Correction: Feasibility of cystatin C as a biomarker for AECOPD severity: a cross-sectional study integrating CAT score, mMRC grade, and GOLD stage

Currently, AECOPD severity assessment primarily relies on clinical symptoms, pulmonary function testing, and scoring scales. The COPD Assessment Test (CAT) is a simple, reliable health status evaluation tool that reflects patient symptom burden (4). The modified Medical Research Council (mMRC) dyspnea scale is used to assess the degree of breathlessness (5). The Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging system evaluates airflow limitation severity based on pulmonary function assessment (6). However, these evaluation methods have limitations including high subjectivity and dependence on patient cooperation. Therefore, identifying objective, reliable biomarkers for AECOPD severity assessment is of paramount importance.Cystatin C (CysC) is a low molecular weight protein produced at a constant rate by all nucleated cells and is primarily eliminated through glomerular filtration (7). Compared to serum creatinine, cystatin C is not influenced by age, sex, muscle mass, or dietary factors, making it an ideal marker for assessing glomerular filtration rate (8). Recent studies have revealed that cystatin C not only reflects renal function status but is also closely associated with inflammatory responses, oxidative stress, and cardiovascular diseases (9-11). In the COPD field, studies have reported correlations between cystatin C levels and disease severity and prognosis (12,13), although systematic research on cystatin C in AECOPD severity assessment remains limited.While the role of cystatin C in COPD and inflammation has been initially explored, its potential as a biomarker for assessing disease severity and its specific diagnostic efficacy in hospitalized patients with acute exacerbations of COPD (AECOPD), particularly regarding the establishment of clinically guiding diagnostic cut-off values, still lack support from large-scale, high-quality research data. Existing studies often focus on stable COPD or fail to provide clear clinical application thresholds. Therefore, this study aims to bridge this gap by comprehensively evaluating the correlation between serum cystatin C and various AECOPD severity indicators through an in-depth analysis of a large cohort of hospitalized AECOPD patients. Furthermore, it seeks to first investigate its feasibility as a diagnostic marker for severe AECOPD and determine its optimal diagnostic cut-off value, with the aim of providing an objective and effective risk assessment tool for clinical practice.This study was a single-center, cross-sectional observational study. The research protocol was approved by the Medical Ethics Committee of our institution (approval number: 2021-KY-089), and written informed consent was obtained from all enrolled patients. The study was conducted in strict accordance with the Declaration of Helsinki and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.Inclusion Criteria: Consecutive enrollment of AECOPD patients hospitalized in the Department of Respiratory and Critical Care Medicine at our institution from 01 January 2024 to 31 December 2025. The inclusion criteria were as follows:①Age ≥40 years;②Meeting the COPD diagnostic criteria according to GOLD 2023 guidelines: post-bronchodilator FEV₁/FVC <0.70 (6);③Meeting AECOPD diagnostic criteria: worsening dyspnea, increased sputum volume and/or purulent sputum, with symptom changes exceeding daily variation and requiring modification of treatment regimen (14);④Completion of all examinations and assessments within 48 hours of admission;⑤Written informed consent obtained from patients or their legal guardians.Exclusion Criteria:①Concurrent respiratory diseases including bronchial asthma, bronchiectasis, pulmonary interstitial fibrosis, pulmonary embolism, or pneumothorax;②Acute coronary syndrome, acute heart failure, or severe cardiac arrhythmias;③Acute cerebrovascular disease;④Severe hepatic dysfunction (Child-Pugh Class C);⑤End-stage renal disease (eGFR <15 mL/min/1.73m²) or dialysis treatment;⑥Active malignancy or hematologic disorders;⑦Autoimmune diseases or use of immunosuppressive agents within the preceding 3 months;⑧Uncontrolled hyperthyroidism or hypothyroidism;⑨Pregnant or lactating women;⑩Inability to cooperate with CAT scoring, mMRC grading, or pulmonary function testing.The following data were collected by uniformly trained research personnel: Demographic information: gender and age. Physical examination: height, weight, body mass index (BMI), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Lifestyle factors: smoking history (defined as cumulative smoking ≥100 cigarettes) and alcohol consumption history (defined as alcohol intake ≥1 time per week on average in the past year). Medical history: diabetes mellitus (based on previous diagnosis or fasting plasma glucose ≥7.0 mmol/L or random blood glucose ≥11.1 mmol/L) and hypertension (based on previous diagnosis or systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg).Blood Sample Collection:All patients underwent fasting venipuncture (8-12 hours fasting) on the morning following admission. A total of 10 mL of cubital venous blood was collected and distributed into EDTA-K₂ anticoagulant tubes, sodium citrate anticoagulant tubes, and serum separator tubes. Samples were analyzed within 2 hours of collection or centrifuged and stored at -80°C.Laboratory Parameters:①Complete blood count: Neutrophil count (NEU, ×10⁹/L); monocyte count (MONO, ×10⁹/L); red blood cell count (RBC, ×10¹²/L); hemoglobin (Hb, g/L); absolute lymphocyte count (LYM, ×10⁹/L); platelet count (PLT, ×10⁹/L).②Coagulation function: D-dimer (mg/L). ③Biochemical markers: Fasting plasma glucose (FPG, mmol/L); creatinine (Cr, μmol/L); blood urea nitrogen (BUN, mmol/L); uric acid (UA, μmol/L); albumin (ALB, g/L); C-reactive protein (CRP, mg/L).④Cystatin C.Arterial Blood Gas Analysis：Radial arterial blood (1 mL) was collected from all patients at admission (before oxygen therapy or 30 minutes after discontinuing oxygen supplementation). Parameters included: pH value; partial pressure of carbon dioxide (PaCO₂, mmHg); partial pressure of oxygen (PaO₂, mmHg); base excess (BE, mmol/L); buffer base (BB, mmol/L); lactate (Lac, mmol/L); bicarbonate concentration (HCO₃⁻, mmol/L).CAT Score Assessment: The validated Chinese version of the COPD Assessment Test questionnaire was employed, encompassing eight domains: cough, sputum production, chest tightness, dyspnea when climbing hills/stairs, limitation in home activities, confidence in leaving home, sleep quality, and energy levels. Each item is scored from 0-5 points, with a total score ranging from 0-40 points. Based on scores, patients were categorized as follows: mild symptoms group (<10 points), moderate symptoms group (10-20 points), severe symptoms group (21-30 points), and very severe symptoms group (>30 points) (4).mMRC Grading: The modified Medical Research Council dyspnea scale was used to assess the degree of breathlessness, with grades ranging from 0-4 (5): Grade 0: breathlessness only during strenuous exercise; Grade 1: short of breath when hurrying on level ground or walking up a slight incline; Grade 2: walks slower than people of the same age on level ground due to breathlessness, or has to stop for breath when walking at own pace; Grade 3: stops for breath after walking approximately 100 meters or after a few minutes on level ground; Grade 4: too breathless to leave the house or breathless when dressing or undressing.GOLD Staging: Pulmonary function testing was performed after clinical stabilization (typically before discharge or on hospital days 5-7) using the German Jaeger MasterScreen PFT system. Staging was based on post-bronchodilator FEV₁ as a percentage of predicted values (6): GOLD Stage 1 (mild): FEV₁ ≥80% predicted; GOLD Stage 2 (moderate): 50% ≤ FEV₁ < 80% predicted; GOLD Stage 3 (severe): 30% ≤ FEV₁ < 50% predicted; GOLD Stage 4 (very severe): FEV₁ < 30% predicted.Comprehensive AECOPD Severity Classification: A comprehensive assessment combining clinical manifestations, laboratory findings, and arterial blood gas analysis was conducted: Mild: CAT score <10 points, no respiratory failure, no hospitalization required; Moderate: CAT score 10-20 points, or PaO₂ <60 mmHg without CO₂ retention; Severe: CAT score ≥21 points, or concurrent respiratory failure (PaO₂ <60 mmHg with PaCO₂ >50 mmHg), or requiring mechanical ventilation or ICU treatment.Statistical analyses were performed using SPSS 26.0, R 4. For comparisons between two groups, independent samples t-test was used for normally distributed data with equal variances, otherwise the Mann-Whitney U test was applied. For multiple group comparisons, one-way ANOVA was used for normally distributed data with equal variances, with post hoc comparisons performed using LSD-t test or Bonferroni correction; otherwise, the Kruskal-Wallis H test was employed with Dunn-Bonferroni method for pairwise comparisons. Categorical variables were compared using χ² test or Fisher's exact test. Trend analysis was conducted using linear trend χ² test or Jonckheere-Terpstra trend test.Bivariate correlations were assessed using Pearson correlation analysis for normally distributed variables and Spearman rank correlation analysis for non-normally distributed or ordinal variables. Partial correlation analysis was performed to examine correlations after controlling for confounding factors. Correlation coefficients were interpreted as follows: |r|<0.3 indicated weak correlation, 0.3≤|r|<0.5 moderate correlation, 0.5≤|r|<0.7 strong correlation, and |r|≥0.7 very strong correlation.Multiple linear regression analysis was conducted with CAT score as the dependent variable, incorporating variables with P<0.05 from univariate analysis into stepwise regression models after testing for multicollinearity (VIF<5 considered acceptable). Binary logistic regression was performed with severe AECOPD (CAT≥21 points) as the dependent variable to analyze the independent predictive effect of cystatin C. Three models were constructed: Model 1 (univariate analysis), Model 2 (adjusted for demographic characteristics including age, gender, and BMI), and Model 3 (further adjusted for clinical indicators including smoking history, diabetes, hypertension, CRP, and creatinine). Odds ratios (OR) with 95% confidence intervals (CI) were calculated, and model goodness-of-fit was evaluated using the Hosmer-Lemeshow test.ROC curve analysis was performed to evaluate the predictive performance of cystatin C for different severities of AECOPD, with calculation of area under the curve (AUC) and 95% CI. Optimal cutoff values were determined using the Youden Index Index and predictive predictive and were test was used to between different analysis was conducted to the between cystatin C and AECOPD with at the and to test for for were with P<0.05 considered total of AECOPD patients were enrolled in this and with a age of The average was the patients a smoking history, patients reported alcohol consumption diabetes mellitus in patients and hypertension in patients patients were by CAT scores, were in of age, systolic blood smoking history, diabetes hypertension, and COPD disease is in of laboratory different CAT score revealed associated with disease inflammatory and including cystatin CRP, fasting creatinine, blood urea and uric acid with CAT absolute lymphocyte red blood cell and albumin levels as CAT increased and platelet no between in C levels in the patient a with a of and of ranging from to patients cystatin C levels the comparisons revealed in cystatin C levels between all CAT score 1 the of cystatin C levels different CAT score blood gas changes to CAT score CAT pH values and PaO₂ levels PaCO₂ and lactate levels base buffer and bicarbonate between in CAT in the patient from 4 to points, with a of and of points. severity was as follows: mild group moderate group severe group and very severe group mMRC dyspnea scale Grade Grade 1 Grade 2 Grade 3 and Grade 4 was between mMRC and CAT score staging Stage 1 Stage 2 Stage 3 and Stage 4 The FEV₁ percentage of predicted was C levels a mMRC dyspnea grades ANOVA revealed between mMRC grades C levels increased stepwise from in Grade to in Grade a Spearman correlation analysis a strong correlation between cystatin C and mMRC comparisons with Bonferroni revealed between all grades between Grade and Grade 1 cystatin C levels an trend GOLD ANOVA C levels from in GOLD Stage 1 to in GOLD Stage an Spearman correlation analysis revealed a correlation between cystatin C and GOLD staging correlation analysis strong between cystatin C and multiple disease severity C a strong correlation with CAT and mMRC dyspnea a moderate correlation with GOLD staging in and in evaluate the of these from potential confounding factors, partial correlation analysis was performed after controlling for age, gender, smoking history, diabetes, hypertension, and creatinine levels. 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