Efficacy and optimal timing of sivelestat in critically ill patients with COVID-19: a multicenter retrospective cohort study

Abstract

Background

The cytokine storm is a pivotal factor in the progression of coronavirus disease 2019 (COVID-19) to severe disease. Sivelestat, recognized for its anti-inflammatory properties, holds promise as a therapeutic intervention for patients with severe COVID-19.

Methods

We conducted a multicenter, retrospective study involving patients admitted to the intensive care unit (ICU) with severe COVID-19 in China. A 1:2 propensity score matching (PSM) was employed to adjust for confounding factors and differences between the sivelestat and non-sivelestat groups.

Results

Our analysis involved 2030 patients with severe COVID-19. After applying a 1:2 PSM ratio, the sivelestat group consisted of 115 patients, while the non-sivelestat group comprised 211 patients. The findings indicated that sivelestat administration was associated with enhanced survival rates at 28 days for patients with severe COVID-19 (53.55% vs. 40.87%; P = 0.03). However, no significant differences were noted in the secondary outcomes, which included ventilator-free days within 28 days, gastrointestinal bleeding, septic shock, acute myocardial injury, venous thrombosis, acute liver injury, and acute kidney injury. Furthermore, this study revealed that early administration of sivelestat could reduce patient mortality.

Conclusions

Our study suggests that sivelestat use may be associated with reduced 28-day mortality in ICU patients with severe COVID-19.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s12890-026-04406-9.

Introduction

Severe coronavirus disease 2019 (COVID-19) is characterized by viral pneumonia, which can progress to acute respiratory distress syndrome (ARDS), a condition caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ARDS and multiple organ failure are the primary factors driving disease progression, leading to severe illness and rapid death [1]. Numerous clinical studies have reported cytokine storms in critically ill patients with COVID-19 [2–6]_, which are considered major contributors to ARDS and multiorgan failure [7, 8]. Therefore, suppressing cytokine storms may be crucial to improving outcomes for patients with severe COVID-19.

Sivelestat is a selective, reversible, competitive inhibitor of neutrophil elastase (NE). Studies have demonstrated that sivelestat effectively reduces interleukin-6 (IL-6) levels, suggesting its potential to alleviate cytokine storms [9–11]. Furthermore, researchers found that sivelestat significantly decreased the incidence of acute lung injury (ALI) in patients with esophageal cancer [12]. In a clinical trial, sivelestat was administered to patients in the intensive care unit (ICU) for 5 days who had ALI/ARDS and disseminated intravascular coagulation (DIC). This treatment regimen resulted in significantly improved lung injury scores and survival rates, reduced durations of ICU stay, and lower incidence of thromboembolic events compared to the control group [13].

The largest retrospective study to date (n = 4,276) demonstrated that ARDS patients receiving sivelestat treatment within 7 days of hospital admission experienced a 17% reduction in 90-day mortality risk [14]. A Japanese retrospective study of 28 patients with severe bacterial pneumonia found that the survival group received sivelestat significantly earlier, with improvements observed in oxygenation index and core vital signs. The authors suggested that early administration of sivelestat may improve outcomes in severe pneumonia [15]. Overall, current research indicates that early use of sivelestat can improve mortality and symptoms in patients with severe pneumonia. However, the precise optimal timing for sivelestat treatment in severe COVID-19 pneumonia remains undetermined.

Given its anti-inflammatory properties, sivelestat has been hypothesized to exert therapeutic effects in patients with severe COVID-19. To investigate this, we aim to conduct a multicenter retrospective study to elucidate the therapeutic value and the optimal time window of sivelestat in treating patients with severe COVID-19.

Methods

Study design and patients

Our retrospective cohort study analyzed the medical records of 1816 patients with severe COVID-19 admitted to 57 ICUs in China between December 31, 2022, and March 31, 2023. The list of these 57 ICUs has been included as Additional file 1: Table S1. COVID-19 diagnosis was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) tests on upper and/or‌ ‌lower respiratory tract specimens. The study protocol, including the plan for retrospective data collection from patients admitted between December 2022 and March 2023, was approved by the IRB of the China-Japan Friendship Hospital (2022-KY-113) prior to any data access. A Data Use Agreement was secured between the participating institutions. Inclusion criteria were as follows: aged 18 years or older, a confirmed diagnosis of COVID-19 with positive SARS-CoV-2 results, clinically classified as severe/critical, and admitted to the ICU. Exclusion criteria were: death within 48 h of ICU admission, pre-ICU treatment with sivelestat sodium, undergoing continuous renal replacement therapy (CRRT), and incomplete essential clinical data.

Data collection

Data on sociodemographic characteristics, medical history, comorbidities, symptoms at admission, vital signs, baseline severity scores (Acute Physiology and Chronic Health Evaluation II [APACHE II] and Sequential Organ Failure Assessment [SOFA]) were extracted from electronic medical records. Additionally, treatment details for COVID-19, duration of mechanical ventilation, and clinical outcomes were recorded. White blood cell (WBC), neutrophil (NEUT), lymphocyte (LYM), and C-reactive protein (CRP) counts were collected on days D1, D2, D3, D5, and D7 following ICU admission. Clinical data from all centers have been standardized.

Standard COVID-19 treatment protocol

During the study period, all participating ICUs adhered to the China National Health Commission’s COVID-19 treatment guidelines (10th edition). Standard care included prone positioning for refractory hypoxemia, corticosteroids (methylprednisolone 1–2 mg/kg/day) in patients with hyperinflammation, and antivirals (nirmatrelvir/ritonavir or remdesivir) when available. IL-6 inhibitors were not routinely used.

Outcomes

The primary outcome was 28-day mortality. The secondary outcomes included ventilator-free days (within 28 days), gastrointestinal bleeding, septic shock, acute myocardial injury, venous thrombosis, acute liver injury, and acute kidney injury.

Statistical analysis

Statistical analyses were conducted using R version 4.5.1. Propensity score matching (PSM) [16] was employed to reduce selection bias and confounding factors arising from varying covariable distributions between the sivelestat and non-sivelestat groups. Nearest neighbor matching was performed with a caliper of 0.05 applied to achieve a 1:2 ratio match. A standardized mean difference (SMD) of less than 0.25 was considered indicative of successful balanced matching.

Categorical variables were expressed as frequencies and percentages, while continuous variables were presented as medians with interquartile ranges (Q1-Q3). To compare baseline characteristics between groups, chi-square tests or Fisher’s exact tests were used for categorical variables, and the Mann-Whitney U test was employed for continuous variables. For the sivelestat group, Day 1 was defined as the day of first sivelestat administration. For the non‑sivelestat group, Day 1 was defined as the day of ICU admission. Laboratory values were then compared at equivalent relative time points (D1, D2, D3, D5, D7) between the two groups. The proportion of missing values for laboratory markers ranged from 4% to 15% (Additional file 1: Table S2). Missing data were imputed using multiple imputation by chained equations (MICE) with 20 imputed datasets, assuming missing at random. Sensitivity analyses using complete-case analysis yielded similar results. For repeated measures, analysis of variance (ANOVA) was applied for normally distributed values, and generalized linear mixed model (GLMM) were used for non-normally distributed data. Restricted cubic spline (RCS) models were employed to evaluate the non-linear relationship between time of sivelestat treatment initiation and survival outcomes. Cox regression analysis was performed on the matched cohort to assess the impact of sivelestat on ICU mortality, adjusting for potential confounding factors. Statistical significance was set at P < 0.05.

Results

A total of 2030 patients with severe COVID-19 were enrolled in this study. To minimize selection bias, we excluded 196 patients who died within 48 h of ICU admission. Additionally, 47 patients receiving sivelestat sodium treatment prior to ICU transfer were excluded. A further 39 cases were eliminated due to critically incomplete medical records compromising essential data analysis. Finally, the sivelestat group comprised 115 patients, while the non-sivelestat group included 1633 patients. After using PSM to balance the differences between groups, a total of 115 patients remained in the sivelestat group, and 211 patients were included in the non-sivelestat group (Fig. 1). The balanced data of variables included in the matching model are shown in Fig. 2.

Fig. 1.

Enrollment and study design. ICU: Intensive Care Unit; COVID-19: Coronavirus Disease 2019

Fig. 2.

Summaries of the balance of variables before and after propensity score matching

Characteristics of the cohort

The demographic and clinical characteristics of both the original and matched cohorts are shown in Additional file 1: Table S2. The use of corticosteroids (36.86% vs. 46.09%; P = 0.04), antibacterials (54.56% vs. 67.83%; P = 0.01), and antivirals (25.72% vs. 37.39%; P = 0.01) was more frequent in the sivelestat group. After PSM, no differences were observed in baseline characteristics between the sivelestat group (n = 211) and the non-sivelestat group (n = 115) .

Outcomes

The sivelestat group exhibited significantly lower 28-day mortality (53.55% vs. 40.87%; P = 0.03). As a sensitivity analysis, a cumulative incidence function (CIF) accounting for discharge alive as a competing event was also estimated; results were consistent with the primary analysis (Additional file 1: Figure S1). In multivariate logistic regression, treatment with sivelestat significantly reduced the risk of death at 28 days after adjusting for age, sex, comorbidities, and concomitant medications, and the OR was not influenced by different covariates (Table 1). For secondary outcomes, no statistically significant differences were observed (Table 2). Following COX regression analysis, a Kaplan-Meier survival curve indicated a significant difference in ICU survival rate (P = 0.03) between the sivelestat group and the non-sivelestat group (Fig. 3).

Table 1.

Comparison of 28-day mortality between patients treated with sivelstat and controls

	Total	Death	Model 1		Model 2		Model 3
			OR (95%CI)	p	OR (95%CI)	P	OR (95%CI)	P
Without treatment	211	113 (53.55%)	Ref	Ref	Ref	Ref	Ref	Ref
Sivelestat	115	47 (40.87%)	0.60 (0.38–0.95)	0.03	0.60 (0.36–0.92)	0.02	0.55 (0.33–0.91)	0.02

Model 1: unadjusted model

Model 2: adjusted for patient’s age, sex

Model 3: adjusted for patient’s age, sex, disease severity, comorbidities and concomitant medications

Table 2.

The secondary outcomes of severe COVID-19 in the sivelestat and non-sivelestat groups

Variables	Non-sivelestat (N = 211)	Sivelestat (N = 115)	P-value
Endotracheal intubation, n (%)	101 (47.87%)	61 (53.04%)	0.37
Tracheostomy, n (%)	31 (14.69%)	24 (20.87%)	0.15
Ventilator-free days within 28 days, median (IQR)	21.0 [0;28.0]	22.0 [0;28.0]	0.14
Septic shock, n (%)	51 (24.17%)	22 (19.13%)	0.30
Acute myocardial injury, n (%)	29 (13.74%)	22 (19.13%)	0.20
Venous thrombosis, n (%)	21 (9.95%)	12 (10.43%)	0.89
Pulmonary embolism, n (%)	3 (1.42%)	1 (0.87%)	1.0
Gastrointestinal bleeding, n (%)	19 (9.00%)	12 (10.43%)	0.68
Acute liver injury, n (%)	19 (9.00%)	12 (10.43%)	0.67

Fig. 3.

Cumulative event curve for 28-day mortality according to sivelestat treatment

Laboratory indicators of inflammation

Generalized estimation equations were employed to compare the levels of laboratory indicators of inflammation from baseline to days 1, 3, 5, and 7 between the sivelestat and non-sivelestat groups. Statistical analysis using the generalized estimation model revealed that the NEUT levels in the sivelestat group were significantly lower on D1 (7.93 vs. 8.58; P = 0.01), D2 (7.68 vs. 9.14; P = 0.05), and D3 (8.15 vs. 9.09; P = 0.05) compared to the non-sivelestat group (Table 3). No statistically significant differences were found in the other laboratory indicators of inflammation (Fig. 4).

Table 3.

Laboratory indicators of inflammation between sivelestat and non-sivelestat groups

Variables	Non-Sivelestat (N = 211)	Sivelestat (N = 115)	P-value
WBC (*10^9/L)
D1	9.40[6.06;14.6]	10.38[6.38;14.6]	0.76
D2	9.65[5.97;14.6]	9.53[6.76;12.5]	0.33
D3	9.65[5.16;14.6]	9.27[6.45;14.4]	0.39
D5	9.93[6.95;14.3]	10.60[8.27;14.4]	0.95
D7	9.89[7.38;14.1]	10.44[7.21;15.2]	0.11
NEUT (*10^9/L)
D1	8.58[5.37;13.3]	7.93[4.49;11.1]	0.01
D2	9.14[5.11;14.8]	7.68[5.40;13.1]	0.05
D3	9.09[5.02;14.0]	8.15[4.65;13.9]	0.05
D5	8.87[5.29;12.2]	8.94[6.45;12.8]	0.17
D7	8.50[5.52;11.6]	8.30[6.36;13.5]	0.08
LYM (*10^9/L)
D1	0.55[0.33;0.95]	0.40[0.26;0.73]	0.58
D2	0.58[0.29;0.83]	0.38[0.29;0.70]	0.54
D3	0.57[0.30;0.83]	0.44[0.27;0.66]	0.20
D5	0.58[0.29;0.80]	0.41[0.29;0.69]	0.50
D7	0.50[0.30;0.77]	0.45[0.22;0.74]	0.64
CRP (mg/dL)
D1	14.66[7.14;50.0]	22.93[8.39;77.0]	0.08
D2	19.02[9.95;65.0]	27.03[7.93;76.5]	0.06
D3	12.60[5.65;27.7]	5.65[77.3;71.7]	0.32
D5	8.82[3.72;17.1]	6.43[47.1;40.7]	0.61
D7	8.30[2.70;30.8]	2.15[2.15;66.2]	0.63

Fig. 4.

The change of laboratory indicators of inflammation between sivelestat and non-sivelestat groups. WBC: White blood cell; NEUT: Neutrophil; LYM: Lymphocyte; CRP: C-reactive protein

Therapeutic time window of sivelestat

The administration of sivelestat within 4 days decreased the risk of death compared to treatment with sivelestat after 5 days of disease onset (52.08% vs. 31.34%; P = 0.03). In multivariate COX regression, treatment with sivelestat within 4 days of disease onset significantly decreased the risk of death after adjusting for age, sex, comorbidities, and concomitant medications, and the HR was not influenced by different covariates (Table 4).

Table 4.

Comparison of mortality between early and delayed administration of sivelestat

	Total	Death	Model 1		Model 2		Model 3
			HR (95%CI)	p	HR (95%CI)	P	HR (95%CI)	P
Treated with sivelestat ≥ 4 days	48	25	Ref	Ref	Ref	Ref	Ref	Ref
Treated with sivelestat<4 days	67	21	0.64 (0.42–0.96)	0.03	0.64 (0.42–0.97)	0.04	0.53 (0.33–0.84)	0.01

*Model 1: unadjusted model

Model 2: adjusted for patient’s age, sex

Model 3: adjusted for patient’s age, sex, disease severity, comorbidities and concomitant medications

RCS modeling based on Cox regression demonstrated the relationship between the timing of sivelestat initiation and ICU mortality (Fig. 5). A turning point was observed around day 4, with significantly increased risk for treatment initiation beyond this point. Wider 95% confidence intervals at both extremes of the RCS curve reflected the smaller sample sizes in these time period.

Fig. 5.

Survival Outcomes by Sivelestat Initiation Time. a Survival curve during ICU admission according to the timing of sivelestat initiation. Shaded areas represent 95% confidence intervals. b Restricted Cubic Spline Analysis of the Association Between Time to Sivelestat Initiation and ICU Mortality. The model was adjusted for age, sex, disease severity, comorbidities and concomitant medications

Sensitivity analyses

We performed sensitivity analyses changing the covariates in the PSM model for ICU mortality (Additional file 1: Table S3). All models showed lower risk of mortality associated with sivelstat use. The sivelestat group exhibited significantly lower 28-day mortality (55.60% vs. 40.87%).

Discussion

Severe COVID-19 is characterized by viral pneumonia that progresses to ARDS as a consequence of SARS-CoV-2 infection. NE plays a crucial role in the pathogenesis of ARDS [17, 18]. As a specific NE inhibitor, sivelestat suppresses NE enzymatic activity. By inhibiting neutrophil aggregation, adhesion, and infiltration, it reduces pulmonary hemorrhage, attenuates exudate formation, and alleviates pulmonary edema, thereby mitigating lung tissue damage [19, 20].

Sivelestat has been used in China for acute lung injury associated with systemic inflammatory response syndrome since 2003 and was included in the Chinese expert consensus on COVID-19 treatment as an adjunctive anti-inflammatory therapy during the pandemic [21]. Its inclusion in this study was based on its established role in local clinical practice during the Omicron surge, not as a prospectively planned investigational intervention. The decision to prescribe sivelestat was made at the discretion of treating physicians according to local hospital protocols, which recommended its use for patients with evidence of neutrophil-mediated lung injury and hyperinflammation.

The study period from December 31, 2022, to March 31, 2023, was defined to capture the initial Omicron surge in China following the relaxation of the zero-COVID policy in December 2022. We defined this window based on the peak hospitalization period at the participating centers, during which ICU admissions reached maximum capacity. While we acknowledge that some reports have characterized the broader outbreak period as extending through May 2023 [22], we deliberately limited our data collection to the first four months for two reasons. First, ICU admissions declined substantially after March 2023 as herd immunity increased and the initial wave subsided. Second, data completeness and quality were highest during this concentrated surge period, as the multicenter coordination infrastructure was specifically activated for emergency response during peak hospitalization. Extending the collection window would have introduced significant heterogeneity in patient acuity, treatment protocols, and data completeness, potentially compromising the internal validity of our findings. We recognize that this truncated period may have excluded patients with different clinical characteristics from the later phase of the outbreak; however, the homogeneity of the study population during this defined window strengthens the internal validity of our findings, and our sensitivity analyses confirmed robust results across multiple model specifications.

Our multicenter retrospective cohort analysis aimed to investigate the potential benefits of sivelestat in treating patients with severe COVID-19. Our findings indicated that the administration of sivelestat in these patients was associated with reduced ICU mortality. There is ongoing debate among researchers regarding the effect of sivelestat on mortality in patients with ARDS. Some studies have suggested that sivelestat treatment could lower the risk of death in patients with ALI/ARDS [15, 23–25]. Kido et al. [14] investigated the effects of sivelestat on mortality in patients with ALI and ARDS. Of the 4,276 patients enrolled, 1,997 received sivelestat, while 2,279 did not receive sivelestat within 7 days of admission. After adjusting for confounding factors, the 3-month mortality rate was significantly lower in the sivelestat group compared to the non-sivelestat group (P < 0.002). To our knowledge, only two studies have conducted comparable analyses in severe COVID-19 patients, both reporting significantly reduced 30-day mortality with sivelestat treatment [23, 24]. However, as retrospective single-center investigations with limited sample size and representativeness, these studies carry an elevated risk of bias.

Conversely, other studies have concluded that sivelestat does not significantly affect the risk of death in patients with ARDS [26, 27]. A systematic review and meta-analysis that included eight clinical studies found no significant difference in mortality rates between 28 and 30 days (risk ratio (RR) = 0.95, 95% confidence interval (CI) 0.72–1.26) [28]. Notably, an international multicenter study has even suggested that sivelestat may increase the risk of death in patients [29]. However, the patients in this study had acute lung injury (ALI) requiring mechanical ventilation and exhibited higher disease severity than those in previous investigations. Our study showed a significantly lower 28-day mortality rate in the sivelestat group. The discrepancy in results may be attributed to several factors. First, our study included patients with severe COVID-19 who were admitted to the ICU, characterized by high levels of inflammation and a need for active anti-inflammatory therapy. Additionally, PSM was employed to balance the differences between groups and minimize the occurrence of bias.

Our study revealed that the administration of sivelestat did not significantly reduce the duration of mechanical ventilation. The STRIVE study in 2004 also demonstrated that sivelestat did not improve mechanical ventilation time in patients [10]. A meta-analysis further demonstrated that sivelestat failed to shorten the duration of mechanical ventilation in patients [30]. However, later studies have shown that sivelestat can significantly reduce mechanical ventilation time [22, 31]. The effect of sivelestat on reducing the duration of mechanical ventilation in patients with ARDS/ALI remains controversial, and further high-quality studies are needed.

Our study found no statistically significant difference in the incidence of adverse reactions associated with sivelestat in patients with severe COVID-19 compared to those not receiving it. Research indicates that patients with severe COVID-19 may present with viral co‑infections (e.g., influenza, RSV, or adenovirus) at the time of admission [32], and that immune hyperactivation during the first week of illness – rather than immunosuppression – contributes to endothelial injury and coagulopathy [33]. Consequently, our findings suggest that sivelestat was not associated with an increased risk of documented adverse events in this cohort; however, prospective monitoring is needed to confirm safety.

Cytokine storms play a crucial role in the progression of COVID-19 to severe disease, and recent studies have confirmed that WBC, CRP, IL-6, and other factors may be involved. Wang et al. [24] found that sivelestat significantly reduced the levels of interferon-alpha (IFNα), interleukin-1 beta (IL-1β), and interleukin-2 (IL-2). However, due to the limited cytokine detection in most centers and the resulting missing values, we did not analyze the impact of sivelestat on cytokines in this study. Our research showed that the number of neutrophils in the sivelestat group was significantly lower on D1 (7.93 vs. 8.58; P = 0.01), D2 (7.68 vs. 9.14; P = 0.05), and D3 (8.15 vs. 9.09; P = 0.05) compared to the non-sivelestat group. These results are consistent with other studies [34]. Additionally, no statistically significant differences were observed in the levels of CRP, WBC, or LYM. These results suggest that sivelestat did not significantly reduce these inflammatory markers after 7 days of combined treatment. We believe the lack of statistical differences may be attributed to the high percentage of patients (85%) treated with corticosteroids in both the treatment and control groups. Corticosteroids primarily function to suppress inflammatory responses, which could potentially mask the effects of sivelestat on CRP and other factors.

Current evidence suggests that early sivelestat administration improves mortality and symptoms in severe pneumonia. However, the precise optimal timing for sivelestat treatment in severe COVID-19 pneumonia remains undetermined. Based on this, Our study found that delayed initiation (> 4 days) was associated with a significantly higher mortality risk compared to early treatment (≤ 4 days) (52.08% vs. 31.34%; P = 0.03), a finding consistent with previous research in this population. Notably, in the RCS curve, the HR for 0–1 day was < 1 but its confidence interval exceeded 1. This is likely attributable to the insufficient number of patients in this subgroup. Large-scale, multicenter, randomized clinical trials are necessary to confirm these findings and to determine the optimal timing of administration.

Our study had certain limitations. Firstly, as a multi-center observational study, it was challenging to ensure standardized treatment for patients, This limitation may restrict the generalizability of our findings due to the relatively modest sample size, even though we employed PSM to mitigate selection bias. Secondly, most patients enrolled in this study were critically ill at the time of admission, were of advanced age, or had multiple underlying diseases, leading to a higher expected mortality rate. The use of sivelestat may lead to irreversible outcomes. Thirdly, the majority of cases in our study were linked to the emerging Omicron variant of SARS-CoV-2. It remains uncertain whether the efficacy of sivelestat in treatment extends to other variants of SARS-CoV-2. Fourthly, our study did not delve into the detailed molecular mechanisms underlying the inhibition of virus intrusion or replication by sivelestat. Further research is required to comprehensively elucidate these mechanisms. Fifthly, the interval between data collection and analysis was longer than ideal due to the complexity of multicenter data harmonization; however, the clinical relevance of the findings remains valid given the absence of more recent large-scale studies on this topic. Lastly, Sivelestat was not administered uniformly; its prescription was based on clinical judgment and local guidelines, introducing potential selection bias. Although PSM adjusted for measured confounders, residual confounding from unmeasured factors (e.g., dynamic disease severity prior to drug initiation) cannot be excluded.

Conclusions

In conclusion, our study suggests that early sivelestat use can reduce 28-day mortality in ICU patients with severe COVID-19, thereby providing a new basis for clinical consideration. However, large-scale, multicenter, randomized clinical trials are necessary to confirm these findings in the future.

Abbreviations

ALI

Acute Lung Injury

ANOVA

Analysis of Variance

APACHE II

Acute Physiology and Chronic Health Evaluation II

ARDS

Acute respiratory distress syndrome

CI

Confidence Interval

COVID-19

Coronavirus Disease 2019

CRP

C–reactive Protein

CRRT

Continuous Renal Replacement Therapy

DIC

Disseminated Intravascular Coagulation

ICU

Intensive Care Unit

IFNα

Interferon Alpha

IL-1β

Interleukin–1 Beta

IL-2

Interleukin–2

IL-6

Interleukin–6

LYM

Lymphocytes

NE

Neutrophil Elastase

NEUT

Neutrophils

PSM

Propensity Score Matching

RT-PCR

Reverse Transcription Polymerase Chain Reaction

RCS

Restricted Cubic Spline

SARS-CoV-2

Severe Acute Respiratory Syndrome Coronavirus 2

SMD

Standardized Mean Difference

WBC

White Blood Cells

Authors’ contributions

Qi Zhang, Yijie Liu, Bowen Ran, Tianshu Zhai, Ying Cai, Chao Zhang, Jingchen Hao, Longxian Jin, and Zhenyuan Huang collected the data. Xiaojing Wu and Qingyuan Zhan designed the study. Qi Zhang, Yijie Liu, and Xiaojing Wu analyzed the data. Qi Zhang, Bowen Ran, Tianshu Zhai, Ying Cai, Chao Zhang, Jingchen Hao, Longxian Jin, and Zhenyuan Huang interpreted the data. Qi Zhang, Yijie Liu, Bowen Ran and Xiaojing Wu repared the manuscript.

Funding

This study was funded by the National Natural Science Foundation of China (82270108) ; the National High Level Hospital Clinical Research Funding & Elite Medical Professionals Project of China-Japan Friendship Hospital (NO.ZRJY2023-GG20) ; the Key Research and Development Program of Jiangxi province (NO.20232BBG7002) ; and the National High Level Hospital Clinical Research Funding (2022-NHLHCRF-LX-01-01).

Data availability

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

Declarations

Ethics approval and consent to participate

This study was approved by the institutional review board (IRB) of the China-Japan Friendship Hospital (Approval No.: 2022-KY-113) and written informed consent was waived by the IRB due to the retrospective nature of this study. All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments. A Data Use Agreement was secured between the participating institutions.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.