High-sensitivity C-reactive Protein is a Predictor of Depression in Patients with Mild Traumatic Brain Injury

doi:10.21203/rs.3.rs-1755728/v1

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High-sensitivity C-reactive Protein is a Predictor of Depression in Patients with Mild Traumatic Brain Injury

https://doi.org/10.21203/rs.3.rs-1755728/v1

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Introduction

Depression is one of the most common psychological problems after mild traumatic brain injury (mTBI) and affects various aspects of life quality. Previous studies demonstrated that systematic inflammation might lead to unfavorable outcomes, including depression after TBI. Therefore, we analyzed the relationship between the serum level of high sensitive C-reactive protein (hsCRP), a sensitive biomarker of systematic inflammation, and depression incidence after mTBI.

Methods

We used data from Korea’s Level-1 trauma center registry between Jan 2018 to Dec 2019. The population of our study was adult mTBI patients who visited the Level-1 trauma center using emergency medical service (EMS). We used the serum level of hsCRP measured just after arrival at the emergency department as the primary data input. The main outcome was depression evaluated 6 months after hospital discharge using the Beck depression inventory. Multivariable logistic regression analyses were performed to estimate the effect of hsCRP level on depression incidence. In addition, interaction analyses of the association between hsCRP and fever on depression incidence were performed.

Results

A total of 257 mTBI patients were enrolled. The multivariable logistic regression analysis showed that an elevated serum level of hsCRP was associated with higher odds of depression (aOR (95% CI): 1.34 (1.03—1.69)). The association was maintained only in the fever group (1.42 (1.14—1.78)).

Conclusions

Elevated serum level of hsCRP was associated with an increased incidence of depression 6 months after hospital discharge. This effect was maintained in the presence of fever. Our study results suggest the need for adopting strategies to prevent depression when systematic inflammation is indicated by CRP elevation and/or fever in mTBI patients.

TBI

hsCRP

depression

Traumatic brain injury (TBI) is a serious public health concern. The global incidence of TBI is estimated to be 823.7 per 100,000 persons annually, resulting in 2.53 million TBI-related emergency department (ED) visits, approximately 288,000 hospitalizations, and 56,800 TBI-related deaths in the US (1). The associated direct and indirect medical costs of TBI are estimated to be $76 billion in the United States (2).

Over 80% of all TBI cases are classified as mild, and most patients with mild TBI (mTBI) return to normal life. However, a significant number of patients may experience physical and psychological functional disabilities for several weeks, and sometimes for months or even years, after the injury (3–5).

Depression is a common psychological problem after TBI caused by physical problems as well as by itself (6, 7). About 40% of all patients with TBI are affected by depression within the first year of injury or even seven years after the injury (6). Although many studies have tried to identify the risk factors of depression after TBI (8, 9), most have focused on the association between systematic inflammation and depression following mTBI. Data from animal models and human studies suggest that mTBI could activate the systemic inflammatory process (10), leading to unfavorable outcomes after TBI (11, 12).

C-reactive protein (CRP) is a non-specific but sensitive biomarker of systemic inflammation in response to infection, cancer, trauma, surgery, burns, and tissue infarction (13–15). Anti-inflammatory therapies are applied to reduce levels of CRP in these and other medical conditions, including cancer (16), auto-immune disease (17), and cardiovascular disease (18). In TBI, an elevated level of serum CRP within 24 hours after injury is associated with intracranial lesions on neuroimaging and more severe TBI. It is also associated with headache, fatigue, and psychiatric and neurocognitive symptoms (19, 20).

Hence, we hypothesized that CRP reflects systemic inflammation after TBI. When the CRP serum level measured at ED admission is increased, depression incidence increases. We analyzed the relationship between the serum level of high sensitive CRP (hsCRP) and 6-month depression incidence. Further, we examined whether the hsCRP level is related to the occurrence of fever at ED, another index reflecting systematic inflammation.

Study design and setting

The present investigation was a retrospective study of patients who experienced TBI and were transported to Chonnam National University Hospital (CNUH) Level-1 trauma center between January 2018 and December 2020 in South Korea by emergency medical service (EMS).

In Korea, with the scoop and run EMS system, EMS technicians perform basic treatment such as neck-brace, simple dressing, splint, and fluid resuscitation at the scene, before transporting the patient. The patient is transported to a Level-1 trauma center when a major trauma is suspected, judged through vital signs, mental status, and mechanism of injury (21).

The CNUH trauma center was established in 2010 and has since run a team of expert physicians in various departments, including general, thoracic, neuro, orthopedic, and plastic surgeries; radiology, anesthesiology; and emergency medicine. If a patient is suspected of having a major trauma, including TBI, it is reported to the hospital by EMS technicians at the scene or during transport. After arriving at the hospital, brain computed tomography is performed as soon as possible. Neurosurgeons and doctors of other departments affiliated with the trauma center are notified to treat brain hemorrhage and other concomitant injuries. If necessary, surgery is performed immediately. These protocols are maintained 24/7 throughout the year. The CNUH trauma center has 20 intensive care beds and 20 general wards; so patients are admitted from the emergency room or after the operation.

Prehospital EMS data were collected from ambulance run sheets and EMS dispatch records. Information on hospital care and patients’ outcomes were abstracted from inpatient discharge records in EDs, intensive care units, and wards. Information on long-term outcomes was captured via follow-up telephone survey 1 and 6 months after hospital discharge. The aggregated data were cleaned and managed by the Data Quality Management Committee (QMC) to address invalid and/or incomplete entries.

Study population

The study population consisted of mTBI patients over 18 years of age who were brought to the Level 1 trauma center by EMS between January 2018 and December 2020. mTBI was defined as a GCS (Glasgow score of 13 to 15 at the patient’s arrival at the hospital (22). Patients whose depression could not be confirmed in the 6-month telephone survey were excluded.

Main outcomes

The main outcome was depression, diagnosed 6 months after hospital discharge using the Beck depression inventory (BDI) (23). BDI consists of 21 questions. Each question is assigned a point 0—3, with 3 points indicating the most severe symptoms. A cumulative point is determined by summing the points of the individual questions. BDI points 0—9 is categorized as no depression, 10—25 as mild to moderate, and 26—63 as severe. We re-categorized the no or mid depression group, including no, mild, and moderate depression and severe depression.

Variables and measurements

The main factor was hsCRP, measured in blood samples within 30 minutes of arriving at the ED using a BN II analyzer (Siemens Healthcare Diagnostics Products GmbH, Marburg, Germany) with the latex-enhanced immunonephelometric assay. The detection limit was 0.0086 mg/L. The analytical variability was 5%. The second factor was fever, defined as a body temperature of 38°C or higher on arrival at the emergency department after brain injury. Patient characteristics were obtained from a chart review by the emergency physician. Patient demographics included age, sex, and comorbidities (e.g., hypertension, diabetes mellitus). Prehospital and hospital information included mechanism and place of injury, vasopressor use, type of hemorrhage, advanced airway, blood transfusion, white blood cell count, and clinical outcome.

Statistical analysis

Patient demographics, injury demographics, prehospital and hospital information, and clinical outcomes according to the serum level of hsCRP measured on ED arrival were compared using the Wilcoxon rank-sum test for continuous variables and the chi-squared test for categorical variables. Univariable and multivariable logistic regression analyses were performed to estimate the effect of hsCRP level on depression occurrence at 6 months after hospital discharge, expressed as crude and adjusted odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Finally, interaction analysis was performed between hsCRP and the occurrence of fever on study outcomes. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).

Ethic statements

This study approved by the ethic committees of CNUH (IRB no. CNUH-2012). All methods were performed in accordance with relevant guidelines and regulations. The informed consent was waived by CNUH due to the retrospective nature of the study.

Demographic findings

Among the 620 mTBI patients in the CNUH trauma center registry, a total of 257 patients were enrolled. Patients with severe TBI with a GCS score of less than 12 and patients with an unknown history of depression or follow-up loss were excluded. In addition, patients whose death was confirmed in a 6-month follow-up telephone survey were excluded (Fig. 1).

The characteristics of the study population according to the hsCRP serum level are shown in Table 1. Of the total 257 patients, 193 (75.1%) patients had elevated hsCRP levels, and 64 (34.9%) patients had normal hsCRP levels. Fever was observed in 14% of patients with elevated hsCRP levels and 23.4% of patients with normal hsCRP levels, but no statistically significant difference existed. In patients with elevated hsCRP levels, 69.4% (134/193) were included in the no depression group (BDI, 0 to 9), 21.2% (41/193) in the mild to moderate group (BDI, 10 to 25), and 9.3% (18/193) in the severe depression group (BDI, 26 to 63). In patients with normal hsCRP levels, 76.6% (49/64) were included in the no depression group (BDI, 0 to 9), 21.2% (10/64) in the mild to moderate group (BDI, 10 to 25), and 7.8% (5/64) in the severe depression group (BDI, 26 to 63). However, there was no significant difference in the distribution of patients among the depression groups according to hsCRP levels (p = 0.3).

Table 1

Characteristics of the study population according to the serum level of hsCRP
Variables	All	hsCRP
	All	Elevated hsCRP (> 1mg/L)	Normal hsCRP ( < = 1mg/L)	p- value
	n(%)	n(%)	n(%)
All	257 (100.0)	193 (100.0)	64 (100.0)
Age				0.34
18–64	164 (63.8)	124 (64.2)	40 (62.5)
65-	93 (36.2)	69 (35.8)	24 (37.5)
Sex, male	185 (72.0)	139 (72.0)	46 (71.9)	0.66
Comorbidity
Hypertension	83 (32.3)	66 (34.2)	17 (26.6)	0.86
Diabetes mellitus	59 (23.0)	45 (23.3)	14 (21.9)	0.78
Mechanism of injury				0.09
Traffic accidenct	100 (38.9)	82 (42.5)	18 (28.1)
Fall down	113 (44.0)	83 (43.0)	30 (46.9)
Other	44 (17.1)	28 (14.5)	16 (25.0)
Place of injury				0.21
Home	64 (24.9)	47 (24.4)	17 (26.6)
Street	104 (40.5)	83 (43.0)	21 (32.8)
Other	89 (34.6)	63 (32.6)	26 (40.6)
Fever at ED, yes	42 (16.3)	27 (14.0)	15 (23.4)	0.21
Vasopressor, yes	20 (7.8)	16 (8.3)	4 (6.3)	0.82
Types of hemorrhage				0.17
SDH	37 (14.4)	28 (14.5)	9 (14.1)
SAH	58 (22.6)	40 (20.7)	18 (28.1)
ICH (including hemorrhagic contusion)	115 (44.7)	88 (45.6)	27 (42.2)
EDH	33 (12.8)	23 (11.9)	10 (15.6)
IVH & other	14 (5.4)	14 (7.3)	(0.0)
Advanced airway, yes	34 (13.2)	26 (13.5)	8 (12.5)	0.68
Blood transfusion, yes	25 (9.7)	20 (10.4)	5 (7.8)	0.57
WBC				0.14
Leukocytosis, > 11000	140 (54.5)	110 (57.0)	30 (46.9)
Leukopenia, < 4000	8 (3.1)	4 (2.1)	4 (6.3)
Clinical outcomes
Depression				0.3
BDI (0–9), no depression	183 (71.2)	134 (69.4)	49 (76.6)
BDI (10–25), mild to moderate depression	51 (19.8)	41 (21.2)	10 (15.6)
BDI (26–63), severe depression	23 (8.9)	18 (9.3)	5 (7.8)
hsCRP, high sensitive C-reactive protein; EM, emergency department; SDH, subdural hematoma; SAH, subarachnoid hemorrhage; ICH, intracranial hemorrhage; EDH, epidural hematoma; IVH, intraventricular hemorrhage; WBC, white blood cell; BDI, Beck Depression Inventory;

The characteristics of the study population according to the presence of fever are shown in Table 2. Of the 257 patients, 42 (16.3%) patients had fever at ED. There was no significant difference in the distribution of depression according to the presence of fever (p = 0.69).

Table 2

Characteristics of the study population according to presence of fever at ED
Variables	All	Fever
	All	Fever (+)	Fever (-)	p value
	n(%)	n(%)	n(%)
All	257 (100.0)	42 (100.0)	215 (100.0)
Age				0.65
18–64	164 (63.8)	27 (64.3)	137 (63.7)
65-	93 (36.2)	15 (35.7)	78 (36.3)
Sex, male	185 (72.0)	30 (71.4)	155 (72.1)	0.03
Comorbidity
Hypertension	83 (32.3)	16 (38.1)	67 (31.2)	0.35
Diabetes mellitus	59 (23.0)	9 (21.4)	50 (23.3)	0.46
Mechanism of injury				0.4
Traffic accidenct	100 (38.9)	18 (42.9)	82 (38.1)
Fall down	113 (44.0)	13 (31.0)	100 (46.5)
Other	44 (17.1)	11 (26.2)	33 (15.3)
Place of injury				0.08
Home	64 (24.9)	5 (11.9)	59 (27.4)
Street	104 (40.5)	21 (50.0)	83 (38.6)
Other	89 (34.6)	16 (38.1)	73 (34.0)
Vasopressor, yes	20 (7.8)	4 (9.5)	16 (7.4)	0.72
Types of hemorrhage				0.73
SDH	37 (14.4)	6 (14.3)	31 (14.4)
SAH	58 (22.6)	10 (23.8)	48 (22.3)
ICH (including hemorrhagic contusion)	115 (44.7)	20 (47.6)	95 (44.2)
EDH	33 (12.8)	4 (9.5)	29 (13.5)
IVH & other	14 (5.4)	2 (4.8)	12 (5.6)
Advanced airway, yes	34 (13.2)	6 (14.3)	28 (13.0)	0.47
Blood transfusion, yes	25 (9.7)	4 (9.5)	21 (9.8)	0.66
WBC				0.46
Leukocytosis, > 11000	140 (54.5)	22 (52.4)	118 (54.9)
Leukopenia, < 4000	8 (3.1)	3 (7.1)	5 (2.3)
Elevated hsCRP, yes (> 1mg/L)	193 (75.1)	27 (64.3)	166 (77.2)	0.21
Clinical outcomes
Depression				0.69
BDI (0–9), no depression	183 (71.2)	29 (69.0)	154 (71.6)
BDI (10–25), mild to moderate depression	51 (19.8)	8 (19.0)	43 (20.0)
BDI (26–63), severe depression	23 (8.9)	5 (11.9)	18 (8.4)
hsCRP, high sensitive C-reactive protein; EM, emergency department; SDH, subdural hematoma; SAH, subarachnoid hemorrhage; ICH, intracranial hemorrhage; EDH, epidural hematoma; IVH, intraventricular hemorrhage; WBC, white blood cell; BDI, Beck Depression Inventory;

Main results

The multivariable logistic regression analysis showed that elevated serum level of hsCRP was significantly associated with higher odds of depression [aOR (95% CI), 1.34 (1.03—1.69)], but the association with severe depression at 6 months after hospital discharge was not statistically significant (Table 3).

Table 3

Multivariable logistic regression analysis on study outcomes by the serum level of hsCRP
	Total	Outcome		Model 1	Model 2
	N	N	%	aOR (95% CI)	aOR (95% CI)
All depression
Total	257	74	28.8
Normal hsCRP	64	15	23.4	ref.	ref.
Elevated hsCRP	193	59	30.6	1.32 (0.99–1.87)	1.34 (1.03–1.69)
Fever (-)	215	61	28.4	ref.	ref.
Fever (+)	42	13	31.0	0.98 (0.54–1.81)	0.94 (0.51–1.74)
Severe depression
Total	257	23	8.9
Normal hsCRP	64	5	7.8	ref.	ref.
Elevated hsCRP	193	18	9.3	1.32 (0.79–2.20)	1.34 (0.80–2.26)
Fever (-)	215	18	8.4	ref.	ref.
Fever (+)	42	5	11.9	0.98 (0.54–1.81)	0.94 (0.51–1.74)
hsCRP, high sensitive C-reactive protein; aOR, adjusted odds ratio; CI, confidence interval;
Model 1 adjusted for age, sex, comorbidities (hypertension and diabetes mellitus), hsCPR, and fever
Model 2 adjusted for variables in Model 1 and mechanism of injury, place of injury, and type of hemorrhage

The outcomes of the interaction analysis showed that there was no association between hsCRP levels and fever.

The positive association between hsCRP levels and depression was maintained in the fever group, whereas it was not significant in the non-fever group: [aOR (95% CIs): 1.42 (1.14—1.78) for the fever group vs. 1.14 (0.88—1.35) for the non-fever group, p-for < 0.05] (Table 4).

Table 4

Interaction analysis between the hsCRP and fever on study outcome
	hsCRP
	Normal hsCRP	Elevated hsCRP	p for interaction
	Normal hsCRP	aOR (95% CI)	<0.05
All depression
Fever (-)	ref.	1.14 (0.88-1.35)
Fever (+)	ref.	1.42 (1.14-1.78)
Severe depression			<0.14
Fever (-)	ref.	1.19 (0.48-2.96)
Fever (+)	ref.	0.79 (0.15-4.20)
hsCRP, high sensitive C-reactive protein; aOR, adjusted odds ratio; CI, confidence interval;

Our study discovered that elevated serum level of hsCRP was associated with a higher probability of depression after 6 months of hospital discharge in adult mTBI patients. Furthermore, the association between elevated hsCRP levels and the occurrence of depression was maintained in patients with fever at ED arrival. This research contributes to understanding the relationship between systematic inflammation after injury and the incidence of depression. It will help in developing strategies to improve clinical outcomes in mTBI patients.

Post-concussion syndrome has been reported weeks, months, and even years after recovery from mTBI (24). The symptoms associated with the post-concussion syndrome are subjective and varied. Although headache, sleep disturbance, and mood disorders such as irritability, anxiety, and depression are the most commonly reported symptoms of post-concussion syndrome, among the symptoms following mTBI, depression severity is strongly associated with the overall quality of life (24, 25).

Depression is one of the most common psychological sequelae of TBI, and in a study of moderate to severe TBI patients, major depressive disorder was observed in 53% of patients within the first year after injury, compared to 7% in the general population (26, 27). Additionally, in the study of mTBI and concussions, depression was reported in 22% of patients within 6 months after injury (28). In our study, depression with a BDI score of 10 or higher was reported in 28.7% of patients, which is higher than that reported for the general population.

Post-TBI depression, like depression in the general population, affects various aspects of life. When mTBI patients return to the workplace after injury, they are reportedly less productive and make more errors compared to before the injury (25). This reduced job performance originates from depression but not physical symptoms (29), indicating that some specific mechanism of depression following injury affects other cognitive functions.

Previous studies have described several biological and pathogenic mechanisms that cause depression after mTBI. A history of mood disorder and other comorbidities before the injury, drug abuse, and psychological factors may contribute to the risk of depression manifestations after injury (24). Although the mechanisms responsible for these association have yet to be elucidated, accumulating evidence indicates that inflammatory pathways contribute to depression in the general population and in patients after mTBI (25, 30).

Evidence for the role of inflammatory marker elevation has been building over the past 30 years. Many biomarkers, including cytokines (e.g., TNF-a, IL-1, IL-6) and acute phase reactant proteins (e.g., CRP) (31, 32) have been implicated. CRP is a sensitive but non-specific biomarker of systematic inflammation in response to infection, surgery, burns, trauma, tissue infarction, and chronic inflammatory conditions. It is a prognostic biomarker for poor survival outcomes and psychological outcomes, including depression (33, 34). Some studies reported that elevated levels of CRP were associated with worsened cognitive function and increased psychological distress and depression (35, 36). Consistent with the results of previous studies, our study also observed an increased risk of depression with a BDI score of 10 or higher when hsCRP levels increased to more than 1.0 mg/L.

Previous studies suggested several possible effects of elevated CRP levels, indicating low-grade systemic inflammation causing various psychological problems such as depression. Systemic inflammation might trigger neuroinflammation in several densely populated microglia brain regions. This may lead to an increase in indoleamine 2,3-dioxygenase expression (37), which in turn may be involved in cognitive impairment and physiological and psychological problems (37, 38). Systemic inflammatory processes can also activate the neuroendocrine hypothalamic-pituitary-adrenal axis, resulting in chronic stress-associated anxiety and depression (39).

Since CRP is not a perfect biomarker for predicting inflammation, we performed an interaction analysis to determine whether there is a difference in the predictive power of hsCRP on depression in the presence of fever, another predictor of inflammation. We found that an elevation of hsCRP level was associated with depression only in the presence of fever. We think that this result emphasizes that systematic inflammation is a risk factor for depression rather than denigrating the predictive power of CRP.

Although the exact mechanisms linking inflammation to depression are still unclear, our study reinforces the results of previous studies that depression occurs through the inflammatory pathway after injury in TBI patients. In addition, since CRP is a non-specific biomarker, the study has made a new observation that when fever, another marker of inflammation, is present, the risk of depression occurence increases. The results of our study provide a theoretical basis for applying a strategic intervention to reduce the occurrence of depression when an increase in hsCRP level and fever are observed in mTBI patients.

Our study has several limitations. First, our study population included mTBI patients presenting with aGCS score of 13 to 15. However, there were cases of severe TBI involved, thus increasing the possibility of affecting the study outcomes. Second, the serum levels of hsCRP were divided into two groups based on a cut-off value of 1 mg/L. Other studies have shown that this standard value is variable. Third, the incidence of depression might have been over- or under-estimated because patients who were lost to follow-up or those who died were excluded. Finally, as this was not a randomized controlled trial, there might have been some potential bias that could not be controlled.

Elevated serum level of hsCRP increase the incidence of depression 6 months after hospital discharge. Furthermore, this effect is enhanced significantly in the presence of fever at ED arrival. The results of our study suggest that measures should be taken for depression prevention when there is evidence of systemic inflammation, indicated by CRP elevation and/or fever, in mTBI patients.

Data availability

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request ([email protected]).

Author Contributions

Dr. Ryu and Jung had full access to all the data in the study and take responsibility for the integrity of the data as well as the accuracy of the data analysis.

Study concept and design: Ryu and Jung

Acquisition, analysis, or interpretation of data: Ryu and Jung

Drafting of the manuscript: Ryu and Jung

Critical revision of the manuscript for important intellectual content: Ryu and Jung

Statistical analysis: Ryu and Jung

Obtained funding: Ryu and Jung

Administrative, technical, or material support: Ryu and Jung

Study supervision: Ryu

Manuscript approval: All authors

Conflicts of interest

None

Funding Acknowledgement

This study was supported by a grant (BCRI-22035) from the Chonnam National University Hospital Biomedical Research Institute.

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No competing interests reported.

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High-sensitivity C-reactive Protein is a Predictor of Depression in Patients with Mild Traumatic Brain Injury

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