Association of immune deficiency with prognosis and corticosteroid treatment benefits among patients with acute respiratory distress syndrome

Introduction

Acute respiratory distress syndrome (ARDS) is a common clinical syndrome characterized by acute hypoxic respiratory failure and non-cardiogenic lung infiltration (1). ARDS arises from a variety of causes, both infectious and non-infectious. These causes can lead to direct lung damage through local inflammation or indirect damage via systemic inflammation (2). Sepsis from different pathogens are notable causes of ARDS, among which pulmonary sepsis being the predominant source (3). Common non-infectious etiologies include pancreatitis, aspiration of stomach contents, severe traumatic injury with shock, transfusion-related acute lung injury (TRALI), and smoke inhalation or environment conditions, i.e., ARDS commonly seen in workers in coal mines “black lung” or gold mine workers (2). In the LUNG SAFE prospective cohort study, encompassing 459 intensive care units (ICUs) across 50 countries on five continents, 10.4% of ICU patients and 23.4% of those on mechanical ventilation met the Berlin definition criteria, a commonly used tool to assess the severity of ARDS by using respiratory parameters such as partial pressure of oxygen to fraction of inspired oxygen ratio (PaO₂/FiO₂) (3,4). The prevalence of ARDS has notably increased during the coronavirus disease 2019 (COVID-19) pandemic (2). The heterogeneity of ARDS, in terms of pathogenesis, clinical features, and treatment responses, presents challenges for clinical management. Advancements in understanding the epidemiology and risk factors, alongside differential diagnosis and personalized clinical management, are crucial for reducing the disease burden and enhancing patient quality of life.

Biomarkers are instrumental in identifying the main etiology of patients, stratifying risk, and predicting clinical outcomes (5). The discovery and verification of diagnostic or prognostic biomarkers for ARDS aid in screening high-risk populations and phenotypic analysis. Biomarkers used to identify alveolar and bronchiolar damage include surfactant protein D, Krebs von den lungen-6 (KL-6), and soluble receptor for advanced glycation end-products (sRAGEs); endothelial injury and coagulation markers like gelsolin, thrombomodulin, protein C, endocan, plasminogen activator inhibitor-1 (PAI or PAI-1), angiopoietin-2, von Willebrand factor (vWF); and treatment response biomarkers, particularly those related to lung inflammation, infection, C-reactive protein (CRP), and white blood cells (WBCs) (5). As understanding of ARDS deepens, research on biomarkers, particularly those related to pulmonary inflammation, is expanding. Current studies are increasingly focusing on the role of immune deficiency in patient prognosis, aligned with the immunopathological mechanisms of ARDS (5,6), such as inflammatory disorder and increased pulmonary endothelial and epithelial permeability (6).

Acute hypoxic respiratory failure is a leading cause for admission of immunocompromised patients to the ICU (7), with ARDS occurring in 35–75% of this population (8). A post hoc analysis of LUNG SAFE data revealed that patients with compromised immune function experienced higher in-hospital mortality compared to those with normal immune function (52.4% vs. 36.2%, P<0.001) (9), indicating that immunosuppression may independently predict mortality in ARDS patients (10). Current research primarily focuses on the causes of immune deficiency in ARDS patients and its impact on the efficacy of standard clinical treatments. Immune deficiency can result from a range of conditions, including genetic diseases, acquired diseases like acquired immune deficiency syndrome (AIDS) and hematologic malignancies, as well as treatments such as prolonged corticosteroid or chemotherapy use (11). Additionally, patients with various chronic and critical illnesses also exhibit degrees of immune suppression (11,12). Consequently, some researchers suggest classifying immune suppression based on specific immune system deficits, namely neutropenia, impaired humoral immunity mediated by B lymphocytes, and impaired cellular immunity mediated by T lymphocytes (11). In terms of treatment correlation, while researchers focus on non-invasive ventilation or extracorporeal membrane oxygenation (ECMO), it is argued that immune-compromised status might not independently predict ECMO weaning failure in ARDS patients (13).

Currently, ARDS treatment encompasses ventilation therapy, prone positioning, extracorporeal support, neuromuscular blockade, and corticosteroids (14). However, the role of corticosteroids in ARDS, septic shock, community-acquired pneumonia, and other severe diseases remains controversial (15). A multicenter randomized controlled trial (RCT) in 17 ICUs in Spain found that early dexamethasone administration reduced both the duration of mechanical ventilation (between-group difference 4.8 days, P<0.0001) and overall mortality (between-group difference 15.3%, P=0.005) in patients with moderate-to-severe ARDS (16). Another systematic review of 14 RCTs indicated that low doses (no more than 10 mg/kg/day methylprednisolone) and prolonged courses (more than 7 days) of corticosteroid treatment reduced ARDS mortality [lower dose: relative risk (RR) =0.69; 95% confidence interval (CI): 0.51–0.93; P=0.02; longer-course therapy: RR =0.60; 95% CI: 0.37–0.99; P=0.04] (17). The most common adverse event was hyperglycemia, though no statistical association was established (16). However, another RCT investigating early methylprednisolone use suggested that corticosteroids might increase long-term mortality if initiated 14 days after ARDS onset (18). These studies primarily focus on the effectiveness and optimal regimen of corticosteroids in treating ARDS patients, without deeply exploring the reasons for these variances in mortality associated with initiation of corticosteroids.

This study aims to investigate risk factors that may influence the effectiveness of corticosteroid treatment in ARDS patients through a retrospective cohort design. It further analyzes whether these factors can serve as independent risk factors for ARDS and identify patients who might benefit more from varying doses of corticosteroid treatment. These results could highlight the clinical significance of such risk factors in ARDS, providing a potential prediction system for ARDS prognosis assessment and a reference for personalized treatment of different ARDS subgroups. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-109/rc).

Methods

Study patients and design

This single-center, retrospective cohort study was conducted at Zhongshan Hospital, Fudan University, Shanghai, China. We identified adult ARDS patients admitted between January 24, 2008, and September 12, 2022, according to the American European Consensus Conference (AECC) criteria, which defined the time of onset, imaging characteristics, oxygenation function, and so on (19). Considering the sample size distribution and data characteristics, we selected 2017 as the time node. The discovery dataset included patients admitted after 2017, while the validation dataset comprised those admitted before 2017. The primary source population consisted of patients experiencing respiratory failure during the study period. Eligible patients were 18 years or older, diagnosed with ARDS based on AECC criteria, which include initial clinical symptoms (such as pneumonia, aspiration, sepsis, and pancreatitis) or worsening respiratory symptoms within a week, bilateral lung infiltration on chest imaging, and hypoxemia. Exclusion criteria encompassed pregnancy or lactation, brain death, severe chronic obstructive pulmonary disease, or congestive heart failure. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Zhongshan Hospital, Fudan University (No. 2021SQCJ2640) and individual consent for this retrospective analysis was waived.

In the discovery dataset, patients were categorized into “no corticosteroid treatment”, “low-dose corticosteroid treatment”, and “high-dose corticosteroid treatment” groups based on their maximum daily methylprednisolone equivalent. We compared baseline characteristics, clinical treatment courses, and outcomes across these groups and analyzed risk factors affecting the primary outcome. The study then examined the impact of this risk factor on the prognosis of different patient subgroups, with results further validated in the validation dataset. The study also discussed the impact on the efficacy of different corticosteroid doses, aiming to provide a basis for personalized medication in ARDS patients.

Definitions

We classified ARDS patients into different severity categories based on the Berlin criteria (4): mild ARDS as 200 mmHg > PaO₂/FiO₂ ≤300 mmHg, moderate ARDS as 100 mmHg > PaO₂/FiO₂ ≤200 mmHg, and severe ARDS as PaO₂/FiO₂ ≤100 mmHg.

The low-dose corticosteroid treatment group primarily comprised ARDS patients receiving a maximum daily dose of less than 80 mg of methylprednisolone equivalent. Conversely, the high-dose group included ARDS patients with a daily dose exceeding 80 mg. To ensure consistency, doses of various corticosteroids, including cortisone, dexamethasone, prednisone, and hydrocortisone, were converted to their methylprednisolone equivalents, considering that 4 mg of methylprednisolone is equivalent to 0.75 mg dexamethasone, 20 mg hydrocortisone, 25 mg cortisone, or 5 mg prednisone (20).

Patients classified as having immune deficiency included those on long-term (>3 months) or high-dose (>0.5 mg/kg/day) steroid therapy or other immunosuppressants, recipients of solid organ transplants, patients with solid tumors or hematological malignancies undergoing chemotherapy within the past 5 years, and those with primary immune deficiencies (i.e., X-linked agammaglobulinemia, DiGeorge syndrome, etc.), regardless of the time since diagnosis and treatment (21).

Data collection

Data were extracted and compiled from the medical record system, including: (I) basic demographic characteristics: age, sex, smoking status, immune deficiency status, pathogenesis, comorbidities, experimental examination results, and Acute Physiologic and Chronic Health Evaluation (APACHE) II score; (II) corticosteroid usage, administered intravenously (including cortisone, methylprednisolone, dexamethasone, prednisone, and hydrocortisone), with dosages converted to methylprednisolone equivalents, and duration of treatment for each patient; (III) respiratory support methods: noninvasive mechanical ventilation, invasive mechanical ventilation, and ECMO; and (IV) outcome measures: primary outcome was 28-day mortality post disease onset, with secondary outcomes including in-hospital mortality and hospitalization duration.

Statistical analysis

Statistical analysis was performed using Stata, version 17.0, with continuous variables grouped using X-tile, version 3.6.1. Categorical variables were expressed as percentages. Baseline characteristics, interventions, and outcomes between different corticosteroid dose groups, and between patients with or without immune deficiency, were compared using Pearson chi-squared test or Fisher’s exact test. Continuous variables were presented as median and interquartile ranges. One-way analysis of variance (ANOVA) or Kruskal-Wallis tests were employed to compare groups receiving different corticosteroid doses, while unpaired, two-tailed Student’s t-test or Mann-Whitney U test were used for comparisons between groups with or without immune deficiency. Kaplan-Meier curves and log-rank tests assessed survival outcomes across different severity subgroup multivariate Cox regression analyzed risk factors impacting patient survival and the effect of immune deficiency on corticosteroid treatment efficacy in various severity groups. All statistical analyses were two-sided, with a P<0.05 considered statistically significant.

Results

Risk factors associated with survival across different corticosteroid dose groups

In the discovery dataset, we compared basic characteristics, clinical treatments, pathological parameters, and prognoses among groups receiving various corticosteroid doses, as detailed in Table S1. Risk factors potentially influencing survival in these groups were analyzed using chi-squared test or Fisher’s exact test (Table S2). This analysis revealed associations between PaO₂/FiO₂, immune deficiency, neutrophil and lymphocyte counts, and overall and subgroup outcomes, suggesting these factors might influence the efficacy of corticosteroid treatment. Subsequently, multivariate Cox regression analysis was utilized to examine the relationship between potential risk factors and survival (Table S3), encompassing age, sex, smoking status, PaO₂/FiO₂, disease etiology, comorbidities, immune deficiency, platelet count (PLT), procalcitonin (PCT), prothrombin time (PT), and CRP. The findings indicated that immune deficiency could be a significant risk factor affecting therapeutic outcomes at different dosages.

Baseline patient characteristics

The study flow is depicted in Figure 1. We screened 6,110 patients with respiratory failure for ARDS, ultimately including 657 ARDS patients in the discovery and validation datasets. In the discovery dataset (n=357), 244 (68.35%) patients were male, with a median age of 67 [57–75] years. Of these, 160 (44.82%) had immune deficiencies, and 197 (55.18%) did not. The validation dataset (n=300) comprised 196 (65.33%) male patients with a median age of 63 [50–73] years, including 101 (33.67%) with immune deficiencies and 199 (66.33%) without (Table 1). Within the discovery dataset, 193 (54.06%) patients died within 28 days, and 219 (61.34%) died in-hospital. In the validation dataset, these outcomes were observed in 161 (53.67%) and 192 (64.00%) patients, respectively (Table 2).

Figure 1 Study design. In this study, 657 patients with ARDS were identified from 6,110 patients with respiratory failure. The association between the presence of immune deficiency and overall survival was studied in two randomly assigned patient datasets: a discovery dataset (n=357) and a validation dataset (n=300). The association between the presence of immune deficiency and the benefit of different doses of corticosteroid treatment was tested in a pooled database of 478 patients with mild to moderate ARDS and 179 patients with severe ARDS in two datasets. ARDS, acute respiratory distress syndrome.

Additional comprehensive characteristics and clinicopathological indicators are presented in Table 1 and Figure 2. Age distribution differed significantly between groups in the discovery dataset (P=0.009). In the validation dataset, except for smoking status, PaO₂/FiO₂ and comorbidities, all other parameters showed significant differences between groups. Both datasets showed notable differences in PT and interleukin (IL)-10.

Figure 2 Distribution of physiological parameters and comparison between groups in discovery dataset and validation dataset. The t-test or Mann-Whitney U test was used to compare any of the above physiological parameters between immune deficiency and non-immune deficiency groups. P1 and P2 represent the statistical test results of discovery dataset and validation dataset, respectively. The distributions of PT and IL-10 were different in both discovery and validation datasets. The difference in PLT between the two groups was only in the validation dataset, and the difference in IL-6 between the two groups was only in the discovery dataset. HCT, hematocrit; NEUT, neutrophil count; PT, prothrombin time; PLT, platelet count; CRP, C-reactive protein; Lym, lymphocyte count; IL, interleukin; TNF, tumor necrosis factor; IL-2R interleukin 2 receptor.

Independent risk factors for mortality in ARDS

After verifying the proportional hazards assumption, we conducted a multivariate Cox regression analysis (Figure 3), incorporating variables such as age, sex, smoking status, immune deficiency, disease severity, comorbidities (diabetes and chronic liver disease), and select physiological parameters (PLT, PCT, PT, CRP). IL-6 and IL-10 were excluded due to multicollinearity or significant data loss. The analysis identified immune deficiency [discovery dataset: hazard ratio (HR) =1.677; 95% CI: 1.192–2.359; P=0.003; validation dataset: HR =1.856; 95% CI: 1.266–2.721; P=0.002] and severe disease severity (discovery dataset: HR =1.551; 95% CI: 1.024–2.349; P=0.04; validation dataset: HR =3.104; 95% CI: 1.315–7.327; P=0.01) as independent risk factors for overall survival. Additionally, increased age in the discovery dataset (HR =1.013; 95% CI: 1.000–1.025; P=0.045) and elevated PCT in the validation dataset (HR =1.036; 95% CI: 1.013–1.059; P=0.002) were identified as potential, albeit weaker, risk factors for overall survival.

Figure 3 Multivariate cox regression analysis for overall survival and the corresponding forest plots. Multivariate cox regression analysis and forest plots were used to explore the association between possible risk factors and overall survival. Patients with immune deficiency and severe illness were risk factors for survival, both in discovery and validation datasets. Age may be related to survival in discovery dataset and PCT may be related to survival in validation dataset with weak association. HR, hazard ratio; CI, confidence interval; PaO₂, partial pressure of oxygen; FiO₂, fraction of inspired oxygen; PLT, platelet count; PCT, procalcitonin; PT, prothrombin time; CRP, C-reactive protein.

Relationship between immune deficiency and prognosis in patients with different severities of ARDS

To assess the impact of immune deficiency on the prognosis of ARDS patients of varying severities, Kaplan-Meier survival analysis was employed (Figure 4). In both the discovery (HR =1.638; 95% CI: 1.233–2.174) and validation datasets (HR =1.830; 95% CI: 1.334–2.510), non-immune deficiency patients exhibited significantly better overall survival compared to their immune-deficient counterparts, with the log-rank test results of both were P<0.001. These findings indicate that immune deficiency is potentially clinically significant for the survival outcome of ARDS patients.

Figure 4 Kaplan-Meier survival curves and log-rank test to evaluate the prognostic value of immune deficiency in discovery dataset and validation dataset. In the two datasets, stratified according to disease severity, survival curves, and log-rank test results were used to analyze the impact of immune deficiency on patient prognosis. For general and mild to moderate ARDS patients, the overall risk of death was higher in immune deficiency patients, and the difference was statistically significant. For patients with severe ARDS in discovery dataset, due to the existence of unknown confounding, “survival time >5 days” was included as a restriction in the analysis model for correction, and the results were consistent. HR, hazard ratio; CI, confidence interval; ARDS, acute respiratory distress syndrome.

We then categorized patients into mild-to-moderate and severe disease subgroups. Among those with mild-to-moderate ARDS, immune-deficient patients showed poorer survival in both the discovery (HR =1.719; 95% CI: 1.229–2.406; log-rank test P=0.001) and validation datasets (HR =1.874; 95% CI: 1.238–2.837; log-rank test P=0.002). Similar trends were observed in patients with severe ARDS (discovery dataset: HR =1.874; 95% CI: 1.007–3.488; log-rank test P=0.04; validation dataset: HR =1.698; 95% CI: 1.042–2.768; log-rank test P=0.03).

Relationship between immune deficiency and corticosteroid treatment benefits in patients with different severities of ARDS

Furthermore, we explored whether ARDS patients with immune deficiency could benefit from corticosteroid treatment. For immune-deficient ARDS patients, a relationship was noted between corticosteroid use and mortality risk. Compared to patients not receiving corticosteroids or those on high-dose treatment, those on low-dose corticosteroid therapy exhibited a lower mortality risk. This trend was consistent across both mild-to-moderate and severe ARDS patients (Table 3).

Further analysis revealed that immune deficiency and corticosteroid treatment may interactively affect overall patient survival. The interaction term statistics were lower than 0.001 and 0.005 for patients with mild-to-moderate and severe ARDS, respectively (Table 4). Considering these interactions, it was observed that patients with mild-to-moderate ARDS and immune deficiency could benefit from low-dose corticosteroid treatment (HR =0.409; 95% CI: 0.249–0.671). Similarly, patients with severe ARDS and immune deficiency might benefit from both low-dose (HR =0.299; 95% CI: 0.136–0.654) and high-dose corticosteroid treatments (HR =0.458; 95% CI: 0.214–0.981).

Discussion

This study initially analyzed risk factors affecting the prognosis of ARDS patients undergoing varying doses of corticosteroid treatment. Immune deficiency was found to influence the 28-day mortality and in-hospital mortality of these patients, demonstrating a beneficial response to different corticosteroid dosages. Additionally, subgroup analysis evaluating the severity of ARDS based on the Berlin criteria (PaO₂/FiO₂) indicated that immune deficiency acted as an independent risk factor for overall survival. Mild to moderate ARDS patients with immune deficiency benefited from low-dose corticosteroid treatment, while severe ARDS patients with immune deficiency benefited from both low and high doses.

Comparing immune-deficient and non-immune-deficient patients revealed that the former had a lower average age (discovery dataset: P=0.009; validation dataset: P=0.002), aligning with findings from Cortegiani et al. (9). ARDS patients with immune deficiency were more commonly affected by pulmonary inflammation (discovery dataset: 81.25% vs. 68.53%, P=0.006; validation dataset: 64.36% vs. 49.25%, P=0.01), and exhibited higher levels of PLT, PT, IL-6, and IL-10. These findings align with the conclusions of most current studies (9,10,13,22). However, Rilinger et al. (10) observed lower WBC, PLT, hemoglobin (HB), and hematocrit (HCT) levels in the immune-deficient group, speculating these as potential causes for increased mortality risk in these patients. Their study, however, only analyzed the impact of immune deficiency on patients with severe ARDS. The in-hospital mortality among our immune-compromised ARDS patients was higher than that in a post hoc analysis of LUNG SAFE data by Cortegiani et al. (9), where 584 (20.8%) of 2,813 ARDS patients were immune deficient.

The body’s immune defense mechanism plays a crucial role in the development of ARDS. Proinflammatory structural components and endogenous molecules related to cell damage can attach to Toll-like receptors on lung epithelial cells and alveolar macrophages, activating the innate immune system (23). The ensuing formation of neutrophil extracellular traps and release of histone proteins aid in capturing pathogenic microorganisms (24), along with the generation of reactive oxygen species, leukocyte proteases, chemokines, and cytokines to neutralize pathogens (25). However, while these mechanisms inhibit inflammation, they may also exacerbate lung injury. Thus, balancing their anti-infective effects and potential for alveolar damage is vital. Corticosteroids, widely used in ARDS since their inception (26,27), are linked to significant improvements in alveolar-capillary membrane permeability and the regulation of inflammation and tissue repair mediators (28). Ameliorating inflammation is fundamental to restoring homeostasis in ARDS patients (29). Variations in inflammation-related factors among immune-deficient patients may influence their prognosis and response to corticosteroid therapy.

Previous research indicates that certain cytokine levels are elevated in immune-deficient ARDS patients, yet levels of C-C motif chemokine ligand 22 (CCL22) are low (30). CCL22 recruits immunosuppressive regulatory T cells (Tregs) to modulate the local immune response (31,32), and diminished Treg levels may increase the likelihood of T lymphocyte dysregulation, potentially explaining the higher mortality in these patients. Additionally, considering the role of neutrophils in both ARDS pathogenesis and immune deficiency (1,33-35), changes in various biomarkers, pro-inflammatory cytokines, and chemokines in neutropenic patients are also noteworthy.

Most current studies have focused on the relationship between immune deficiency and non-pharmacological treatments, such as ventilation strategies, with less exploration into the response of immune-deficient patients to corticosteroid treatment. Our study integrated immune deficiency with disease severity to more accurately predict patient outcomes. Moreover, in analyzing the response to corticosteroids, we accounted for different dosages, potentially advancing personalized management of ARDS.

The study has several limitations. First, as a single-center retrospective cohort study, there are inherent risks of selection and reporting biases, and the potential for unknown confounders affecting the analysis. To mitigate this, patients were divided into discovery and validation datasets to enhance the reliability of the conclusions. Second, the study did not use the widely accepted Berlin definition to enroll ARDS patients, primarily due to limitations of the Berlin definition and the prolonged enrollment period, during which some patients in the validation cohort were diagnosed with ARDS prior to the introduction of the Berlin definition. Third, the classification of the immune-deficient population within the ARDS cohort was solely based on the definition and baseline characteristics of patients. Aside from malignancies and long-term corticosteroid use, current data struggle to accurately differentiate between immune-deficient and non-immune-deficient patients, potentially leading to misclassification bias. Fourth, the study did not consider the use of pharmacological and non-pharmacological treatments other than corticosteroids. However, the prognosis of patients with immune deficiency may depend on the nature of the underlying disease and associated treatments. The exclusion of these factors could limit the generalizability of our findings. Therefore, while our results may offer a foundation for personalized treatment of ARDS patients, due to the retrospective design of our study, the findings require validation through large-scale, multicenter, prospective studies.

Conclusions

This study showed that immune deficiency is an independent risk factor for mortality in ARDS. Patients with mild to moderate ARDS and immune deficiency may benefit from low-dose glucocorticoid treatment, while those with severe ARDS and immune deficiency may benefit from both low and high-dose glucocorticoid therapy, providing a basis for personalized medication in ARDS management.

Acknowledgments

Funding: This study was supported by the Shanghai Municipal Science and Technology Major Project (No. ZD2021CY001), the National Natural Science Foundation of China (Nos. 82130001, 82200090, and 82272243), the Science and Technology Commission of Shanghai Municipality (Nos. 20Z11901000, 20DZ2261200, 20XD1401200, and 22Y11900800), the Clinical Research Plan of SHDC (No. SHDC2020CR5010-002), the Shanghai Municipal Key Clinical Specialty (No. shslczdzk02201), and the Shanghai Municipal Health Commission and Shanghai Municipal Administrator of Traditional Chinese Medicine [No. ZY(2021-2023)-0207-01].

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-109/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-109/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-109/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-109/coif). Y.W. reports that this study was supported by the National Natural Science Foundation of China (No. 82200090). Y.S. reports that this study was supported by the Shanghai Municipal Science and Technology Major Project (No. ZD2021CY001), the National Natural Science Foundation of China (Nos. 82130001 and 82272243), the Science and Technology Commission of Shanghai Municipality (Nos. 20Z11901000, 20DZ2261200, 20XD1401200, and 22Y11900800), the Clinical Research Plan of SHDC (No. SHDC2020CR5010-002), the Shanghai Municipal Key Clinical Specialty (No. shslczdzk02201), and the Shanghai Municipal Health Commission and Shanghai Municipal Administrator of Traditional Chinese Medicine [No. ZY(2021-2023)-0207-01]. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Zhongshan Hospital, Fudan University (No. 2021SQCJ2640) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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