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

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.

The Interaction Between Pulmonary Fibrosis and COVID-19 and the Application of Related Anti-Fibrotic Drugs

“…A growing number of studies support a significant correlation between elevated KL-6 levels and the development of pulmonary fibrosis ( Crisan-Dabija et al, 2021 ; Peng et al, 2021 ; Xue et al, 2021 ). For example, a clinical study involving 289 COVID-19 patients finds that KL-6, which is rising earlier than the fibrotic-like change of CT imaging in the lungs, could predict not only the onset of pulmonary fibrosis, but also whether it was reversible ( Xue et al, 2021 ). This is good for both clinicians and COVID-19 patients.…”

“…Early in the disease, when extensive lung injury occurs, repair mechanisms of pulmonary epithelial cell is synchronously activated which causing the elevated level of KL-6 ( Major et al, 2020 ). Some studies find that KL-6 were not significantly elevated in some COVID-19 patients with secondary pulmonary fibrosis, possibly because the time when found the occurance of pulmonary fibrosis is later than the time when repair mechanisms was activated and KL-6 was released in large quantities ( Xue et al, 2021 ). In addition, studies have shown that c-reactive protein (CRP), interleukin-6(IL-6), D-dimer and hepatic cytokines (HGF) and C-X-C motif chemokine 13 (CXCL13) are associated with the occurrence of pulmonary fibrosis in patients with COVID-19 ( Francone et al, 2020 ; Yu et al, 2020 ; Perreau et al, 2021 ).…”

Krebs von den Lungen-6 glycoprotein circulating levels are not useful as prognostic marker in COVID-19 pneumonia: A large prospective cohort study

“…In our prospective study with more patients (159 who worsened and 677 who did not), we observed opposite results (sensitivity, 46%, specificity 65%, PPV 24%, and NPV 84%; AUC 0.56), though with a similar threshold peak of sKL-6 (408 U/ml). More studies have analyzed the sensitivity and specificity of sKL-6 in COVID-19 ( 24 , 25 , 28 , 42 ) but their main goals were different than ours since they analyzed the levels of this biomarker to predict irreversible ILD or death. We did not explore sKL-6 levels and their usefulness to predict outcomes after COVID-19 pneumonia.…”

Exploring the Role of Krebs von den Lungen-6 in Severe to Critical COVID-19 Patients

“…Interestingly, it has been reported that patients infected with SARS-CoV-2 with a KL-6 value persistently above 505 U/mL may be prone to develop pulmonary fibrosis, which may be irreversible when KL-6 raises above 674 U/mL [ 28 ].…”