Background: COVID-19 is currently undergoing a pandemic worldwide, including in Japan, and many lives have been lost. So, there is an urgent need to develop new biomarkers for estimating progression or prognosis of COVID-19 patient. Lung-specific serum SERO biomarkers, SP-A, SP-D and KL-6 have been used clinically for diagnosis of interstitial lung disease MESHD (ILDs), but their use in COVID-19 has not been investigated. To determine whether serum SERO levels of SP-A, SP-D and KL-6 correlate with the severity of COVID-19 as indicated by clinical symptoms and radiological findings. Methods: In a cohort of 46 consecutive COVID-19 patients, laboratory data including serum SERO SP-A, SP-D and KL-6 concentrations of 82 blood SERO samples were analyzed and compared between severe and non-severe cases. In addition, the disease MESHD severity as indicated by these markers and chest HRCT images were compared.Results: Serum SERO SP-A was significantly elevated from the early stage of pneumonia MESHD pneumonia HP. In addition, serum SERO SP-A and SP-D were significantly higher in severe than in non-severe cases. KL-6 was also significantly higher in severe-cases, but its mean was below the cut-off level for ILDs. AUC and their cut-off levels to detect severe cases in patients with COVID-19 infection MESHD were 0.796 for 94.9 ng/ml of SP-A, 0.827 for 116 ng/ml of SP-D and 0.640 for 275 U/ml of KL-6. HRCT image severity scores showed moderate correlations with SP-A (ρ=0.5996, p<0.001), SP-D (ρ=0.6268, p<0.001), and weak with KL-6 (ρ=0.3489, p<0.001). In the typical course of patients whose pneumonia MESHD pneumonia HP worsened from non-severe to severe, the serum SERO SP-A and SP-D levels increased nearly in parallel with clinical findings and HRCT images.Conclusions: Lung-specific serum SERO SP-A and SP-D level increased with symptom and radiological findings. These elevations can be detected from relatively early pneumonia MESHD pneumonia HP. These results indicated that these might become a novel biomarker in COVID-19 pneumonia MESHD pneumonia HP.