Krebs Von den Lungen-6 as a predictive indicator for the risk of secondary pulmonary fibrosis and its reversibility in COVID-19 patients

Mingshan Xue, Teng Zhang, Hao Chen, Yifeng Zeng, Runpei Lin, Yingjie Zhen, Ning Li, Zhifeng Huang, Haisheng Hu, Luqian Zhou, Hui Wang, Xiaohua Douglas Zhang, Baoqing Sun, Mingshan Xue, Teng Zhang, Hao Chen, Yifeng Zeng, Runpei Lin, Yingjie Zhen, Ning Li, Zhifeng Huang, Haisheng Hu, Luqian Zhou, Hui Wang, Xiaohua Douglas Zhang, Baoqing Sun

Abstract

Dysregulated immune response and abnormal repairment could cause secondary pulmonary fibrosis of varying severity in COVID-19, especially for the elders. The Krebs Von den Lungen-6 (KL-6) as a sensitive marker reflects the degree of fibrosis and this study will focus on analyzing the evaluative efficacy and predictive role of KL-6 in COVID-19 secondary pulmonary fibrosis. The study lasted more than three months and included total 289 COVID-19 patients who were divided into moderate (n=226) and severe groups (n=63) according to the severity of illness. Clinical information such as inflammation indicators, radiological results and lung function tests were collected. The time points of nucleic acid test were also recorded. Furthermore, based on Chest radiology detection, it was identified that 80 (27.7%) patients developed reversible pulmonary fibrosis and 34 (11.8%) patients developed irreversible pulmonary fibrosis. Receiver operating characteristic (ROC) curve analysis shows that KL-6 could diagnose the severity of COVID-19 (AUC=0.862) and predict the occurrence of pulmonary fibrosis (AUC = 0.741) and irreversible pulmonary fibrosis (AUC=0.872). Importantly, the cross-correlation analysis demonstrates that KL-6 rises earlier than the development of lung radiology fibrosis, thus also illuminating the predictive function of KL-6. We set specific values (505U/mL and 674U/mL) for KL-6 in order to assess the risk of pulmonary fibrosis after SARS-CoV-2 infection. The survival curves for days in hospital show that the higher the KL-6 levels, the longer the hospital stay (P<0.0001). In conclusion, KL-6 could be used as an important predictor to evaluate the secondary pulmonary fibrosis degree for COVID-19.

Keywords: Coronavirus disease 2019; Krebs von den Lungen-6; Pulmonary fibrosis.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

© The author(s).

Figures

Figure 1
Figure 1
The trend of KL-6 and high-resolution CT in COVID-19 patients. (A). The trend of KL-6 in COVID-19 patients without fibrosis, with reversible fibrosis and with irreversible fibrosis. (B). The trend of lesion area (%) shown by CT results in COVID-19 patients without fibrosis, with reversible fibrosis and with irreversible fibrosis. (C). The trend of fibrosis area (%) in COVID-19 patients with reversible fibrosis and with irreversible fibrosis. The characteristic of irregular fibrotic shadow (interlobular septa thickened, reticular or linear opacities pattern) appears clearly about 20 days after symptom onset of COVID-19. Spagnolo et al 2020 also indicates this manifestation appearing after the onset of symptoms. At the same time, in the acute phase, extensive ground glass and patchy opacity may also obscure the fibrosis manifestation. Therefore, we use the time point of 20 days as the starting point for the evaluation of pulmonary fibrosis lesions. (D). The cross-correlation function between the trend of KL-6 and the trend of CT.
Figure 2
Figure 2
The difference of KL-6 levels at admission in COVID-19 patients and the diagnostic efficiency of KL-6. (A). The difference of KL-6 levels in COVID-19 patients with and without fibrosis. (B). The difference of KL-6 levels in COVID-19 patients with reversible fibrosis and with irreversible fibrosis. (C). The ROC curve illustrating performance of KL-6 to distinguish COVID-19 patients with and without fibrosis. The AUC is 0.741(0.677,0.804) and the optimal threshold is 505, with a sensitivity of 0.535 and a specificity of 0.914. (D). The ROC curve illustrating performance of KL-6 to distinguish COVID-19 patients with reversible fibrosis and with irreversible fibrosis. The AUC is 0.872(0.794,0.951) and the optimal threshold is 674, with a sensitivity of 0.824 and a specificity of 0.838. ("***" < 0.001, "**" < 0.01, "*" < 0.05).
Figure 3
Figure 3
Survival curve of days in hospital for COVID-19 patients. The patients are grouped according to the first KL-6 test after admission. The green line: KL-6<505U/mL; The blue line: 505U/mL<KL-6<674U/mL; The red line: KL-6>674U/mL.

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