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. 2023 Aug 4;16(8):1107.
doi: 10.3390/ph16081107.

Medications Modulating the Acid Sphingomyelinase/Ceramide System and 28-Day Mortality among Patients with SARS-CoV-2: An Observational Study

Nicolas Hoertel  1   2 , Katayoun Rezaei  2 , Marina Sánchez-Rico  2   3 , Alfonso Delgado-Álvarez  2   3   4 , Johannes Kornhuber  5 , Erich Gulbins  6 , Mark Olfson  7 , Charles Ouazana-Vedrines  8 , Alexander Carpinteiro  6   9 , Céline Cougoule  10 , Katrin Anne Becker  6 , Jesús M Alvarado  3 , Frédéric Limosin  1   2 , On Behalf Of The Ap-Hp/Université Paris Cité/Inserm Covid-Research Collaboration Ap-Hp Covid Cdr Initiative And Entrepôt de Données de Santé Ap-Hp Consortium
Affiliations

Medications Modulating the Acid Sphingomyelinase/Ceramide System and 28-Day Mortality among Patients with SARS-CoV-2: An Observational Study

Nicolas Hoertel et al. Pharmaceuticals (Basel). .

Abstract

Prior evidence indicates the potential central role of the acid sphingomyelinase (ASM)/ceramide system in the infection of cells with SARS-CoV-2. We conducted a multicenter retrospective observational study including 72,105 adult patients with laboratory-confirmed SARS-CoV-2 infection who were admitted to 36 AP-HP (Assistance Publique-Hôpitaux de Paris) hospitals from 2 May 2020 to 31 August 2022. We examined the association between the ongoing use of medications functionally inhibiting acid sphingomyelinase (FIASMA), which reduces the infection of cells with SARS-CoV-2 in vitro, upon hospital admission with 28-day all-cause mortality in a 1:1 ratio matched analytic sample based on clinical characteristics, disease severity and other medications (N = 9714). The univariate Cox regression model of the matched analytic sample showed that FIASMA medication use at admission was associated with significantly lower risks of 28-day mortality (HR = 0.80; 95% CI = 0.72-0.88; p < 0.001). In this multicenter observational study, the use of FIASMA medications was significantly and substantially associated with reduced 28-day mortality among adult patients hospitalized with COVID-19. These findings support the continuation of these medications during the treatment of SARS-CoV-2 infections. Randomized clinical trials (RCTs) are needed to confirm these results, starting with the molecules with the greatest effect size in the study, e.g., fluoxetine, escitalopram, and amlodipine.

Keywords: COVID-19; FIASMA; SARS-CoV-2; antidepressant; ceramide; mortality.

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Conflict of interest statement

N.H., M.S.R., J.K., E.G., A.C. and F.L. are the inventors of a patented application related to methods of treating COVID-19, filed by the Assistance Publique—Hopitaux de Paris in France. The other authors declare no conflict of interest related to this work.

Figures

Figure 1
Figure 1
Biological mechanisms proposed by Carpinteiro et al. [13,15], underlying the potential effects of the functional inhibitors of acid sphingomyelinase (FIASMAs) on SARS-CoV-2 infection. SARS-CoV-2 may activate the acid sphingomyelinase/ceramide pathway, which, in turn, facilitates viral entry into cells through gel-like platforms that favor the clustering of activated SARS-CoV-2 cellular ACE2 receptors. Inhibition of the ASM by FIASMAs may result in a reduced concentration of ceramides, decreased viral entry, and subsequent inflammation.
Figure 2
Figure 2
Study cohort.
Figure 3
Figure 3
FIASMA medication use and 28-day mortality in the matched analytic sample (N = 9714).
Figure 4
Figure 4
FIASMA medication use and 28-day mortality in the matched analytic sample, stratified by sex (A,B), age (C,D), and period of hospitalization (E,F).
See this image and copyright information in PMC

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