Association between Functional Inhibitors of Acid Sphingomyelinase and Reduced Risk of Intubation or Death in Individuals Hospitalized for Severe COVID-19: results from an observational multicenter study

Hoertel, N.; Sanchez-Rico, M.; Gulbins, E.; Kornhuber, J.; Carpinteiro, A.; Lenze, E. J.; Reiersen, A. M.; Abellan, M.; de la Muela, P.; Vernet, R.; Blanco, C.; Beeker, N.; Neuraz, A.; Gorwood, P.; Alvarado, J. M.; Meneton, P.; Limosin, F.

Several medications commonly used for a number of medical conditions share a property of functional inhibition of acid sphingomyelinase (ASM), or FIASMA. Preclinical and clinical evidence suggest that the (ASM)/ceramide system may be central to SARS-CoV-2 infection. We examined the potential usefulness of FIASMA use among patients hospitalized for severe COVID-19 in an observational multicenter retrospective study conducted at Greater Paris University hospitals. Of 2,846 adult patients hospitalized for severe COVID-19, 277 (9.7%) were taking a FIASMA medication at the time of their hospital admission. The primary endpoint was a composite of intubation and/or death. We compared this endpoint between patients taking vs. not taking a FIASMA medication in time-to-event analyses adjusted for sociodemographic characteristics and medical comorbidities. The primary analysis was a Cox regression model with inverse probability weighting (IPW). Over a mean follow-up of 9.2 days (SD=12.5), the primary endpoint occurred in 104 patients (37.5%) who were taking a FIASMA medication, and 1,060 patients (41.4%) who were not. Taking a FIASMA medication was associated with reduced likelihood of intubation or death in both crude (HR=0.71; 95%CI=0.58-0.87; p<0.001) and the primary IPW (HR=0.58; 95%CI=0.46-0.72; p<0.001) analyses. This association remained significant in multiple sensitivity analyses and was not specific to one FIASMA class or medication. These results show the potential importance of the ASM/ceramide system as a treatment target in COVID-19. Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed.