Introduction

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection [1]. Nowadays, immunotherapy draws increasing attention as a novel therapeutic option in patients with sepsis [2, 3]. Immune suppression in patients with sepsis not only undermines the ability of anti-infection, but also aggravates multiple organ injuries. Because of the rising emergence of antibiotic-resistant bacterial strains, there is an increase in demand for new treatment options.

Thymosin alpha 1 (Tα1) acts as an endogenous regulator of immune homeostasis, and it has been approved in different countries for the treatment of certain cancers, hepatitis, and other infections in recent years [4–6]. Its vital role in the course of sepsis has been reported in some human studies in which mortality was often used to evaluate the efficacy of Tα1 [7–9]. Though mortality is an objective endpoint, it can easily be influenced by multiple factors and cannot be used to predict outcomes in clinical practice. Therefore, an earlier indicator that can be used during the early stage of the course of sepsis could be of clinical importance. Though monocyte human leukocyte antigen-DR (mHLA-DR) and other immune indicators are ideal indicators to evaluate the efficacy of Tα1, their use in everyday clinical practice is limited by access to resources [10, 11].

According to sepsis and septic shock (Sepsis-3) definitions, immune dysfunction can cause a series of organ damage, indicating that the recovery of organ damage has the potential to be an appropriate indicator when seeking alternative and probably safer therapeutic solutions targeting the immune system. Sequential organ failure assessment (SOFA) score is used to clinically evaluate organ dysfunction, and its score is positively correlated with the mortality of sepsis patients [12, 13]. A recent study demonstrated that the trend of SOFA scores within a week was an appropriate indicator for efficacy of sepsis treatment [14]. This retrospective cohort study was implemented to determine the value of Tα1 treatment in alleviating organ dysfunction measured by SOFA score in sepsis patients.

Materials and methods

Results

Baseline characteristics of sepsis patients

Among 288 enrolled sepsis patients, 149 patients received both Tα1 therapy and standard therapy (Tα1 group), and 139 patients received both placebo and standard therapy (placebo group) (Figure 1). There was no statistical difference in baseline characteristics between the two groups (Table 1). As for outcomes, no statistically significant difference was found between the Tα1 group and placebo group in survival rate. Compared with the control group, the Tα1 group had longer 28-day ICU-free days (17.8: 11.3–20.4 vs. 11.8: 0.9–18.3, P = 0.001).

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Figure 1. 

Flow chart of patients with sepsis

Table 1.

Baseline clinical characteristics of patients with sepsis

Characteristics	Total (n = 288)		P value
	Tα1 group (n = 149)	Placebo group (n = 139)
Age (years)	65.1 ± 13.9	66.8 ± 12.4	0.276
Sex (male)	118 (79)	100 (72)	0.152
Pre-existing conditions	125 (84)	113 (81)	0.561
Congestive cardiomyopathy	3	4
Hypertension	69	66
Coronary heart disease	18	13
Liver disease	7	7
COPD	24	25
Diabetes	34	28
Recent trauma	7	5
Cancer	50	42
Recent surgical history			0.702
No history of surgery	77	78
Elective surgery	39	35
Emergency surgery	33	26
Other indicators of disease severity			0.201
MV	118	108
Shock	47	47
Use of vasopressor	55	46
RRT	24	13
Low dose corticoid	16	12
Blood transfusion	51	42
Acute organ dysfunctions			0.303
Pulmonary	142	132
Renal	41	34
Cardiovascular	100	81
Hematological	55	49
Hepatic	23	24
Number of acute organ dysfunctions			0.798
1	24	30
2	64	59
3	40	32
4	16	14
5	5	4
Site of infection			0.598
Lung	113	105
Abdomen	38	36
Positive blood culture	9	7
Urinary tract	2	5
Other	11	11
Result of pathogens			0.542
Gram negative	33	30
Gram positive	9	13
Fungus	15	18
Mixed	59	56
No	33	22
APACHE II score	22.4 ± 6.3	21.2 ± 7.6	0.169
C reactive protein (mg/L)	129.0 (73.9, 189.5)	114.0 (66.8, 175.5)	0.153
White blood cell (× 109/L)	14.6 (10.2, 19.9)	14.5 (11.0, 17.7)	0.526
Neutrophil (%)	86.4 (80.8, 90.7)	86.6 (80.9, 91.1)	0.772
Monocyte (%)	5.0 (2.9, 7.5)	4.9 (3.3, 7.4)	0.865
Lymphocyte (× 109/L)	0.9 (0.5, 1.5)	0.9 (0.5, 1.4)	0.909
Platelet (× 109/L)	165.0 (86.3, 253.8)	170.0 (116.0, 272.3)	0.452
Lactate (mmol/L)	2.1 (1.3, 3.1)	2.0 (1.3, 2.8)	0.419
Creatinine (μmol/L)	102.9 (71.5, 196.3)	93.0 (61.2, 180.2)	0.183
Total bilirubin (μmol/L)	14.5 (9.2, 23.6)	13.0 (8.4, 23.2)	0.375
ICU mortality	7 (14.0)	13 (13.1)	0.884
Hospital mortality	10 (20.0)	23 (23.2)	0.652
28-day mortality	8 (16.0)	19 (19.2)	0.630
ICU-free days (median, IQR)	17.8 (11.3, 20.4)	11.8 (0.9, 18.3)	0.001
MV free days (median, IQR)	21.0 (16.3, 25.5)	19.4 (10.8, 24.9)	0.275

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Values are described by number (percentage), mean ± SD or median IQR. COPD: chronic obstructive pulmonary disease; RRT: renal replacement therapy; MV: mechanical ventilation

Tα1 treatment could significantly improve ΔSOFAday07

Among enrolled sepsis patients, ΔSOFAday07 of the Tα1 group was higher than that of the placebo group (37.1, 14.9–62.7 vs. 33.1, –3.1–58.8, P = 0.12) (Figure 2). After PSM, the Tα1 group had significantly higher ΔSOFAday07 (45.5, 19.4–68.7 vs. 32.6, –3.3–59.8, P = 0.012). When the amplitude of ΔSOFAday07 was graded, one third of patients in the Tα1 group had an improvement in SOFA score by more than 60%, and 14% of them had no change or even worse SOFA score (Figure 3), while in the placebo group only 22% patients had an improvement in SOFA score by more than 60% and one third had no change or even worse SOFA score in the placebo group. Logistic regression further demonstrated that Tα1 therapy contributed to the higher ΔSOFAday07 (Table 3).

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Figure 2. 

ΔSOFAday07 between Tα1 and placebo group. A: Total patients; B: PSM patients. *: P < 0.05

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Figure 3. 

ΔSOFAday07 classification in patients with sepsis. A: Total patients in Tα1 group (left) and placebo group (right); B: PSM patients in Tα1 group (left) and placebo group (right)

Table 3.

Tα1 treatment was associated with higher ΔSOFAday07 in patients with sepsis

	Model 1	Model 2a	Model 3b
Sample size (n)	288	288	222
Tα1 treatment	0.510 (0.299–0.869)	0.523 (0.301–0.909)	0.336 (0.170–0.663)

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Values are ORs (95% CIs) unless stated otherwise. ^aAdjusted for sex, age, pre-existing condition, initial SOFA score, and baseline mHLA-DR; ^badjusted for covariates in model 2 after PSM

Discussion

In this study comparing change in SOFA score in sepsis patients treated with Tα1 or placebo, we found that Tα1 therapy can alleviate organ dysfunction in sepsis patients, and change in SOFA from initial to day 7 (ΔSOFAday07) can be used as an alternative indicator of its therapeutic effect.

It is well-established that sepsis is a complicated illness with extremely high heterogeneity, causing multi-organ dysfunction [18, 19]. The updated definition of sepsis highlighted the bridging function of immune disorder during infection and multiple organ dysfunction syndrome (MODS) [20]. The connection between immune and other systems in sepsis needs to be further explored. In our study, we found that immune therapy can accelerate the improvement of SOFA score in the first week, indicating that treatments targeting immune disorders contribute to the reverse of organ dysfunction.

Tα1 is a peptide separated from thymus, which modulates the immune response via several pathways and helps to boost immunity [21, 22]. Studies have indicated that Tα1 interacts preferentially with negative regions of the membrane [sodium dodecyl sulfate (SDS) mixed with dodecylphosphocholine] due to the phosphatidylserine exposure, after that it may interact with nearby proteins and/or receptors acting as an effector and causing a biological signaling cascade [23, 24]. To date, several reports have attested that low serum Tα1 levels are associated with different pathological conditions such as hepatitis B, psoriatic arthritis, multiple sclerosis and sepsis. Tα1 is able to target different cell types by increasing the expression of major histocompatibility complex class I (MHC class I), MHC class II, and β2-microglobulin [25–27]. Unlike other immunotherapeutic drugs such as anti-programmed cell death protein 1 (anti-PD-1) antibodies or granulocyte-macrophage colony-stimulating factor (GM-CSF), its target receptor stays unknown, and many researchers still rely on the mortality rate to evaluate its therapeutic effect [28, 29]. In recent years, mHLA-DR acts as an ideal marker for the immune function of sepsis [16, 30]. However, though equipment for simple point-of-care testing of mHLA-DR is under rapid development, we still encounter various difficulties to use mHLA-DR as the primary endpoint in a multicenter study [31, 32].

The ΔSOFA score has been selected as the primary outcome in several clinical trials involving patients with sepsis and septic shock, along with mortality reported [33, 34]. It allows doctors to compare the trajectory of organ dysfunction from baseline in the trial, which can not only predict mortality, but also indicate prognosis and guide following therapies. Compared with traditional mortality endpoints, ΔSOFA provides an earlier and simpler assessment of sepsis treatment. Soo et al. [35] conducted a cohort study involving 20,007 critically ill patients and found that compared with the average rate of change at later time points, the slope of the SOFA score on day 1 and day 7 was higher, and was better correlated with the endpoint results (ICU and hospital mortality). Iba et al. [36] investigated patients with sepsis-related diffuse intravascular coagulation (DIC) and found that ΔSOFA between day 1 and day 7 was an effective early predictor of 28-day mortality [area under the curve (AUC): 0.81]. Karakike et al. [14], using the data from two randomized controlled trial (RCT) studies, further confirmed that ΔSOFA on day 7 was an early prognostic indicator of the 28-day mortality [area under the receiver operating characteristic curve (AUROC) 95% CI 0.84 (0.80–0.89); P < 0.001]. Our results also showed that Tα1 group had significantly higher ΔSOFAday07, which suggests that the change in ΔSOFA can be used as one of the early indicators of the therapeutic effect of Tα1.

This study had some limitations. First of all, this is a post hoc analysis of an RCT trial. Secondly, this study only collected SOFA scores for 3 time points within a week. Further prospective and longitudinal studies and clinical trials are necessary to further our understanding of Tα1’s effect on organ function during longer clinical course in sepsis patients. However, the research data was carefully selected from an RCT and was strictly implemented, and thus the results are somewhat representative. The SOFA score can easily be obtained in the ICU settings, and its continuous monitoring may be more conducive to the evaluation of therapeutic efficacy of Tα1.

In conclusion, the present study demonstrated the value of Tα1 in reducing organ damage in sepsis patients by monitoring the dynamic changes of SOFA score, indicating the need for further explorations of the interaction between immune disorders and organ damage. In addition, ΔSOFAday07 can be used as an appropriate indicator for evaluating the efficacy of Tα1.