The characteristics of the 368 patients were summarized in Table 1. In the development set, from the total of 240 patients, 144 (60.0%) survived until day 28 after ICU admission, whereas 96 (40.0%) patients did not. The abdomen was the most common source of infection, followed by lung infection. Non-survivors were presented with more severe disease, as reflected by higher APACHE II and SOFA scores, as well as higher lactate levels. The 28-day mortality occurred in 31.3% of patients in the ICU. There were no significant differences in age, sex, BMI, body temperature, respiratory rate, heart rate, coronary artery disease, chronic obstructive pulmonary disease (COPD), hypertension, and diabetes mellitus, between two groups. However, blood lactate, APACHE II and SOFA scores, lengths of ICU and hospital stay in two groups showed significant differences. In the validation set, from the total of 128 patients, lactate levels, APACHE II score, SOFA score, and length of hospital stay displayed significant differences.
Variables
|
Non-survivors
|
Survivors
|
p-value
|
Development set
|
|
|
|
N
|
96
|
144
|
|
Age (years)
|
62.4±10.0
|
62.2±11.5
|
0.878
|
BMI (kg/m2)
|
22.4±3.5
|
22.8±3.2
|
0.308
|
Sex (male, %)
|
64 (66.7)
|
90 (62.5)
|
0.51
|
Body temperature (℃)
|
36.7 (36.4–37.0)
|
36.6 (36.4–37.0)
|
0.63
|
Respiratory rate (rate/min)
|
23 (19–30)
|
24 (19–31)
|
0.664
|
HR (bpm)
|
118±29
|
113±30
|
0.175
|
Lactate (mmol/L)
|
3.2 (1.5–6.0)
|
1.6 (1.0–3.0)
|
< 0.001
|
APACHE II score
|
18 (14–24)
|
17 (13–20)
|
0.001
|
SOFA score
|
9 (7–12)
|
8 (6–9)
|
<0.001
|
Infection site of origin,
number (%)
|
|
|
|
Lung
|
28 (29.2)
|
33 (22.9)
|
0.276
|
Abdomen
|
56 (58.3)
|
100 (69.4)
|
0.077
|
Urinary tract
|
6 (6.3)
|
4 (2.8)
|
0.187
|
Other
|
6 (6.3)
|
7 (4.9)
|
0.641
|
Organism, n (%)
|
|
|
|
Gram-positive
|
28 (29.2)
|
40 (27.8)
|
0.815
|
Gram-negative
|
54 (56.3)
|
79 (54.9)
|
0.832
|
Mixed
|
8 (8.3)
|
15 (10.4)
|
0.591
|
Fungal
|
6 (6.3)
|
10 (6.9)
|
0.833
|
Comorbidities, n (%)
|
|
|
|
Coronary artery disease
|
10 (10.4)
|
19 (13.2)
|
0.518
|
COPD
|
1 (1.0)
|
0 (0)
|
0.220
|
Hypertension
|
12 (12.5)
|
27 (18.8)
|
0.199
|
Diabetes mellitus
|
8 (8.3)
|
15 (10.4)
|
0.591
|
Length of ICU stay,
median (IQR)
|
3 (1-5)
|
4 (2-7.8)
|
0.001
|
Length of hospital stay,
median (IQR)
|
16.5 (8.0-22.8)
|
27.0 (18.0-36.0)
|
< 0.001
|
ICU mortality (%)
|
30 (31.3)
|
8 (5.6)
|
< 0.001
|
Validation set
|
|
|
|
N
|
45
|
83
|
|
Age (years)
|
67.7±10.1
|
66.4±10.3
|
0.488
|
BMI (kg/m2)
|
23.5±3.7
|
23.1±3.9
|
0.561
|
Sex (male, %)
|
29 (64.4)
|
59 (71.1)
|
0.439
|
Body temperature (℃)
|
36.7 (36.5–37.0)
|
36.8 (36.5–37.0)
|
0.281
|
Respiratory rate (rate/min)
|
16 (14–22)
|
16 (15–21)
|
0.607
|
HR (bpm)
|
97±35
|
96±26
|
0.9
|
Lactate (mmol/L)
|
2.4 (1.4–3.9)
|
1.7 (1.3–3.2)
|
0.022
|
APACHE II score
|
27 (24–30)
|
25 (23–27)
|
0.037
|
SOFA score
|
7 (6–10)
|
7 (5–8)
|
0.023
|
Infection site of origin, number (%)
|
|
|
|
Lung
|
17 (37.8)
|
24 (28.9)
|
0.305
|
Abdomen
|
26 (57.8)
|
59 (71.1)
|
0.128
|
Urinary tract
|
1 (2.2)
|
0 (0)
|
0.173
|
Other
|
1 (2.2)
|
0 (0)
|
0.173
|
Organism, n (%)
|
|
|
|
Gram-positive
|
10 (22.2)
|
21 (25.3)
|
0.698
|
Gram-negative
|
27 (60.0)
|
42 (50.6)
|
0.308
|
Mixed
|
4 (8.9)
|
11 (13.3)
|
0.464
|
Fungal
|
4 (8.9)
|
9 (10.8)
|
0.727
|
Comorbidities, n (%)
|
|
|
|
Coronary artery disease
|
9 (20.0)
|
21 (25.3)
|
0.499
|
COPD
|
2 (4.4)
|
3 (3.6)
|
0.817
|
Hypertension
|
7 (15.6)
|
24 (28.9)
|
0.092
|
Diabetes mellitus
|
4 (8.9)
|
14 (16.9)
|
0.215
|
Length of ICU stay, median (IQR)
|
3 (1-5)
|
2 (1-2)
|
0.092
|
Length of hospital stay, median (IQR)
|
19.0 (15.5-24.0)
|
26.0 (19.0-36.0)
|
< 0.001
|
ICU mortality (%)
|
6 (13.3)
|
4 (4.8)
|
0.087
|
Table 1
Table 1 Baseline characteristics of patients stratified by 28-day survival status after admission.
Data are expressed as means (SD) or percentage. SD, standard deviation; BMI, body mass index; HR, heart rate; CEA, carcinoembryonic antigen; ICU, Intensive Care Unit; SOFA, Sepsis Related Organ Failure Assessment; APACHE, Acute Physiology and Chronic Health Evaluation; IQR, 25%, 75% interquartile range; COPD, chronic obstructive pulmonary disease.
The distributions of the white blood cell (WBC), ALCs, and absolute neutrophil count during the first four days after the diagnosis of sepsis between survivors and non-survivors were presented in Fig. 1. On day 1, the WBC and absolute neutrophil count levels were increased in the survivors comparing with those in non-survivors. However, there were no significant difference in ALCs between the survivors and non-survivors. On day 3, the ALCs were reduced in the non-survivors, comparing with those in the survivors (p = 0.003 and 0.007 in the development set and the validation set, respectively). However, the WBC, ALCs, and absolute neutrophil count in survivors and non-survivors were not significantly different on day 2 and day 4. Similar results were observed both in the development set and the validation set.
The association between day-3 ALCs and survival of cancer patients with sepsis was investigated by Kaplan-Meier analysis and log-rank test. The day-3 ALCs were classified into severe lymphopenia, moderate lymphopenia, and no lymphopenia. Statistically, severe lymphopenia and moderate lymphopenia significantly reduced 28-day (p = 0.002 and 0.007 in the development set and the validation set, successively) and 90-day (p = 0.001 and 0.002 in the development set and the validation set, consecutively) survival rate compared to no lymphopenia, both in the development and validation sets (Fig. 2 and Fig. 3).
Regarding the development set, univariate analysis demonstrated that APACHE II and SOFA scores, day-3 ALCs, and lactate levels were greatly related to 28-day mortality in cancer patients with sepsis (Table 2). Multivariate analysis, using the Cox proportional hazards model for all variables that were significant in the univariate analysis, indicated that the day-3 ALCs were an independent prognostic factor for 28-day mortality in cancer patients with sepsis. Similarly, for 90-day mortality, the day-3 ALCs were found to be an independent prognostic factor, with HR of 0.761 (95% CI: 0.625–0.927, p = 0.007). The validation set confirmed that the day-3 ALCs were the independent prognostic factor (p = 0.006) (Table 2).
|
Univariate analysis
|
|
Multivariate analysis
|
|
|
HR (95% CI) p-value
|
HR (95% CI) p-value
|
Development set
|
|
|
|
|
28-day mortality
|
|
|
|
|
APACHE II score
|
1.088 (1.054–1.122)
|
<0.001
|
1.046 (1.009–1.085)
|
0.014
|
SOFA score
|
1.190 (1.115–1.269)
|
< 0.001
|
1.120 (1.042–1.204)
|
0.002
|
Lactate (mmol/L)
|
1.118 (1.083–1.153)
|
< 0.001
|
1.080 (1.041–1.120)
|
< 0.001
|
Day 3 ALC
|
0.628 (0.480–0.821)
|
0.001
|
0.743 (0.559–0.986)
|
0.04
|
90-day mortality
|
|
|
|
|
APACHE II score
|
1.062 (1.036–1.088)
|
<0.001
|
1.033 (1.005–1.062)
|
0.021
|
SOFA score
|
1.109 (1.052–1.169)
|
< 0.001
|
1.055 (0.998–1.116)
|
0.06
|
Lactate (mmol/L)
|
1.116 (1.082–1.150)
|
< 0.001
|
1.087 (1.050–1.126)
|
< 0.001
|
Day 3 ALC
|
0.711 (0.588–0.861)
|
<0.001
|
0.761 (0.625–0.927)
|
0.007
|
|
|
|
|
|
Validation set
|
|
|
|
|
28-day mortality
|
|
|
|
|
APACHE II score
|
1.123 (1.041–1.212)
|
0.003
|
1.124 (1.026–1.230)
|
0.012
|
SOFA score
|
1.319 (1.149–1.513)
|
< 0.001
|
1.204 (1.046–1.387)
|
0.01
|
Lactate (mmol/L)
|
1.162 (1.075–1.257)
|
< 0.001
|
1.101 (1.017–1.192)
|
0.018
|
Day 3 ALC
|
0.344 (0.165–0.714)
|
0.004
|
0.431 (0.202–0.920)
|
0.03
|
90-day mortality
|
|
|
|
|
APACHE II score
|
1.113 (1.043–1.187)
|
0.001
|
1.120 (1.040–1.206)
|
0.003
|
SOFA score
|
1.253 (1.109–1.415)
|
< 0.001
|
1.163 (1.028–1.316)
|
0.016
|
Lactate (mmol/L)
|
1.147 (1.062–1.238)
|
< 0.001
|
1.092 (1.011–1.180)
|
0.025
|
Day 3 ALC
|
0.360 (0.198–0.654)
|
0.001
|
0.417 (0.223–0.779)
|
0.006
|
Table 2
Table 2 The predictors of mortality in cancer patients with sepsis.
HR, Hazard ratio; CI, confidence interval. Abbreviations: see to Table 1.
The baseline characteristics are stratified by the day-3 ALCs (Table 3). For the development set, patients with severe lymphopenia had lower BMI, and higher APACHE II and SOFA scores. According to the validation set, patients with severe lymphopenia had higher lactate levels, higher SOFA score, and longer ICU length of stay.
Variables
|
No
Lymphopenia
|
Moderate Lymphopenia
|
Severe Lymphopenia
|
p-value
|
Development set
|
|
|
|
|
Number
|
64
|
98
|
78
|
|
Age (years)
|
60.2±12.9
|
63.2±9.7
|
62.8±10.4
|
0.192
|
BMI (kg/m2)
|
23.4±3.0
|
22.7±3.0
|
21.9±3.8
|
0.02
|
Sex (male, %)
|
35 (54.7)
|
66 (67.3)
|
53 (67.9)
|
0.181
|
Body temperature (℃)
|
36.7 (36.4-37.0)
|
36.5 (36.4-37.0)
|
36.7 (36.4-37.0)
|
0.411
|
Respiratory rate (rate/min)
|
23 (20-32)
|
24 (18-29)
|
24 (16-32)
|
0.412
|
HR (bpm)
|
115±34
|
114±30
|
116±25
|
0.939
|
Lactate (mmol/L)
|
1.5 (1.0-2.9)
|
2.0 (1.1-4.4)
|
2.2 (1.3-5.0)
|
0.058
|
APACHE II score
|
17 (13-19)
|
17 (12-22)
|
18 (15-24)
|
0.012
|
SOFA score
|
7 (5-9)
|
8 (7-10)
|
9 (7-11)
|
< 0.001
|
Infection site of origin
|
|
|
|
|
Lung
|
13 (20.3)
|
30 (30.6)
|
18 (23.1)
|
0.286
|
Abdomen
|
48 (75.0)
|
62 (63.3)
|
52 (66.7)
|
0.291
|
Other
|
3 (4.7)
|
6 (6.1)
|
8 (10.3)
|
0.389
|
Organism, n (%)
|
|
|
|
|
Gram-positive
|
16 (25.0)
|
24 (24.5)
|
28 (35.9)
|
0.196
|
Gram-negative
|
41 (64.1)
|
53 (54.1)
|
39 (50.0)
|
0.231
|
Mixed
|
5 (7.8)
|
11 (11.2)
|
7 (9.0)
|
0.752
|
Fungal
|
2 (3.1)
|
5 (5.1)
|
9 (11.5)
|
0.098
|
Comorbidities, n (%)
|
|
|
|
|
Coronary artery disease
|
10 (15.6)
|
10 (10.2)
|
9 (11.5)
|
0.576
|
COPD
|
0 (0)
|
0 (0)
|
1 (1.3)
|
0.352
|
Hypertension
|
13 (20.3)
|
12 (12.2)
|
14 (17.9)
|
0.351
|
Diabetes mellitus
|
10 (15.6)
|
8 (8.2)
|
5 (6.4)
|
0.147
|
Length of ICU stay, median (IQR)
|
3 (2-5)
|
4 (2-6)
|
3 (2-7)
|
0.601
|
Length of hospital stay, median(IQR)
|
28 (16-35)
|
22 (16-30)
|
20 (10-34)
|
0.152
|
ICU mortality (%)
|
9 (14.1)
|
11 (11.2)
|
18 (23.1)
|
0.091
|
|
|
|
|
|
Validation set
|
|
|
|
|
Number
|
55
|
50
|
23
|
|
Age (years)
|
66.3±11.2
|
66.9±9.0
|
68.1±10.2
|
0.778
|
BMI (kg/m2)
|
23.5±3.4
|
22.4±3.4
|
24.2±5.1
|
0.142
|
Sex (male, %)
|
34 (61.8)
|
37 (74.0)
|
18 (78.3)
|
0.241
|
Body temperature (℃)
|
36.7 (36.4-37.0)
|
36.8 (36.5-37.0)
|
36.8 (36.6-37.1)
|
0.201
|
Respiratory rate (rate/min)
|
16 (14-21)
|
17 (15-22)
|
15 (14-21)
|
0.744
|
HR (bpm)
|
99±30
|
92±28
|
101±28
|
0.385
|
Lactate (mmol/L)
|
1.9 (1.3-3.2)
|
1.9 (1.3-2.6)
|
3.0 (1.3-6.2)
|
0.048
|
APACHE II score
|
26 (23-28)
|
25 (23-27)
|
27 (24-29)
|
0.324
|
SOFA score
|
7 (5-8)
|
7 (6-8)
|
9 (7-10)
|
0.004
|
Infection site of origin
|
|
|
|
|
Lung
|
18 (32.7)
|
14 (28.0)
|
9 (39.1)
|
0.632
|
Abdomen
|
37 (67.3)
|
34 (68.0)
|
14 (60.9)
|
0.822
|
Other
|
0 (0)
|
2 (4.0)
|
0 (0)
|
0.25
|
Organism, n (%)
|
|
|
|
|
Gram-positive
|
16 (29.1)
|
12 (24.0)
|
3 (13.0)
|
0.32
|
Gram-negative
|
27 (49.1)
|
27 (54.0)
|
15 (65.2)
|
0.428
|
Mixed
|
5 (9.1)
|
7 (14.0)
|
3 (13.0)
|
0.72
|
Fungal
|
7 (12.7)
|
4 (8.0)
|
2 (8.7)
|
0.702
|
Comorbidities, n (%)
|
|
|
|
|
Coronary artery disease
|
13 (23.6)
|
13 (26.0)
|
4 (17.4)
|
0.722
|
COPD
|
3 (5.5)
|
1 (2.0)
|
1 (4.3)
|
0.655
|
Hypertension
|
15 (27.3)
|
12 (24.0)
|
4 (17.4)
|
0.649
|
Diabetes mellitus
|
8 (14.5)
|
7 (14.0)
|
3 (13.0)
|
0.985
|
Length of ICU stay, median (IQR)
|
1 (1-3)
|
3 (1-5)
|
3 (2-5)
|
0.001
|
Length of hospital stay, median(IQR)
|
21 (16-28)
|
24 (18-33)
|
21 (17-31)
|
0.533
|
ICU mortality (%)
|
4 (7.3)
|
2 (4.0)
|
4 (17.4)
|
0.138
|
Table 3
Table 3 Characteristics of patients stratified by day 3 absolute lymphocyte count.
Data are expressed as means (SD) or percentage. SD, standard deviation; BMI, body mass index; COPD, chronic obstructive pulmonary disease; HR, heart rate; ICU, Intensive Care Unit; SOFA, Sepsis Related Organ Failure Assessment; APACHE, Acute Physiology and Chronic Health Evaluation; IQR, 25%, 75% interquartile range.