diseases such as asthma, chronic obstructive pulmonary diseases, diabetes mellitus, hypertension, uremia, liver cirrhosis, malignancy and chronic heart or lung disease. Control group consisted of individuals who came to our hospital for healthy examination during the period of May 2015 to September 2015. Exclusion criteria contained < 18 years, surgery or trauma during the preceding 2 months, neurological disease including ischemic or hemorrhagic stroke, use of antiplatelet or anticoagulant medication, immunosuppressive therapy, acute and chronic infections at study enrollment, and presence of other prior systemic diseases such as asthma, chronic obstructive pulmonary diseases, diabetes mellitus, hypertension, uremia, liver cirrhosis, malignancy and chronic heart or lung disease. The study was approved by the ethics committee of the Hangzhou First People's Hospital. The subjects or their legal guardians were informed of the study protocol and their written informed consent was obtained, according to the Declaration of Helsinki.
2.4. Statistical analysis The normality of data distribution was tested using the KolmogorovSmirnov test or Shapiro-Wilk test. All continuous variables were presented as median (interquartile range) due to their non-normal distribution. Categorical variables were reported as counts (percentage). Intergroup comparisons were conducted using χ2 test or Fisher exact test for categorical variables. For continuous variables, differences between two groups were analyzed with Mann-Whitney U test and differences among multiple groups were assessed using KruskalWallis H test. Bivariate linear relationships between serum periostin concentrations and other parameters were evaluated using Spearman's correlation coefficient, followed by a multivariate linear regression. Overall survival was calculated using Kaplan–Meier method and intergroup comparison was performed using the log-rank test. All significant variables in univariate analysis were further incorporated into multivariate Cox's proportional hazard model to identify predictors for 30-day overall survival. Hazard ratio (HR) values and the corresponding 95% confidence intervals (CIs) were estimated. A binary Logistic regression model was constructed to identify independent predictors for 30-day mortality. The logistic regression results were presented as odds ratio (OR) and 95% confidence interval (CI). Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive values of serum periostin concentrations for 30-day mortality. Subsequently, area under curve (AUC) and the corresponding 95% CI were calculated. In a combined logisticregression model, we estimated the additive benefit of periostin concentrations to GCS scores. All data were analyzed using SPSS ver. 19.0 and MedCalc ver. 9.6.4.0. A P < 0.05 was considered to be statistically significant.
2.2. Clinical and radiological assessment Upon entry into emergency department, we collected information including demographic data (age and gender), initial arterial pressure, pupil reactivity, time from trauma to admission, mechanisms of injury and comorbidities. Trauma severity was evaluated using the postresuscitation GCS at admission. Computerized tomography (CT) scans were performed to assess abnormal cisterns, midline shift > 5 mm and subarachnoid hemorrhage. CT classification was performed using Traumatic Coma Data Bank criteria on initial postresuscitation CT scan according to the method of Marshall et al. [29]. Diagnosis of progressive hemorrhagic injury and posttraumatic cerebral infarction was made on the follow-up CT scan. Progressive hemorrhagic injury was defined as any increase in size or number of the hemorrhagic lesion, including newly developed ones [30]. Diagnosis of posttraumatic cerebral infarction was made according to the following criteria: (1) distinctly hypodense lesions within a defined cerebral vascular territory; (2) hypodense lesions located in boundary zones between the defined cerebral vascular territories or situated in the terminal zones of perforating arteries within the deep white matter [31]. All CT scans were performed according to the neuroradiology department protocol. Investigators who read them were blinded to clinical information. Acute lung injury was diagnosed according to the international consensus criteria, which include acute onset, the ratio of partial pressure of arterial oxygen to fractional inspired oxygen ≤ 300, bilateral infiltrates on chest radiograph, and no clinical evidence of left arterial hypertension [32]. The endpoint of the study was 30-day mortality.
3. Results 3.1. Study population characteristics Initially, a total of 181 severe TBI patients were assessed. We excluded fifty-one patients with Injury Severity Score in non-cranial aspects > 9 points (5 cases), time from trauma to admission > 6 h (6 cases), < 18 years (3 cases), surgery or trauma during the preceding 2 months (4 cases), neurological disease (7 cases), use of antiplatelet or anticoagulant medication (5 cases), immunosuppressive therapy (3 cases), acute and chronic infections at study enrollment (3 cases), presence of other prior systemic diseases (9 cases), refusal to participate (1 case), incomplete information (2 cases), unavailable sample (1 case) or loss to follow-up (2 cases). Finally, a total of 130 patients were included in this study. Additionally, 130 healthy individuals constituted control group, who had similar age and sex when compared with the patients. This group of severe TBI patients was composed of 79 males and 51 females, as well as there was a median age of 43 (interquartile range, 25–56) years (range, 18–71 years). In terms of mechanisms of injury, head trauma in 64 patients (49.2%) was caused by automobile/motorcycle; 45 patients (34.6%), fall/jump; 21 patients (16.2%), others. The median GCS score was 5 (interquartile range, 4–7) (range, 3–8). A total of 59 patients (45.4%) had unreactive pupils at admission; 55 patients (42.3%), CT classification 5 or 6; 61 patients (46.9%), abnormal cisterns on initial CT scan; 70 patients (53.9%), midline shift > 5 mm on initial CT scan; 79 patients (60.8%), presence of traumatic subarachnoid hemorrhage on initial CT scan. Alternatively, acute lung injury, acute traumatic coagulopathy, progressive
2.3. Blood collection and laboratory test Blood samples were obtained from severe TBI patients at admission and from the controls at study entry. After centrifugation, aliquots of the samples were immediately stored −80 °C before assay. Biomarker concentrations were measured by investigators blinded to the clinical outcome and neuroimaging findings. Coagulation test, blood routine test and blood biochemical test were measured at admission using standard laboratory methods. Acute traumatic coagulopathy was defined as an activated partial thromboplastic time > 40 s and/or international normalized ratio > 1.2 and/or a platelet count < 120 × 109/l [33,34]. Serum periostin concentrations were tested in duplicate 299
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Fig. 1. Comparisons between healthy controls and severe traumatic brain injury patients as well as between non-survivors and survivors within 30 days after severe traumatic brain injury in terms of serum periostin concentrations.
traumatic subarachnoid hemorrhage, acute lung injury, acute traumatic coagulopathy, progressive hemorrhagic injury, posttraumatic cerebral infarction, blood glucose concentrations and plasma C-reactive protein concentrations. When the preceding variables were incorporated into a multivariate linear regression model, serum periostin concentrations were demonstrated to be negatively and highly correlated with GCS scores (t = − 6.199, P < 0.001). In Fig. 2, serum periostin concentrations were statistically significantly increased with increasing severity.
hemorrhagic injury and posttraumatic cerebral infarction were found in 30 (23.1%), 51 (39.2%), 35 (26.9%) and 23 (17.7%) patients respectively. Moreover, eighty-six patients (66.2%) underwent intracranial surgery in first 24 h. Patients were admitted at hospital from 0.5 h to 6.0 h after trauma (median, 2.0 h; interquartile range, 1.5–4.0 h). We collected blood samples at a median time of 3.0 (interquartile range, 2.5–6.0) h (range, 0.8–9.0 h) after trauma. The median systolic arterial pressure was 124 (interquartile range, 99–143) mm Hg (range, 72–174 mm Hg) and the mean diastolic arterial pressure was 77 (interquartile range, 57–90) mm Hg (range, 42–108 mm Hg). Within 30 days after head trauma, a total of 29 patients (22.3%) were dead.
3.3. ROC curve analysis In accordance with ROC curve, the optimal cutoff value of serum periostin concentrations as an indicator for discrimination of 30-day mortality was projected to be 308.2 ng/ml, which yielded a sensitivity of 72.4% and a specificity of 78.2%, with the AUC at 0.815 (95% CI = 0.737–0.878, P < 0.001; Fig. 3). Its AUC was in the range of GCS scores (AUC 0.869, 95% CI 0.798–0.922, P = 0.281).When a combined logistic-regression model was configured, periostin improved the AUC of GCS scores to 0.893 (95% CI 0.827–0.941), but the difference did not appear to be statistically significant (P = NS).
3.2. Serum periostin concentrations and other variables In Fig. 1, the median serum periostin concentrations were 246.5 ng/ ml (interquartile range, 164.5–328.6 ng/ml) in the patients and 61.8 ng/ml (interquartile range, 37.9–77.9 ng/ml) in the controls. As compared with the controls, serum periostin concentrations were significantly increased in the patients (P < 0.001). Additionally, periostin concentrations were markedly higher in non-survivors than in survivors with 30 days after head trauma [(median, 352.9 ng/ml; interquartile range, 274.0–477.9 ng/ml) vs. (median, 216.7 ng/ml; interquartile range, 128.8–301.4 ng/ml), P < 0.001]. In Table 1, serum periostin concentrations were found to be significantly associated with GCS scores, unreactive pupils, CT classification 5 or 6, abnormal cisterns, midline shift > 5 mm, presence of
3.4. Mortality prediction In the current study, serum periostin concentrations were dichotomized in terms of its median value (246.5 ng/ml). In Table 2, a univariate logistic regression analysis demonstrated that the parameters closely related to 30-day mortality were serum periostin concentrations > 246.5 ng/ml, GCS scores, unreactive pupils, CT classification 5 or 6, abnormal cisterns, midline shift > 5 mm, presence of traumatic subarachnoid hemorrhage, acute lung injury, acute traumatic coagulopathy, progressive hemorrhagic injury, posttraumatic cerebral infarction, blood glucose concentrations and plasma C-reactive protein concentrations. When the aforementioned significant parameters were included in a multivariate logistic regression model, serum periostin concentrations higher than 246.5 ng/ml (OR = 3.829, 95% CI = 1.104–13.281, P = 0.004) and GCS scores (OR = 0.245, 95% CI = 0.122–0.492, P < 0.001) were identified as the independent predictors for 30-day mortality after head trauma.
Table 1 Correlative analysis between serum periostin levels and other parameters in 130 patients with severe traumatic brain injury.
Gender (male/female) Age (y) Mechanisms of injury GCS scores on admission Pupils unreactive on admission CT classification 5 or 6 Abnormal cisterns on initial CT scan Midline shift > 5 mm on initial CT scan Traumatic SAH on initial CT scan Progressive hemorrhagic injury Posttraumatic cerebral infarction Acute traumatic coagulopathy Acute lung injury Intracranial surgery in first 24 h Admission time (h) Plasma-sampling time (h) Systolic arterial pressure (mm Hg) Diastolic arterial pressure (mm Hg) Blood glucose level (mmol/l) Plasma C-reactive protein (mg/l)
r Value
P value
0.092 0.127 − 0.042 − 0.652 0.474 0.375 0.349 0.301 0.242 0.264 0.295 0.317 0.232 0.121 0.135 0.100 0.117 0.106 0.197 0.226
NS NS NS < 0.001 < 0.001 < 0.001 < 0.001 0.001 0.006 0.002 0.001 < 0.001 0.008 NS NS NS NS NS 0.025 0.010
3.5. Survival analysis In this study, the mean overall survival time of all patients was 25.3 days (95% CI, 23.8–26.9 days) during follow-up of 30 days. Table 3 showed that serum periostin concentrations higher than 246.5 ng/ml in addition to other parameters had a strong relation to 30day overall survival. In Fig. 3, patients with serum periostin concentrations higher than 246.5 ng/ml had significantly shorter 30-day overall survival time than other remaining patients (mean time 22.0 days, 95% CI 19.4–24.7 days vs. 28.7 days, 95% CI 27.4–30.0 days; P < 0.001). After adjusting for all other significant outcome predictors in univariate analysis, serum periostin
Bivariate correlative analysis was conducted using Spearman's correlation coefficient. GCS indicates Glasgow Coma Scale; CT, computerized tomography; SAH, subarachnoid hemorrhage.
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Fig. 2. Correlative analysis of serum periostin levels with Glasgow Coma Scale scores using Spearman's correlation coefficient or Kruskal-Wallis H test.
concentrations higher than 246.5 ng/ml and GCS scores remained as the independent predictors for 30-day overall survival with HR values of 5.667 (95% CI, 1.953–16.443, P = 0.001) and 0.391 (95% CI, 0.250–0.611, P < 0.001) respectively.
Table 2 Clinical and biochemical characteristics associated with 30-day mortality in 130 patients with severe traumatic brain injury.
Gender (male/female) Age (y) Mechanisms of injury GCS scores on admission Pupils unreactive on admission CT classification 5 or 6 Abnormal cisterns on initial CT scan Midline shift > 5 mm on initial CT scan Traumatic SAH on initial CT scan Progressive hemorrhagic injury Posttraumatic cerebral infarction Acute traumatic coagulopathy Acute lung injury Intracranial surgery in first 24 h Admission time (h) Plasma-sampling time (h) Systolic arterial pressure (mm Hg) Diastolic arterial pressure (mm Hg) Blood glucose level (mmol/l) Plasma C-reactive protein level (mg/l) Serum periostin > 246.5 ng/ml
4. Discussion The current study enrolled a group of severe TBI patients and investigated relationship between serum periostin concentrations and trauma severity in addition to outcomes after head trauma, as well as subsequently found some interesting results as follows. First, serum periostin concentrations were significantly higher in all patients with severe TBI than in healthy controls and especially, in 30-day non-surviving patients, this sort of elevation was more obvious. Secondly, serum periostin concentrations were independently and negatively associated with GCS scores. Thirdly, periostin in serum was an independent predictor for 30-day mortality and overall survival after head trauma. Lastly, as compared to GCS scores, serum periostin concentrations showed similar prognostic value in terms of AUC. Hence, periostin in serum might represent a novel prognostic biomarker of TBI. Periostin is first cloned from a mouse calvarial cell line, hence its original designation as osteoblast-specific factor 2 [14,15]. The human periostin gene maps to chromosome 13q13.3 and encodes a secreted 90-kDa protein [14,15]. Periostin plays an important role in the maintenance and development of bones, teeth and the heart, and contributes to tumor progression in several tumor cells [16–18]. A lot of evidence has recently accumulated showing that expression of periostin is involved in various pathophysiological statuses of fibrosis, including the healing process in myocardial infarction and bone marrow fibrosis [14,35]. These data indicate that periostin might exert a protective effect on tissue injury. However, other researches demonstrated a detrimental effect of periostin. Exogenously over-expression of periostin gene in the heart led to impaired cardiac function, including left ventricle dilation, cardiac myocytes decrease and collagen deposition increase, which suggested a correlation between increased periostin with deteriorated cardiac function. Furthermore, inhibition of periostin
Odds ratio (95% CI)
P value
1.073 (0.459–2.509) 1.016 (0.992–1.040) 1.230 (0.710–2.129) 0.234 (0.124–0.441) 9.051 (3.177–25.790) 5.173 (2.076–12.889) 6.355 (2.374–17.010) 7.778 (2.522–23.982) 27.451 (3.597–209.524) 3.556 (1.486–8.509) 2.796 (1.062–7.364) 5.018 (2.054–12.258) 3.255 (1.326–7.987) 0.964 (0.404–2.301) 1.081 (0.830–1.408) 1.188 (0.985–1.433) 1.005 (0.987–1.019) 1.013 (0.993–1.035) 1.139 (1.016–1.278) 1.182 (1.049–1.332) 9.531 (3.084–29.455)
NS NS NS < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 0.001 0.004 0.037 < 0.001 0.010 NS NS NS NS NS 0.026 0.006 < 0.001
Odds ratio values were calculated using univariate logistic regression analysis. GCS indicates Glasgow Coma Scale; CT, computerized tomography; SAH, subarachnoid hemorrhage.
expression was able to improve cardiac systolic ejection function and animal survival rate [36]. Thus, the net effect of periostin has not reached a consensus. Nevertheless, there is no doubt that this molecule acts as an important regulator in tissue repair. In central nervous system, periostin expressions can be highly upregulated in glioma tissue [37,38]. However, recently, this protein was found to be highly expressed in animal brain tissues affected by ischemia or hemorrhage; moreover, exogenous periostin exhibited neuroprotective effects and accelerated neurite outgrowth [27,28]. In this study, we demonstrated that serum periostin concentrations were Fig. 3. Receiver operating characteristic curve analysis using serum periostin levels as a predictor of mortality at 30 days and survival curve analysis at 30 days using serum periostin concentrations higher or lower than 246.5 ng/ml.
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admission GCS scores and short-term mortality reflected by 30-day mortality and overall survival after head trauma, indicating that periostin in serum might have the potential to be a useful prognostic biomarker in Chinese patients with severe TBI.
Table 3 Clinical and biochemical characteristics associated with 30-day overall survival in 130 patients with severe traumatic brain injury.
Gender (male/female) Age (y) Mechanisms of injury GCS scores on admission Pupils unreactive on admission CT classification 5 or 6 Abnormal cisterns on initial CT scan Midline shift > 5 mm on initial CT scan Traumatic SAH on initial CT scan Progressive hemorrhagic injury Posttraumatic cerebral infarction Acute traumatic coagulopathy Acute lung injury Intracranial surgery in first 24 h Admission time (h) Plasma-sampling time (h) Systolic arterial pressure (mm Hg) Diastolic arterial pressure (mm Hg) Blood glucose level (mmol/l) Plasma C-reactive protein level (mg/l) Serum periostin > 246.5 ng/ml
Hazard ratio (95% CI)
P value
1.069 (0.505–2.263) 1.013 (0.993–1.035) 1.183 (0.732–1.911) 0.342 (0.222–0.528) 7.020 (2.676–18.416) 4.361 (1.930–9.856) 5.262 (2.141–12.936) 6.373 (2.216–18.325) 22.046 (2.998–162.114) 2.995 (1.444–6.211) 2.372 (1.079–5.214) 4.132 (1.879–9.085) 2.668 (1.273–5.593) 0.957 (0.445–2.057) 1.069 (0.848–1.348) 1.150 (0.981–1.348) 1.004 (0.989–1.017) 1.011 (0.992–1.031) 1.124 (1.020–1.238) 1.148 (1.042–1.266) 7.462 (2.595–21.462)
NS NS NS < 0.001 < 0.001 < 0.001 < 0.001 0.001 0.002 0.003 0.032 < 0.001 0.009 NS NS NS NS NS 0.018 0.005 < 0.001
Acknowledgements We thank all staffs in Department of Neurosurgery, The Hangzhou First People's Hospital (Hangzhou, China) for their technical support. This study was supported financially by Zhejiang Province Medical and Health Project （2014KYA177，2016RCB016) and Hangzhou Medical Research Fund Project (2014Z06, 2016Z10). References [1] H.Y. Shi, S.L. Hwang, I.C. Lee, I.T. Chen, K.T. Lee, C.L. Lin, Trends and outcome predictors after traumatic brain injury surgery: a nationwide population-based study in Taiwan, J. Neurosurg. 121 (2014) 1323–1330. [2] J.T. Flaada, C.L. Leibson, J.N. Mandrekar, N. Diehl, P.K. Perkins, A.W. Brown, et al., Relative risk of mortality after traumatic brain injury: a population-based study of the role of age and injury severity, J. Neurotrauma 24 (2007) 435–445. [3] M. Lippert-Gruner, M. Maegele, H. Haverkamp, N. Klug, C. Wedekind, Health-related quality of life during the first year after severe brain trauma with and without polytrauma, Brain Inj. 21 (2007) 451–455. [4] T. Amoroso, K.M. Iverson, Acknowledging the risk for traumatic brain injury in women veterans, J. Nerv. Ment. Dis. 205 (2017) 318–323. [5] P.J.D. Andrews, A. Rodriguez, P. Suter, C.G. Battison, J.K.J. Rhodes, I. Puddu, et al., Mortality risk stratification after traumatic brain injury and hazard of death with titrated hypothermia in the Eurotherm3235Trial, Crit. Care Med. 45 (2017) 883–890. [6] M. Majdan, A. Brazinova, M. Rusnak, J. Leitgeb, Outcome prediction after traumatic brain injury: comparison of the performance of routinely used severity scores and multivariable prognostic models, J. Neurosci. Rural Pract. 8 (2017) 20–29. [7] L.J. Shen, S.B. Yang, Q.W. Lv, G.H. Zhang, J. Zhou, M. Guo, et al., High plasma adiponectin levels in patients with severe traumatic brain injury, Clin. Chim. Acta 427 (2014) 37–41. [8] E. Ozyurt, E. Goksu, M. Cengiz, M. Yilmaz, A. Ramazanoglu, Retrospective analysis of prognostic factors of severe traumatic brain injury in a university hospital in Turkey, Turk. Neurosurg. 25 (2015) 877–882. [9] T.M. Andriessen, B. Jacobs, P.E. Vos, Clinical characteristics and pathophysiological mechanisms of focal and diffuse traumatic brain injury, J. Cell. Mol. Med. 14 (2010) 2381–2392. [10] Z.Y. Zhang, L.X. Zhang, X.Q. Dong, W.H. Yu, Q. Du, D.B. Yang, et al., Comparison of the performances of copeptin and multiple biomarkers in long-term prognosis of severe traumatic brain injury, Peptides 60 (2014) 13–17. [11] K.Y. Wang, G.F. Yu, Z.Y. Zhang, Q. Huang, X.Q. Dong, Plasma high-mobility group box 1 levels and prediction of outcome in patients with traumatic brain injury, Clin. Chim. Acta 413 (2012) 1737–1741. [12] X.Q. Dong, M. Huang, S.B. Yang, W.H. Yu, Z.Y. Zhang, Copeptin is associated with mortality in patients with traumatic brain injury, J. Trauma 71 (2011) 1194–1198. [13] S. Azar, A. Hasan, R. Younes, F. Najdi, L. Baki, H. Ghazale, et al., Biofluid proteomics and biomarkers in traumatic brain injury, Methods Mol. Biol. 1598 (2017) 45–63. [14] T. Oka, J. Xu, R.A. Kaiser, et al., Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling, Circ. Res. 101 (2007) 313–321. [15] K. Ruan, S. Bao, G. Ouyang, The multifaceted role of periostin in tumorigenesis, Cell. Mol. Life Sci. 66 (2009) 2219–2230. [16] J. Qin, F. Yuan, Z. Peng, K. Ye, X. Yang, L. Huang, et al., Periostin enhances adiposederived stem cell adhesion, migration, and therapeutic efficiency in Apo E deficient mice with hind limb ischemia, Stem Cell Res Ther 6 (2015) 138. [17] F. Qiu, C.H. Shi, J. Zheng, Y.B. Liu, Periostin mediates the increased pro-angiogenic activity of gastric cancer cells under hypoxic conditions, J. Biochem. Mol. Toxicol. 27 (2013) 364–369. [18] Y. Taniyama, N. Katsuragi, F. Sanada, J. Azuma, K. Iekushi, N. Koibuchi, et al., Selective blockade of periostin exon 17 preserves cardiac performance in acute myocardial infarction, Hypertension 67 (2016) 356–361. [19] L. Ling, Y. Cheng, L. Ding, X. Yang, Association of serum periostin with cardiac function and short-term prognosis in acute myocardial infarction patients, PLoS One 9 (2014) e88755. [20] R. Semprini, R. Caswell-Smith, J. Fingleton, C. Holweg, J. Matthews, M. Weatherall, et al., Longitudinal variation of serum periostin levels in adults with stable asthma, J. Allergy Clin. Immunol. 139 (2017) 1687–1688. [21] K. Górska, M. Maskey-Warzęchowska, P. Nejman-Gryz, P. Korczyński, M. Prochorec-Sobieszek, R. Krenke, Comparative study of periostin expression in different respiratory samples in patients with asthma and chronic obstructive pulmonary disease, Pol. Arch. Med. Wewn. 126 (2016) 124–137. [22] C.H. Xu, W. Wang, Y. Lin, L.H. Qian, X.W. Zhang, Q.B. Wang, et al., Diagnostic and prognostic value of serum periostin in patients with non-small cell lung cancer, Oncotarget 8 (2017) 18746–18753. [23] M. Tajiri, M. Okamoto, K. Fujimoto, T. Johkoh, J. Ono, M. Tominaga, et al., Serum
Hazard ratio values were estimated univariate Cox regression analysis. GCS indicates Glasgow Coma Scale; CT, computerized tomography; SAH, subarachnoid hemorrhage.
significantly increased after head trauma. According to the preceding evidence [27,28], it is suggested that periostin might be beneficial to brain tissue repair after trauma. However, this explanation warrants to be verified in future. A growing body of data have pointed to the prognostic role of circulating periostin concentrations in various kinds of cancers including gastric cancer, breast cancer and brain glioma [39–41]. Considering the effect of periostin on ventricular remodeling [42], increased serum periostin concentrations have been demonstrated to be in negative correlation with left ventricular ejection fraction and left atrium diameter and in positive association with Killip class and to predict worse short-term disease prognosis indicated as more composite cardiovascular events six months after acute myocardial infarction [19]. However, the prognostic value of periostin in TBI remains unexplored. This study found that serum periostin concentrations were independently associated with GCS scores negatively after adjustment for other confounding factors, which were verified significantly in bivariate correlative analysis, i.e., unreactive pupils, CT classification 5 or 6, abnormal cisterns, midline shift > 5 mm, presence of traumatic subarachnoid hemorrhage, acute lung injury, acute traumatic coagulopathy, progressive hemorrhagic injury, posttraumatic cerebral infarction, blood glucose concentrations and plasma C-reactive protein concentrations. This finding indicates that serum periostin concentrations could reflect extent of brain injury following TBI. In this study, we found that serum periostin concentrations were significantly higher in non-survivors than in survivors within 30 days after head trauma in a group of severe TBI patients. Moreover, periostin in serum was identified as an independent prognostic predictor for 30day mortality and overall survival. Furthermore, as compared with GCS score, a common determinant of poor outcome after head trauma, which was also associated independently with 30-day poor prognosis in the current study, serum periostin concentrations had similar ability, in terms of AUC, to discriminate patients at risk of death within 30 days post trauma. As a whole, it is plausible that increased serum periostin concentrations should be associated with poor prognosis of TBI. 5. Conclusions This study confirmed that increased serum periostin concentrations at admission are strongly relevant to the severity determined by 302
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[24]
[25]
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[33] G. Franschman, C. Boer, T.M. Andriessen, J. van der Naalt, J. Horn, I. Haitsma, et al., Multicenter evaluation of the course of coagulopathy in patients with isolated traumatic brain injury: relation to CT characteristics and outcome, J. Neurotrauma 29 (2012) 128–136. [34] S. Greuters, A. van den Berg, G. Franschman, V.A. Viersen, A. Beishuizen, S.M. Peerdeman, et al., Acute and delayed mild coagulopathy are related to outcome in patients with isolated traumatic brain injury, Crit. Care 15 (2011) R2. [35] E. Oku, T. Kanaji, Y. Takata, et al., Periostin and bone marrow fibrosis, Int. J. Hematol. 88 (2008) 57–63. [36] N. Katsuragi, R. Morishita, N. Nakamura, T. Ochiai, Y. Taniyama, Y. Hasegawa, et al., Periostin as a novel factor responsible for ventricular dilation, Circulation 110 (2004) 1806–1813. [37] X. Guo, H. Xue, Q. Shao, J. Wang, X. Guo, X. Chen, et al., Hypoxia promotes gliomaassociated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR, Oncotarget 7 (2016) 80521–80522. [38] A.M. Mikheev, S.A. Mikheeva, A.D. Trister, M.J. Tokita, S.N. Emerson, C.A. Parada, et al., Periostin is a novel therapeutic target that predicts and regulates glioma malignancy, Neuro-Oncology 17 (2015) 372–382. [39] T. Moniuszko, A. Wincewicz, M. Koda, I. Domysławska, S. Sulkowski, Role of periostin in esophageal, gastric and colon cancer, Oncol. Lett. 12 (2016) 783–787. [40] P.V. Nuzzo, A. Rubagotti, L. Zinoli, S. Salvi, S. Boccardo, F. Boccardo, The prognostic value of stromal and epithelial periostin expression in human breast cancer: correlation with clinical pathological features and mortality outcome, BMC Cancer 16 (2016) 95. [41] B. Tian, Y. Zhang, J. Zhang, Periostin is a new potential prognostic biomarker for glioma, Tumour Biol. 35 (2014) 5877–5883. [42] H. Morita, I. Komuro, Periostin isoforms and cardiac remodeling after myocardial infarction: is the dispute settled? Hypertension 67 (2016) 504–505.
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Serum periostin concentrations and outcomes after severe traumatic brain injury
MARK
Xiao-Qiao Dong, Wen-Hua Yu⁎, Quan Du, Hao Wang, Qiang Zhu, Ding-Bo Yang, Zhi-Hao Che, Yong-Feng Shen, Li Jiang Department of Neurosurgery, The Hangzhou First People's Hospital, Nanjing Medical University, 261 Huansha Road, Hangzhou 310006, China
A R T I C L E I N F O
A B S T R A C T
Keywords: Traumatic brain injury Periostin Severity Mortality Outcome Prognosis Biomarker
Background: Periostin, a neurite outgrowth-promoting factor, is increasingly expressed in rat brain tissues after cerebral ischemia or subarachnoid hemorrhage. However, periostin concentrations are undetermined in peripheral blood from patients with traumatic brain injury (TBI). Methods: In this prospective, observational study, serum periostin concentrations were measured in 130 controls and 130 severe TBI patients. We investigated its association with trauma severity reflected by Glasgow Coma Scale (GCS) score and prognosis (i.e., 30-day mortality and 30-day overall survival). Results: As compared with the controls, serum periostin concentrations were significantly increased in the patients [(median, 246.5 ng/ml; interquartile range, 164.5–328.6 ng/ml) vs. (median, 61.8 ng/ml; interquartile range, 37.9–77.9 ng/ml), P < 0.001]. Periostin concentrations independently correlated with GCS scores (t = −6.199, P < 0.001). Serum periostin concentrations higher than 308.2 ng/ml predicted 30-day mortality with a sensitivity of 72.4% and a specificity of 78.2% [area under curve, 815; 95% confidence interval (CI), 0.737–0.878]. Periostin concentrations higher than 246.5 ng/ml were independently related to 30-day mortality and 30-day overall survival with odds ratio value of 3.829 (95% CI, 1.104–13.281) and hazard ratio value of 5.667 (95% CI, 1.953–16.443) respectively. Conclusions: Increased serum periostin concentrations clearly reflect trauma severity and mortality following TBI.
1. Introduction Traumatic brain injury (TBI) is a set of secondary pathological and/ or functional alteration within brain because of a sudden external force and represents a problem of enormous public health importance [1–3]. An early risk assessment with estimate of the severity of disease and prognosis is crucial for optimized care and allocation of healthcare resources to improve outcome [4–6]. To date, Glasgow Coma Scale (GCS) has been the most accepted clinical system to assess trauma severity and to predict the TBI outcome [7–9]. However, recently, the interests of clinicians have focused on the potential role of circulating markers in TBI [10–13]. Periostin is a 90-kD extracellular matrix protein, containing an amino-terminal cysteine-rich EMI domain in its N-terminal portion, four tandemly lined fasciclin I domains in the middle, and an alternative splicing domain in its C-terminal portion [14,15]. Accumulating evidence has shown that periostin plays pivotal roles in cell survival
under hypoxic conditions, migration of cancer cells and proliferation of cardiomyocytes after acute myocardial infarction [16–18]. Moreover, periostin concentrations in peripheral blood are markedly enhanced in asthma, chronic obstructive pulmonary diseases, cancers, idiopathic pulmonary fibrosis, atopic dermatitis and acute myocardial infarction [19–24]. Interestingly, periostin has been identified as a neurite outgrowth-promoting factor, which significantly enhances neural stem cell proliferation and differentiation after hypoxia-ischemia [25,26]. Recently, it is verified that periostin expression is up-regulated in brain tissues after ischemic stroke or subarachnoid hemorrhage [27,28]. 2. Materials and methods 2.1. Study population In this prospective and observational study, we consecutively recruited all severe TBI patients at the Hangzhou First People's Hospital
Abbreviations: CT, computerized tomography; GCS, Glasgow Coma Scale; TBI, traumatic brain injury ⁎ Corresponding author. E-mail address: [email protected] (W.-H. Yu). http://dx.doi.org/10.1016/j.cca.2017.06.020 Received 12 June 2017; Received in revised form 23 June 2017; Accepted 27 June 2017 Available online 28 June 2017 0009-8981/ © 2017 Elsevier B.V. All rights reserved.
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samples with a quantitative sandwich enzyme-linked immunosorbent assay kit (Wuhan USCN Science Co., Ltd.) according to the manufactures' instructions. Intra-assay CV revealed a coefficient of variation of 9.8%, with an accuracy of 99%. The inter-assay CV was 11.5%, with an accuracy of 97%. Recovery was 94%.
from August 2011 to September 2015. Severe TBI was defined as GCS < 9 points. Exclusion criteria included Injury Severity Score in non-cranial aspects > 9 points, time from trauma to admission > 6 h, < 18 years, surgery or trauma during the preceding 2 months, neurological disease including ischemic or hemorrhagic stroke, use of antiplatelet or anticoagulant medication, immunosuppressive therapy, acute and chronic infections at study enrollment (based on history report and physical examination), and presence of other prior systemic diseases such as asthma, chronic obstructive pulmonary diseases, diabetes mellitus, hypertension, uremia, liver cirrhosis, malignancy and chronic heart or lung disease. Control group consisted of individuals who came to our hospital for healthy examination during the period of May 2015 to September 2015. Exclusion criteria contained < 18 years, surgery or trauma during the preceding 2 months, neurological disease including ischemic or hemorrhagic stroke, use of antiplatelet or anticoagulant medication, immunosuppressive therapy, acute and chronic infections at study enrollment, and presence of other prior systemic diseases such as asthma, chronic obstructive pulmonary diseases, diabetes mellitus, hypertension, uremia, liver cirrhosis, malignancy and chronic heart or lung disease. The study was approved by the ethics committee of the Hangzhou First People's Hospital. The subjects or their legal guardians were informed of the study protocol and their written informed consent was obtained, according to the Declaration of Helsinki.
2.4. Statistical analysis The normality of data distribution was tested using the KolmogorovSmirnov test or Shapiro-Wilk test. All continuous variables were presented as median (interquartile range) due to their non-normal distribution. Categorical variables were reported as counts (percentage). Intergroup comparisons were conducted using χ2 test or Fisher exact test for categorical variables. For continuous variables, differences between two groups were analyzed with Mann-Whitney U test and differences among multiple groups were assessed using KruskalWallis H test. Bivariate linear relationships between serum periostin concentrations and other parameters were evaluated using Spearman's correlation coefficient, followed by a multivariate linear regression. Overall survival was calculated using Kaplan–Meier method and intergroup comparison was performed using the log-rank test. All significant variables in univariate analysis were further incorporated into multivariate Cox's proportional hazard model to identify predictors for 30-day overall survival. Hazard ratio (HR) values and the corresponding 95% confidence intervals (CIs) were estimated. A binary Logistic regression model was constructed to identify independent predictors for 30-day mortality. The logistic regression results were presented as odds ratio (OR) and 95% confidence interval (CI). Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive values of serum periostin concentrations for 30-day mortality. Subsequently, area under curve (AUC) and the corresponding 95% CI were calculated. In a combined logisticregression model, we estimated the additive benefit of periostin concentrations to GCS scores. All data were analyzed using SPSS ver. 19.0 and MedCalc ver. 9.6.4.0. A P < 0.05 was considered to be statistically significant.
2.2. Clinical and radiological assessment Upon entry into emergency department, we collected information including demographic data (age and gender), initial arterial pressure, pupil reactivity, time from trauma to admission, mechanisms of injury and comorbidities. Trauma severity was evaluated using the postresuscitation GCS at admission. Computerized tomography (CT) scans were performed to assess abnormal cisterns, midline shift > 5 mm and subarachnoid hemorrhage. CT classification was performed using Traumatic Coma Data Bank criteria on initial postresuscitation CT scan according to the method of Marshall et al. [29]. Diagnosis of progressive hemorrhagic injury and posttraumatic cerebral infarction was made on the follow-up CT scan. Progressive hemorrhagic injury was defined as any increase in size or number of the hemorrhagic lesion, including newly developed ones [30]. Diagnosis of posttraumatic cerebral infarction was made according to the following criteria: (1) distinctly hypodense lesions within a defined cerebral vascular territory; (2) hypodense lesions located in boundary zones between the defined cerebral vascular territories or situated in the terminal zones of perforating arteries within the deep white matter [31]. All CT scans were performed according to the neuroradiology department protocol. Investigators who read them were blinded to clinical information. Acute lung injury was diagnosed according to the international consensus criteria, which include acute onset, the ratio of partial pressure of arterial oxygen to fractional inspired oxygen ≤ 300, bilateral infiltrates on chest radiograph, and no clinical evidence of left arterial hypertension [32]. The endpoint of the study was 30-day mortality.
3. Results 3.1. Study population characteristics Initially, a total of 181 severe TBI patients were assessed. We excluded fifty-one patients with Injury Severity Score in non-cranial aspects > 9 points (5 cases), time from trauma to admission > 6 h (6 cases), < 18 years (3 cases), surgery or trauma during the preceding 2 months (4 cases), neurological disease (7 cases), use of antiplatelet or anticoagulant medication (5 cases), immunosuppressive therapy (3 cases), acute and chronic infections at study enrollment (3 cases), presence of other prior systemic diseases (9 cases), refusal to participate (1 case), incomplete information (2 cases), unavailable sample (1 case) or loss to follow-up (2 cases). Finally, a total of 130 patients were included in this study. Additionally, 130 healthy individuals constituted control group, who had similar age and sex when compared with the patients. This group of severe TBI patients was composed of 79 males and 51 females, as well as there was a median age of 43 (interquartile range, 25–56) years (range, 18–71 years). In terms of mechanisms of injury, head trauma in 64 patients (49.2%) was caused by automobile/motorcycle; 45 patients (34.6%), fall/jump; 21 patients (16.2%), others. The median GCS score was 5 (interquartile range, 4–7) (range, 3–8). A total of 59 patients (45.4%) had unreactive pupils at admission; 55 patients (42.3%), CT classification 5 or 6; 61 patients (46.9%), abnormal cisterns on initial CT scan; 70 patients (53.9%), midline shift > 5 mm on initial CT scan; 79 patients (60.8%), presence of traumatic subarachnoid hemorrhage on initial CT scan. Alternatively, acute lung injury, acute traumatic coagulopathy, progressive
2.3. Blood collection and laboratory test Blood samples were obtained from severe TBI patients at admission and from the controls at study entry. After centrifugation, aliquots of the samples were immediately stored −80 °C before assay. Biomarker concentrations were measured by investigators blinded to the clinical outcome and neuroimaging findings. Coagulation test, blood routine test and blood biochemical test were measured at admission using standard laboratory methods. Acute traumatic coagulopathy was defined as an activated partial thromboplastic time > 40 s and/or international normalized ratio > 1.2 and/or a platelet count < 120 × 109/l [33,34]. Serum periostin concentrations were tested in duplicate 299
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Fig. 1. Comparisons between healthy controls and severe traumatic brain injury patients as well as between non-survivors and survivors within 30 days after severe traumatic brain injury in terms of serum periostin concentrations.
traumatic subarachnoid hemorrhage, acute lung injury, acute traumatic coagulopathy, progressive hemorrhagic injury, posttraumatic cerebral infarction, blood glucose concentrations and plasma C-reactive protein concentrations. When the preceding variables were incorporated into a multivariate linear regression model, serum periostin concentrations were demonstrated to be negatively and highly correlated with GCS scores (t = − 6.199, P < 0.001). In Fig. 2, serum periostin concentrations were statistically significantly increased with increasing severity.
hemorrhagic injury and posttraumatic cerebral infarction were found in 30 (23.1%), 51 (39.2%), 35 (26.9%) and 23 (17.7%) patients respectively. Moreover, eighty-six patients (66.2%) underwent intracranial surgery in first 24 h. Patients were admitted at hospital from 0.5 h to 6.0 h after trauma (median, 2.0 h; interquartile range, 1.5–4.0 h). We collected blood samples at a median time of 3.0 (interquartile range, 2.5–6.0) h (range, 0.8–9.0 h) after trauma. The median systolic arterial pressure was 124 (interquartile range, 99–143) mm Hg (range, 72–174 mm Hg) and the mean diastolic arterial pressure was 77 (interquartile range, 57–90) mm Hg (range, 42–108 mm Hg). Within 30 days after head trauma, a total of 29 patients (22.3%) were dead.
3.3. ROC curve analysis In accordance with ROC curve, the optimal cutoff value of serum periostin concentrations as an indicator for discrimination of 30-day mortality was projected to be 308.2 ng/ml, which yielded a sensitivity of 72.4% and a specificity of 78.2%, with the AUC at 0.815 (95% CI = 0.737–0.878, P < 0.001; Fig. 3). Its AUC was in the range of GCS scores (AUC 0.869, 95% CI 0.798–0.922, P = 0.281).When a combined logistic-regression model was configured, periostin improved the AUC of GCS scores to 0.893 (95% CI 0.827–0.941), but the difference did not appear to be statistically significant (P = NS).
3.2. Serum periostin concentrations and other variables In Fig. 1, the median serum periostin concentrations were 246.5 ng/ ml (interquartile range, 164.5–328.6 ng/ml) in the patients and 61.8 ng/ml (interquartile range, 37.9–77.9 ng/ml) in the controls. As compared with the controls, serum periostin concentrations were significantly increased in the patients (P < 0.001). Additionally, periostin concentrations were markedly higher in non-survivors than in survivors with 30 days after head trauma [(median, 352.9 ng/ml; interquartile range, 274.0–477.9 ng/ml) vs. (median, 216.7 ng/ml; interquartile range, 128.8–301.4 ng/ml), P < 0.001]. In Table 1, serum periostin concentrations were found to be significantly associated with GCS scores, unreactive pupils, CT classification 5 or 6, abnormal cisterns, midline shift > 5 mm, presence of
3.4. Mortality prediction In the current study, serum periostin concentrations were dichotomized in terms of its median value (246.5 ng/ml). In Table 2, a univariate logistic regression analysis demonstrated that the parameters closely related to 30-day mortality were serum periostin concentrations > 246.5 ng/ml, GCS scores, unreactive pupils, CT classification 5 or 6, abnormal cisterns, midline shift > 5 mm, presence of traumatic subarachnoid hemorrhage, acute lung injury, acute traumatic coagulopathy, progressive hemorrhagic injury, posttraumatic cerebral infarction, blood glucose concentrations and plasma C-reactive protein concentrations. When the aforementioned significant parameters were included in a multivariate logistic regression model, serum periostin concentrations higher than 246.5 ng/ml (OR = 3.829, 95% CI = 1.104–13.281, P = 0.004) and GCS scores (OR = 0.245, 95% CI = 0.122–0.492, P < 0.001) were identified as the independent predictors for 30-day mortality after head trauma.
Table 1 Correlative analysis between serum periostin levels and other parameters in 130 patients with severe traumatic brain injury.
Gender (male/female) Age (y) Mechanisms of injury GCS scores on admission Pupils unreactive on admission CT classification 5 or 6 Abnormal cisterns on initial CT scan Midline shift > 5 mm on initial CT scan Traumatic SAH on initial CT scan Progressive hemorrhagic injury Posttraumatic cerebral infarction Acute traumatic coagulopathy Acute lung injury Intracranial surgery in first 24 h Admission time (h) Plasma-sampling time (h) Systolic arterial pressure (mm Hg) Diastolic arterial pressure (mm Hg) Blood glucose level (mmol/l) Plasma C-reactive protein (mg/l)
r Value
P value
0.092 0.127 − 0.042 − 0.652 0.474 0.375 0.349 0.301 0.242 0.264 0.295 0.317 0.232 0.121 0.135 0.100 0.117 0.106 0.197 0.226
NS NS NS < 0.001 < 0.001 < 0.001 < 0.001 0.001 0.006 0.002 0.001 < 0.001 0.008 NS NS NS NS NS 0.025 0.010
3.5. Survival analysis In this study, the mean overall survival time of all patients was 25.3 days (95% CI, 23.8–26.9 days) during follow-up of 30 days. Table 3 showed that serum periostin concentrations higher than 246.5 ng/ml in addition to other parameters had a strong relation to 30day overall survival. In Fig. 3, patients with serum periostin concentrations higher than 246.5 ng/ml had significantly shorter 30-day overall survival time than other remaining patients (mean time 22.0 days, 95% CI 19.4–24.7 days vs. 28.7 days, 95% CI 27.4–30.0 days; P < 0.001). After adjusting for all other significant outcome predictors in univariate analysis, serum periostin
Bivariate correlative analysis was conducted using Spearman's correlation coefficient. GCS indicates Glasgow Coma Scale; CT, computerized tomography; SAH, subarachnoid hemorrhage.
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Fig. 2. Correlative analysis of serum periostin levels with Glasgow Coma Scale scores using Spearman's correlation coefficient or Kruskal-Wallis H test.
concentrations higher than 246.5 ng/ml and GCS scores remained as the independent predictors for 30-day overall survival with HR values of 5.667 (95% CI, 1.953–16.443, P = 0.001) and 0.391 (95% CI, 0.250–0.611, P < 0.001) respectively.
Table 2 Clinical and biochemical characteristics associated with 30-day mortality in 130 patients with severe traumatic brain injury.
Gender (male/female) Age (y) Mechanisms of injury GCS scores on admission Pupils unreactive on admission CT classification 5 or 6 Abnormal cisterns on initial CT scan Midline shift > 5 mm on initial CT scan Traumatic SAH on initial CT scan Progressive hemorrhagic injury Posttraumatic cerebral infarction Acute traumatic coagulopathy Acute lung injury Intracranial surgery in first 24 h Admission time (h) Plasma-sampling time (h) Systolic arterial pressure (mm Hg) Diastolic arterial pressure (mm Hg) Blood glucose level (mmol/l) Plasma C-reactive protein level (mg/l) Serum periostin > 246.5 ng/ml
4. Discussion The current study enrolled a group of severe TBI patients and investigated relationship between serum periostin concentrations and trauma severity in addition to outcomes after head trauma, as well as subsequently found some interesting results as follows. First, serum periostin concentrations were significantly higher in all patients with severe TBI than in healthy controls and especially, in 30-day non-surviving patients, this sort of elevation was more obvious. Secondly, serum periostin concentrations were independently and negatively associated with GCS scores. Thirdly, periostin in serum was an independent predictor for 30-day mortality and overall survival after head trauma. Lastly, as compared to GCS scores, serum periostin concentrations showed similar prognostic value in terms of AUC. Hence, periostin in serum might represent a novel prognostic biomarker of TBI. Periostin is first cloned from a mouse calvarial cell line, hence its original designation as osteoblast-specific factor 2 [14,15]. The human periostin gene maps to chromosome 13q13.3 and encodes a secreted 90-kDa protein [14,15]. Periostin plays an important role in the maintenance and development of bones, teeth and the heart, and contributes to tumor progression in several tumor cells [16–18]. A lot of evidence has recently accumulated showing that expression of periostin is involved in various pathophysiological statuses of fibrosis, including the healing process in myocardial infarction and bone marrow fibrosis [14,35]. These data indicate that periostin might exert a protective effect on tissue injury. However, other researches demonstrated a detrimental effect of periostin. Exogenously over-expression of periostin gene in the heart led to impaired cardiac function, including left ventricle dilation, cardiac myocytes decrease and collagen deposition increase, which suggested a correlation between increased periostin with deteriorated cardiac function. Furthermore, inhibition of periostin
Odds ratio (95% CI)
P value
1.073 (0.459–2.509) 1.016 (0.992–1.040) 1.230 (0.710–2.129) 0.234 (0.124–0.441) 9.051 (3.177–25.790) 5.173 (2.076–12.889) 6.355 (2.374–17.010) 7.778 (2.522–23.982) 27.451 (3.597–209.524) 3.556 (1.486–8.509) 2.796 (1.062–7.364) 5.018 (2.054–12.258) 3.255 (1.326–7.987) 0.964 (0.404–2.301) 1.081 (0.830–1.408) 1.188 (0.985–1.433) 1.005 (0.987–1.019) 1.013 (0.993–1.035) 1.139 (1.016–1.278) 1.182 (1.049–1.332) 9.531 (3.084–29.455)
NS NS NS < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 0.001 0.004 0.037 < 0.001 0.010 NS NS NS NS NS 0.026 0.006 < 0.001
Odds ratio values were calculated using univariate logistic regression analysis. GCS indicates Glasgow Coma Scale; CT, computerized tomography; SAH, subarachnoid hemorrhage.
expression was able to improve cardiac systolic ejection function and animal survival rate [36]. Thus, the net effect of periostin has not reached a consensus. Nevertheless, there is no doubt that this molecule acts as an important regulator in tissue repair. In central nervous system, periostin expressions can be highly upregulated in glioma tissue [37,38]. However, recently, this protein was found to be highly expressed in animal brain tissues affected by ischemia or hemorrhage; moreover, exogenous periostin exhibited neuroprotective effects and accelerated neurite outgrowth [27,28]. In this study, we demonstrated that serum periostin concentrations were Fig. 3. Receiver operating characteristic curve analysis using serum periostin levels as a predictor of mortality at 30 days and survival curve analysis at 30 days using serum periostin concentrations higher or lower than 246.5 ng/ml.
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admission GCS scores and short-term mortality reflected by 30-day mortality and overall survival after head trauma, indicating that periostin in serum might have the potential to be a useful prognostic biomarker in Chinese patients with severe TBI.
Table 3 Clinical and biochemical characteristics associated with 30-day overall survival in 130 patients with severe traumatic brain injury.
Gender (male/female) Age (y) Mechanisms of injury GCS scores on admission Pupils unreactive on admission CT classification 5 or 6 Abnormal cisterns on initial CT scan Midline shift > 5 mm on initial CT scan Traumatic SAH on initial CT scan Progressive hemorrhagic injury Posttraumatic cerebral infarction Acute traumatic coagulopathy Acute lung injury Intracranial surgery in first 24 h Admission time (h) Plasma-sampling time (h) Systolic arterial pressure (mm Hg) Diastolic arterial pressure (mm Hg) Blood glucose level (mmol/l) Plasma C-reactive protein level (mg/l) Serum periostin > 246.5 ng/ml
Hazard ratio (95% CI)
P value
1.069 (0.505–2.263) 1.013 (0.993–1.035) 1.183 (0.732–1.911) 0.342 (0.222–0.528) 7.020 (2.676–18.416) 4.361 (1.930–9.856) 5.262 (2.141–12.936) 6.373 (2.216–18.325) 22.046 (2.998–162.114) 2.995 (1.444–6.211) 2.372 (1.079–5.214) 4.132 (1.879–9.085) 2.668 (1.273–5.593) 0.957 (0.445–2.057) 1.069 (0.848–1.348) 1.150 (0.981–1.348) 1.004 (0.989–1.017) 1.011 (0.992–1.031) 1.124 (1.020–1.238) 1.148 (1.042–1.266) 7.462 (2.595–21.462)
NS NS NS < 0.001 < 0.001 < 0.001 < 0.001 0.001 0.002 0.003 0.032 < 0.001 0.009 NS NS NS NS NS 0.018 0.005 < 0.001
Acknowledgements We thank all staffs in Department of Neurosurgery, The Hangzhou First People's Hospital (Hangzhou, China) for their technical support. This study was supported financially by Zhejiang Province Medical and Health Project （2014KYA177，2016RCB016) and Hangzhou Medical Research Fund Project (2014Z06, 2016Z10). References [1] H.Y. Shi, S.L. Hwang, I.C. Lee, I.T. Chen, K.T. Lee, C.L. Lin, Trends and outcome predictors after traumatic brain injury surgery: a nationwide population-based study in Taiwan, J. Neurosurg. 121 (2014) 1323–1330. [2] J.T. Flaada, C.L. Leibson, J.N. Mandrekar, N. Diehl, P.K. Perkins, A.W. Brown, et al., Relative risk of mortality after traumatic brain injury: a population-based study of the role of age and injury severity, J. Neurotrauma 24 (2007) 435–445. [3] M. Lippert-Gruner, M. Maegele, H. Haverkamp, N. Klug, C. Wedekind, Health-related quality of life during the first year after severe brain trauma with and without polytrauma, Brain Inj. 21 (2007) 451–455. [4] T. Amoroso, K.M. Iverson, Acknowledging the risk for traumatic brain injury in women veterans, J. Nerv. Ment. Dis. 205 (2017) 318–323. [5] P.J.D. Andrews, A. Rodriguez, P. Suter, C.G. Battison, J.K.J. Rhodes, I. Puddu, et al., Mortality risk stratification after traumatic brain injury and hazard of death with titrated hypothermia in the Eurotherm3235Trial, Crit. Care Med. 45 (2017) 883–890. [6] M. Majdan, A. Brazinova, M. Rusnak, J. Leitgeb, Outcome prediction after traumatic brain injury: comparison of the performance of routinely used severity scores and multivariable prognostic models, J. Neurosci. Rural Pract. 8 (2017) 20–29. [7] L.J. Shen, S.B. Yang, Q.W. Lv, G.H. Zhang, J. Zhou, M. Guo, et al., High plasma adiponectin levels in patients with severe traumatic brain injury, Clin. Chim. Acta 427 (2014) 37–41. [8] E. Ozyurt, E. Goksu, M. Cengiz, M. Yilmaz, A. Ramazanoglu, Retrospective analysis of prognostic factors of severe traumatic brain injury in a university hospital in Turkey, Turk. Neurosurg. 25 (2015) 877–882. [9] T.M. Andriessen, B. Jacobs, P.E. Vos, Clinical characteristics and pathophysiological mechanisms of focal and diffuse traumatic brain injury, J. Cell. Mol. Med. 14 (2010) 2381–2392. [10] Z.Y. Zhang, L.X. Zhang, X.Q. Dong, W.H. Yu, Q. Du, D.B. Yang, et al., Comparison of the performances of copeptin and multiple biomarkers in long-term prognosis of severe traumatic brain injury, Peptides 60 (2014) 13–17. [11] K.Y. Wang, G.F. Yu, Z.Y. Zhang, Q. Huang, X.Q. Dong, Plasma high-mobility group box 1 levels and prediction of outcome in patients with traumatic brain injury, Clin. Chim. Acta 413 (2012) 1737–1741. [12] X.Q. Dong, M. Huang, S.B. Yang, W.H. Yu, Z.Y. Zhang, Copeptin is associated with mortality in patients with traumatic brain injury, J. Trauma 71 (2011) 1194–1198. [13] S. Azar, A. Hasan, R. Younes, F. Najdi, L. Baki, H. Ghazale, et al., Biofluid proteomics and biomarkers in traumatic brain injury, Methods Mol. Biol. 1598 (2017) 45–63. [14] T. Oka, J. Xu, R.A. Kaiser, et al., Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling, Circ. Res. 101 (2007) 313–321. [15] K. Ruan, S. Bao, G. Ouyang, The multifaceted role of periostin in tumorigenesis, Cell. Mol. Life Sci. 66 (2009) 2219–2230. [16] J. Qin, F. Yuan, Z. Peng, K. Ye, X. Yang, L. Huang, et al., Periostin enhances adiposederived stem cell adhesion, migration, and therapeutic efficiency in Apo E deficient mice with hind limb ischemia, Stem Cell Res Ther 6 (2015) 138. [17] F. Qiu, C.H. Shi, J. Zheng, Y.B. Liu, Periostin mediates the increased pro-angiogenic activity of gastric cancer cells under hypoxic conditions, J. Biochem. Mol. Toxicol. 27 (2013) 364–369. [18] Y. Taniyama, N. Katsuragi, F. Sanada, J. Azuma, K. Iekushi, N. Koibuchi, et al., Selective blockade of periostin exon 17 preserves cardiac performance in acute myocardial infarction, Hypertension 67 (2016) 356–361. [19] L. Ling, Y. Cheng, L. Ding, X. Yang, Association of serum periostin with cardiac function and short-term prognosis in acute myocardial infarction patients, PLoS One 9 (2014) e88755. [20] R. Semprini, R. Caswell-Smith, J. Fingleton, C. Holweg, J. Matthews, M. Weatherall, et al., Longitudinal variation of serum periostin levels in adults with stable asthma, J. Allergy Clin. Immunol. 139 (2017) 1687–1688. [21] K. Górska, M. Maskey-Warzęchowska, P. Nejman-Gryz, P. Korczyński, M. Prochorec-Sobieszek, R. Krenke, Comparative study of periostin expression in different respiratory samples in patients with asthma and chronic obstructive pulmonary disease, Pol. Arch. Med. Wewn. 126 (2016) 124–137. [22] C.H. Xu, W. Wang, Y. Lin, L.H. Qian, X.W. Zhang, Q.B. Wang, et al., Diagnostic and prognostic value of serum periostin in patients with non-small cell lung cancer, Oncotarget 8 (2017) 18746–18753. [23] M. Tajiri, M. Okamoto, K. Fujimoto, T. Johkoh, J. Ono, M. Tominaga, et al., Serum
Hazard ratio values were estimated univariate Cox regression analysis. GCS indicates Glasgow Coma Scale; CT, computerized tomography; SAH, subarachnoid hemorrhage.
significantly increased after head trauma. According to the preceding evidence [27,28], it is suggested that periostin might be beneficial to brain tissue repair after trauma. However, this explanation warrants to be verified in future. A growing body of data have pointed to the prognostic role of circulating periostin concentrations in various kinds of cancers including gastric cancer, breast cancer and brain glioma [39–41]. Considering the effect of periostin on ventricular remodeling [42], increased serum periostin concentrations have been demonstrated to be in negative correlation with left ventricular ejection fraction and left atrium diameter and in positive association with Killip class and to predict worse short-term disease prognosis indicated as more composite cardiovascular events six months after acute myocardial infarction [19]. However, the prognostic value of periostin in TBI remains unexplored. This study found that serum periostin concentrations were independently associated with GCS scores negatively after adjustment for other confounding factors, which were verified significantly in bivariate correlative analysis, i.e., unreactive pupils, CT classification 5 or 6, abnormal cisterns, midline shift > 5 mm, presence of traumatic subarachnoid hemorrhage, acute lung injury, acute traumatic coagulopathy, progressive hemorrhagic injury, posttraumatic cerebral infarction, blood glucose concentrations and plasma C-reactive protein concentrations. This finding indicates that serum periostin concentrations could reflect extent of brain injury following TBI. In this study, we found that serum periostin concentrations were significantly higher in non-survivors than in survivors within 30 days after head trauma in a group of severe TBI patients. Moreover, periostin in serum was identified as an independent prognostic predictor for 30day mortality and overall survival. Furthermore, as compared with GCS score, a common determinant of poor outcome after head trauma, which was also associated independently with 30-day poor prognosis in the current study, serum periostin concentrations had similar ability, in terms of AUC, to discriminate patients at risk of death within 30 days post trauma. As a whole, it is plausible that increased serum periostin concentrations should be associated with poor prognosis of TBI. 5. Conclusions This study confirmed that increased serum periostin concentrations at admission are strongly relevant to the severity determined by 302
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