Clinical manifestations of anxiety and depression in sepsis-associated encephalopathy and multi-omics identification of cluster of differentiation 38 as an early biomarker

Table 1 Comparison of basic characteristics between the sepsis and control groups, mean ± SD/n (%)

	Control group (n = 30)	All sepsis group (n = 58)	χ2/t/Z	P value
Age (IQR)	71.00 (69.00, 79.50)	78.00 (71.00, 85.00)	1.897	0.058
Weight	62.19 ± 11.57	62.24 ± 11.66	0.022	0.982
Height (IQR)	161.00 (155.50, 166.00)	165.00 (157.25, 170.00)	1.895	0.058
BMI (IQR)	23.44 (21.41, 25.69)	22.89 (20.72, 25.20)	0.527	0.598
Gender			1.161	0.281
Male	19 (54.3)	38 (65.5)
Female	16 (45.7)	20 (34.5)
Hypertension			1.887	0.170
No	19 (54.3)	23 (39.7)
Yes	16 (45.7)	35 (60.3)
Diabetes			0.573	0.449
No	25 (71.4)	37 (63.8)
Yes	10 (28.6)	21 (36.2)
Hyperlipidemia			0.406	0.524
No	32 (91.4)	55 (94.8)
Yes	3 (8.6)	3 (5.2)

IQR: Interquartile range; BMI: Body mass index.

Table 2 Comparison of basic characteristics between the sepsis-associated encephalopathy group and the sepsis without encephalopathy group, mean ± SD/n (%)

	Sepsis-no encephalopathy(n = 29)	Sepsis-associated encephalopathy (n = 29)	χ2/t/Z	P value
Age (IQR)	78.00 (73.00, 85.00)	78.00 (70.00, 85.00)	0.226	0.821
Weight (kg)	60.28 ± 10.80	64.21 ± 12.34	1.291	0.202
Height (cm)	162.66 ± 6.73	164.55 ± 7.81	0.991	0.326
BMI (IQR)	22.49 (19.49, 24.96)	23.31 (22.03, 25.95)	1.213	0.225
APACHE2 score (IQR)	16.00 (11.00, 21.00)	18.00 (13.00, 24.00)	0.716	0.474
Total bilirubin (μmol/L) (IQR)	10.00 (6.60, 17.40)	10.10 (8.10, 14.40)	0.614	0.539
Urea nitrogen (mmol/L) (IQR)	12.60 (8.60, 14.80)	14.20 (10.40, 24.30)	1.781	0.075
IL-5 (pg/mL) (IQR)	1.59 (1.59, 1.67)	1.59 (1.18, 1.69)	1.339	0.180
α-interferon (pg/mL) (IQR)	0.98 (0.39, 3.07)	1.47 (0.92, 1.65)	0.132	0.895
IL-2 (pg/mL) (IQR)	1.27 (0.79, 2.00)	1.54 (1.22, 2.21)	1.486	0.137
IL-6A (pg/mL) (IQR)	34.66 (16.65, 76.00)	35.54 (11.27, 92.62)	0.148	0.883
IL-1β (pg/mL) (IQR)	3.00 (2.33, 6.76)	2.33 (1.85, 8.74)	0.828	0.407
IL-10 (pg/mL) (IQR)	2.23 (1.46, 3.98)	2.44 (1.42, 3.75)	0.156	0.876
γ-interferon (pg/mL) (IQR)	2.36 (2.28, 3.52)	2.36 (2.28, 3.21)	1.140	0.254
IL-8 (pg/mL) (IQR)	1.54 (1.54, 6.73)	4.41 (1.54, 10.87)	1.777	0.076
IL-17 (pg/mL) (IQR)	4.19 (4.19, 5.67)	4.19 (4.19, 5.24)	0.665	0.506
IL-4 (pg/mL) (IQR)	0.76 (0.65, 0.82)	0.67 (0.65, 0.82)	0.083	0.934
IL-12 (pg/mL) (IQR)	1.62 (1.08, 1.62)	1.62 (1.12, 1.62)	0.081	0.936
WBC (109/L) (IQR)	11.18 (8.30, 12.92)	12.51 (9.56, 14.55)	1.050	0.294
CRP (mg/L) (IQR)	59.00 (25.00, 108.00)	94.00 (36.00, 125.00)	0.996	0.319
NSE (ng/mL) (IQR)	10.67 (8.33, 14.89)	17.54 (11.23, 22.15)	2.877	0.004
CD38 (ng/mL) (IQR)	7.37 (6.06, 7.88)	8.86 (8.30, 10.09)	4.471	< 0.001
PCT (ng/mL) (IQR)	0.22 (0.06, 3.34)	1.84 (0.58, 6.83)	2.512	0.012
Lactate (mmol/L) (IQR)	1.80 (1.30, 2.80)	2.60 (2.10, 4.50)	2.522	0.012
Gender			1.221	0.269
Male	17 (58.62)	21 (72.41)
Female	12 (41.38)	8 (27.59)
Diabetes			0.648	0.421
No	19 (65.52)	16 (55.17)
Yes	10 (34.48)	13 (44.83)
Hyperlipidemia			0.358	0.550
No	28 (96.55)	27 (93.10)
Yes	1 (3.45)	2 (6.90)
Hypertension			3.658	0.056
No	14 (48.28)	7 (24.14)
Yes	15 (51.72)	22 (75.86)
Coronary artery disease			1.105	0.293
No	17 (58.62)	13 (44.83)
Yes	12 (41.38)	16 (55.17)
CKD/AKI			2.559	0.110
No	15 (51.72)	9 (31.03)
Yes	14 (48.28)	20 (68.97)
Liver dysfunction			2.747	0.097
No	22 (75.86)	16 (55.17)
Yes	7 (24.14)	13 (44.83)
Fever			0.672	0.412
No	12 (41.38)	9 (31.03)
Yes	17 (58.62)	20 (68.97)
Pulmonary infection			0.345	0.557
No	9 (31.03)	7 (24.14)
Yes	20 (68.97)	22 (75.86)
Urinary tract infection			0.892	0.345
No	21 (72.41)	24 (82.76)
Yes	8 (27.59)	5 (17.24)
Bloodstream infection			3.219	0.073
No	24 (82.76)	28 (96.55)
Yes	5 (17.24)	1 (3.45)

IQR: Interquartile range; BMI: Body mass index; APACHE2: Acute Physiology and Chronic Health Evaluation II; WBC: White blood cell; CRP: C-reactive protein; IL: Interleukin; NSE: Neuron-specific enolase; PCT: Procalcitonin; CD: Cluster of differentiation; CKD: Chronic kidney disease; AKI: Acute kidney injury.

Table 3 Comparison of anxiety symptoms between the sepsis and sepsis-associated encephalopathy groups (Hamilton anxiety rating scale), mean ± SD

	Sepsis-no encephalopathy (n = 29)	Sepsis-associated encephalopathy (n = 29)	P value
Anxiety symptoms score (HAM-A)	10.4 ± 3.0	15.2 ± 4.0	0.012
Emotional restlessness	2.1 ± 1.3	3.4 ± 1.5	0.023
Tension	2.3 ± 1.0	3.8 ± 1.3	0.021
Panic attacks	1.0 ± 0.8	2.2 ± 1.1	0.045
Excessive worry	1.2 ± 0.7	2.1 ± 1.0	0.036

HAM-A: Hamilton Anxiety Rating Scale.

Table 4 Comparison of depression symptoms between the sepsis and sepsis-associated encephalopathy groups (Hamilton Depression Rating Scale), mean ± SD

	Sepsis-no encephalopathy (n = 29)	Sepsis-associated encephalopathy (n = 29)	P value
Depression symptoms score (HAM-D)	9.1 ± 2.3	16.0 ± 3.5	0.003
Low mood	2.1 ± 1.0	4.5 ± 1.2	0.004
Loss of interest	1.8 ± 0.9	3.9 ± 1.1	0.008
Insomnia	1.2 ± 0.6	2.6 ± 0.9	0.019
Low self-esteem	1.0 ± 0.5	2.0 ± 0.8	0.028

HAM-D: Hamilton depression rating scale.

Table 5 Comparison of cognitive function between the sepsis and sepsis-associated encephalopathy groups (Montreal Cognitive Assessment), mean ± SD

	Sepsis-no encephalopathy (n = 29)	Sepsis-associated encephalopathy (n = 29)	P value
Cognitive function score (MoCA)	24.5 ± 3.2	18.5 ± 4.0	0.007
Memory	2.0 ± 0.7	1.2 ± 0.5	0.010
Attention	2.1 ± 0.8	1.5 ± 0.6	0.017
Language ability	2.3 ± 0.6	1.8 ± 0.7	0.025
Visuospatial ability	3.0 ± 0.5	2.3 ± 0.6	0.004

MoCA: Montreal Cognitive Assessment.

Table 6 Comparison of quality of life and functional status between the sepsis and sepsis-associated encephalopathy groups (36-Item Short Form Health Survey), mean ± SD

	Sepsis-no encephalopathy (n = 29)	Sepsis-associated encephalopathy (n = 29)	P value
Quality of life score (SF-36)	72.5 ± 12.5	45.0 ± 15.2	0.015
Physical functioning	78.3 ± 10.1	52.1 ± 11.4	0.008
Emotional health	73.4 ± 14.0	42.5 ± 13.8	0.003
Social functioning	70.1 ± 12.0	45.6 ± 10.2	0.020
Mental health	74.0 ± 11.8	40.3 ± 13.5	0.004

SF-36: 36-Item Short Form Health Survey.

Table 7 Diagnostic value of cluster of differentiation 38, neuron-specific enolase, lactate, procalcitonin, and combined markers for sepsis-associated encephalopathy

	Cut-off	AUC (95%CI)	P value	Sensitivity	Specificity
CD38	≥ 8.18	0.842 (0.739-0.945)	< 0.001	0.759	0.862
NSE	≥ 17.52	0.720 (0.589-0.851)	0.004	0.517	0.862
Lactate	≥ 1.75	0.693 (0.555-0.830)	0.012	0.862	0.483
PCT	≥ 0.31	0.692 (0.556-0.828)	0.012	0.828	0.552
Probabilities	≥ 0.396	0.904 (0.826-0.982)	< 0.001	0.862	0.862

NSE: Neuron-specific enolase; PCT: Procalcitonin; CD: Cluster of differentiation; AUC: Area under the curve; CI: Confidence interval.

Table 8 Comparison of basic characteristics between validation and modeling sets, mean ± SD/n (%)

	Modeling set (n = 58)	Validation set (n = 42)	χ2/t/Z	P value
Age (IQR)	78.00 (71.00, 85.00)	77.50 (70.25, 87.50)	0.059	0.953
Weight (kg)	62.24 ± 11.66	62.24 ± 10.99	0.001	0.999
Height (cm)	163.60 ± 7.29	164.64 ± 7.91	0.679	0.499
BMI (IQR)	22.89 (20.72, 25.20)	22.90 (20.76, 25.38)	0.878	0.889
APACHE2 score (IQR)	16.00 (12.00, 22.75)	18.00 (10.00, 21.00)	0.276	0.782
Total bilirubin (μmol/L) (IQR)	10.05 (7.00, 15.60)	11.85 (7.10, 16.03)	0.475	0.635
Urea nitrogen (mmol/L) (IQR)	12.85 (9.35, 18.25)	10.20 (6.25, 17.12)	1.826	0.068
IL-5 (pg/mL) (IQR)	1.59 (1.47, 1.68)	1.91 (0.72, 2.88)	0.137	0.891
α-interferon (pg/mL) (IQR)	1.35 (0.72, 1.91)	1.64 (1.25, 1.89)	1.823	0.068
IL-2 (pg/mL) (IQR)	1.43 (1.08, 2.16)	1.54 (0.87, 2.21)	0.388	0.698
IL-6A (pg/mL) (IQR)	35.10 (11.59, 86.34)	55.60 (11.86, 425.99)	1.690	0.091
IL-1β (pg/mL) (IQR)	2.50 (2.33, 6.89)	2.83 (1.55, 5.16)	1.513	0.130
IL-10 (pg/mL) (IQR)	2.29 (1.42, 3.92)	2.75 (1.07, 16.67)	1.017	0.309
γ-interferon (pg/mL) (IQR)	2.36 (2.28, 3.38)	2.77 (2.20, 4.72)	0.744	0.457
IL-8 (pg/mL) (IQR)	2.55 (1.54, 7.40)	6.06 (1.64, 12.38)	1.265	0.206
IL-17 (pg/mL) (IQR)	4.19 (4.19, 5.53)	4.56 (1.89, 11.00)	0.032	0.975
IL-4 (pg/mL) (IQR)	0.72 (0.65, 0.82)	0.73 (0.67, 1.03)	1.761	0.078
IL-12 (pg/mL) (IQR)	1.62 (1.09, 1.62)	1.48 (0.80, 1.62)	1.710	0.087
WBC (109/L) (IQR)	11.49 (9.45, 14.01)	12.04 (6.03, 15.48)	0.381	0.703
CRP (mg/L) (IQR)	79.50 (27.25, 121.75)	89.00 (50.25, 151.25)	1.550	0.121
Gender			0.016	0.899
Male	38 (65.52)	27 (64.29)
Female	20 (34.48)	15 (35.71)
Diabetes			0.312	0.577
No	35 (60.34)	23 (54.76)
Yes	23 (39.66)	19 (45.24)
Hyperlipidemia			0.166	0.684
No	55 (94.83)	39 (92.86)
Yes	3 (5.17)	3 (7.14)
Hypertension			0.300	0.584
No	21 (36.21)	13 (30.95)
Yes	37 (63.79)	29 (69.05)
Coronary artery disease			0.090	0.764
No	30 (51.72)	23 (54.76)
Yes	28 (48.28)	19 (45.24)
CKD/AKI			0.731	0.392
o	24 (41.38)	21 (50.00)
Yes	34 (58.62)	21 (50.00)
Liver dysfunction			0.137	0.711
No	38 (65.52)	29 (69.05)
Yes	20 (34.48)	13 (30.95)
Fever			1.750	0.186
No	21 (36.21)	10 (23.81)
Yes	37 (63.79)	32 (76.19)
Pulmonary infection			2.532	0.112
No	16 (27.59)	18 (42.86)
Yes	42 (72.41)	24 (57.14)
Urinary tract infection			0.027	0.870
No	45 (77.59)	32 (76.19)
Yes	13 (22.41)	10 (23.81)
Bloodstream infection			1.532	0.216
No	52 (89.66)	34 (80.95)
Yes	6 (10.34)	8 (19.05)

IQR: Interquartile range; BMI: Body mass index; APACHE2: Acute Physiology and Chronic Health Evaluation II; WBC: White blood cell; CRP: C-reactive protein; IL: Interleukin; CKD: Chronic kidney disease; AKI: Acute kidney injury.