Persistently higher serum sCD40L levels are associated with outcome in septic patients

doi:10.21203/rs.3.rs-39594/v3

Background: Soluble CD40 ligand (sCD40L) exhibits proinflammatory and procoagulant effects. Recent data indicated that sCD40L plays a significant role in septic patients. The aim of the present study was to determine sCD40L changes in surgical patients without sepsis (SWS) and in surgical sepsis patients (SS) during the first three days at intensive care unit (ICU) admission and to observe the association between sCD40L and mortality.

Methods: Time changes in sCD40L levels were assessed for 3 days after ICU admission in 49 patients with SS and compared with 19 SWS patients. Serum sCD40L concentration was detected by ELISA. Survival at 28 days was used as the endpoint.

Results: SS had significantly higher sCD40L levels than SWS and control patients. We observed an association between sCD40L levels ≥1028.75 pg/ml at day 2 and 28-day mortality (odds ratio = 7.888; 95% confidence interval = 1.758 to 35.395; P= 0.007). We could not discover any significant differences in gender, presence of septic shock, site of infection, length of stay in the ICU, PaO₂/FiO₂ratio, incidence of AKI, ARDS, or type of surgery between nonsurvivors and survivors.

Conclusions: Septic patients show persistently higher circulating sCD40L levels in the first three days at ICU admission, and the serum sCD40L levels are associated with the mortality of patients with sepsis; thus, serum sCD40L may be used as a reliable biomarker and therapeutic target in sepsis.

Critical Care & Emergency Medicine

Soluble CD40 ligand

Sepsis

Mortality

Sepsis is the overwhelming inflammatory host response to the infectious agent causing the overexpression of inflammatory mediators(1). Moreover, sepsis is also almost associated with coagulation abnormalities, present as manifest thromboembolic disease or clinically less apparent microvascular fibrin deposition(2). In sepsis, inflammation and coagulation are cross-linked, and inflammation causes coagulation activation. In contrast, coagulation also affects the activation of inflammation, which promotes the progression of disease and leads to organ dysfunction(3).

CD40 ligand (CD40L) and the soluble form of CD40L (sCD40L) are members of the tumor necrosis factor (TNF) family and are expressed in a diversity of cell types, including B cells, epithelial cells, fibroblasts, endothelial cells (ECs), and platelets. CD40L and sCD40L exhibit proinflammatory and procoagulant effects(4, 5). Previous studies have found that serum CD40L levels are elevated in patients with sepsis and are associated with mortality in these patients(6-9).

In surgical patients, endothelial cell damage, inflammation, and coagulation changes occurred after surgery. Therefore, the purpose of this study was to determine sCD40L changes in surgical patients without sepsis (SWS) and in surgical sepsis patients (SS) during the first three days at ICU admission and to observe the relationship between sCD40L and mortality.

Design and subjects

This was a prospective, observational study. Sixty-eight patients who underwent abdominal surgery were enrolled in the Intensive Care Unit of the First Affiliated Hospital, China Medical University, from October 1, 2013 to February 28, 2014. These patients included 49 SS and 19 SWS. Six healthy controls were selected. The Ethical Committee of the First Affiliated Hospital of China Medical University approved this study, and informed consent was signed by the patients’ family members (No. 2015-113-2).

Forty-nine SS patients had abdominal infections or pulmonary infections, except for other sites of the infection. Sepsis and septic shock were diagnosed according to the Surviving Sepsis Campaign guidelines committee 2012(10). The exclusion criteria were age <18 years, pregnancy, lactation, human immunodeficiency virus (HIV), hematological tumor, or immunosuppressive, steroid or radiation therapy.

Variables recorded

In all the patients, age, sex, Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) score, Sepsis-related Organ Failure Assessment (SOFA) score, sCD40L, International Society on Thrombosis and Haemostasis (ISTH) score, Japanese Association for Acute Medicine (JAAM) score, platelets, prothrombin time international normalized ratio (PT-INR), activated partial thromboplastin time (aPTT), fibrinogen, D-dimer, Fibrinogen degradation product (FDP), leukocytes, lactate, site of infection, length of stay in the ICU numbers of organ affected, acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), pressure of arterial oxygen/fraction inspired oxygen (PaO₂/FiO₂) ratio, sepsis-induced liver injury, invading organisms, the culprit organ with primary sepsis were recorded. Survival at 28 days was used as the endpoint of our study.

Blood samples

For patients, blood samples were drawn on days 1, 2 and 3 at ICU admission. For healthy controls, fasting blood samples were taken at 8:00 am. Serum blood samples were centrifuged at 1500 g for 15 minutes. The temperature was kept at 4°C in all steps after blood collection. Aliquots were stored at -80°C for further analysis. Samples were thawed only once. Blood samples from each patient with SS were cultured and analyzed to identify the pathogenic bacteria.

Soluble CD40L determination

Serum sCD40L concentration was detected by enzyme-linked immunosorbent assays (ELISA) using Life Science Inc., China). Each sample was measured in duplicate. The detection limit was 6.1 pg/mL. The intratest variability among the duplicate items of all samples was less than 10%.

Statistical analysis

Continuous variables were analyzed as medians and interquartiles (IQ) 25% and 75% (Q25-Q75), and categorical variables were analyzed as frequencies and percentages. Significant differences in continuous variables between groups were analyzed using the Mann-Whitney U test, and categorical variables were calculated by the chi-square test and Fisher’s exact test, as appropriate. Receiver operating characteristic (ROC) curves were used for analyzing serum sCD40L levels at days 1, 2 and 3 and selecting cut off values. Survival analysis was performed with Kaplan-Meier method curves. Multiple logistic regression analysis was applied to predict 28-day mortality. To determine the association between serum levels of sCD40L and other continuous variables at days 1, 2 and 3, Spearman's rank correlation coefficient was used. All p values ＜0.05 were considered statistically significant. SPSS 20.0 (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses.

Patient characteristics

Baseline characteristics of 49 SS, 19 SWS and 6 age- and sex-matched healthy controls are shown in Table 1. The levels of sCD40L in healthy controls were 469.50 (406.83-547.36) pg/ml, and the sCD40L levels in SWS and SS were significantly increased; the difference between the two groups was statistically significant (Table 1, P=0.000 vs healthy controls). In addition, compared with SWS, SS also exhibited a higher incidence of higher APACHE-II (P=0.001), SOFA (P<0.001), ISTH (P<0.001), JAAM (P<0.001) scores, AKI (P=0.000) and ARDS (P=0.000), higher PT-INR (P=0.001), fibrinogen (P=0.022), FDP (P<0.001), D-dimer (P<0.001), lactate (P=0.006), 28-day mortality (P=0.001), longer length of stay in the ICU, and lower PaO₂/FiO₂ ratio (Table 1). However, there was no difference in the type of surgery between the SS and SWS groups.

Table 1, Baseline demographic and clinical characteristics of the studied population group

	Healty control n=6	SS n=19	SWS n=49	P
Sex(male/female)	3/3	12/7	34/15	0.586
Age(years)-median(p25-p75)	53.00(42.25-62.00)	76.00(71.00-81.00)	61.00(45.00-73.00)	0.005
sCD40L(pg/ml)-median(p25-p75)	469.50(406.83-547.36)	831.36(526.58-981.72)	1022.68(554.85-2215.13)	0.000
APACHE Ⅱ score-median(p25-p75)		9.00(7.00-11.00)	14.00(11.00-16.00)	0.001
SOFA score-median(p25-p75)		1.00(0.00-2.00)	8.00(6.00-10.00)	0.000
ISTH score-median(p25-p75)		0.00(0.00-2.00)	3.00(2.50-4.50)	0.000
JAAM score-median(p25-p75)		1.00(0.00-2.00)	4.00(3.00-5.00)	0.000
PT-INR-median(p25-p75)		1.16(1.12-1.34)	1.41(1.21-1.66)	0.001
aPTT(seconds)-median(p25-p75)		41.10(36.10-81.40)	49.40(41.55-60.85)	0.080
fibrinogen(g/L)-median(p25-p75)		3.10(1.96-3.60)	3.94(2.50-5.88)	0.022
FDP(ug/dl)-median(p25-p75)		5.46(3.60-13.42)	21.81(12.24-48.66)	0.000
D-Dimer(ug/ml)-median(p25-p75)		1.71(0.80-3.58)	4.81(3.24-10.11)	0.000
platelet-median*10³/mm³ (p25-p75)		157.00(136.00-191.00)	136.00(77.00-214.50)	0.305
leukocytes-median*10³/mm³(p25-p75)		7.87(5.28-11.90)	10.62(7.50-15.44)	0.030
Lactate(mmol/L)-median(p25-p75)		1.50(0.90-1.80)	2.00(1.30-3.90)	0.006
28 days mortality (%)		0/19(0)	20/49(40.82)	0.000
length of stay in the ICU(days)-median(p25-p75)		3.74(3-5)	21.57(13-28)	0.000
AKI-n (%)		0/19(0)	16/49(32.65)	0.000
sepsis-induced liver injury-n (%)		0/19(0)	3/49(6.12)	0.277
ARDS-n (%)		0/19(0)	21/49(42.86)	0.000
PaO₂/FiO₂ ratio		318.9(300-330)	234.1(170-300)	0.000
Subtotal gastrectomy		3/19(15.79)	10/49(20.41)	0.549
enteroanastomosis		8/19(42.11)	19/49(38.77)	0.805
Cholecystectomy		3/19(15.79)	8/49(16.33)	0.958
Choledocholithotomy		5/19(26.31)	12/49(24.49)	0.878

SWS=surgical patients without sepsis; SS=surgical sepsis patients; p 25-75 = percentile 25th-75^th; APACHE II = Acute Physiology and Chronic Health Evaluation II; SOFA =Sepsis-related Organ Failure Assessment; ISTH =International Society on

Thrombosis and Haemostasis , JAAM =Japanese Association for Acute Medicine; PT-INR =prothrombin time international normalized ratio; aPTT=activated partial thromboplastin time; FDP=Fibrinogen degradation product; AKI=acute kidney injury; ARDS=acute respiratory distress syndrome; PaO₂/FiO₂ =pressure of arterial oxygen/fraction inspired oxygen

A total of 27 strains were isolated from the blood samples of 20 patients in the SS group, including seven strains with methicillin-resistant coagulase-negative Staphylococcus; five with Acinetobacter baumannii; five with non-Candida albicans; three with Enterococcus faecium, two each with methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae; and one with Escherichia coli. More than two strains were isolated from the blood samples of 8 patients.

Demographic and clinical characteristics of nonsurvivors and survivors in surgical sepsis patients

In SS, 20 patients died, and 29 patients survived, all of whose demographic and clinical features are shown in Table 2 and Supplemental Table 1. Nonsurviving patients had higher serum sCD40L (P=0.009) and aPTT than surviving patients at day 2 (P=0.020) and higher lactate at day 3 (P=0.001). In addition, older age (P=0.023) was observed in the group of nonsurviving patients than in the group of surviving SS patients. We could not discover any significant differences in gender, presence of septic shock, site of infection, length of stay in the ICU, PaO₂/FiO₂ratio, incidence of AKI, ARDS, or type of surgery between nonsurvivors and survivors. In addition, on days 1, 2, and 3 at ICU admission, there were no statistically significant differences in APACHE II score, SOFA score, ISTH score, JAAM score, PT-INR, fibrinogen, FDP, D-dimer, platelet and leukocytes between the nonsurviving and surviving groups of SS.

Table 2, Biochemical characteristics of survivor and nonsurvivor surgical sepsis patients on day 2 of ICU admission

	Survivor(n=29)	Non-survivor(n=20)	P
Gender(male/female)	22/7	12/8	0.236
Age(years)-median(p25-p75)	56.00(31.50-64.00)	71.00(52.25-77.25)	0.023
Septic shock− n (%)	17(58.6)	10(50.0)	0.551
Site of infection			0.508
Respiratory − n (%)	5(17.2)	5(25.0)
Abdominal − n (%)	24(82.8)	15(75.0)
APACHE Ⅱ score-median(p25-p75)	12.00(8.00-16.50)	14.00(11.25-17.00)	0.156
SOFA score-median(p25-p75)	6.00(5.00-10.00)	8.50(6.00-10.00)	0.216
ISTH score-median(p25-p75)	4.00(2.00-5.00)	3.00(3.00-4.75)	0.901
JAAM score-median(p25-p75)	4.00(2.50-5.00)	4.00(2.50-4.75)	0.835
PT-INR-median(p25-p75)	1.36(1.25-1.72)	138.5(128.25-170.75)	0.760
aPTT(seconds)-median(p25-p75)	51.00(43.60-66.95)	68.65(53.20-113.95)	0.020
fibrinogen(g/L)-median(p25-p75)	3.74(2.55-6.70)	2.83(1.70-4.78)	0.106
FDP(ug/dl)-median(p25-p75)	16.96(10.43-33.01)	20.40(7.37-32.33)	0.823
D-Dimer(ug/ml)-median(p25-p75)	3.96(2.95-7.61)	3.86(2.19-7.86)	0.502
platelet- median*10³/mm³ (p25-p75)	109.00(47.00-191.00)	124.50(65.25-174.25)	0.903
leukocytes-median*10³/mm³(p25-p75)	13.71(6.83-17.93)	13.91(9.06-19.22)	0.376
Lactate(mmol/L)-median(p25-p75)	2.10(1.30-3.15)	2.75(1.65-5.60)	0.203
sCD40L(pg/ml)-median(p25-p75)	747.21(422.46-981.47)	1214.72(696.28-2089.57)	0.009
length of stay in the ICU(days)- median(p25-p75)	17.62（5-20）	12.55（7-19）	0.341
AKI –n (%)	10/29(34.48)	6/20(30.00)	0.749
ARDS-n (%)	12/29(41.38)	9/20(45.00)	0.806
PaO₂/FiO₂ratio	232.9(170-300)	236.0(170-310)	0.900
Subtotal gastrectomy	5/29(17.24)	5/20(25.00)	0.518
enteroanastomosis	11/29(37.93)	8/20(40.00)	0.889
Cholecystectomy	5/29(17.24)	3/20(15.00)	0.839
Choledocholithotomy	8/29(27.59)	4/20(20.00)	0.554

p25-75 = percentile 25th-75^th; APACHE II = Acute Physiology and Chronic Health Evaluation II; SOFA =Sepsis-related Organ Failure Assessment; ISTH =Thrombosis and Haemostasis , JAAM =Japanese Association for Acute Medicine; PT-INR =prothrombin time international normalized ratio; aPTT=activated partial thromboplastin time; FDP=Fibrinogen degradation product; AKI=acute kidney injury; ARDS=acute respiratory distress syndrome; PaO₂/FiO₂ =pressure of arterial oxygen/fraction inspired oxygen

Predictive factors for 28-day mortality

The area under the curve (AUC) for serum sCD40L levels at day 2 (95% confidence interval (CI)=0.570-0.871, P=0.009) could predict mortality at 28 days, and the sensitivity and specificity approached 60.0% and 79.3%, respectively (Figure 1). Kaplan-Meier survival analysis showed that patients with higher serum sCD40L levels at day 1 (P=0.035), day 2 (P=0.005), and day 3 (P=0.003) had a risk of death at 28 days than patients with lower levels (Fig 2). In addition, patient age ≥65 years (odds ratio = 7.929; 95% CI = 1.809 to 34.750; P=0.006) and serum sCD40L levels at day 2 ≥1028.75 pg/ml (odds ratio = 7.888; 95% CI= 1.758 to 35.395; P=0.007) were significant predictive factors for 28-day mortality in multiple logistic regression analysis.

Association between sCD40L levels and other clinical parameters in patients with surgical sepsis

In addition, no relationship was observed between serum sCD40L levels and APACHE II, SOFA, ISTH, JAAM score, PT-INR, fibrinogen, FDP, D-dimer, leukocytes, platelets and lactate in the SS group on days 1, 2, and 3 at ICU admission (Table 3).

Table 3, Association between sCD40L levels and other clinical parameters in patients with surgical sepsis

	sCD40L day1		sCD40L day2		sCD40L day3
	Rho	P	Rho	P	Rho	P
APACHE Ⅱ score	-0.215	0.138	-0.045	0.761 -0.208		0.151
SOFA score	-0.158	0.279	-0.073	0.617 0.069		0.639
ISTH score	0.016	0.914	-0.051	0.726 0.098		0.501
JAAM score	-0.016	0.916	0.016	0.912 0.216		0.136
PT-INR	0.146	0.318	0.166	0.255 0.055		0.708
aPTT	0.132	0.367	-0.027	0.851 -0.043		0.769
fibrinogen	-0.092	0.529	-0.065	0.655 -0.202		0.163
FDP	0.131	0.370	0.137	0.347 0.085		0.562
D-Dimer	0.171	0.240	0.077	0.600 0.069		0.636
platelet	0.046	0.752	0.122	0.405 -0.003		0.983
leukocytes	0.223	0.124	0.158	0.277 0.061		0.679
lactate	-0.050	0.733	0.194	0.181 0.111		0.447

APACHE II = Acute Physiology and Chronic Health Evaluation II; SOFA =Sepsis-related Organ Failure Assessment; ISTH =Thrombosis and Haemostasis , JAAM =Japanese Association for Acute Medicine; PT-INR =prothrombin time international normalized ratio; aPTT=activated partial thromboplastin time; FDP=Fibrinogen degradation product

It can be concluded from this study that serum sCD40L levels of SS persistently increased significantly in the first three days after admission to the intensive care unit, and the circulating sCD40L was higher on the second day of admission in the nonsurviving group than in the surviving group. A novel finding of this study was that SWS also has a slight increase in sCD40L, but not as much as in SS.

Several studies have reported that the sCD40L level can predict the prognosis of patients with sepsis(8, 11). In our study, we found that serum sCD40L levels ≥ 1028.75 pg/mL at day 2 were associated with higher death risk during the 28-day period in the multiple logistic regression analysis. Serum sCD40L levels could be used as a 28-day mortality biomarker. However, we did not find a relationship between sCD40L levels and sepsis severity criteria, such as APACHE II score and SOFA score. We only observed higher lactatemia in nonsurviving than in surviving SS at day 3 admission. The serum blood samples were obtained at admission to the ICU, but APACHE II or SOFA was calculated at 24 hours of admission to the ICU. We were not sure if this time gap can affect the association between the two variables.

sCD40L has a dual prothrombotic and proinflammatory role. sCD40L connects to circulating monocytes through its receptor CD40, promoting their adhesion to the vascular endothelium. sCD40L also binds to CD40 on endothelial cell surfaces. Studies have shown that sCD40L stimulates its own expression by interacting with CD40 on the surface of these cells(12). In sepsis, EC activation induced adhesion receptors and released inflammatory mediators such as interleukin (IL)-1, IL-6 and tumor necrosis factor(13, 14). sCD40L also affects the neutrophil oxidative burst and neutrophil extracellular trap(5, 15). Previous studies and our studies suggested that sCD40L has no correlation with other coagulation factors except tissue factor (TF)(8). The main reason was that activated ECs initiate the exogenous coagulation pathway by upregulating TF and downregulating the expression of thrombomodulin(16), favoring a local procoagulant status. In experimental models, sCD40L enhanced platelet activation and aggregation and induced thrombus formation(17). All these effects contribute to the development of organ dysfunction and death(18). After intraoperative operation, the ECs were damaged, and the body produced a stress response and inflammatory factors(19). Therefore, the sCD40L level was also increased after surgery in patients with nonsepsis. In patients with sepsis, EC damage, intravascular microthrombus formation and production of inflammatory factors are more obvious, and sCD40L levels are much higher than those in patients with simple surgery.

We did not find an association between serum sCD40L levels and platelet count, although 95% of sCD40L was derived from platelets(20). CD40L is stored in α-granules in unstimulated platelets, which undergo conformational changes during platelet activation, migrates to the surface of platelets and releases into the blood(21). Soluble CD40L can enhance platelet activation, aggregation, and platelet-leukocyte conjugation. Therefore, sCD40L was implicated in platelet activation(12). Activated platelets, via interaction with ECs, play a key role in inflammatory and procoagulant responses to a pathogen(22).

There were some limitations in our study. First, the sample size was relatively small. Second, the subjects came from a single center. Third, we only determined sCD40L levels at admission in the ICU for 3 days but did not observe it for a week or longer, unable to better conclude the time course of serum sCD40L levels in sepsis patients. Finally, an association between sCD40L levels and the activation function of platelets has been reported; we did not examine markers of platelet activation to analyze a relationship with sCD40L levels.

Septic patients show persistently higher circulating sCD40L levels in the first three days at ICU admission, and the serum sCD40L levels are associated with the mortality of patients with sepsis; thus, serum sCD40L may be used as a reliable biomarker and therapeutic target in sepsis.

CD40L CD40 ligand

sCD40L soluble CD40 ligand

TNF tumor necrosis factor

ECs endothelial cells

SWS surgical patients without sepsis

SS surgical sepsis patients

APACHE Ⅱ acute physiology and chronic health evaluation Ⅱ

SOFA sepsis-related organ failure assessment

ISTH international society on thrombosis and haemostasis

JAAM Japanese association for acute medicine

PT-INR prothrombin time international normalized ratio

aPTT activated partial thromboplastin time

FDP Fibrinogen degradation product

AKI acute kidney injury

ARDS acute respiratory distress syndrome

PaO₂/FiO₂pressure of arterial oxygen/fraction inspired oxygen

Ethics approval and consent to participate: The Ethical Committee of the First Affiliated Hospital of China Medical University approved this study and the informed consents were signed by patients’ family members.

Consent for publication: Not applicable.

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests: The authors declare that they have no competing interests.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors' contributions: YJL and XM participated in the conception of the idea, conduct of the study, and preparation of the manuscript. CZ, YS, ZL provided data collection and critical revision. LW, YNL, XL participated in data analysis and critical revision. All authors reviewed and approved the submitted form of this manuscript.

Acknowledgements: Not applicable.

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Supplementaltable1.docx
Supplemental Table 1, Biochemical characteristics of survivor and nonsurvivor surgical sepsis patients on day 1 and day 3 at ICU admission
Supplementaltable1.docx
Supplemental Table 1, Biochemical characteristics of survivor and nonsurvivor surgical sepsis patients on day 1 and day 3 at ICU admission

Persistently higher serum sCD40L levels are associated with outcome in septic patients

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