In this retrospective prognostic study, we correlated KL-6 values at ICU admission with disease severity in COVID-19 patients during the second wave of the pandemic in a COVID-dedicated hospital. Our findings showed that elevated KL-6 (> 680 U/ml) was strongly associated with mortality in ICU, thereby contributing to the growing body of evidence for the utility of KL-6 in the context of COVID-19 infection.
KL-6 glycoprotein is mainly expressed on alveolar type 2 cells in the lung, and it is produced more prominently by proliferating, or regenerating, injured type 2 cells than by healthy type 2 cells. The presence of KL-6 has been used to monitor severity of disease in idiopathic pulmonary fibrosis . Liu et al. , in a lung proteomics animal experimental research (rhesus monkeys), quantified the overall difference of protein expression pattern between control and COVID-infected groups. When compared to the control group, in the lung, 757 proteins were differentially expressed in the infected group. Our study did not check total protein expression in the lungs of COVID patients, but it aimed to identify an easy and available biomarker that physicians could use to risk stratify COVID-19 patients. The use of biomarkers to predict disease severity has proven essential for resource allocation, particularly for respiratory support needs. In a previous study on a population of 67 COVID survivors , median KL-6 was 365 U/ml (IQR 233–493), and the authors concluded that “high KL-6 levels at 12 weeks with persisting CT abnormalities (GGO/fibrosis) is a finding that requires further exploration”. D’Alessandro et al. , in 14 severe COVID patients, found very elevated serum KL-6 concentrations (median IQR, 1125; 495–2034). These previous works, with the others included in the above-cited meta-analysis , let the search for cutoff values in COVID patients still open. KL-6 pathophysiological role in lung diseases is not completely understood. KL-6 belongs to the mucin family, and proteins aimed to improve mucosal barrier integrity and functionality. Hurasawa et al. identified KL-6 as human MUC1 . Mucins, both secreted or cell bound, create a protective mucus layer on the host cells, reducing pathogens access to their receptors. Up to now, MUC1/KL-6 has been studied as a diagnostic marker for respiratory disease severity, but there has been no extensive research assessing the mechanism of its overexpression. Whether a mechanistic proof is to be done (does KL-6 cause some aspect of COVID pathophysiology?) or if a prediction model only is possible (KL-6 adds to other markers to discriminate an outcome, such as mortality) should be clarified. Kost-Alimova et al.  identified fostamatinib, which was previously approved by the FDA for chronic immune thrombocytopenia, as a drug that significantly reduces MUC1 protein abundance. Their experimental findings indicated the potential of repurposing fostamatinib for the treatment of CARDS (https://clinicaltrials.gov/ct2/show/NCT04579393), even if, unfortunately, KL6/MUC1 has already been a failed target in oncology .
Lorenzoni et al. , through a machine learning approach for predicting ICU mortality in COVID-19 patients, proved that age was the leading predictor, followed by total SOFA score at ICU admission, and the P/F used for SOFA calculation. In our previous experience  and in the present study too, patients’ characteristics at ICU admission severely conditionate the success of advanced therapeutic strategies. In this paper, when SOFA score is higher than 5, prognosis is already compromised, and consequently, the prognostic power of KL-6 is reduced, while it can still be helpful to identify lung injury in patients with a lower organ failure score (SOFA < 5).
Ru et al.  reported that mean serum PCT levels were over eight times higher in critical COVID patients than in moderate patients. PCT levels may be associated with bacterial coinfection which might justify such an increase. In our experience, PCT was not a marker of severity of COVID lung failure at ICU admission. Nevertheless, we think that an increase in PCT should always be investigated for the presence of a concomitant bacterial infection.
Changes in KL-6 serum levels may be related to barotrauma and volutrauma too, even if it is very difficult to distinguish the origin of the biomarker release in a complex context as COVID ARDS.
The main limitation of this research is that is an observational study with retrospective enrolment. Moreover, we think that KL-6 value as prognostic index should be tested in different COVID populations or timing, i.e. at emergency room admission, and the dynamic of its changes should be tested, to understand if it shows prognostic value for long-term COVID effects on the lung functions. In our retrospective study, in fact, multiple unmeasured variables may have affected the outcomes. Conclusions should be validated by larger, definite prospective studies in the future.