Serum KL-6 levels predict clinical outcomes and are associated with MUC1 polymorphism in Japanese patients with COVID-19

Abstract

Background: Krebs von den Lungen-6 (KL-6) is a known biomarker for diagnosis and monitoring of interstitial lung diseases. However, the role of serum KL-6 and the mucin 1 (MUC1) variant (rs4072037) in COVID-19 outcomes remains to be elucidated. We aimed to evaluate the relationships among serum KL-6 levels, critical outcomes and the MUC1 variant in Japanese patients with COVID-19.

Methods: This is a secondary analysis of a multicentre retrospective study using data from the Japan COVID-19 Task Force collected from February 2020 to November 2021, including 2226 patients with COVID-19 whose serum KL-6 levels were measured. An optimal serum KL-6 level cut-off to predict critical outcomes was determined and used for multivariable logistic regression analysis. Furthermore, the relationship among the allele dosage of the MUC1 variant, calculated from single nucleotide polymorphism typing data of genome-wide association studies using the imputation method, serum KL-6 levels and COVID-19 critical outcomes was evaluated.

Results: Serum KL-6 levels were significantly higher in patients with COVID-19 with critical outcomes (511±442 U/mL) than those without (279±204 U/mL) (p<0.001). Serum KL-6 levels ≥304 U/mL independently predicted critical outcomes (adjusted OR (aOR) 3.47, 95% CI 2.44 to 4.95). Moreover, multivariable logistic regression analysis with age and sex indicated that the MUC1 variant was independently associated with increased serum KL-6 levels (aOR 0.24, 95% CI 0.28 to 0.32) but not significantly associated with critical outcomes (aOR 1.11, 95% CI 0.80 to 1.54).

Conclusion: Serum KL-6 levels predicted critical outcomes in Japanese patients with COVID-19 and were associated with the MUC1 variant. Therefore, serum KL-6 level is a potentially useful biomarker of critical COVID-19 outcomes.

Keywords: COVID-19; viral infection.

Figure 1

Population flow chart of the study cohort. 3424 patients with COVID-19 were hospitalised during the study period. 1198 patients were excluded for reasons indicated in the figure. Therefore, 2226 patients were included for analysis and 1119 patients for whom GWAS data were available were included in the SNP analysis. GWAS, genome-wide association studies; KL-6, Krebs von den Lungen-6; SNP, single nucleotide polymorphism.

Figure 2

Differences in serum KL-6 levels based on the chest imaging findings on admission. Group comparisons were performed using Dunnett’s multiple comparisons test. *P<0.05, **P<0.01, ***P<0.001. CXR, chest X-ray; GGO, ground glass opacity; KL-6, Krebs von den Lungen-6.

Figure 3

Comparison of serum KL-6 levels with and without post-hospitalisation complications (bacterial infection, thrombosis, heart failure and fungal infection). Unpaired t-test was performed. ***P<0.001. KL-6, Krebs von den Lungen-6.

Figure 4

(A) Comparison of serum KL-6 levels following the severity of COVID-19. Group comparisons were performed using Dunnett’s multiple comparisons tests. (B) Serum KL-6 levels of patients with or without critical outcomes. Unpaired t-tests were performed. (C) Alluvial plot showing trends on admission, worst oxygen demand and mortality by serum KL-6 level on admission. ‘KL-6 High’ means serum KL-6 ≥304 U/mL and ‘KL-6 Low’ means serum KL-6 <304 U/mL. ‘High Flow’ means that high-flow nasal cannula or non-invasive positive pressure ventilation was used for treatment. ‘Low Flow’ means some oxygen demand without IPPV or high-flow nasal cannula or non-invasive positive pressure high-flow nasal cannula or non-invasive positive pressure was used for treatment. (D) Receiver operating characteristic curve for outcomes of COVID-19 based on the serum levels of KL-6. ***P<0.001. AUC, area under the curve; IPPV, invasive positive pressure ventilation; KL-6, Krebs von den Lungen-6.

Figure 5

Multivariable logistic regression analysis for ascertaining the relationship between critical outcomes and serum KL-6 and already known risk factors for COVID-19. Forest plot showing the adjusted OR, 95% CI and p value of the parameters of the analysis. BMI, body mass index; COPD, chronic obstructive pulmonary disease; HbA1c, haemoglobin A1c; KL-6, Krebs von den Lungen-6.