Serum Cytokeratin 18 and Fragment as Biomarkers for Severity and Prognosis in Acute Exacerbation of Chronic Obstructive Pulmonary Disease

Abstract

Background: Cytokeratin (CK)18 is present in the bronchi and alveolar epithelium of the lung, and its cleavage product, CK-18M30, serves as a biological marker of apoptosis. However, the specific roles of CK-18 and CK-18M30 in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) remain unclear.

Methods: This study enrolled 289 patients with AECOPD who met the inclusion criteria. Demographic information and clinical characteristics of the patients were documented. A 3-year follow-up period was implemented to evaluate acute exacerbations and mortality. Serum CK-18 and CK-18M30 concentrations were measured using enzyme-linked immunosorbent assays.

Results: Serum concentrations of CK-18/CK-18M30 at admission in patients with AECOPD were higher than those in the control group. As severity increased, serum CK-18/CK-18M30 levels increased progressively in AECOPD patients. Pearson's correlation analysis revealed that serum CK-18/CK-18M30 concentrations were positively correlated with several clinical parameters. Linear and logistic regression models demonstrated positive correlations between serum CK-18 and CK-18M30 levels at admission and severity scores. Furthermore, higher serum CK-18/CK-18M30 levels at admission were associated with increased frequency of death and acute exacerbation in patients with AECOPD within 3 years.

Conclusion: Serum CK-18/CK-18M30 levels at admission were positively correlated with severity and poor prognosis in patients with AECOPD within 3 years. Therefore, serum CK-18 and CK-18M30 concentrations may serve as novel diagnostic and prognostic biomarkers for patients with AECOPD.

Keywords: AECOPD; CK-18M30; Cohort study; Cytokeratin 18; Prognosis; Severity.

Fig. 1

The levels of serum CK-18/CK-18M30 in AECOPD patients and control subjects at baseline and follow-up periods. A–D The levels of CK-18 and CK-18M30 were detected in serum of AECOPD patients and healthy volunteers via ELISA at baseline and follow-up periods. A The level of serum CK-18 in AECOPD patients and control subjects at baseline. B The level of serum CK-18M30 in AECOPD patients and control subjects at baseline. C The level of serum CK-18 in AECOPD patients and control subjects at follow-up period. D The level of serum CK-18M30 in AECOPD patients and control subjects at follow-up period. E The correlation of serum CK-18 between baseline and follow-up was estimated by Lin’s concordance correlation coefficient (CCC). F The agreement of serum CK-18M30 between baseline and follow-up was analyzed using CCC. The orange circles represented the control group, and the blue circles represented the AECOPD patients. The adjusted r2, β, and the unadjusted P value from the two-sided linear regression were shown in each panel, respectively. The solid lines indicated the correlations. The dashed lines represented the reference lines generated if the two measurements yield the same result and provided the CCC. **P < 0.01

Fig. 2

The levels of serum CK-18/CK-18M30 in AECOPD patients with different severity three years later. A–C The concentrations of serum CK-18 was measured in serum of AECOPD patients with different severity scores three years later. A CAT score. B mMRC score. C CCQ score. D-F The concentrations of serum CK-18M30 was determined in serum of AECOPD patients with different severity scores three years later. D CAT score. E mMRC score. F CCQ score. *P < 0.05

Fig. 3

The associations between serum CK-18/CK-18M30 and clinical characteristics in AECOPD patients. The correlations between serum CK18/CK18M30 concentration and different clinical features were explored by Pearson correlative analysis. The main clinical features include white blood cell (WBC), neutrophil, lymphocyte, monocyte, eosinophil, uric acid, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK), creatine kinase isoenzyme (CKMB), cardiac troponin I (cTnI), myoglobin (Myb), lactate dehydrogenase (LDH), D-Dimer, interleukin-6 (IL-6), and C-reactive protein (CRP). *P < 0.05 **P < 0.005 ***P < 0.001 ****P < 0.0001