Multiple organ dysfunction, defined as more than one organ system deranged, is a complex and lethal clinical feature with highly heterogeneous causes and clinical manifestations. Different diseases, such as sepsis, malignant tumor, cardiovascular/cerebrovascular diseases, and surgery or trauma can lead to multiple organ dysfunction. The most common organs affected are kidneys, lungs, heart, hematologic system, liver, and central nervous system (1). Prognoses of critically ill patients with multiple organ dysfunction are usually poor. Therefore, accurate prediction of outcomes in these patients can guide physicians in their communication and decision making. However, the outcome of these patients at risk has many relative effects including age, gender, the severity of illness, comorbidities, diagnosis, and response to therapy, which makes the prediction of prognosis difficult and inaccurate. During the last three decades, several physiology-based ICU prognostic models have emerged. The main prognostic models for assessing the overall severity of illness in critically ill adults are Acute Physiology and Chronic Health Evaluation (APACHE), Simplified Acute Physiology Score (SAPS), and Mortality Prediction Model (MPM) (2). These models, as well as Sequential Organ Failure Assess (SOFA), which was primarily designed to describe the degree of organ dysfunction in critically ill patients (3), have been found to predict mortality effectively in different clinical conditions (4–6). However, limitations for these scoring systems do exist since they are all obtained by calculating a lot of components, which makes their clinical practice complicated. So, new effective outcome examination and guidance in critically ill patients with multiple organ dysfunction are strongly demanded.

Serum tenascin-C (TNC) has been reported to be significantly increased in critically ill patients and associated with the severity of diseases (7). TNC is a matricellular protein that is widely expressed during embryonic development and absent in most of the adult tissues, but re-induced following injury (8). TNC contains multiple functional domains that primarily regulate the interaction of cells with other extracellular matrix components and growth factors, thereby modulating cellular processes such as cell adhesion, proliferation, survival, migration, and differentiation (8, 9). Previous studies showed that TNC expression can be induced in different organs without disease specificity, such as heart tissue with myocarditis (10, 11), acute myocardial infarction (12), and dilated cardiopathy (10, 13), liver tissue with hepatitis (14), lung tissue with fibrosis (15, 16), and kidney tissue with glomerulonephritis and fibrosis (17, 18). The increased TNC in injured tissues can be released into a circulating system that results in serum TNC elevation. There were several studies, which revealed that serum TNC was associated with the mortality of different critical illnesses, such as sepsis, acute aortic dissection (AD), and myocarditis (7, 19, 20). However, the clinical significance of serum TNC levels in critically ill patients with multiple organ dysfunction remains uncertain.

Based on the previous studies, we hypothesized that serum TNC, representative of the quantity and severity of organ damage, was associated with mortality of critically ill patients with multiple organ dysfunction. In this prospective study, we detected serum TNC in critically ill patients with multiple organ dysfunction from two independent cohorts (emergency cohort and inpatient cohort) and aimed to evaluate the serum TNC. First, we investigated the association between serum TNC and mortality, and then examined the predictive performance of serum TNC for 28-day mortality in the emergency cohort and validated it in the inpatient cohort. We determined the cut-off value using the Youden index and evaluated the dichotomized predictive ability, and further combined the TNC value with critical scores to improve the predictive values. This work provided a strong basis for the adoption of serum TNC as an effective prognostic biomarker in critically ill patients with multiple organ dysfunction.

In this prospective study, we found that serum TNC was significantly higher in the critically ill patients with multiple organ dysfunction who died within 28 days in two independent cohorts. We revealed that the AUC of serum TNC for predicting mortality was similar to SOFA, APACHE II, and SAPS II. Kaplan–Meier analysis showed that the survival of patients with higher serum TNC was significantly worse than that of patients with lower serum TNC in both cohorts. These findings suggested that serum TNC was a useful prognostic tool for predicting 28-day mortality in critically ill patients with multiple organ dysfunction.

Previous studies had developed several models to predict the prognosis of critically ill patients. Among them, the APACHE II score and SAPS II, which were initially developed to predict hospital mortality in general ICU patients, have good prognostic performance (22, 23). However, they are calculated using the worst values from data collected in the first 24 h after ICU admission and are therefore not immediately available at the time of admission. They use 14 or 17 variables, also making their clinical practice not convenient. SOFA, another confirmed useful predictive model of critical illness, which is much simpler than APACHE II score and SAPS II, also measures six variables (4–6). Even so, the discrimination of these models remains unsatisfactory with AUCs varied from 0.7 to 0.9 in previous studies (24). It has been also reported that C-reactive protein (CRP), procalcitonin (PCT), lactate, and the markers of platelet function (such as thrombocytopenia and impaired platelet aggregation) were associated with the severity and mortality of multiple organ dysfunction (25–27). However, these biomarkers were more relevant to inflammation and infection and only showed limited value in predicting mortality in sepsis. Differently, serum TNC was upregulated in response to tissue injury regardless of causes and could be used to predict mortality in multiple organ dysfunction patients with the AUC as high as SOFA. As a single biomarker, it was convenient in clinical application.

The elevation of serum TNC may be explained by the upregulation of TNC in the injured tissues. It was postulated that persistent TNC expression was caused by prolonged inflammation and tissue injury. For example, intense TNC expression was observed at the site of infarction or active inflammation of the heart during the active phase but not in scar tissue during the healing phase (10, 11, 13, 28). Increased TNC expression was also found in lungs with progressive idiopathic pulmonary fibrosis (16), and in synovium with arthritis such as rheumatoid arthritis (29). Basic studies revealed that TNC could be induced by inflammatory and growth factors, oxidative stress, and hypoxia (30). Therefore, the increased TNC expression may reflect disease activity and progression of various diseases without organ specificity. This was the rationale we included patients with acute organ injury by an increase of SOFA ≥ 2 points within 7 days.

Consistent with TNC in tissues, serum TNC was also associated with the activity of various diseases (31–33). Page et al. reported that serum TNC, in rheumatoid arthritis, was associated with ultrasound-determined erosion scores and was decreased after treatment with infliximab and methotrexate (31). Zavada et al. found that serum TNC was positively associated with the disease activity score (SLEDAI) in SLE patients (34). Serum TNC was also associated with the severity and prognosis of various diseases (35–38). For example, serum TNC was correlated with the total occlusion and inflammation in myocardial infarction (39), and levels on day 5 after admission was an independent predictor for cardiac events during the follow-up period (24 ± 13 months) (40). In patients with heart failure, serum TNC was also positively correlated with the severity of left ventricular dysfunction and was an independent predictor for 12-month major adverse cardiac events (37). In patients with acute AD, serum TNC was a valuable biomarker for predicting in-hospital deaths (38). Acute, active, and systemic injury is a common feature of critically ill patients with multiple organ dysfunction, and serum TNC is probably significantly increased. But now, only a few studies focus on the predictive value of serum TNC for mortality in these patients. Meijer et al. examined plasma TNC during sepsis and non-septic critical illness and found that plasma TNC was reflective of disease severity more than an independent predictor of mortality (7). However, serum TNC, in our study, was not only positively associated with the critical illness scores such as SOFA, APACHE II, and SAPS II, but also independently associated with mortality after adjusting for these scores. This result was also supported by another study that focused on patients with sepsis and showed that serum TNC was positively correlated with SOFA scores and associated with 30-day mortality (41).

This study has several limitations. First, serum TNC in different stages may show different clinical significance. For example, higher serum TNC on admission predicted more hospitalization deaths in patients with acute AD (19), whereas a higher serum TNC on hospital day 7 predicted a lower risk of enlargement of the aortic lesion during the chronic stage (42). However, our study measured serum TNC one time in the acute stage. So, further studies with dynamic changes of serum TNC or in the chronic stage are required in the future. Second, the clinical utility of serum TNC may lie in the low negative predictive value, especially in patients with acute cardiovascular events. For example, patients with acute myocardial infarction or acute cerebral hemorrhage will probably die very soon after the events, but their basic serum TNC will not be as high as the patients with multiple organs injury, because the injured tissues may be limited to heart or brain in the early stage. By contrast, serum TNC is relatively useful for the assessment of illness severity in patients with multiple organ dysfunction. Third, the inpatient cohort enrolled the patients from different departments but not consecutive patients in ICUs. Selective bias included that more patients with kidney injury were enrolled than with other organs involved. The imbalance of patient enrollment influenced the interpreter of the results. However, the emergency cohort enrolling patients from the emergency department did not have this limitation. Fourth, there was no specific definition for critical illness, which also led to the various types of mortalities in different studies on this population. The inclusion criteria of our study were the patients with at least two organ dysfunction, which might be different from the traditional critically ill patients in the ICUs. Fifthly, TNC has multiple protein isoforms and which isoform has the strongest relationship with the outcome remains unknown. The ELISA kit used in this study measured the large TNC variant which was characteristic for some tumors. Finally, the low sample size also influenced the power of this study. So, larger, independent validation studies with consecutive patients in ICUs are needed to further support the utility of serum TNC in critically ill patients.

In summary, serum TNC, representative of tissue injury, is a novel, promising predictive marker for mortality in critically ill patients with multiple organ dysfunction. Incorporation of serum TNC into clinical practice and future investigation may bring better understanding and management in critically ill patients.

Serum TNC was positively associated with the severity of illness and mortality, and could be used as a prognostic tool for predicting mortality in critically ill patients with multiple organ dysfunction.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethics Review Board at Huashan Hospital, Fudan University. The patients/participants provided their written informed consent to participate in this study.

YX collected, analyzed, interpreted data, and drafted the manuscript. NL and JG collected and analyzed the data. DS and YS collected the data. QX and MC conceived the study, participated in its design and coordination, analyzed and interpreted data, drafted the manuscript, had full access to all the study data, and assume responsibility for the integrity of the data and the accuracy of the analysis. C-MH conceived the study, participated in its design, and helped to draft the manuscript. All authors approved the final manuscript.

The study was supported by the National Natural Science Foundation of China Grants 81520108006, 81930120, and 81700673.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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