Association Between FIASMAs and Reduced Risk of Intubation or Death in Individuals Hospitalized for Severe COVID‐19: An Observational Multicenter Study
Nicolas Hoertel, Marina Sánchez‐rico, Erich Gulbins, Johannes Kornhuber, Alexander Carpinteiro, Eric J Lenze, Angela M Reiersen, Miriam Abellán, Pedro Muela, Raphaël Vernet, Carlos Blanco, Céline Cougoule, Nathanaël Beeker, Antoine Neuraz, Philip Gorwood, Jesús M Alvarado, Pierre Meneton, Frédéric Limosin, Pierre‐yves Ancel, Alain Bauchet, Nathanaël Beeker, Vincent Benoit, Mélodie Bernaux, Ali Bellamine, Romain Bey, Aurélie Bourmaud, Stéphane Breant, Anita Burgun, Fabrice Carrat, Charlotte Caucheteux, Julien Champ, Sylvie Cormont, Christel Daniel, Julien Dubiel, Catherine Ducloas, Loic Esteve, Marie Frank, Nicolas Garcelon, Alexandre Gramfort, Nicolas Griffon, Olivier Grisel, Martin Guilbaud, Claire Hassen‐khodja, François Hemery, Martin Hilka, Anne Sophie Jannot, Jerome Lambert, Richard Layese, Judith Leblanc, Léo Lebouter, Guillaume Lemaitre, Damien Leprovost, Ivan Lerner, Kankoe Levi Sallah, Aurélien Maire, Marie‐france Mamzer, Patricia Martel, Arthur Mensch, Thomas Moreau, Antoine Neuraz, Nina Orlova, Nicolas Paris, Bastien Rance, Hélène Ravera, Antoine Rozes, Elisa Salamanca, Arnaud Sandrin, Patricia Serre, Xavier Tannier, Jean‐marc Treluyer, Damien Van Gysel, Gaël Varoquaux, Jill Jen Vie, Maxime Wack, Perceval Wajsburt, Demian Wassermann, Eric Zapletal
Clinical Pharmacology & Therapeutics, doi:10.1002/cpt.2317
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.
SUPPORTING INFORMATION Supplementary information accompanies this paper on the Clinical Pharmacology & Therapeutics website (www.cpt-journal.com).
ACKNOWLEDGMENTS The authors warmly thank the EDS APHP COVID consortium integrating the APHP Health Data Warehouse team as well as all the APHP staff and volunteers who contributed to the implementation of the EDS-COVID database and operating solutions for this database.
FUNDING No funding was received for this work.
CONFLICT OF INTEREST
DISCLAIMER The information contained in this study is provided for research purpose and should not be used as a substitute or replacement for diagnosis or treatment recommendations or other clinical decisions or judgment. The views presented in this manuscript are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies, or the National Institute on Drug Abuse or any US Government Agency.
APPENDIX 1 EDS APHP Covid consortium
References
Austin, Using the standardized difference to compare the prevalence of a binary variable between two groups in observational research, Commun. Stat.-Simul. Comput,
doi:10.1080/03610910902859574Carpinteiro, Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells, J. Biol. Chem,
doi:10.1016/j.jbc.2021.100701Carpinteiro, Pharmacological inhibition of acid sphingomyelinase prevents uptake of SARS-CoV-2 by epithelial cells, Cell Rep. Med,
doi:10.1016/j.xcrm.2020.100142Chevance, Ensuring mental health care during the SARS-CoV-2 epidemic in France: A narrative review, L'Encephale
Chouchana, Association of antihypertensive agents with the risk of in-hospital death in patients with COVID-19, Cardiovasc. Drugs Ther,
doi:10.1007/s10557-021-07155-5Efron, Nonparametric standard errors and confidence intervals, Can. J. Stat,
doi:10.2307/3314608Gordon, Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms, Science,
doi:10.1126/science.abe9403Gulbins, Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs, Nat. Med,
doi:10.1038/nm.3214Hashimoto, Activation of sigma-1 receptor chaperone in the treatment of neuropsychiatric diseases and its clinical implication, J. Pharmacol. Sci,
doi:10.1016/j.jphs.2014.11.010Hoertel, Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study, Mol. Psychiatry,
doi:10.1038/s41380-021-01021-4Hoertel, Association between hydroxyzine use and reduced mortality in patients hospitalized for coronavirus disease 2019: results from a multicenter observational study,
doi:10.1101/2020.10.23.20154302Hoertel, Blachier, Sánchez-Rico, Limosin, Leleu, Impact of the timing and adherence to face mask use on the course of the COVID-19 epidemic in France, J. Travel Med,
doi:10.1093/jtm/taab016Hoertel, Dexamethasone use and mortality in hospitalized patients with coronavirus disease 2019: a multicenter retrospective observational study, Br. J. Clin. Pharmacol,
doi:10.1111/bcp.14784Hojyo, How COVID-19 induces cytokine storm with high mortality, Inflamm. Regen
Ishikawa, High occupancy of sigma-1 receptors in the human brain after single oral administration of fluvoxamine: a positron emission tomography study using [11C] SA4503, Biol. Psychiatry,
doi:10.1016/j.biopsych.2007.04.001Ishima, Fujita, Hashimoto, Interaction of new antidepressants with sigma-1 receptor chaperones and their potentiation of neurite outgrowth in PC12 cells, Eur. J. Pharmacol,
doi:10.1016/j.ejphar.2014.01.064Kornhuber, Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications, Cell. Physiol. Biochem,
doi:10.1159/000315101Kornhuber, Identification of new functional inhibitors of acid sphingomyelinase using a structure-property-activity relation model, J. Med. Chem,
doi:10.1021/jm070524aKrutetskaya, Melnitskaya, Antonov, Nozdrachev, Sigma-1 receptor antagonists haloperidol and chlorpromazine modulate the effect of glutoxim on Na+ transport in frog skin, Doklady Biochem. Biophys,
doi:10.1134/S1607672919010186Köhler, Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: systematic review and meta-analysis, Mol. Neurobiol
Lenze, Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: A randomized clinical trial, JAMA,
doi:10.1001/jama.2020.22760Mengozzi, Chlorpromazine specifically inhibits peripheral and brain TNF production, and up-regulates IL-10 production, in mice, Immunology
Neuraz, Natural language processing for rapid response to emergent diseases: Case study of calcium channel blockers and hypertension in the COVID-19 pandemic, J. Med. Internet Res,
doi:10.2196/20773Obuchowicz, Bielecka-Wajdman, Paul-Samojedny, Nowacka, Different influence of antipsychotics on the balance between pro-and anti-inflammatory cytokines depends on glia activation: an in vitro study, Cytokine,
doi:10.1016/j.cyto.2017.04.004Robins, Hernán, Brumback, Marginal structural models and causal inference in epidemiology, Epidemiology
Schloer, Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine, Emerg. Microbes Infect,
doi:10.1080/22221751.2020.1829082Seftel, Boulware, Prospective cohort of fluvoxamine for early treatment of coronavirus disease 19, Open Forum Infect. Dis,
doi:10.1093/ofid/ofab050Solaimanzadeh, Nifedipine and amlodipine are associated with improved mortality and decreased risk for intubation and mechanical ventilation in elderly patients hospitalized for COVID-19, Cureus,
doi:10.7759/cureus.8069Stuart, Lee, Leacy, Prognostic score-based balance measures can be a useful diagnostic for propensity score methods in comparative effectiveness research, J. Clin. Epidemiol,
doi:10.1016/j.jclinepi.2013.01.013Sugino, Futamura, Mitsumoto, Maeda, Marunaka, Atypical antipsychotics suppress production of proinflammatory cytokines and up-regulate interleukin-10 in lipopolysaccharide-treated mice, Prog. Neuropsychopharmacol. Biol. Psychiatry,
doi:10.1016/j.pnpbp.2008.12.006Sukhatme, Reiersen, Vayttaden, Sukhatme, Fluvoxamine: A review of its mechanism of action and its role in COVID-19, Front. Pharmacol
Therneau, Patricia, Grambsch Modeling Survival Data: Extending the Cox Model
Vela, Repurposing sigma-1 receptor ligands for Covid-19 therapy?, Front. Pharmacol
Zhang, Calcium channel blocker amlodipine besylate therapy is associated with reduced case fatality rate of COVID-19 patients with hypertension, Cell Discov,
doi:10.1038/s41421-020-00235-0Zhang, Kim, Lonjon, Zhu, Written on behalf of AME Big-Data Clinical Trial Collaborative Group, Ann. Transl. Med,
doi:10.21037/atm.2018.12.10Zimniak, The serotonin reuptake inhibitor Fluoxetine inhibits SARS-CoV-2 in human lung tissue, Sci. Rep
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