## 3 Results
Besides, KL-6 was found to be associated with lung lesions area on computed tomography (\(p<0.001\)) and with coagulation disorders (prothrombin time, international normalized ratio, and fibrin degradation products). A relatively small number of patients with a severe form of disease (\(n=17\), 10.2%) could have led to a lower prediction value of KL-6, but it still was statistically significant. [PERSON] et al. [19] revealed that KL-6 levels were associated with lung disease severity, as defined by median SpO\({}_{2}\) at admission (\(p=0.013\)). Regarding other outcomes investigated, results were discrepant, as KL-6 levels were not associated with severe dyspnea, intensive care unit admission, and mortality (\(p>0.05\)). A provocative observation in this study was that KL-6 concentrations in patients with pre-existing interstitial lung disease were significantly higher than in patients with COVID-19, highlighting the importance of an individualized approach in interpreting the results. One study included almost only patients requiring oxygen therapy at baseline (\(n=32\), 94.1%) [20]. Results reported by [PERSON] et al. were different from those reported in the study above, in the sense that KL-6 levels (>1000 U/mL) were significantly associated with mortality, an effect which maintained even after multivariate analysis (OR 11.29, 95% CI, 1.04-122.00). The other biomarker investigated, namely interleukin-6 (IL-6), was associated with mortality only in univariate analysis (cut-off > 100 pg/mL), an effect which was lost at multivariate analysis (OR 4.03, 95% CI, 0.39-41.78). Noteworthy, KL-6 concentration at the time of enrolment had an excellent predictive value for mortality (AUC = 0.849). Surprisingly, a more advanced age (>60 years) was not associated with death in univariate analysis (OR 1.17, 95% CI, 0.28-4.83, \(p=0.83\)). Figure 1: Flow diagram of selected studies for inclusion in the systematic review. \begin{table}
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A similar results' direction was observed by [PERSON] et al. [21]. Patients with severe disease had greater levels of KL-6, which had a good predictive value (AUC = 0.8266) for disease severity, even though the optimal cut-off value was lower than in the above studies (278.3 U/mL). The authors also studied the association between pulmonary fibrosis and KL-6 and observed a statistically significant relationship as patients with pulmonary fibrosis had greater KL-6 levels (\(p<0.05\)). In contrast to KL-6, the association of fibronectin with pulmonary fibrosis was not statistically significant. [PERSON] et al. [22] confirmed that KL-6 levels were higher in patients with a severe or critical form of COVID-19 (\(p<0.05\)). Also, as compared to healthy controls, patients infected with SARS-CoV-2 had higher levels of KL-6. Noteworthy, from five severe patients with a progressive aggravation of the general condition, KL-6 levels continued to increase in two of them, suggesting that KL-6 could be an early marker of the disease progression. A similar increase in KL-6 concentrations was also documented as clinically worsening in one of two patients with non-severe forms of infection. Moreover, KL-6 levels were associated with pulmonary lesion area (\(p<0.05\)). [PERSON] et al. [23] also reported that KL-6 levels were higher in patients with severe disease than those with non-severe phenotypes of COVID-19. KL-6, when combined with two other markers of severity, namely IL-6 and C-reactive protein (CRP), had an exceptional discriminatory power, with AUC 0.95 (95% CI, 0.86-1), evoking the importance of an integrative approach of existing biomarkers in order to predict the course of the disease. The quality assessment of included studies using the Newcastle-Ottawa scale is presented in Table S2. Overall, as all studies were observational, the quality estimated was fair to poor.