Krebs von den Lungen-6 as a potent indicator of the frequency of chronic obstructive pulmonary disease exacerbation

Abstract

Objective

To evaluate the potential of systemic Krebs von den Lungen-6 level in predicting acute exacerbations of chronic obstructive pulmonary disease.

Methods

This two-phase study included a derivation phase (January 2022 to December 2022) involving 156 patients with stable chronic obstructive pulmonary disease, in which optimal Krebs von den Lungen-6 thresholds were identified through multivariate modeling. Serum levels of Krebs von den Lungen-6 and surfactant protein D were analyzed for correlations with exacerbation frequency, Chronic Obstructive Pulmonary Disease Assessment Test score, modified British Medical Research Council score, forced expiratory volume in 1 second percent predicted, and forced expiratory volume in 1 second/forced vital capacity ratio. Prospective validation was performed in a separate cohort (January 2023 to December 2023, n = 121) stratified by Krebs von den Lungen-6 thresholds.

Results

Krebs von den Lungen-6 and surfactant protein D levels were significantly correlated with exacerbation frequency, Chronic Obstructive Pulmonary Disease Assessment Test, and modified British Medical Research Council scores and were inversely associated with forced expiratory volume in 1 second percent predicted and forced expiratory volume in 1 second/forced vital capacity ratio. Multivariate analysis identified Krebs von den Lungen-6, but not surfactant protein D, as an independent predictor of high-exacerbation phenotypes (≥2 events/year). In the validation phase, the high-Krebs von den Lungen-6 group (≥400.5 U/mL) exhibited significantly higher annual exacerbation rates than the low-Krebs von den Lungen-6 group after adjustment for baseline characteristics.

Conclusions

Serum Krebs von den Lungen-6 at ≥400.5 U/mL is an independent risk factor for frequent exacerbations of chronic obstructive pulmonary disease. Its association with inflammatory markers and lung function decline suggests potential utility in personalized treatment strategies.

Keywords

Krebs von den Lungen-6 risk factor prediction stable chronic obstructive pulmonary disease exacerbation

Introduction

Chronic obstructive pulmonary disease (COPD), a chronic inflammatory respiratory disorder that poses a significant global health burden, ranks as the fifth leading cause of mortality in China and the fourth worldwide.^1,2 Persistent systemic inflammatory responses are associated with abnormal mucus secretion and unfavorable clinical outcomes in patients with COPD. Chronic low-grade inflammation serves as a critical driver of recurrent acute episodes.³ These pathophysiological interactions contribute to accelerated disease progression, deteriorated health-related quality metrics, and increased mortality risks.^4,5 Reducing the frequency of COPD exacerbations is a key therapeutic objective within this clinical framework, underscoring the importance of modeling in exacerbation risk stratification during post-diagnostic monitoring.^6,7

A defining clinical characteristic of COPD is the occurrence of acute exacerbation of COPD episodes (AECOPDs), marked by abrupt symptom deterioration and a substantial disease burden.^8,9 These recurrent events are associated with increased mortality, accelerated decline in pulmonary function, and impaired health-related quality of life.¹⁰ Consequently, prophylactic strategies aimed at preventing AECOPDs are crucial for the effective management of patients with COPD. Notably, clinical manifestations vary markedly among patients; certain patient subgroups maintain prolonged clinical stability, whereas others experience frequent exacerbations despite optimized therapeutic interventions.¹¹ The frequent exacerbation phenotype is clinically defined by the occurrence of two or more AECOPDs per year.¹⁰ Minimizing the frequency of these exacerbations remains a central objective in COPD management. Moreover, accurately forecasting the incidence of acute exacerbations in the year following diagnosis is particularly relevant. Therefore, identifying potential biomarkers that facilitate in assessing the risk of future acute exacerbations is essential for effectively managing patients with COPD.

Blood biomarkers represent a promising option owing to their ease of collection and potential for standardized measurement protocols. Various inflammatory biomarkers, such as C-reactive protein (CRP), exhibit strong associations with disease severity and may be linked to adverse health outcomes in patients with mild-to-moderate disease.¹² Although CRP is a reliable indicator of cardiovascular events, its effectiveness as a predictive marker for respiratory health outcomes or lung function decline remains limited.^13,14 The primary source of circulating CRP is the liver rather than the lungs.¹⁵ Therefore, identifying lung-specific biomarkers is essential for monitoring respiratory health events.^12,14

Surfactant protein D (SP-D) and Krebs von den Lungen-6 (KL-6) are primarily synthesized in the lungs and may serve as valuable markers for tracking disease progression and assessing the health status of patients with COPD.^16–18 Although SP-D and KL-6 play important roles in the pathophysiology of COPD, the relationship between their circulating levels and AECOPDs remains unclear.^19,20 To address this gap, we conducted a cohort study to examine the correlation between serum KL-6 concentrations and the frequency of AECOPDs during a 1-year follow-up and provide further evidence supporting KL-6 as a potential biomarker for AECOPDs.

Methods

Study design and cohort selection

This study was conducted in two phases. In the first phase, serum KL-6 concentrations in patients with stable COPD (n = 156) were retrospectively analyzed from January 2022 to December 2022 to establish the optimal diagnostic threshold for predicting acute exacerbation frequency. In the second phase, an outpatient cohort (n = 121) was prospectively enrolled between January 2023 and December 2023. Using the predefined cutoff, patients were stratified into low- and high-KL-6 subgroups. All participants were prospectively monitored every 3 months for 12 months to record exacerbation events. The study protocol is illustrated in Figure 1.

Figure 1.

Study flow diagram. COPD: chronic obstructive pulmonary disease; KL-6: Krebs von den Lungen-6.

This investigation was conducted in strict accordance with the ethical principles for medical research involving human subjects, as outlined in the World Medical Association’s Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of Pingxiang People’s Hospital (Jiangxi Province, China; Ethics Approval Code: SW-2023Z065-HS02). All patient details were de-identified for this study. All eligible participants provided written informed consent before enrollment, in compliance with institutional regulations and international research governance standards.

Retrospective analysis

Eligible participants were consecutively enrolled through the Department of Respiratory and Critical Care Medicine at a tertiary care center in southern China. The inclusion criteria were as follows: (a) confirmed diagnosis of COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria; (b) age of ≥40 years at enrollment; (c) documented adherence to maintenance therapy with inhaled corticosteroids (ICS) and bronchodilators for ≥30 consecutive days; (d) clinical stability, defined as the absence of acute exacerbations requiring antimicrobial therapy or systemic corticosteroids in the 30 days preceding enrollment; and (e) provision of written informed consent and demonstrated ability to complete the questionnaire. Patients with clinically significant comorbidities (cardiovascular, metabolic, or neoplastic disorders) or concurrent respiratory conditions (asthma, interstitial lung disease, or bronchiectasis) were excluded from the study.

Comprehensive clinical parameters, including demographic characteristics, smoking history, diagnostic classification, annualized AECOPD rates, pulmonary function measurements, COPD Assessment Test (CAT) scores, modified British Medical Research Council (mMRC) dyspnea grades, and complete hematological profiles with therapeutic regimens, were extracted from institutional electronic health records. Serum KL-6 and SP-D concentrations were measured using enzyme-linked immunosorbent assay (ELISA) kits (Beyotime Biotechnology, Shanghai, China). A predictive threshold for AECOPD frequency was determined using receiver operating characteristic (ROC) curve analysis, and the biomarker-derived cutoff value was subsequently applied in the longitudinal validation cohort.

Procedures in the 1-year follow-up study

The inclusion criteria for the longitudinal study were consistent with those used in the retrospective analysis. Baseline assessments, including pulmonary function tests, CAT scores, mMRC dyspnea scale ratings, and hematological parameters, were performed during the initial visit. Participants were evaluated in the outpatient clinic every 3 months. In cases of COPD symptom exacerbation requiring medical attention, patients were instructed to contact the study physician immediately and visit the hospital promptly. For patients in a stable phase who were unable to attend in-person follow-ups, telephone interviews were conducted biannually to assess the frequency of acute exacerbations. Throughout the 1-year follow-up period, AECOPDs were documented and verified using medical records and treatment histories.

Clinical outcome assessments

Participants were evaluated using the CAT and the mMRC dyspnea scale at enrollment. Pulmonary function tests were performed in the hospital’s respiratory diagnostics unit in accordance with established guidelines, and the results obtained within the preceding 6 months were considered valid. Comprehensive hematological analyses, including complete blood counts and serum biochemical profiles, were conducted. Serum concentrations of KL-6 and SP-D were quantified using a commercially available ELISA kit.

Ethics

Our study was conducted in accordance with the ethical principles for medical research involving human subjects outlined in the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Pingxiang People’s Hospital, and written informed consent was obtained from all participants before enrollment. All patient data were anonymized, and confidentiality was strictly maintained.

Statistical analyses

Statistical evaluations were performed using Statistical Package for the Social Sciences (SPSS) version 22.0 (IBM Corp., Armonk, NY, USA). Data normality was assessed using the Shapiro–Wilk test. Continuous variables with normal distributions were presented as mean ± SD, whereas nonparametric data were expressed as medians with interquartile ranges (IQRs). Bivariate correlations were analyzed using Spearman’s rank correlation coefficient. Binary logistic regression models were applied to identify independent associations between serum KL-6 concentrations and the frequency of acute exacerbations. The diagnostic accuracy of KL-6 was evaluated using ROC curve analysis. Categorical variables were compared using the chi-square test, and nonparametric variables were analyzed using the Mann–Whitney U test. A two-tailed p-value of <0.05 was considered statistically significant.

Results

Demographic and clinical characteristics

The retrospective cohort comprised 156 patients with clinically stable COPD who received care at our tertiary center between January 2022 and December 2022. Table 1 presents the baseline characteristics of this cohort, including demographic data, clinical indices, pulmonary function parameters, and hematological markers. The median annual acute exacerbation rate was 1.00, and 44.9% (n = 70) of patients experienced recurrent exacerbations (≥2 events/year). The median serum KL-6 concentration was 230.1 U/mL (IQR: 127.80–445.4).

Table 1.

Characteristics of patients with COPD (n = 156).

Variables	Median (IQR)/n (%)
Demographic
Age (years; median, IQR)	72.0 (67.0, 79.0)
Male/Female (n, %)	120/36 (76.9/23.1)
BMI (kg/m²; median, IQR)	23.2 (20.1, 25.1)
Smoking status (n, %)
Smoker	118 (75.6)
Ex-smoker	20 (12.8)
Clinical symptoms
Course of disease (years; median, IQR)	7.0 (5.0, 10.0)
Frequency of acute exacerbation in the past 1 year (median, IQR)	1.0 (1.0,2.0)
Exacerbation frequency >2 (n, %)	70 (44.9)
CAT score (median, IQR)	15.0 (13.0, 17.0)
mMRC score (median, IQR)	1.0 (1.0, 2.0)
Lung function
FEV₁ (L; median, IQR)	1.3 (1.2, 1.5)
FEV₁ (%pred) (median, IQR)	54.0 (47.7, 65.1)
FEV₁/FVC% (median, IQR)	55.5 (49.4, 67.6)
Hematological indexes
WBC (×10⁹/L; median, IQR)	7.0 (5.0, 9.6)
CRP (mg/L; median, IQR)	9.2 (5.1, 15.0)
IL-6 (pg/mL; median, IQR)	9.5 (6.2, 20.6)
SP-D (pg/mL; median, IQR)	68.3 (54.3, 93.8)
KL-6 (pg/mL; median, IQR)	230.1 (127.8, 445.4)

Significant difference is a p-value of <0.05.

COPD: chronic obstructive pulmonary disease; IQR: interquartile range (25th–75th percentile); n: number; BMI: body mass index; CAT: Chronic Obstructive Pulmonary Disease Assessment Test; mMRC: modified British Medical Research Council; FEV₁: forced expiratory volume in 1 ;second; FEV₁%pred: FEV₁ as a percentage of the predicted value; FVC: forced vital capacity; WBC: white blood cell count; CRP: C-reactive protein; IL-6: interleukin-6; SP-D: surfactant protein D; KL-6: Krebs von den Lungen-6.

Association between serum KL-6 and SP-D levels and clinical features in patients with COPD

The associations between circulating SP-D and KL-6 levels and clinically relevant parameters predictive of COPD progression were analyzed. Serum KL-6 concentrations showed significant positive correlations with annualized acute exacerbation rates (r = 0.781), CAT scores (r = 0.645), and mMRC dyspnea grades (r = 0.532) (all p < 0.001). In contrast, KL-6 levels were inversely correlated with post-bronchodilator forced expiratory volume in 1 second percent predicted (FEV₁%pred) (r = −0.212) and the forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) ratio (r = −0.174) (both p < 0.05). SP-D exhibited similar but weaker correlations with these clinical indices than KL-6 (Table 2).

Table 2.

Correlation between KL-6, SP-D, and clinical data.

Variables	SP-D		KL-6
Variables	r	p-value	r	p-value
Frequency of acute exacerbation in the past 1 year	0.738	<0.001	0.781	<0.001
CAT score	0.614	<0.001	0.645	<0.001
mMRC score	0.477	<0.001	0.532	<0.001
FEV₁/FVC%	−0.216	0.007	−0.174	0.029
FVC (%pred)	−0.331	<0.001	−0.212	0.007

Significant difference is a p-value of <0.05.

CAT: Chronic Obstructive Pulmonary Disease Assessment Test; mMRC: modified British Medical Research Council; FEV₁: forced expiratory volume in 1 second; FEV₁%pred: FEV₁ as a percentage of the predicted value; FVC: forced vital capacity; SP-D: surfactant protein D; KL-6: Krebs von den Lungen-6.

KL-6 elevation as a risk factor for ≥2 AECOPDs

The frequency of AECOPDs is a key determinant of patient prognosis. According to the GOLD classification, experiencing two or more exacerbations per year indicates greater disease severity and categorizes patients as group E. Based on the observed correlations between serum KL-6, SP-D levels, and acute exacerbation frequency (Table 2), we performed binary logistic regression analysis to identify risk factors for recurrent exacerbations (≥2 events/year). Elevated serum KL-6 concentrations were significantly associated with an increased risk of recurrent exacerbations within 1 year (odds ratio (OR), 1.012), supporting KL-6 as a predictive biomarker for exacerbation frequency (Table 3).

Table 3.

Risk factors of the frequency of acute exacerbation of COPD ≥2 using binary regression analysis.

Variables	OR	95% CI	p
SP-D	0.991	0.982–1.012	0.424
KL-6	1.012	1.001–1.015	<0.001

SP-D: surfactant protein D; KL-6: Krebs von den Lungen-6; OR: odds ratio; CI: confidence interval.

ROC curve analysis of KL-6 in predicting the frequency of acute exacerbations

Serum KL-6 levels effectively predicted the risk of recurrent acute exacerbations (≥2 events/year) in patients with COPD. As illustrated in Figure 2, the ROC curve analysis demonstrated excellent diagnostic accuracy, with an area under the curve (AUC) of 0.925 (95% confidence interval (CI): 0.884–0.966; p < 0.001). Using the optimal cutoff value of 400.5 U/mL, serum KL-6 predicted recurrent COPD exacerbations with a sensitivity of 81.8% and a specificity of 91.1%.

Figure 2.

ROC curve analysis of KL-6 in predicting the frequency of AECOPD ≥2. ROC: receiver operating characteristic; KL-6: Krebs von den Lungen-6; AECOPD: acute exacerbation of chronic obstructive pulmonary disease.

Frequency of acute exacerbations by group after 1-year follow-up

Based on the predefined threshold, patients with COPD were categorized into low KL-6 (<400.5 U/mL) and high KL-6 (>400.5 U/mL) cohorts. No significant differences were observed between the two groups in terms of demographic characteristics, pulmonary function parameters, CAT scores, or mMRC dyspnea scale assessments (Table 4). However, the frequency of AECOPDs over 1 year was significantly higher in the high KL-6 group than in the low KL-6 group (2.00 vs. 1.00, p < 0.001). Furthermore, a greater proportion of patients in the high KL-6 group experienced ≥2 exacerbations than in the low KL-6 group (79.31% vs. 38.89%, p = 0.001).

Table 4.

Comparison of the frequency of acute exacerbation between different groups after 1-year follow-up.

Variables	Low KL-6 (n = 76)	High KL-6 (n = 45)	p-value
Demographic
Age (years; median, IQR)	72.0 (66.8, 77.0)	72.0 (68.0, 79.0)	0.347
Male (n, %)	58 (76.3)	35 (77.8)	0.854
Smokers (n, %)	52 (68.4)	37 (82.2)	0.096
BMI (kg/m²; median, IQR)	23.6 (21.2, 25.1)	23.1 (20.8, 25.0)	0.7172
Clinical
Frequency of acute exacerbation in the past 1 year (median, IQR)	1.0 (1.0, 2.0)	2.0 (1.0,3.0)	0.001
Exacerbation frequency >2 (n, %)	29 (38.2)	34 (75.5)	<0.001
CAT score (median, IQR)	15.0 (13.0, 17.0)	16.0 (14.0, 18.0)	0.376
mMRC score (median, IQR)	1.0 (1.0, 2.0)	2.0 (1.0, 2.0)	0.093
Lung function (%)
FEV₁%pred (median, IQR)	55.1 (47.7, 63.3)	54.2 (48.2, 66.0)	0.8792
FEV₁/FVC% (median, IQR)	55.6 (50.8, 67.2)	56.2 (48.6, 69.3)	0.7742
Hematological indexes
SP-D (pg/mL, median, IQR)	68.3 (56.6, 89.7)	71.3 (57.0, 104.7)	0.2122
KL-6 (U/mL, median, IQR)	168.0 (123.9, 255.3)	441.1 (252.1, 726.0)	<0.001

KL-6: Krebs von den Lungen-6; IQR: interquartile range (25th–75th percentile); n: number; BMI: body mass index; CAT: Chronic Obstructive Pulmonary Disease Assessment Test; mMRC: modified British Medical Research Council; FEV₁: forced expiratory volume in 1 second; FEV₁%pred: FEV₁ as a percentage of the predicted value; FVC: forced vital capacity; SP-D: surfactant protein D.

Discussion

Acute exacerbations play a vital role in the progression of COPD. Therefore, accurately predicting the frequency of such episodes within the following year is essential for optimizing disease management. Our findings indicate that elevated serum KL-6 levels measured during the stable phase of COPD are associated with a higher frequency of AECOPDs during a 1-year follow-up period. These results suggest that KL-6 may serve as a valuable biomarker to enhance the predictive accuracy of clinical models for exacerbation risk.

Exacerbation frequency has a major impact on the health status and quality of life of patients with COPD.^7,21 Previous studies have demonstrated its pivotal role in influencing the natural course of the disease.²² Recurrent acute exacerbations substantially contribute to long-term pulmonary function decline in patients with COPD.²² Furthermore, individuals who experience frequent exacerbations within a single year are at a greater risk of sustained high-exacerbation rates in subsequent years.²³ Patients with severe COPD are particularly vulnerable to severe exacerbations, often presenting with acute respiratory failure.⁸ The development of new therapeutic strategies for COPD has been hindered by the lack of reliable surrogate biomarkers for monitoring disease progression and predicting clinical outcomes.^24,25 Serum biomarkers offer practical advantages due to established protocols for sample collection, processing, and measurement standardization.^25–27 Despite its common use in COPD research, CRP reflects nonspecific systemic inflammation.^15,28 Therefore, extrapulmonary comorbidities and infections complicate the interpretation of CRP levels.^12–14 In our study, two lung-derived serum biomarkers, KL-6 and SP-D, were assessed as predictors of clinical outcomes in patients with COPD. Our findings indicate that circulating KL-6 levels are strongly correlated with exacerbation frequency and dynamically reflect changes in patient health status over 1 year.

KL-6 is a highly glycosylated macromolecule with mucin-like properties.^18,29 It is primarily expressed in the membranes of type II pneumocytes within pulmonary alveoli.³⁰ Therefore, elevated serum KL-6 levels indicate alveolar epithelial injury, particularly following disruption of the alveolar–capillary barrier.^30,31 Clinical studies have shown that increased KL-6 levels correspond to changes in blood–gas barrier permeability.^29,30 In patients with acute respiratory distress syndrome (ARDS), elevated KL-6 levels are strongly correlated with cytokine-driven inflammation.³² Thus, KL-6 serves as a useful biomarker for monitoring epithelial–endothelial dysfunction during systemic inflammation.¹⁹ Altered KL-6 levels have also been associated with the progression of several pulmonary diseases, including idiopathic pulmonary fibrosis, asthma, acute lung injury, and COVID-19.^32,33 Additionally, KL-6 concentrations are higher in patients with COPD than in healthy individuals. In the present study, the relationship between serum KL-6 levels and the clinical characteristics of COPD in 156 stable patients at our institution were investigated. Our results demonstrated that KL-6 levels were positively correlated with COPD severity scores and the frequency of acute exacerbation in the preceding year. These findings confirm the prognostic utility of KL-6 for assessing outcomes in AECOPD. Accordingly, clinicians should consider intensifying treatment strategies and initiating early interventions when elevated KL-6 levels are detected during hospitalization.

Management strategies guided by KL-6 levels may substantially reduce hospitalization duration and the risk of recurrent acute exacerbations. The diagnostic and prognostic value of KL-6 in patients with COPD presents a promising framework for personalized clinical management, as timely and targeted interventions may mitigate the future disease burden associated with COPD. Therefore, elevated plasma KL-6 represents an important pathobiological marker for the onset and progression of the disease.

Airway remodeling, a major contributor to airway obstruction in COPD, is generally considered a consequence of abnormal mucus production.⁴ This process is associated with decline in lung function and increased frequency of COPD exacerbations.^8,34 Another lung-specific biomarker, SP-D, has been linked to disease severity and adverse health outcomes in patients with mild-to-moderate COPD.^16,35 Therefore, we also assessed SP-D concentrations as a potential lung-specific biomarker for monitoring clinical outcomes in patients with COPD. KL-6 and SP-D levels were positively correlated with acute exacerbation frequency and higher CAT and mMRC scores and negatively correlated with FEV₁%pred and FEV₁/FVC ratio, indicating that elevated levels of these markers were associated with worse clinical outcomes. However, binary logistic regression analysis identified KL-6, but not SP-D, as an independent predictor of ≥2 AECOPD events/year. Mucus hypersecretion also emerged as a key clinical feature across all GOLD stages. ROC curve analysis determined the optimal predictive threshold for KL-6 to be 400.5 U/mL (AUC = 0.82).

To assess the prognostic potential of KL-6 while controlling for confounding variables, we used propensity score matching based on age, sex, smoking history, and baseline clinical parameters (CAT score, mMRC grade, and lung function). In our cohort of 121 patients with COPD, stratification according to KL-6 thresholds identified low- and high-risk subgroups. The high KL-6 subgroup demonstrated a greater frequency of exacerbations (79% vs. 39% of patients with multiple exacerbations). These findings confirm that KL-6 serves as a robust longitudinal biomarker in patients with COPD and an independent predictor of exacerbation risk in chronic airway diseases.

The mechanistic role of KL-6 in COPD pathogenesis remains unclear. Evidence from other pulmonary disorders suggests several possible mechanisms.^17,18 KL-6 serves as a biomarker of structural lung damage and airway remodeling in severe asthma and may promote pulmonary fibroblast motility and suppress apoptosis.^19,29 Chronic inflammation, a hallmark of COPD pathophysiology, involves smoke- or pathogen-induced activation of inflammatory cascades, epithelial cell-driven cytokine release (TNF-α, IL-1β, IL-6, and IL-8), and subsequent tissue injury.^20,30 Elevated KL-6 levels are also strongly correlated with inflammatory markers such as CRP and IL-6 in patients with COPD.¹⁷ Thus, KL-6 may act as an inflammatory mediator released during alveolar damage-induced cytokine storms.^20,30 We propose that chronic exposure to cigarette smoke disrupts the alveolar epithelium and basement membrane, leading to KL-6 elevation. However, this hypothesis requires validation through mechanistic studies using cellular and animal models.

This study has several limitations. Our findings were derived from a single center, and the relatively small sample size may limit the generalizability and reliability of the results. Therefore, further validation through multicenter studies with larger cohorts is warranted.

Conclusion

Frequent exacerbations of COPD, driven by persistent systemic inflammation, markedly impair quality of life and shorten life expectancy. Monitoring serum KL-6 levels may serve as a valuable approach for predicting exacerbation risk in the following year, enabling timely and effective preventive interventions by both clinicians and patients.

Footnotes

Acknowledgments

We thank all patients for their participation. The authors thank all of the medical staff in the laboratory and respiratory departments.

Author contributions

XLC conceived and designed the study. ZPY and SHL collected the data and performed the literature search. JHC was involved in the writing of the manuscript. All authors read and approved the final manuscript.

Data availability statement

The data generated in the present study are available from the corresponding author upon reasonable request.

Declaration of conflicting interest

The authors declare that they have no competing interests.

Funding

The study was supported by the Jiangxi Provincial Health Commission Science and Technology Project Plan (Number: 202311691).

ORCID iD

Xiaolin Chen

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