The clinical features of COVID-19 patients are diverse, with some patients having mild symptoms and some progressing into severe cases, which can be life-threatening. Early identification of severely ill patients will be beneficial to improve patient’s prognosis and reduce mortality. In the present study, we investigated potential biomarkers in severely ill patients by analyzing the results of serological index indicators in patients at the early stage of hospitalization.
The results of the present study showed that serum KL-6 and IgA levels were significantly elevated in severely ill patients compared with moderately ill patients. KL-6 is a high-molecular-weight mucin expressed by type II alveolar epithelial cells (AECII). When AECII is injured, more KL-6 is secreted through its proliferation and differentiation and leaks through the basement membrane into the blood circulation, thereby increasing KL-6 levels in serum [16, 17]. KL-6 is one of the important markers of pulmonary fibrosis, and KL-6 is elevated in the serum of patients with interstitial pneumonia, and the degree of elevation has a correlation with the occurrence and severity of interstitial lung disease [18–19]. d'Alessandro et al. also confirmed that the serum KL-6 could diagnose severe COVID-19, with a cut-off of 406.5 U/ml, an AUC of 0.824, and a sensitivity and specificity of 83% and 89%, respectively . In the report of Awano et al., serum KL-6 value of 371 U/ml was used as the optimal cut-off to evaluate disease severity with a sensitivity of 85.7% and specificity of 96.6% . In the present study, the cut-off of using KL-6 alone for the diagnosis of severely ill patients was 298.91 U/mL, with an AUC of 0.737, a sensitivity of 100%, and a specificity of 43%. Although the sensitivity was good, the specificity was low, and the cut-off was also different from the findings of d'Alessandro et al . The diagnostic efficacy of KL-6 for severe disease in patients with COVID-19 remains to be confirmed by larger cohort studies.
IL-6 is a commonly used rapid detection indicator of infectious diseases and one of the important inflammatory factors triggering cytokine storm in patients with COVID-19 [22, 23]. After SARS-CoV-2 virus infection, pathogenic T cells are rapidly activated and factors such as Granulocyte-macrophage Colony Stimulating Factor (GM-CSF) and IL-6 are abundantly produced, thus forming an inflammatory storm and leading to severe immune damage in lungs and other organs . IL-6 levels progressively increase in severely ill patients with COVID-19 and have been demonstrated to be an early warning indicator of progression into severe disease . In the present study, the serum IL-6 levels were elevated in severely ill patients compared with moderately ill patients, but the difference was not statistically significant (Table 2). However, the results of ROC curve analysis still showed that IL-6 had some efficacy in diagnosing severely ill patients: The AUC was 0.720, and the sensitivity and specificity were 64% and 80%, respectively. IL-6 had better diagnostic efficacy combined with KL-6, with an AUC of 0.776 and sensitivity and specificity of 82% and 69%, respectively. The present study also found that IgA was significantly elevated in severely ill patients with COVID-19 and could be used as one of the potential markers for the diagnosis of progression into critical disease, and the results were consistent with the results of the study conducted by Ma et al. .
At the three-month follow-up, a number of serum marker levels changed in patients with coronavirus disease 2019, suggesting that the patients’ condition had recovered. In addition to a significant decrease in the level of the inflammatory factor CRP, KL-6, an indicator of pulmonary fibrosis, was also significantly reduced. In addition, all three antibodies specific to SARS-CoV-2, IgA, IgM, and IgG, were very significantly down-regulated, consistent with the results reported in previous studies [14, 26]. It is worth investigating whether recovered patients will have the same risk of infection as that of previously uninfected people when encountering the SARS-CoV-2 virus again .
In summary, close monitoring and tracking of serum KL-6, IL-6 and IgA, three potential risk indicators of severe disease, and early intervention will likely avoid the progression into severe disease of COVID-19 and improve patient prognosis, which has important clinical significance. However, disease progression is an ongoing process, and the present study is limited by no continuous monitoring in patients due to condition restrictions. In addition, although the present study suggested that KL-6, IL-6 and IgA had potential value in the diagnosis of progression into severe coronavirus disease 2019, the limitations of this study, which include the limited number of cases and the retrospective nature of study, indicate that this value needs to be confirmed by a larger cohort study.