Acute respiratory distress syndrome (ARDS) is characterized by alveolar epithelial and vascular endothelial injury in the lungs that is triggered by a wide range of predisposing conditions such as pneumonia, sepsis, and trauma [
Endocan, also called endothelial cell-specific molecule-1, is a soluble 50 kDa dermatan sulfate proteoglycan that is secreted from pulmonary and kidney vascular endothelial cells [
This was a multicenter clinical study conducted at the Second Affiliated Hospital of Chongqing Medical University, First Affiliated Hospital of Chongqing Medical University and Xinqiao Hospital from January 2012 to August 2013. We enrolled 42 critical ill adult patients with acute respiratory distress syndrome [
Patients were excluded if they were less than 18 years old or pregnant or if they had a coexisting malignancy. The study protocol had been reviewed and approved by the local Institutional Review Board, and written informed consent was obtained from either the patient or from each patient’s next of kin or legal representative before enrollment.
Plasma specimens were obtained from patients with ARDS as soon as possible after the patient met defining criteria, but those obtained more than 24 hours after admission were excluded.
Demographic characteristics and clinical data including age, gender, etiology of ARDS, and admission comorbidities were recorded from each subject. The acute physiology and chronic health evaluation (APACHE) II score [
When patients admitted, the WBCs, neutrophils, PCT, and CRP concentrations were routinely inspected and we recorded the results. We used a sandwich-based enzyme-linked immunosorbent assay (ELISA; LUNGINNOV Systems, Lille, France) to measure endocan plasma concentrations in duplicate.
For continuous variables, descriptive results were presented as the median (IQR) unless stated otherwise; we used the Student
42 critical ill adult patients with ARDS were initially enrolled in this study. Table
Baseline demographics, clinical characteristics, and comorbidity of 42 patients with acute respiratory distress syndrome.
Survivors |
Nonsurvivors |
|
|
---|---|---|---|
Age, years, mean (SD) | 63.9 (17.3) | 72.5 (10.8) | 0.064 |
Male sex, |
13 (59) | 14 (70) | 0.531 |
APACHE II score, median (IQR) | 21 (18–24) | 24 (22–30) | 0.03 |
PaO2/FIO2 ratio, median (IQR) | 131 (100–150.5) | 89.5 (64–111) | 0.000 |
Etiology of ARDS, |
|||
Pulmonary infection | 18 (81.8) | 17 (85) | |
Bacterial pneumonia | 14 (63.6) | 15 (75) | |
Virus pneumonia | 2 (9) | 2 (10) | |
Active tuberculosis | 2 (9) | 0 (0) | |
Aspiration | 0 | 1 (5) | |
Blood transfusion | 2 (9) | 0 (0) | |
Others | 2 (9) | 2 (10) | |
Abdominal infection | 1 (4.5) | 2 (10) | |
Mediastinal abscess | 1 (4.5) | 0 (0) | |
Comorbidity, |
|||
Obstructive airway disease | 6 (27.2) | 7 (35) | 0.741 |
Hypertension | 10 (45.4) | 14 (70) | 0.131 |
Cardiovascular disease | 8 (36.3) | 13 (65) | 0.121 |
Cerebrovascular accident | 1 (4.5) | 2 (10) | 0.598 |
Diabetes | 10 (45.4) | 11 (55) | 0.758 |
Duration of Mechanical ventilation, mean (SD) | 12 (4.5) | 15 (10.5) | 0.216 |
Length of Intensive Care Unit stay, mean (SD) | 16 (6.5) | 16 (12) | 0.846 |
Length of hospital stay | 28.0 (8.0) | 17.5 (12.0) | 0.002 |
MODS | |||
MODS = 2 organs, |
6 (27.2) | 5 (25) | 1.0 |
MODS = 3 organs, |
1 (4.5) | 7 (35) | 0.018 |
MODS ≥ 4 organs, |
2 (9) | 4 (20) | 0.4 |
Shock | 3 (13.6) | 11 (55) | 0.008 |
Shock (<7 days) | 3 (13.6) | 7 (35) | 0.152 |
Renal failure | 3 (13.6) | 10 (50) | 0.114 |
Renal failure (<7 days) | 1 (4.5) | 5 (25) | 0.087 |
Coagulopathy | 2 (9) | 7 (35) | 0.062 |
Coagulopathy (<7 days) | 0 (0) | 6 (30) | 0.007 |
Hepatic dysfunction | 6 (27.2) | 6 (30) | 1.0 |
Hepatic dysfunction (<7 days) | 0 (0) | 6 (30) | 0.007 |
APACHE = acute physiology and chronic health evaluation;
ARDS = acute respiratory distress syndrome; MODS = multiple-organ dysfunction syndrome.
All patients were classified in 3 Berlin’s subclasses: mild, moderate, or severe ARDS, but mild group had no patient in our study. Endocan levels had no significant statistical significance between moderate ARDS group (median (IQR) 3.21 (2.38–4.96) ng/mL;
In the ARDS group, the median endocan levels in nonsurvivor plasma were significantly higher than in survivor plasma (median (IQR) 5.01 (2.98–8.44) ng/mL versus 3.01 (2.36–4.36), respectively;
Comparison of plasma biomarkers between survivors and nonsurvivors of acute respiratory distress syndrome.
Survivors ( |
Nonsurvivors ( |
|
|
---|---|---|---|
Endocan (ng/mL), median (IQR) | 3.01 (2.36–4.36) | 5.01 (2.98–8.44) | 0.017 |
PCT (ng/mL), median (IQR) | 2.59 (0.95–6.25) | 9.26 (3.88–16.46) | 0.007 |
CRP (mg/L), median (IQR) | 113.4 (85.5–170.3) | 139.9 (101.2–196.3) | 0.385 |
WBC ( |
14.58 (8.84–19.50) | 15.25 (10.9–19.57) | 0.706 |
N ( |
13.20 (7.70–19.76) | 14.08 (9.76–18.80) | 0.762 |
PCT = procalcitonin, CRP = C-reactive protein, WBC = white blood cell, and N = Neutrophil counts.
Figure
Correlations of plasma endocan with procalcitonin (PCT), C-reactive protein (CRP), white blood cells (WBC), and APACHE II in 42 patients with acute respiratory distress syndrome (Spearman rank analysis).
To investigate the predictive properties of endocan levels regarding survival, we use the ROC-curve analysis and forward stepwise multivariate Cox regression. As shown in Figure
Motality prediction by plasma levels of endocan, PCT, CRP, WBC and Neutrophil counts and APACHE II scores in patients with acute respiratory distress syndrome using the receiver operating characteristic (ROC) curves.The optimal cutoff points for each plasma biomarker level and severity score were listed in the attached table,
For further risk assessment, we performed a forward stepwise multivariate Cox regression to compute the univariate analysis and hazard ratios, which are displayed in Table
Cox proportional hazards models for mortality prediction by biomarkers and severity scores.
Variable | Univariate Cox model | Multivariate Cox model | ||
---|---|---|---|---|
HR (95% CI) |
|
HR (95% CI) |
|
|
Endocan | 1.386 (1.171–1.641) | 0.000 | 1.374 (1.150–1.641) | 0.000 |
PaO2/FIO2 | 0.96 (0.943–0.978) | 0.000 | 0.958 (0.938–0.978) | 0.000 |
CRP | NA | NA | NA | NA |
WBC | NA | NA | NA | NA |
PCT | 1.063 (1.023–1.105) | 0.002 | NA | NA |
APAHCE II | 1.155 (1.040–1.282) | 0.007 | NA | NA |
HR = hazard ratio; NA = not applicable;
We also compared plasma markers using the area under the ROC curves to predict multiple-organ dysfunction (Table
Areas under receiver operating characteristic curves for plasma biomarker levels in predicting organ dysfunction in patients with acute respiratory distress syndrome.
Endocan | PCT | CRP | WBC | APACHE II | |
---|---|---|---|---|---|
Organ dysfunction |
|||||
Septic shock | 0.772* | 0.624 | 0.529 | 0.658 | 0.770# |
Renal failure | 0.714* | 0.593 | 0.615 | 0.432 | 0.662 |
Coagulopathy | 0.650 | 0.694 | 0.444 | 0.458 | 0.625 |
Hepatic dysfunction | 0.490 | 0.535 | 0.311 | 0.503 | 0.575 |
Organ dysfunction |
|||||
Septic shock | 0.786* | 0.566 | 0.511 | 0.531 | 0.787# |
Renal failure | 0.773* | 0.495 | 0.620 | 0.481 | 0.715 |
Coagulopathy | 0.852# | 0.718 | 0.519 | 0.444 | 0.715 |
Hepatic dysfunction | 0.690 | 0.715 | 0.370 | 0.519 | 0.752 |
Organ dysfunctions in patients with acute respiratory distress syndrome with low or high plasma endocan levels.
Endocan ≥ 4.96 ng/mL |
Endocan < 4.96 ng/mL |
|
||
---|---|---|---|---|
Organ dysfunction |
||||
Septic shock, |
9 (60) | 5 (18.5) | 0.015* | |
Renal failure, |
8 (53) | 5 (18.5) | 0.035* | |
Coagulopathy, |
5 (33) | 4 (14.8) | 0.242 | |
Hepatic dysfunction, |
4 (27) | 8 (30) | 1.0 | |
Organ dysfunction |
||||
Septic shock, |
7 (47) | 3 (11) | 0.020* | |
Renal failure, |
4 (27) | 2 (7.4) | 0.164 | |
Coagulopathy, |
5 (33) | 1 (3.7) | 0.016* | |
Hepatic dysfunction, |
3 (20) | 3 (11) | 0.649 |
The occurrence of organ dysfunctions was compared in patient groups with low (<4.96 ng/mL) and high (≥4.96 ng/mL) plasma levels of endocan during hospital stay or within 7 days. Asterisk indicates statistically significant difference between patient groups with low and high plasma endocan levels (
Demographic and baseline clinical characteristics of them were shown in Table
Demographic and baseline clinical characteristics of pneumonia with ARDS or without ARDS.
With ARDS ( |
Without ARDS ( |
|
|
---|---|---|---|
Age, years, mean (SD) | 68 (14) | 63.5 (15) | 0.194 |
Male/female | 22/15 | 26/18 | 0.818 |
APACHE II score, median (IQR) | 23 (19–27) | — | |
PaO2/FIO2 ratio, median (IQR) | 108 (84–130) | — | |
Duration of mechanical ventilation, mean (SD) | 13.5 (8) | — | |
Length of Intensive Care Unit stay, mean (SD) | 15.5 (8.5) | — | |
Length of hospital stay, mean (SD) | 22 (11) | 11 (4) | 0.000 |
Death in hospital, |
17 (48.6%) | 0 |
Comparison of plasma biomarkers between pneumonia with ARDS and those without ARDS.
With ARDS |
Without ARDS |
|
|
---|---|---|---|
Endocan (ng/mL), median (IQR) | 3.22 (2.47–5.14) | 2.45 (2.23–2.79) | 0.000 |
PCT (ng/mL), median (IQR) | 4.25 (1.95–9.27) | 2.49 (0.55–9.95) | 0.186 |
CRP (mg/L), median (IQR) | 135 (88.15–185.08) | 124.27 (95.78–165.57) | 0.961 |
WBC ( |
14.78 (11.51–18.22) | 12.59 (10.19–16.52) | 0.108 |
N ( |
13.45 (9.65–17.23) | 11.07 (8.43–14.52) | 0.056 |
Pulmonary infection is the primary risk factor of ARDS in china, but not every patient with pneumonia would develop into acute lung injury, so which person is at risk for ARDS is unknown. In our observational cohort study, levels of plasma endocan were significantly elevated in pneumonia patients with ARDS compared with those without ARDS. As we all know, neutrophils play a critical role in the pathogenesis of ARDS and when activated they release harmful mediators including cytokines, proteases, reactive oxygen species, and matrix metalloproteinases leading to further damage. However, endocan was shown to inhibit the interaction between intercellular adhesion molecule-1 (ICAM-1) and the integrin (lymphocyte function-associated antigen-1) LFA-1 on leukocytes,and can modulate LFA-1 mediated leukocyte functions, such as the firm adhesion of leukocytes to the endothelium and the leukocyte transmigration [
In the last decades, the focus of biomarker research in ARDS got significant progress. Ms. Terpstra and Dr. Aman conducted a systematic review and meta-analysis of all studies on plasma biomarkers associated with either diagnosis of ARDS in the at-risk population or ARDS-related mortality.They showed that increased plasma levels of KL-6, LDH, sRAGE, and vWF are most strongly associated with ARDS diagnosis in the at-risk population, whereas the strongest association with ARDS mortality was found for IL-4, IL-2, Ang-2, and KL-6 [
Multiple-organ dysfunction (MODS) indicates the exacerbation of patients with ARDS.
Endocan levels above 4.96 ng/mL were more likely to develop into septic shock and renal failure, in which the AUROC of endocan was 0.772 for septic shock and 0.714 for renal failure. By contrast, PCT, CRP, and WBC did not show discriminative power for an early prediction of organ failure and sepsis severity.
Furthermore, APACHE II is frequently used to measure disease severity in intensive care units, but widely adopted APACHE II scoring system has its limitations in predicting the outcome in ARDS. Endocan has high reproducibility of measurement and accessibility of specimens, had a good correlation with APACHE II, and was associated with an increased risk of ARDS death; therefore, it may well complement the APACHE II scoring in outcome prediction and guide therapeutic choices in the early stages of the ARDS aimed at prevention and provide patient benefits using evidence-based therapies.
Plasma endocan Levels elevated dramatically in pneumonia patients with ARDS compared with those without ARDS. It suggested that patients with elevated levels of endocan may develop into ARDS more easily. However, Dr. Mikkelsen et al. found that lower levels of serum endocan on admission are associated with subsequent development of ALI in trauma patients [
The present study has some limitations. First, the number of patients recruited was relatively small, it would be useful to repeat the study on a larger sample of patients in future. Second, the concentration of endocan was measured only initially, in the first 24 h after the inclusion in the study, and the dynamics of concentration during the ARDS evolution has not been evaluated. Third, the study lacks evaluation of the correlation between the plasma endocan and other biomarkers of ARDS. Fourth, we did not evaluate the diagnose performance of endocan associated with ARDS in the at-risk population; therefor, further studies involving large critical ill subjects at risk for ARDS are needed.
In conclusion, our study is one of the few studies to study the predictive value of endocan for ARDS. We have demonstrated that endocan can predict the MODS development and mortality of ARDS independently. It may guide effective rescue therapies such as lung protective ventilation strategy, liquid negative balance management, and organ protective treatment, thus reducing the mortality of ARDS. In addition, combined clinical variables with biological biomarkers such as endocan may play an important role in early therapeutics or preventative approaches for ARDS.
None of the authors has a financial relationship with any commercial entity that has an interest in the subject of this paper.
The authors thank Shu Chang for her excellent comments and sample collection, Li Qi and Huang Shicong for their assist in recruiting subjects, and also the nurses and physicians, as well as our patients and their families, who supported this study. This work was supported by a Grant from the National Natural Science Foundation of China (no. 81270141).