## 4 Discussion  
As the SARS-CoV-2 pandemic still exerts a high pressure on health care providers, efficient patient triage to detect those with severe forms of disease or at high risk of worse outcomes is of great importance. For this purpose, various biological and imagistic markers were reported in the literature, including KL-6. This is the first systematic review addressing the relationship between KL-6 biomarker and COVID-19 outcomes, to the best of our knowledge. High KL-6 levels are associated with worse outcomes, prognosis, and mortality in patients with interstitial lung diseases, other than SARS-CoV-2 infection [10], even in the stable states of diseases [24]. In one study, patients with idiopathic pulmonary fibrosis (IPF) and high KL-6 levels or continuous increase had a worse prognosis than those with lower KL-6 concentrations and without increase over time [25]. Although challenging in approach and a frequent misdiagnosis subject [26], IPF patients can benefit from this relatively simple monitoring method by having their KL-6 levels measured to predict an acute exacerbation with great sensitivity [27], especially during these pandemic times. All this data suggests the importance of a serial evaluation rather than a single measurement, but the predictions and outcomes can be significantly more beneficial for the patients [28]. That is why the prognostic implications of KL-6 in COVID-19 are of great interest. One study [16] showed that KL-6 at admission was significantly increased in severe COVID-19 patients when compared to healthy subjects or those with non-severe forms, with an excellent predictive value. Those with non-severe phenotype had similar levels with healthy controls. All severe patients included in this trial were intubated and admitted to ICU. Although a small number of patients were included, these results were also confirmed by other studies. Another study [17] also documented that patients with severe SARS-CoV-2 infection had higher KL-6 values at admission. In addition to dosage at admission, KL-6 at peak levels within one week had the best predictive value for disease severity from all markers investigated. Other studies [18; 19; 21; 22; 23] included in the present systematic results revealed similar results, as patients with a more severe disease had significantly higher levels of KL-6. Since KL-6 overlaps with existing pulmonary modifications, mainly in patients with chronic lung damage, KL-6 can be used as a reliable method to evaluate the extent of the lesions and, hence, the disease's progression [13] (Figure 2). A single KL-6 measurement at admission could be a good marker of disease severity in COVID-19 patients and might be used in patients' triage to detect those requiring advanced monitoring and a more aggressive treatment strategy. Moreover, serial evaluations of KL-6 concentrations during hospitalization could identify patients with a higher risk of clinical deterioration. However, more studies are needed with larger populations in order to confirm these observations. In addition, it is not compulsory to use KL-6 alone to predict the severity of the disease. One study [23] showed that a combination of three markers, KL-6, IL-6, and CRP, had an exceptional predictive value for COVID-19 severity with an AUC of 0.95 (95% CI, 0.86-1). More studies to investigate the importance of different clinical models, including biomarkers and imagistic signs in disease severity prediction, are warranted. Regarding the association of KL-6 with mortality in COVID-19, research data are discordant in two studies included in our systematic review. One study [19] did not find any statistically significant association between KL-6 levels and mortality or ICU admission. However, in another study, [20] the authors observed that patients with higher KL-6 levels had a higher risk of death, an effect which maintained at multivariable analysis.