## 3 Results  
Our search in prespecified databases retrieved 96 references screened for duplicates, and 14 citations were excluded. An additional 61 references were excluded based on title and abstract, leaving 21 studies for full-text review. After eligibility assessment, eight studies were finally included in the present systematic review, as 13 citations were excluded because inclusion criteria were not met (Figure 1). The included studies' design and the population's characteristics from each study are illustrated in Table 1.  
All analyzed studies were observational and single-center [16; 17; 18; 19; 20; 21; 22]. Three studies were performed in Italy, [16; 20; 23] one--in Japan, [17] three--in China, [18; 21; 22], and one--in Belgium [19]. In addition, six studies were retrospective [17; 18; 19; 21; 22; 23] and two trials had a prospective design [16; 20]. Results reported in clinical studies are summarized in Table 2.  
In one study, [PERSON] et al. [16] reported higher KL-6 concentrations at admission for COVID-19 patients prone to more severe disease (bilateral diffuse interstitial pneumonia or focal bilateral pneumonia), compared to patients with non-severe disease course (\(p=0.0118\)) and healthy controls (\(p=0.012\)). Interestingly, there was no significant difference between KL-6 levels in patients with non-severe disease and healthy participants (\(p=0.5277\)). In addition, KL-6 had an excellent discriminatory power between severe and non-severe cases, with an AUC of 82.4% for a cut-off value set at 406.5 U/mL. For the prespecified cut-off value, KL-6 had 83% sensitivity and 89% specificity. Additionally, the level of natural killer (NK) cells was reported to be decreased in patients with severe infection. Similar results were reported by [PERSON] et al. [17]. KL-6 levels at diagnosis, as well as within one week after diagnosis, were significantly higher (respectively, \(p<0.001\) and \(p<0.001\)) in the case of patients with a more severe form of COVID-19. It is essential to mention that KL-6 at peak levels within one week had the best predictive power for severe disease than other biomarkers investigated (AUC = 0.95). The predictive values of KL-6 and lactate dehydrogenase (LDH) at diagnosis were similar (AUC 0.84). At a cut-off value of 371 U/mL (within one week), KL-6 had 85.7% specificity and 96.6% specificity. Other biomarkers significantly increased in patients with severe SARS-CoV-2 infection were represented by LDH and soluble interleukin-2-receptor. \begin{table}
\begin{tabular}{c c c c c c c c} \hline \hline
**Author, Year** & **Design** & **Patients, No** & **Age Median/ Mean \(\pm\) SD** & **Parameters** & **Severe** & **Timing** \\ \hline [PERSON] & Observational, & & & & & & \\  & prospective, & & & & & & \\  & single center & & & & & & \\  & & & & & & & \\ \hline [PERSON] et al., & Observational, & & & & & & & \\  & retrospective, & & & & & & \\  & single center & & & & & & \\  & & & & & & & \\ \hline  & & & & & & & \\  & & & & & & & \\  & & & & & & & \\  & & & & & & & \\ \hline  & & & & & & & \\  & & & & & & & \\  & & & & & & & \\ \hline  & & & & & & & \\  & & & & & & & \\ \hline  & & & & & & & \\ \end{tabular} COVID-19 = coronavirus disease 2019; CRP = C-reactive protein; ICU = intensive care unit; IL-6 = interleukin 6; ILD = interstitial lung disease; KL-6 = Krebs von den Lungen 6 factor; LC = lymphocyte count; LDH = lactate dehydrogenase; NK = natural killer cells; PLR = platelets/lymphocyte ratio; slL2-R = soluble interleukin-2-receptor; WBC = white blood cells count.  
\end{table} 
Table 1: General characteristics included in present systematic review. KL-6 levels were confirmed to be higher in patients with severe disease in another study by [PERSON] et al. [18], though the prediction power was slightly lower from those reported in studies above (AUC = 0.793). When the cut-off value was set at 642.3 U/mL, KL-6 had a sensitivity of 75.3% and a specificity of 73.3%. At a cut-off value of 788.2 U/mL, the sensitivity was higher (86.4%), but specificity was lower (62.2%).