Clinical neuroscience 33
Serum procalcitonin as a diagnostic marker in acute ischemic stroke Da Tiana, Shengwu Zhangb, Xuwei Hec and Hong Liuc The aim of the study was to assess the relationship between procalcitonin (PCT) serum levels and acute ischemic stroke (AIS) in a Chinese sample. All consecutive patients with first-ever AIS between January 2012 and December 2013 were recruited to participate in the study. PCT levels and National Institutes of Health Stroke Scale scores were evaluated at the time of admission. Logistic regression analysis was used to evaluate the risk for stroke according to serum PCT levels. The results indicated that serum PCT levels were significantly higher in AIS patients as compared with normal controls (P < 0.0001). PCT levels increased with increasing severity of stroke, as defined by the National Institutes of Health Stroke Scale score. After adjusting for all other possible covariates, PCT level was found to be associated with an increased risk for AIS, with an adjusted odds ratio of 2.244 (95% confidence interval 1.563–3.756, P < 0.0001). On the basis of the receiver operating characteristic curve, the optimal cutoff value of
Introduction Stroke is the second most common cause of death and the leading cause of adult disability in China . Early detection and control of risk factors is thought to be crucial in reducing the risk for stroke and providing effective care . The ability of biomarkers to improve the diagnostic accuracy of stroke is attractive. The causes of stroke are not fully known, but inflammation plays a pathogenic role. Basic and clinical research provides evidence that inflammatory mechanisms play a central role in the pathogenesis and progression of stroke . Inflammatory biomarkers such as high-sensitivity C-reactive protein (hs-CRP) have been identified as predictors of first stroke . Procalcitonin (PCT), a protein comprising 116 amino acids, with a molecular weight of 13 kDa, was discovered 25 years ago as a prohormone of calcitonin produced by C-cells of the thyroid gland and intracellularly cleaved by proteolytic enzymes to form the active hormone. Mimoz et al.  found that early and transient release of PCT into the circulation was observed after severe trauma, and the amount of circulating PCT seemed to be proportional to the severity of tissue injury and hypovolemia, yet unrelated to infection, indicating an inflammation-related induction of PCT . Katan et al.  reported that higher levels of PCT were independently associated with ischemic stroke risk in a multiethnic, urban cohort. However, to our knowledge, the value of measurement 0959-4965 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
serum PCT levels as an indicator for auxiliary diagnosis of AIS was projected to be 1.20 ng/ml, which yielded a sensitivity of 79.6% and a specificity of 72.1%, with the area under the curve at 0.801 (95% confidence interval 0.762–0.844). An elevated serum level of PCT was a novel, independent diagnostic marker of AIS in the Chinese sample. Further study is needed to confirm these results. NeuroReport 26:33–37 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. NeuroReport 2015, 26:33–37 Keywords: acute ischemic stroke, diagnosis, marker, procalcitonin Departments of aNeurosurgery, bNeurology and cEmergency, People’s Hospital of Lishui, Lishui, People’s Republic of China Correspondence to Hong Liu, No. 15 Dazhong Street, Liandu District, Lishui, 323000, Zhejiang Province, Peoples Republic of China Tel: + 86 0578 278 0220; fax: + 86 0578 278 0220; e-mail: [email protected]
Received 30 October 2014 accepted 6 November 2014
of PCT levels in Chinese patients with stroke and the association with stroke risk have not yet been examined well. Thus, we sought to investigate the significance of serum PCT levels in a cohort of Chinese patients with acute ischemic stroke (AIS) and to compare these levels with those of a control group.
Methods All consecutive patients with first-ever AIS from the People’s Hospital of Lishui, China, between January 2012 and December 2013 were recruited to participate in the study. Our hospital is the best hospital in the region, serving around one million people. The hospital is located in the main city, and aging is a serious problem. Patients were defined according to the WHO criteria and had symptom onset within 24 h. Exclusion criteria were malignant tumor, intracerebral hemorrhage, and systemic infections. Other types of stroke (transient ischemic attack, subarachnoid hemorrhage, embolic brain infarction, brain tumors, and cerebrovascular malformation) and severe systemic diseases [collagenosis, endocrine and metabolic diseases (except for diabetes mellitus), inflammation, and neoplastic, liver, or renal diseases] were also in the range of exclusion. The control participants (N = 100) were of similar age and sex as the AIS patients. They had no known disease and were not using any medication. The present study has been approved by the ethics committee of the People’s Hospital of Lishui. All participants or their relatives were DOI: 10.1097/WNR.0000000000000298
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
34 NeuroReport 2015, Vol 26 No 1
informed of the study protocol and their written informed consent was obtained. Demographic and clinical data, including sex, age, and history of conventional vascular risk factors (hypertension, diabetes mellitus, atrial fibrillation, hyperlipoproteinemia, habitual smoking, and alcohol abuse), were obtained. Alcohol abuse was defined as failure to fulfill responsibilities, drinking in dangerous situations, legal concerns associated with alcohol use, and continued drinking despite problems that are caused or worsened by drinking, whereas habitual smoking was defined as daily consumption of more than 10 cigarettes. A neurologist assessed the stroke severity on admission on the basis of the National Institutes of Health Stroke Scale (NIHSS) . The stroke subtype was classified according to the Trial of Org 10172 in Acute Stroke Treatment criteria , which distinguished large-artery arteriosclerosis, small-artery occlusion, cardioembolism, other causative factors, and undetermined causative factors. The clinical stroke syndrome was determined by applying the criteria of the Oxfordshire Community Stroke Project: total anterior circulation syndrome, partial anterior circulation syndrome, lacunar syndrome, and posterior circulation syndrome . The Trial of Org 10172 in Acute Stroke Treatment and Oxfordshire Community Stroke Project classifications were verified by brain imaging. Brain imaging (either computed tomography or MRI) was performed routinely within 24 h after admission. MRI with diffusion-weighted imaging was performed in some patients. In those patients, diffusionweighted imaging lesion volumes were determined by an experienced neurologist who was unaware of the clinical and laboratory results. The infarct volume was calculated using the formula 0.5 × a × b × c (where a is the maximal longitudinal diameter, b is the maximal transverse diameter perpendicular to a, and c is the number of 10-mm slices containing infarcts) . Fasting venous blood was collected from all participants in vacutainer tubes and quickly centrifuged to avoid glycolysis. Serum samples were kept at − 80°C until assay. PCT levels were measured by Time Resolved Amplified Cryptate Emission (TRACE) Assay analysis on the B.R.A.H.M.S. Kryptor Compact instrument (B.R. A.H.M.S. Aktiengesellschaft, Hennigsdorf, Germany), and hs-CRP levels were analyzed using the Roche Cobas Integra 800 analyzer (Roche Diagnostic, Indianapolis, Indiana, USA). The interassay and intraassay coefficients of variation for PCT were shown to be 1.8–4.9 and 2.7–5.9%. The median serum PCT level in 100 healthy individuals was 0.25 ng/ml. The results were expressed as percentages for categorical variables and as medians [interquartile ranges (IQRs)] for continuous variables. The Mann–Whitney U-test and the χ2-test were used to compare the two groups. Correlations among laboratory parameters were analyzed using
Spearman’s rank correlation test. Associations between the severity of stroke evaluated in terms of the NIHSS scores and the serum levels of PCT were assessed using ordered logistic regression models with multivariate adjustment for possible confounders, for instance, age, sex, stroke risk factors, infarct volume, and serum levels of white blood cells, hs-CRP, and homocysteine (HCY). Logistic regression analysis was used to evaluate the risk for stroke according to serum PCT levels, after adjustment for the above possible confounders. The results were expressed as adjusted odds ratios (ORs), with the corresponding 95% confidence intervals (CIs). Receiver operating characteristic curves were used to evaluate the accuracy of serum PCT levels in predicting AIS. The area under the curve (AUC) was calculated as a measure of the accuracy of the test. All calculations were performed using SPSS for Windows, version 17.0 (SPSS Inc., Chicago, Illinois, USA), and STATA 9.2 (StataCorp, College Station, Texas, USA), R version 2.8.1.
Results Of 586 screened patients, a total of 442 patients with firstever AIS were included in this study. Table 1 shows the baseline characteristics of these patients, among whom 241 (54.5%) were male. The median age was 70 years (IQR 59–78). The median NIHSS score on admission was 9 points (IQR 6–13). The median time from symptom recognition to hospital admission was 7.0 h (IQR 4.1–13.2), and 345 patients (78.1%) were admitted within 12 h of symptom recognition. The results indicated that the serum PCT levels were significantly higher in stroke patients as compared with normal controls [1.04 ng/ml (IQR 0.21–2.33) vs. 0.25 ng/ ml (IQR 0.07–0.66); Z = 8.784, P < 0.0001; Fig. 1]. Similarly, the serum levels of hs-CRP and HCY in stroke patients were also higher than in normal cases (Z = 4.123, P < 0.001 and Z = 3.763, P < 0.001, respectively). PCT levels increased with increasing severity of stroke, as defined by the NIHSS score. There was a positive correlation between the level of PCT and the NIHSS score (r = 0.334, P < 0.0001). There was still a significant positive trend between serum PCT levels and NIHSS scores (P = 0.006) on using ordered logistic regression after multivariate adjustment for the above possible confounders. In addition, there was a weak but significant positive correlation between PCT and hs-CRP levels (r = 0.199, P = 0.002). Statistical analysis here revealed no influence of age, sex, time from symptom onset, risk factors for stroke, homocysteine level, WBC count, and glucose level on PCT levels in AIS patients (P > 0.05, respectively). In addition, there were no significant correlations between the serum levels of PCT and stroke syndrome and stroke etiology (P > 0.05). In the subgroup of patients (n = 318) in whom MRI was performed, serum PCT levels paralleled with the size of
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Serum procalcitonin as a diagnostic marker in AIS Tian et al. 35
Baseline characteristics of acute ischemic stroke patients and controls
Patients (n = 442)
Age [median (IQR)] (years) 70 Male sex (%) 241 Infarct volume (n = 318) 14 [median (IQR)] (ml) Stroke severity [median 9 NIHSS score (IQR)] The time from symptom 7.0 onset to admission [median (IQR)] (h) Vascular risk factors (%) Hypertension Diabetes mellitus Atrial fibrillation Coronary heart disease Hypercholesterolemia Family history of stroke Alcohol abuse Smoking habit Clinical findings [median (IQR)] Temperature (°C) 37.1 Heart rate (beats/min) 85 2 23.9 BMI (kg/m ) Systolic blood pressure 156 (mmHg) Diastolic blood pressure 95 (mmHg) Laboratory findings [median (IQR)] 8.5 Leucocyte count (×103 m/l) Glucose (mmol/l) 6.08 Hs-CRP (mg/dl) 0.86 HCY(μmol/l) 20.6 Stroke syndrome no. (%) TACS PACS LACS POCS Stroke etiology no. (%) Small-vessel occlusive Large-vessel occlusive Cardioembolic Other Unknown
(59–78) (54.5) (8–29)
Normal cases (n = 100) 70 (58–78) 55 (55.0) −
− − − − − 12.0 11.0 15.0
71.5 28.1 22.2 24.0 29.4 23.5 21.7 20.4 (36.4–37.5) (72–91) (22.6–26.8) (144–175)
36.4 80 23.8 130
(36.2–36.7) (71–86) (22.4–26.4) (125–136)
10.00 NS NS
0.027 NS NS 0.011
5.42 (5.22–5.80) 0.25 (0.14–0.35) 15.8 (13.2–18.9)
12.7 40.3 20.8 26.2
19.9 20.4 41.6 9.1 9.0
6.00 Z = 8.784, P < 0.0001 4.00
0.00 0.021 0.034 NS
(5.68–6.54) (0.32–2.01) (16.8–24.5)
∗∗ ∗∗ ∗
Serum levels of PCT (ng/ml)
0.014 < 0.001 < 0.001
− − −
Hs-CRP, high-sensitivity C-reactive protein; IQR, interquartile range; LACS, lacunar syndrome; HCY, homocysteine; NIHSS, National Institutes of Health Stroke Scale; NS, not significant; PACS, partial anterior circulation syndrome; POCS, posterior circulation syndrome; TACS, total anterior circulation syndrome.
the lesions. There was a significant positive association between serum PCT levels and infarct volume (r = 0.299, P < 0.0001). Similarly, there was still a significant positive trend between serum PCT levels and infarct volume (P = 0.009), on the basis of ordered logistic regression after multivariate adjustment for the above possible confounders. In univariate logistic regression analysis, PCT as a continuous variable was found to be associated with an increased risk for AIS, with an unadjusted OR of 3.390 (95% CI 2.244–5.122, P < 0.0001). After adjusting for all other possible covariates, the PCT level that remained is considered an independent risk factor for AIS with an adjusted OR of 2.244 (95% CI 1.563–3.756, P < 0.0001). This relationship was confirmed in the dose– response model.
Stroke patients (N = 442)
Normal cases(N = 100)
Serum PCT levels in AIS patients and normal cases. Mann–Whitney U-test. All data are medians and interquartile ranges (IQRs). AIS, acute ischemic stroke; PCT, procalcitonin.
On the basis of the receiver operating characteristic curve, the optimal cutoff value of the serum PCT level as an indicator for auxiliary diagnosis of AIS was projected to be 1.20 ng/ml, which yielded a sensitivity of 79.6% and a specificity of 72.1%, with an area under the curve of 0.801 (95% CI 0.762–0.844). With an AUC of 0.801, PCT levels showed a significantly greater discriminatory ability as compared with hs-CRP (AUC 0.601; 95% CI 0.544–0.665, P < 0.001) and HCY (AUC 0.635; 95% CI 0.576–0.755, P