Clinical Significance of C - Reactive Protein in Patients with Trauma on Arrival

Objective : To investigate to investigate significance of C-reactive protein (CRP) in patients with trauma on arrival. Materials : From September 2017 to February 2018, a medical chart review was retrospectively performed for all patients with trauma who were admitted to our department. Methods : The subjects were divided into two groups: a CRP-negative group (initial CRP level ≤ 0.3 mg/d l ) and a CRP-positive group (>0.3 mg/d l ). For the CRP-positive group, we additionally investigated the cause of the increased level of CRP. Results : There were 33 cases in the CRP-positive group and 168 in the CRP-negative group. The age and ratio of lymphocytes in the CRP-positive group was significantly higher than those in the CRP-negative group. Twenty-two to twenty-eight of the 33 cases (67-85%) had an infection, 3 of 33 (9%) had a delayed visit (over 24 h from the onset of the trauma) to the emergency department, and 2 cases (6%) had malignancy in the CRP-positive group. All subjects with an increased CRP level on arrival potentially had underlying diseases that might have caused their trauma. Conclusion : Some traumatized patients may have elevated CRP levels on arrival due to underlying diseases capable of causing trauma. An increased initial level of CRP did not significantly affect the clinical outcome; however, physicians should pay attention to the cause of the increased CRP level, which may affect the patientʼs outcome. Exploring increased CRP levels may be useful for identifying the mechanism underlying the occurrence of trauma.


Introduction
C-reactive protein (CRP) is an acute inflammatory protein that is increased up to 1,000 -fold at sites of infection or inflammation. 1)-3) CRP is produced as a homopentameric protein, termed native CRP (nCRP), which can irreversibly dissociate at sites of inflammation and infection into five separate monomers, termed monomeric CRP (mCRP). CRP is synthesized primarily in liver hepatocytes but also by smooth muscle cells, macrophages, endothelial cells, lymphocytes, and adipocytes. Having been traditionally utilized as a marker of infection and cardiovascular events, there is now growing evidence that CRP plays important roles in inflammatory processes and host responses to infection, including the complement pathway, apoptosis, phagocytosis, nitric oxide (NO) release, and the production of cytokines, particularly interleukin-6 and tumor necrosis factor-α. 1)- 3) In Japan, traditional biomarkers for infection, such as CRP and neutrophil counts, are widely used for the rapid and accurate detection of causative pathogens, infective foci, and the severity of illness in critical care settings because measuring the CRP level and neutrophil counts is convenient and low in cost. 4) In our institute, CRP is routinely examined for the evaluation of patients with trauma on arrival in order to assess the initial level of the patient and detect complications of infection. 5) Sometime, we experience an increase in the CRP level, which may not be due to infection. However, no reports have investigated the significance of CRP in patients with trauma on arrival. Accordingly, we retrospectively analyzed trauma patients who were transported to our department in order to investigate the significance of CRP in patients with trauma on arrival.

Materials and Methods
The protocol of this retrospective study was approved by the review board of Shizuoka Hospital, Juntendo University, and all examinations were conducted in accordance with the standards of good clinical practice and the Declaration of Helsinki.
Shizuoka Hospital, Juntendo University, which is a hospital with 577 beds and a medical emergency center in eastern Shizuoka Prefecture, located near Tokyo, serves a population of approximately 1,230,000. A physician-staffed helicopter parks at Juntendo Shizuoka Hospital and mainly treats patients with severe trauma, acute coronary syndrome, stroke, cardiopulmonary arrest, drowning, decompression sickness, intoxication, and unstable vital signs. Our emergency department routinely performed blood examinations, including CRP assessments, electrocardiogram, chest and pelvic roentgen, ultrasound, and whole-body computed tomography (from head to pelvis) for patients with trauma on arrival. 6) 7) The purpose of the present study was to investigate the significance of CRP in patients with trauma on arrival. From September 2017 to February 2018, a medical chart review was retrospectively performed for all patients with trauma who were admitted to our department, and these patients were included as subjects in the present study. The exclusion criterion was a lack of data for CRP levels on arrival. The subjects were divided into two groups: a CRP-negative group (initial CRP level ≤0.3 mg/dl) and a CRP-positive group (> 0.3 mg /dl). We collected data on each subjectʼs sex, age, mechanism of trauma (fall, traffic accident, or other), Glasgow Coma Scale on arrival, systolic blood pressure, heart rate, body temperature, injury severity score (ISS), CRP level, white blood cell count, ratio of lymphocytes, duration of admission, and survival rate. We compared the differences in each variable between the two groups. For the CRP-positive group, we also investigated the cause of the increased CRP level.
The statistical analyses were performed using a paired Studentʼs t-test. A p-value of < 0.05 was considered to indicate a statistically significant difference. All of the data are presented as the mean ± standard deviation.

Results
During the investigation period, a total of 208 patients were admitted. Among them, 7 cases did not have their CRP level examined on arrival. After excluding these 7 cases, 201 cases were enrolled as subjects. A total of 33 cases were ultimately designated as the CRP-positive group and 168 as the CRP-negative group.
The results of the analyses of the two groups are shown in Table-1. There were no significant differences in the sex, mechanism of trauma, Glasgow Coma Scale on arrival, systolic blood pressure, heart rate, body temperature, ISS, white blood cell count, duration of admission and survival rate between the two groups. However, the age and ratio of lymphocytes in the CRP-positive group was significantly higher than those in the CRP-negative group.
The causes of the increased CRP level in the CRP-positive group are shown in Table-2. There was no duplication of cause for CRP elevation. Twenty-two to Twenty-eight of the 33 cases (67-85%) had an infection, 3 of 33 (9%) had a delayed visit (over 24 h from the onset of the trauma) to the emergency department, and 2 cases (6%) had malignancy in the CRP-positive group. In 6 patients from the CRP-positive group, the cause of CRP elevation was a mere cold or unknown cause. One patient with rickettsia died due to multiple organ failure based on a delayed diagnosis. All subjects with an increased CRP level on arrival potentially had underlying diseases that might have caused their trauma.

Discussion
This is the first study to demonstrate that, among 201 trauma patients admitted to our department, 33 (16%) had an elevated CRP level on arrival, and elderly patients also tended to have elevated levels. However, an increased initial level of CRP did not markedly affect the duration of admission. The main cause of an elevated CRP level was infection, and most infections were controlled, except for one case of rickettsia. Some patients delayed visiting the emergency department following the onset of trauma or malignancy.
One possible reason for the elevated CRP levels on arrival among elderly patients is the age-related deterioration of the immune system. Immunosenescence affects the function and phenotype of immune cells, such as the expression and function of receptors for immune cells, which contributes to a loss of the immune function (chemotaxis, intracellular killing). 8) Furthermore, these alterations decrease the response to pathogens, which leads to several age-related diseases, including cardiovascular disease, Alzheimerʼs disease, and diabetes in older individuals. 8) In addition, the risk of autoimmune disease and chronic infection increases with the aging of the immune system, which is characterized by a pro-inflammatory environment, ultimately leading to accelerated biological aging. 8) The present study showed that the main cause of an increased CRP level on arrival among traumatized patients was infection, but this increased CRP level did not significantly affect the clinical outcome. The main etiological categories of inflammation in the human body are infections, neoplasms, noninfectious inflammatory diseases (connectivetissue diseases or vasculitis), and miscellaneous conditions. 9) 10) Among them, infection is reportedly the most frequent, with similar findings noted in the present study. 11) Bacterial infection, such as that at the upper airway, lower airway, or urinary tract, is typically controlled by appropriate antibiotics. 12) 13) Virus infection, such as the common cold, is also controlled by supportive therapy. 14) In addition, CRP itself induces an anti-inflammatory  Concerning the minor etiology underlying the increased CRP levels on arrival among patients with trauma in our study, one patient died of rickettsia due to a delay in their diagnosis; this patient might have survived if the diagnosis had been made earlier and they had received appropriate antibiotics. 15) Two patients were incidentally diagnosed with a neoplasm that required other treatments. 16) Trauma also triggers an inflammatory response, so delaying visiting a medical facility can inadvertently cause an increase in the CRP level. 5) 17) Patients who do not immediately visit the emergency department may suffer from either physical abuse or neglect on the part of their relatives; such patients require special support in order to obtain the most favorable outcome. 18)-20) Accordingly, physician should pay attention to the cause of increased CRP levels, even among traumatized patients.
There is a possibility that an inflammatory reaction based on underlying diseases may have caused trauma in the present study. Increases in the levels of CRP or inflammatory cytokines occur independently of factors known to be associated with aberrant neural activity resulting in neurocognitive dysfunction, including visuospatial attention deficits. 21)-23) Accordingly, thoroughly investigating increased CRP levels may be useful for identifying mechanisms underlying the occurrence of trauma.
During the investigating period in the present study, we did not use other types of inflammatory biomarker such as presepsin and procalcitonin. This is because these assays cannot be measured by in-hospital laboratories and blood samples must be sent to an external organization for the analysis of presepsin, and procalcitonin. Procalcitonin is a 116amino acid which demonstrates a positive correlation between high serum levels of PCT and patients with positive findings for bacterial infection and sepsis. 24) Further, procalcitonin does not normally show an increased level during viral infections. 24) In addition, CRP lacks the specificity required to diagnose bacterial versus non-bacterial infections accurately. In addition, presepsin is a subtype of the soluble form of CD14, which comes off the monocyte surface during the inflammatory response and then is released into the blood. 25) Therefore, presepsin can serve as a circulating marker of infection. Presepsin, has recently been described as a powerful diagnostic tool, not only to detect sepsis, but also to distinguish different degrees of severity. Moreover, the level of presepsin typically increases within 2 h and reaches the peak at 3 h after infection. 26) Presepsin and procalcitonin are more specific than CRP concerning bacterial infection, and they may be used in combination with CRP to determine the presence or absence of infection more sensitively. 27) 28) However, these assays take time since they require the collection of blood samples and also have cost issues, so they may not therefore be useful from a clinical aspect. In contrast, the CRP measurement is a simple and easy test. This biomarker is widespread among many medial institutions and known to medical personnel, so we think CRP is useful in the initial care of trauma. In addition, as CRP has a high sensitivity for detecting inflammatory diseases, and not only infection, but also autoimmune, autoinflammatory or some malignant diseases, 29) and that is why this modality is useful for detecting preexisting diseases before trauma.
The major limitations associated with this study were its retrospective nature and small patient population. We also did not investigate patients with mild trauma who were able to return home after their initial treatment. Therefore, future prospective studies involving a greater number of patients and including those with mild trauma are needed in order to build upon the present findings.

Conclusion
Some traumatized patients may have elevated CRP levels on arrival due to underlying diseases capable of causing trauma. An increased initial level of CRP did not significantly affect the clinical outcome; however, physicians should pay attention to the cause of the increased CRP level, which may affect the patientʼs outcome. Exploring increased CRP levels may be useful for identifying the mechanism underlying the occurrence of trauma.

None.
Nagasawa, et al: CRP-positive of trauma on arrival