The focus of sepsis has shifted from inflammation to organ dysfunction on the basis of a recent definition based on the sequential organ failure score (SOFA). A diagnostic and prognostic marker is necessary under this definition but is currently unknown. We enrolled 80 sepsis patients consecutively admitted to an intensive care unit through the emergency department and 80 healthy control patients who received routine health check-ups from August 2018 to January 2019. SEPSIS-3 criteria were used for the diagnosis of patients based on
Sepsis is an organ dysfunction caused by a dysregulated host response to infection [
Immune dysregulation represents an imbalance of proinflammatory and anti-inflammatory aspects of immune function or of innate immunity- and adaptive immunity-related functions [
Molecules associated with sepsis include chemokines and acute phase reactants. In sepsis patients, a subset of CC motif chemokines, including CCL1, CCL2, CCL8, CCL20, or CXC motif chemokines that include CXCL8, CXCL10, and CXCL12, along with cytokines is increased compared to normal controls [
Various molecules, including cytokines, chemokines, and acute phase reactants are involved in these processes that are interactive and dynamic [
In this study, we evaluated the levels of 45 molecules that are typically examined in sepsis patients, which included cytokines, chemokines, and growth factors. Their levels were also determined in healthy normal controls. Twenty-eight cytokines included interferon- (IFN-)
This was a single-center study that was performed using remnant samples. The protocol was approved by the institutional review board of Incheon St. Mary’s Hospital (OC18TESI0121). We enrolled 80 consecutive sepsis patients (≥18 years of age) who were admitted to the intensive care unit (ICU) through the emergency department (ED). Eighty healthy substitutes who participated in a routine health check-up program were enrolled from August 2018 to February 2019. Patients were excluded if they had evidence of an immune compromised state (e.g., malignancy and chemotherapy administration). Demographic data, baseline characteristics, and initial laboratory data of patients were collected at the time of ICU admission through the ED (Table
Clinical characteristics and baseline demographics of the 80 sepsis patientsa.
Characteristics | ||
---|---|---|
Female/male ( |
36/44 | (45/55%) |
Age (years, range) | 74.5 | (38-87) |
Age >65/<65 | 58/22 | (72.5/27.5%) |
APACHE II score | 26.2 | (3-38.9) |
SOFA score | 4 | (2-13) |
PaO2/FiO2 | 140 | (45-920) |
Lactate (mmol/L) | 2.1 | (0.3-14.4) |
White blood cells (×109/L) | 12.8 | (0.42-51.55) |
Platelet (×109/L) | 196 | (9-445) |
Hemoglobin (g/dL) | 11.4 | (4.3-17.3) |
Hematocrit (%) | 33.8 | (12.5-49.2) |
Prothrombin time in INR, ratio | 1.18 | (0.93-3.62) |
Total bilirubin (mg/dL) | 0.8 | (0.3-3.8) |
AST (U/dL) | 27 | (8-1470) |
ALT (U/dL) | 19 | (5-2100) |
Lactate dehydrogenase (IU/dL) | 521 | (138-2492) |
BUN (mg/dL) | 24.05 | (8.2-184.1) |
Creatinine (mg/dL) | 1.06 | (0.3-23.8) |
Urinary tract infection ( |
32 | (40%) |
Respiratory tract infection ( |
36 | (45%) |
Digestive tract infection ( |
4 | (5%) |
Hepatobiliary tract infection ( |
3 | (3.7%) |
Others ( |
5 | (6.3%) |
HTN/DM ( |
10/6 | (12.5/7.5%) |
HTN + DM ( |
13 | (16.3%) |
Survivor ( |
63 | (78.7%) |
Nonsurvivor ( |
17 | (21.2%) |
aData are presented as median (range) for continuous variables and frequency (%) for categorical variables. APACHE: acute physiology and chronic health evaluation; SOFA: sequential organ failure assessment; AST: aspartate aminotransferase; ALT: alanine aminotransferase; HTN: hypertension; DM: diabetes mellitus.
Sepsis was diagnosed based on SEPSIS-3 criteria, which were based on SOFA (sequential organ failure score)
After entering the ED, routine microbiology examination for patients included more than one pair of blood cultures. Blood samples were drawn immediately after admission to the ED before treatment and were analyzed in a central laboratory within 2 hours [
Leftover serum samples after routine laboratory tests were collected and stored at -80°C before analysis of cytokines. Cytokines were measured simultaneously using the Cytokine/Chemokine/Growth Factor 45-plex Human ProcartaPlex Panel 1 (Thermo Fisher Scientific, Waltham, MA, USA). In brief, serum samples were thawed on ice and centrifuged at 10,000 g for 10 minutes. The addition of 50
Molecules included for analysis included IFN-
The comparison of 80 sepsis patients and 80 normal control patients were performed using the Mann-Whitney
The median age (range) of the control group was 70 years (38-85) and for the sepsis group 74.5 years (38-87). In the control group, 64 individuals (80%) were >65 years of age and 16 (20%) were <65 years of age. The control group comprised 38 (47.5%) females and 42 (52.5%) males. The sepsis group comprised 36 (45%) females and 44 (55%) males (Table
Twenty-eight cytokines, eight chemokines, and nine growth factors were measured in the sepsis and control groups (Table
Comparison of cytokines, chemokines, and growth factors between control and sepsis groups.
Molecules (pg/mL) | Control ( |
Sepsis ( |
Bonferroni | ||
---|---|---|---|---|---|
Mean | SD | Mean | SD | correction ( | |
Cytokines | |||||
IFN- |
0.05 | 0.48 | 7.82 | 63.18 | NS |
IFN- |
0.00 | 0.00 | 20.82 | 142.23 | <0.05 |
IL-1RA | 216.65 | 348.15 | 17564.94 | 32132.31 | NS |
IL-1 |
2.18 | 7.23 | 18.02 | 55.50 | <0.05 |
IL-1 |
0.45 | 1.62 | 3.26 | 7.92 | NS |
IL-2 | 10.57 | 10.26 | 17.40 | 24.54 | NS |
IL-4 | 0.00 | 0.00 | 8.88 | 33.03 | <0.05 |
IL-5 | 0.00 | 0.00 | 4.95 | 18.71 | <0.05 |
IL-6 | 4.72 | 17.12 | 1931.93 | 4803.73 | NS |
IL-7 | 2.21 | 1.94 | 6.42 | 7.94 | NS |
IL-8 | 12.43 | 36.10 | 310.08 | 945.84 | <0.05 |
IL-9 | 0.00 | 0.00 | 13.63 | 96.09 | <0.05 |
IL-10 | 0.07 | 0.44 | 88.55 | 321.44 | <0.05 |
IL-12p70 | 0.19 | 1.72 | 0.36 | 2.39 | <0.05 |
IL-13 | 0.48 | 1.94 | 6.77 | 19.59 | <0.05 |
IL-15 | 10.35 | 12.49 | 17.45 | 31.95 | NS |
IL-17A | 1.04 | 2.44 | 7.05 | 16.59 | <0.05 |
IL-18 | 1.50 | 5.51 | 53.49 | 85.48 | <0.05 |
IL-21 | 5.12 | 19.14 | 102.14 | 460.64 | <0.05 |
IL-22 | 10.06 | 45.38 | 494.81 | 2857.13 | <0.05 |
IL-23 | 2.11 | 15.13 | 58.33 | 272.71 | <0.05 |
IL-27 | 0.99 | 8.77 | 46.00 | 201.57 | <0.05 |
IL-31 | 0.65 | 5.75 | 30.31 | 158.07 | <0.05 |
LIF | 6.22 | 7.71 | 45.19 | 131.78 | NS |
GM-CSF (CSF2) | 0.00 | 0.00 | 6.71 | 40.87 | NS |
SCF (KITLG) | 11.12 | 8.92 | 28.70 | 34.10 | <0.05 |
TNF- |
1.64 | 5.73 | 4.43 | 14.96 | NS |
TNF- |
0.00 | 0.00 | 9.48 | 72.78 | <0.05 |
Chemokines | |||||
CCL2 (MCP-1) | 65.96 | 48.52 | 811.06 | 1335.39 | <0.05 |
CCL3 (MIP-1 |
16.07 | 21.33 | 22.90 | 36.19 | <0.05 |
CCL4 (MIP-1 |
264.96 | 163.90 | 729.02 | 1870.12 | NS |
CCL5 (RANTES) | 185.57 | 185.20 | 604.49 | 565.59 | NS |
CCL11 (eotaxin) | 112.30 | 49.84 | 126.04 | 100.40 | <0.05 |
CXCL1 (GRO- |
1.81 | 11.51 | 82.01 | 301.55 | <0.05 |
CXCL10 (IP-10) | 31.98 | 18.56 | 234.04 | 549.42 | <0.05 |
CXCL12 (SDF-1) | 691.12 | 207.49 | 1325.08 | 1204.70 | NS |
Growth factors | |||||
BDNF | 262.82 | 226.55 | 604.23 | 589.93 | <0.05 |
EGF | 43.62 | 30.99 | 35.90 | 58.03 | <0.05 |
FGF-2 | 0.08 | 0.74 | 28.01 | 110.35 | <0.05 |
HGF | 184.27 | 142.38 | 1111.45 | 1570.22 | <0.05 |
NGF | 7.46 | 15.35 | 31.18 | 50.72 | <0.05 |
PDGF-BB | 119.25 | 132.24 | 565.48 | 1157.25 | <0.05 |
PLGF-1 | 141.03 | 86.31 | 237.79 | 271.32 | <0.05 |
VEGF-A | 204.48 | 212.45 | 831.87 | 1088.99 | <0.05 |
VEGF-D (FIGF) | 6.84 | 8.46 | 27.58 | 28.21 | <0.05 |
IFN: interferon; IL: interleukin; LIF: leukemia inhibitory factor; TNF: tumor necrosis factor; CCL: CC motif chemokine ligand; CXCL: CXC motif ligand; BDNF: brain-derived neurotrophic factor; EGF: epidermal growth factor; FGF: fibroblast growth factor; GM-CSF: granulocyte macrophage colony stimulating factor; HGF: hepatocyte growth factor; NGF: nerve growth factor; PDGF: platelet-derived growth factor; PLGF: placental growth factor; SCF: stem cell factor; VEGF: vascular endothelial growth factor.
ROC curve analysis results for cytokines are presented in Table
Receiver operating characteristic curve analysis of 28 cytokines for diagnosis of sepsis.
Biomarkers | AUC | Cut-off | Sensitivity | (95% CI) | Specificity | (95% CI) | PPV | (95% CI) | NPV | (95% CI) | Accuracy | (95% CI) |
---|---|---|---|---|---|---|---|---|---|---|---|---|
IFN- |
0.531 | 1.0 | 7.5 | (5.8-9.1) | 98.8 | (98.1-99.4) | 86.2 | (40.5-62.7) | 51.6 | (40.5-62.7) | 53.2 | (44.7-61.5) |
IFN- |
0.556 | 1.0 | 11.3 | (9.3-13.2) | 100 | (99.9-100) | 100 | (99.9-100) | 0.10 | (3.4-16.8) | 19.3 | (12.6-26.1) |
IL-1RA | 0.893 | 581.6 | 80.1 | (77.6-82.5) | 92.5 | (90.8-94.1) | 91.4 | (84.2-98.5) | 82.2 | (73.8-90.7) | 86.3 | (80.5-92.1) |
IL-1 |
0.598 | 1.9 | 27.5 | (24.7-30.2) | 96.3 | (95.1-97.4) | 88.1 | (79.8-96.3) | 43.1 | (46.1-68.1) | 61.9 | (53.7-70.1) |
IL-1 |
0.672 | 1.4 | 47.4 | (44.3-50.4) | 87.5 | (85.4-89.5) | 79.1 | (68.7-89.5) | 62.4 | (51.7-73.2) | 67.4 | (59.5-75.3) |
IL-2 | 0.583 | 1.0 | 75.0 | (72.3-77.6) | 38.8 | (35.8-41.8) | 55.1 | (42.3-67.7) | 60.8 | (49.9-71.6) | 56.9 | (48.5-62.5) |
IL-4 | 0.556 | 1.0 | 11.3 | (9.3-13.2) | 100 | (99.9-100) | 100 | (99.9-100) | 52.9 | (41.9-64.1) | 55.6 | (47.2-64.1) |
IL-5 | 0.575 | 1.0 | 15.1 | (12.8-17.3) | 100 | (99.9-100) | 100 | (99.9-100) | 54.1 | (43.0-65.1) | 57.6 | (59.2-65.9) |
IL-6 | 0.830 | 40.8 | 67.5 | (64.5-70.4) | 95.5 | (94.2-96.8) | 93.7 | (87.6-99.9) | 74.6 | (64.9-84.2) | 81.5 | (74.9-88.1) |
IL-7 | 0.707 | 3.2 | 57.5 | (54.4-60.5) | 85.1 | (82.8-87.3) | 79.4 | (69.1-89.7) | 66.7 | (56.2-77.1) | 71.3 | (63.7-78.9) |
IL-8 | 0.781 | 11.2 | 71.3 | (68.4-74.1) | 81.3 | (78.8-83.7) | 79.2 | (68.8-89.6) | 73.9 | (64.1-83.4) | 76.3 | (69.1-83.4) |
IL-9 | 0.519 | 1.0 | 3.8 | (2.6-4.9) | 100 | (99.9-100) | 100 | (99.9-100) | 50.9 | (39.8-62.1) | 51.9 | (43.4-60.3) |
IL-10 | 0.820 | 1.0 | 65.1 | (62.1-68.1) | 97.5 | (96.5-98.5) | 96.3 | (91.4-100) | 73.6 | (63.8-83.4) | 81.3 | (74.7-87.9) |
IL-12 | 0.506 | 1.0 | 2.5 | (1.5-3.5) | 98.7 | (97.9-99.4) | 65.7 | (53.6-77.8) | 50.3 | (39.2-61.4) | 50.6 | (42.2-59.1) |
IL-13 | 0.606 | 10.5 | 21.3 | (18.7-23.8) | 100 | (99.9-100) | 100 | (99.9-100) | 55.9 | (44.9-66.9) | 60.6 | (52.4-68.8) |
IL-15 | 0.513 | 24.7 | 25.0 | (22.1-27.3) | 91.3 | (89.5-93.0) | 73.9 | (62.7-85.1) | 54.8 | (43.7-65.8) | 58.0 | (49.6-66.3) |
IL-17A | 0.641 | 2.15 | 42.5 | (39.4-45.6) | 88.8 | (86.8-90.7) | 79.1 | (68.7-89.5) | 60.7 | (49.8-71.5) | 65.7 | (57.6-73.6) |
IL-18 | 0.746 | 1.0 | 53.8 | (50.7-56.8) | 92.5 | (90.8-94.1) | 87.7 | (79.4-96.1) | 66.7 | (56.2-77.1) | 73.1 | (65.6-80.6) |
IL-21 | 0.685 | 1.0 | 23.8 | (21.1-26.4) | 92.5 | (90.8-94.1) | 76.0 | (65.1-86.9) | 54.8 | (43.7-65.8) | 58.1 | (49.8-66.4) |
IL-22 | 0.615 | 1.0 | 28.7 | (25.8-31.5) | 93.8 | (92.3-95.2) | 82.2 | (72.4-91.9) | 56.8 | (45.8-67.8) | 61.2 | (53.0-69.4) |
IL-23 | 0.601 | 1.0 | 22.5 | (19.9-25.1) | 97.5 | (96.5-98.4) | 90.0 | (82.3-97.6) | 55.7 | (44.6-66.7) | 60.0 | (51.7-68.2) |
IL-27 | 0.613 | 1.0 | 23.8 | (21.1-26.4) | 98.7 | (97.9-99.4) | 94.8 | (89.1-100) | 56.4 | (45.4-67.4) | 61.2 | (53.0-69.4) |
IL-31 | 0.575 | 1.0 | 16.5 | (14.1-18.8) | 98.8 | (98.1-99.4) | 93.2 | (86.8-99.6) | 54.2 | (43.1-65.2) | 57.6 | (49.3-65.9) |
LIF | 0.760 | 6.1 | 78.8 | (76.2-81.3) | 62.5 | (59.4-65.5) | 67.7 | (55.8-79.6) | 74.7 | (65.0-84.2) | 70.6 | (62.9-78.3) |
GM-CSF (CSF2) | 0.519 | 1.0 | 3.8 | (2.6-4.9) | 100 | (99.0-100) | 100 | (99.0-100) | 50.9 | (39.8-62.0) | 51.9 | (43.5-60.3) |
SCF (KITLG) | 0.721 | 14.8 | 60.1 | (57.1-63.1) | 77.5 | (74.9-80.1) | 72.7 | (61.4-84.1) | 66.0 | (55.5-76.5) | 68.8 | (60.9-76.6) |
TNF- |
0.531 | 1.0 | 15.1 | (12.8-17.3) | 91.3 | (89.5-93.0) | 63.4 | (51.2-75.7) | 51.8 | (40.7-62.9) | 53.2 | (44.7-61.6) |
TNF- |
0.513 | 1.0 | 2.5 | (1.5-3.4) | 100 | (99.0-100) | 100 | (99.0-100) | 50.6 | (39.5-61.7) | 51.3 | (42.8-59.6) |
AUC: area under receiver operating characteristic curve; PPV: positive predictive value; NPV: negative predictive value: CI; confidence intervals; IFN: interferon; IL: interleukin; LIF: leukemia inhibitory factor; TNF: tumor necrosis factor; GM-CSF: granulocyte macrophage colony stimulating factor; SCF: stem cell factor.
Receiver operating characteristic curve analysis of eight chemokines and nine growth factors for diagnosis of sepsis.
Biomarkers | AUC | Cut-off | Sensitivity | (95% CI) | Specificity | (95% CI) | PPV | (95% CI) | NPV | (95% CI) | Accuracy | (95% CI) |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Chemokines | ||||||||||||
CCL2 (MCP-1) | 0.840 | 105.5 | 67.5 | (64.5-70.4) | 93.0 | (91.5-94.5) | 0.90 | (82.3-97.6) | 75.4 | (65.9-85.1) | 80.7 | (74.1-87.3) |
CCL3 (MIP-1 |
0.530 | 9.8 | 52.5 | (49.4-55.6) | 56.3 | (53.2-59.3) | 54.5 | (41.8-67.3) | 54.2 | (41.8-67.2) | 75.4 | (45.9-62.8) |
CCL4 (MIP-1 |
0.653 | 411.8 | 47.5 | (44.3-50.5) | 87.5 | (85.5-89.5) | 79.2 | (68.8-89.5) | 62.5 | (51.7-73.2) | 67.5 | (59.9-75.4) |
CCL5 (RANTES) | 0.887 | 179.6 | 90.1 | (89.2-92.7) | 76.3 | (64.3-70.2) | 73.3 | (62.0-84.6) | 88.3 | (81.2-95.4) | 79.1 | (72.2-85.9) |
CCL11 (eotaxin) | 0.508 | 49.6 | 22.5 | (19.9-25.1) | 93.7 | (92.1-95.2) | 78.1 | (67.5-88.6) | 54.7 | (43.6-65.7) | 58.1 | (49.8-66.4) |
CXCL1 (GRO- |
0.759 | 1.0 | 55.0 | (51.9-58.1) | 96.3 | (95.1-97.4) | 93.6 | (87.4-99.8) | 68.1 | (57.8-78.5) | 75.6 | (68.4-82.8) |
CXCL10 (IP-10) | 0.851 | 46.5 | 71.3 | (68.4-74.1) | 92.5 | (90.8-94.1) | 90.4 | (82.9-97.8) | 76.3 | (66.8-85.8) | 81.9 | (75.4-88.4) |
CXCL12 (SDF-1) | 0.766 | 895.6 | 60.1 | (57.1-63.1) | 90.1 | (88.2-91.9) | 85.9 | (76.9-94.7) | 69.3 | (59.0-79.5) | 75.1 | (67.8-82.3) |
Growth factors | ||||||||||||
BDNF | 0.690 | 393.3 | 57.5 | (54.4-60.5) | 82.5 | (80.1-84.8) | 76.6 | (65.8-87.4) | 66.0 | (55.4-76.5) | 70.0 | (62.2-77.7) |
EGF | 0.663 | 20.4 | 58.8 | (55.7-61.8) | 77.5 | (74.9-80.8) | 72.3 | (60.9-83.7) | 65.3 | (54.7-75.8) | 68.2 | (60.3-76.0) |
FGF-2 | 0.601 | 1.0 | 21.5 | (18.9-24.0) | 98.8 | (98.1-99.4) | 94.7 | (89.1-100) | 55.7 | (44.7-66.7) | 60.2 | (51.9-68.4) |
HGF | 0.899 | 341.2 | 76.3 | (73.6-78.9) | 92.5 | (90.8-94.1) | 91.1 | (83.7-98.3) | 79.6 | (70.1-88.5) | 84.4 | (78.2-90.5) |
NGF | 0.636 | 21.9 | 40.1 | (37.1-43.1) | 86.3 | (84.2-88.4) | 74.5 | (63.4-85.6) | 59.1 | (48.1-69.9) | 63.2 | (55.1-71.3) |
PDGF-BB | 0.677 | 279.6 | 38.8 | (35.7-41.8) | 90.1 | (88.2-91.5) | 79.6 | (69.4-89.9) | 59.5 | (48.6-70.4) | 64.4 | (56.3-72.5) |
PLGF-1 | 0.626 | 87.2 | 81.3 | (78.8-83.7) | 41.3 | (38.2-44.3) | 58.1 | (45.4-70.6) | 68.8 | (58.6-79.1) | 61.3 | (53.1-69.5) |
VEGF-A | 0.790 | 313.5 | 67.5 | (64.5-70.4) | 80.1 | (77.6-82.5) | 77.2 | (66.5-87.9) | 71.1 | (61.1-81.1) | 73.8 | (66.8-81.2) |
VEGF-D (FIGF) | 0.772 | 13.8 | 63.5 | (60.5-66.4) | 83.8 | (81.5-88.1) | 79.6 | (69.4-89.9) | 69.6 | (59.4-79.8) | 73.7 | (66.2-81.1) |
AUC: area under receiver operating characteristic curve; PPV: positive predictive value; NPV: negative predictive value: CI; confidence intervals; CCL: CC motif chemokine ligand; CXCL: CXC motif ligand; BDNF: brain-derived neurotrophic factor; EGF: epidermal growth factor; FGF: fibroblast growth factor; GM-CSF: granulocyte macrophage colony stimulating factor; HGF: hepatocyte growth factor; NGF: nerve growth factor; PDGF: platelet-derived growth factor; PLGF: placental growth factor; SCF: stem cell factor; VEGF: vascular endothelial growth factor.
Receiver operating characteristic curves for the diagnosis of sepsis that showed the highest values among tested molecules. Comparison of HGF and IL6 (
Correlation between SOFA and APACHE score and molecules was studied using Spearman’s method. Correlation coefficient and
Prediction of the 28-day all-cause mortality was studied by univariate and multivariate analyses. Age, SOFA score, IL-10, IL-17A, IL-18, CXCL10, EGF, NGF, SCF, and VEGF-D were included in the univariate analysis. Age, SOFA score, and EGF revealed statistical significance in multivariate analysis (Table
Univariate and multivariate analysis for the prediction of prognosis among sepsis patients.
Univariate | Multivariate | |||||||
---|---|---|---|---|---|---|---|---|
Odds ratio | 95% CI | Odds ratio | 95% CI | |||||
Age | 1.058 | 0.999 | 1.121 | 0.038 | 1.092 | 1.012 | 1.177 | 0.022 |
AST | NS | |||||||
ALT | NS | |||||||
CRP | NS | |||||||
PCT | NS | |||||||
Creatinine | NS | |||||||
Total bilirubin | NS | |||||||
APACHE II score | NS | |||||||
SOFA score | 1.279 | 1.064 | 1.539 | 0.009 | 1.349 | 1.074 | 1.695 | 0.010 |
IL-10 | 1.001 | 1.000 | 1.002 | 0.034 | ||||
IL-17A | 1.019 | 1.001 | 1.037 | 0.036 | ||||
IL-18 | 1.010 | 1.000 | 1.019 | 0.047 | ||||
CXCL10 | 1.002 | 1.000 | 1.004 | 0.014 | ||||
EGF | 0.973 | 0.957 | 0.989 | 0.001 | 0.979 | 0.959 | 1.001 | 0.050 |
NGF | 0.984 | 0.974 | 0.995 | 0.005 | ||||
SCF | 0.975 | 0.958 | 0.993 | 0.007 | ||||
VEGF-D | 0.998 | 0.975 | 1.000 | 0.050 |
AST: aspartate aminotransferase; ALT: alanine aminotransferase; CRP: C-reactive protein; PCT: procalcitonin; APACHE: acute physiology and chronic health evaluation; SOFA: sequential organ failure assessment; IL: interleukin; CXCL: chemokine (C-X-C motif) ligand; EGF: epidermal growth factor; NGF: nerve growth factor; SCF: stem cell factor; VEGF-D: vascular endothelial growth factor D precursor.
Molecular levels among the control group and survivors/nonsurvivors of sepsis. Asterisks indicate statistical significance compared to that of the control group.
Supplemental Figure
This study evaluated 45 molecules, including cytokines, chemokines, and growth factors by the multiplexing method. The focus of the definition of sepsis was changed from inflammation to organ dysfunction and immune dysregulation [
As expected, all of the cytokines were increased in the sepsis group compared to the healthy control group, except for EGF, which was lower in the sepsis group (Table
Previous studies compared systemic inflammatory response syndrome and sepsis based on the previous SEPSIS-1 definition [
Multivariate analysis revealed age, SOFA score, and EGF as independent and statistically significant predictors of prognosis. For EGF, we hypothesize that tissue recovery or regeneration by growth factors might be associated with prognosis of sepsis. Deterioration of tissue by microbes or immune dysregulation are thought to be recovered by growth factors, such as EGF, NGF, SCF, and VEGF, or by other proteins related with damage control. However, if recovery of tissue is insufficient with these growth factors, or if growth factors are depleted, organ failure can eventually occur. Presently, the concentrations of EGF, NGF, SCF, and VEGF were decreased in nonsurvivors compared to survivors, without statistical significance (Figure
To predict SOFA and APACHE II scores from the tested molecules, correlation analysis was performed. The correlation coefficient was lower, ranging from 0.2 to 0.3. These results indicated that other factors might affect organ dysfunction or disease severity. Hierarchical clustering analysis resulted in three clusters: cluster 1 (
The limitations of this study are the relatively small sample sizes and the lack of proper hierarchical clustering analysis. Age and sex between the control and sepsis groups were not perfectly matched and the age of the patient group was slightly higher than that of the control group; age is a known risk factor for sepsis. As there are scant data related to growth factors in prior studies, further studies will be required to verify the present results.
HGF and IL-1RA demonstrated diagnostic capability, and EGF predicted favorable prognosis among sepsis patients. Most of the growth factors were decreased in nonsurvivors of sepsis, which may be associated with the pathogenesis of sepsis. Further studies are required to verify the use of cytokines, chemokines, and growth factors for sepsis diagnosis and prediction of prognosis.
The data used to support the findings of this study are included within the supplementary information files.
The authors declare that there is no conflict of interest regarding the publication of this article.
We thank Hyunyu Choi for excellent technical assistance. This study was supported by The Catholic Medical Center Research Foundation (2015).
Supplementary Figure 1: dendrogram of clustering analysis that resulted in 3 clusters. Supplementary Table 1: cultured pathogens from sepsis patients. Supplementary Table 2: cytokine levels in the normal control group that showed statistical significance tested by the Mann-Whitney