Association Between FIASMAs and Reduced Risk of Intubation or Death in Individuals Hospitalized for Severe COVID-19: An Observational Multicenter Study

Abstract

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 severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. We examined the potential usefulness of FIASMA use among patients hospitalized for severe coronavirus disease 2019 (COVID-19) in an observational multicenter study conducted at Greater Paris University hospitals. Of 2,846 adult patients hospitalized for severe COVID-19, 277 (9.7%) were taking an FIASMA medication at the time of their hospital admission. The primary end point was a composite of intubation and/or death. We compared this end point between patients taking vs. not taking an 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 end point occurred in 104 patients (37.5%) receiving an FIASMA medication, and 1,060 patients (41.4%) who did not. Despite being significantly and substantially associated with older age and greater medical severity, FIASMA medication use was significantly associated with reduced likelihood of intubation or death in both crude (hazard ratio (HR) = 0.71, 95% confidence interval (CI) = 0.58-0.87, P < 0.001) and 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 particular FIASMA class or medication. These results show the potential importance of the ASM/ceramide system in COVID-19 and support the continuation of FIASMA medications in these patients. Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed.

Figure 1

Biological mechanisms proposed by Carpinteiro et al., underlying the potential inhibition by Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) of cell infection with severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). Initial binding of SARS‐CoV‐2 spike protein to its ACE2 receptor may result in activation of the acid sphingomyelinase (ASM), formation of surface ceramide molecules that spontaneously form ceramide‐enriched membrane platforms. These platforms alter membrane properties and thereby may serve to trap and cluster activated ACE2 receptors, and facilitate viral entry; inhibition of the ASM by FIASMAs may result in reduced concentration of ceramides and decreased viral entry.

Figure 2

Study cohort. *A participant may receive two or more FIASMA medications at baseline. COVID‐19, coronavirus disease 2019; FIASMA, Functional Inhibitors of Acid Sphingomyelinase; ICU, intensive care unit; RT‐PCR, reverse‐transcriptase–polymerase‐chain‐reaction.

Figure 3

Kaplan‐Meier curves for the composite endpoint of intubation or death in the full sample crude analysis (N = 2846) (a), in the full sample analysis with IPW (N = 2846) (b), and in the matched analytic sample using a 1:1 ratio (N = 554) (c) among patients hospitalized for severe COVID‐19, according to FIASMA medication use at baseline. The shaded areas represent pointwise 95% confidence intervals. COVID‐19, coronavirus disease 2019; IPW, inverse probability weighting; FIASMA, Functional Inhibitors of Acid Sphingomyelinase Activity.