Linking surfactant proteins and genetic variants to COVID-19 severity

COVID-19 presents with variable clinical severity. Surfactant proteins (SPs) are critical to lung function and host defense, but their role as biomarkers for COVID-19 severity, and the impact of SP genetic variants, remains unclear. Therefore, we asked whether plasma SP levels and SP genetic variants are associated with COVID-19 severity in adults. We conducted a cohort study of 261 adults with PCR-confirmed COVID-19, classified as non-severe (n = 117) or severe (n = 144) based on WHO severity criteria. Plasma SP-A, SP-B, and SP-D levels were measured. Genetic variants in SFTPA1 , SFTPA2 , SFTPB , SFTPC , and SFTPD were analyzed. Quantile regression, receiver operating curve analysis, and logistic regression were used to assess associations. To compare model performance, the corrected Akaike Information Criterion (AICC) was used. Mediation analysis evaluated interactions among SP-A levels, genetic variant and disease severity. Severe COVID-19 was associated with higher plasma SP-A (9.8 vs. 8.4 ng/mL, p = 0.04) and SP-B (4119.2 vs. 3137.2 ng/mL, p = 0.01) levels, but not SP-D. SP-A and SP-B showed moderate predictive value for severity (AUC = 0.71). Inclusion of plasma SP-A (AICC = 219.7) or SP-B (AICC = 221.0) levels along with demographics improved performance over the demographics-only model (AICC = 300.2). Although significance was lost after Bonferroni correction, rs10351 in SFTPA1 was associated with lower risk of severe disease (OR = 0.40, p = 0.03); and lower SP-A level. Mediation analysis suggested the association was driven by disease severity. No associations were found for other SP gene variants. Elevated SP-A and SP-B levels are associated with severe COVID-19 and may serve as biomarkers. Predictive models combining either SP-A or SP-B levels with clinical information offer strong potential for risk stratification. The SFTPA1 variant rs10351 may confer protection through reduced alveolar injury, though further validation is warranted. Clinical trial registration : ClinicalTrials.gov. Study ID# NCT04650191, 30th November, 2020.