Hydroxyzine Use and Mortality in Patients Hospitalized for COVID-19: A Multicenter Observational Study
Marina Sánchez-Rico, Frédéric Limosin, Raphaël Vernet, Nathanaël Beeker, Antoine Neuraz, Carlos Blanco, Mark Olfson, Cédric Lemogne, Pierre Meneton, Christel Daniel, Nicolas Paris, Alexandre Gramfort, Guillaume Lemaitre, Pedro De La Muela, Elisa Salamanca, Mélodie Bernaux, Ali Bellamine, Anita Burgun, Nicolas Hoertel
Journal of Clinical Medicine, doi:10.3390/jcm10245891
1) Background: Based on its antiviral activity, anti-inflammatory properties, and functional inhibition effects on the acid sphingomyelinase/ceramide system (FIASMA), we sought to examine the potential usefulness of the H1 antihistamine hydroxyzine in patients hospitalized for COVID-19. (2) Methods: In a multicenter observational study, we included 15,103 adults hospitalized for COVID-19, of which 164 (1.1%) received hydroxyzine within the first 48 h of hospitalization, administered orally at a median daily dose of 25.0 mg (SD = 29.5). We compared mortality rates between patients who received hydroxyzine at hospital admission and those who did not, using a multivariable logistic regression model adjusting for patients' characteristics, medical conditions, and use of other
Acknowledgments: The authors 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. Collaborators of the EDS APHP COVID consortium are: 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.
Conflicts of Interest: All authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare: no support from any organization for the submitted work;..
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:10.1080/03610910902859574Blaess, Kaiser, Sommerfeld, Rentschler, Csuk et al., Rational Drug Repurposing: Focus on Lysosomotropism, Targets in Disease Process, Drug Profile, and Pulmonary Tissue Accumulation in SARS-CoV-2 Infection/COVID-19, Front. Pharmacol,
doi:10.3389/fphar.2020.584881Carpinteiro, Edwards, Hoffmann, Kochs, Gripp et al., Pharmacological Inhibition of Acid Sphingomyelinase Prevents Uptake of SARS-CoV-2 by Epithelial Cells, Cell Rep. Med,
doi:10.1016/j.xcrm.2020.100142Carpinteiro, Gripp, Hoffmann, Pöhlmann, Hoertel et al., Inhibition of Acid Sphingomyelinase by Ambroxol Prevents SARS-CoV-2 Entry into Epithelial Cells, J. Biol. Chem,
doi:10.1016/j.jbc.2021.100701Chevance, Gourion, Hoertel, Llorca, Thomas et al., Ensuring mental health care during the SARS-CoV-2 epidemic in France: A narrative review, L'Encephale,
doi:10.1016/j.encep.2020.03.001Darquennes, Le Corre, Le Moine, Loas, Association between Functional Inhibitors of Acid Sphingomyelinase (Fiasmas) and Reduced Risk of Death in COVID-19 Patients: A Retrospective Cohort Study, Pharmaceuticals,
doi:10.3390/ph14030226Dei Cas, Ottolenghi, Morano, Rinaldo, Roda et al., Link between Serum Lipid Signature and Prognostic Factors in COVID-19 Patients, Sci. Rep,
doi:10.1038/s41598-021-00755-zElm, Altman, Egger, Pocock, Gøtzsche et al., The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies, Ann. Intern. Med,
doi:10.7326/0003-4819-147-8-200710160-00010Ge, Wang, Hou, Lv, Wang et al., Repositioning of Histamine H1 Receptor Antagonist: Doxepin Inhibits Viropexis of SARS-CoV-2 Spike Pseudovirus by Blocking ACE2, Eur. J. Pharmacol,
doi:10.1016/j.ejphar.2021.173897Gordon, Jang, Bouhaddou, Xu, Obernier et al., A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug Repurposing, Nature,
doi:10.1038/s41586-020-2286-9Hoertel, Blachier, Blanco, Olfson, Massetti et al., A Stochastic Agent-Based Model of the SARS-CoV-2 Epidemic in France, Nat. Med,
doi:10.1038/s41591-020-1001-6Hoertel, Blachier, Blanco, Olfson, Massetti et al., Facing the COVID-19 Epidemic in NYC: A Stochastic Agent-Based Model of Various Intervention Strategies, medRxiv,
doi:10.1101/2020.04.23.20076885Hoertel, 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, Do the Selective Serotonin Reuptake Inhibitor Antidepressants Fluoxetine and Fluvoxamine Reduce Mortality among Patients with COVID-19?, JAMA Netw. Open,
doi:10.1001/jamanetworkopen.2021.36510Hoertel, Sánchez-Rico, Cougoule, Gulbins, Kornhuber et al., Repurposing Antidepressants Inhibiting the Sphingomyelinase Acid/Ceramide System against COVID-19: Current Evidence and Potential Mechanisms, Mol. Psychiatry,
doi:10.1038/s41380-021-01254-3Hoertel, Sánchez-Rico, Gulbins, Kornhuber, Carpinteiro et al., Association Between FIASMAs and Reduced Risk of Intubation or Death in Individuals Hospitalized for Severe COVID-19: An Observational Multicenter Study, Clin. Pharmacol. Ther,
doi:10.1002/cpt.2317Hoertel, Sánchez-Rico, Gulbins, Kornhuber, Carpinteiro et al., Association between Psychotropic Medications Functionally Inhibiting Acid Sphingomyelinase and Reduced Risk of Intubation or Death among Individuals with Mental Disorder and Severe COVID-19: An Observational Study, medRxiv,
doi:10.1101/2021.02.18.21251997Hoertel, Sánchez-Rico, Vernet, Beeker, Jannot et al., 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, Sánchez-Rico, Vernet, Beeker, Neuraz et al., Dexamethasone Use and Mortality in Hospitalized Patients with Coronavirus Disease 2019: A Multicentre Retrospective Observational Study, Br. J. Clin. Pharmacol,
doi:10.1111/bcp.14784Hoertel, Sánchez-Rico, Vernet, Jannot, Neuraz et al., Observational Study of Chlorpromazine in Hospitalized Patients with COVID-19, Clin. Drug Investig,
doi:10.1007/s40261-021-01001-0Hoertel, Sánchez-Rico, Vernet, Jannot, Neuraz et al., Observational Study of Haloperidol in Hospitalized Patients with COVID-19, PLoS ONE,
doi:10.1371/journal.pone.0247122Kornhuber, Muehlbacher, Trapp, Pechmann, Friedl et al., Identification of Novel Functional Inhibitors of Acid Sphingomyelinase, PLoS ONE,
doi:10.1371/journal.pone.0023852Kornhuber, Tripal, Reichel, Mühle, Rhein et al., Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): A Novel Pharmacological Group of Drugs with Broad Clinical Applications, Cell. Physiol. Biochem,
doi:10.1159/000315101Lagunas-Rangel, Neutrophil-to-Lymphocyte Ratio and Lymphocyte-to-C-Reactive Protein Ratio in Patients with Severe Coronavirus Disease 2019 (COVID-19): A Meta-Analysis, J. Med. Virol,
doi:10.1002/jmv.25819Lenze, Mattar, Zorumski, Stevens, Schweiger et al., Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients with Symptomatic COVID-19: A Randomized Clinical Trial, JAMA,
doi:10.1001/jama.2020.22760Mandhane, Shah, Bahekar, Mehetre, Pawar et al., Characterization of Anti-Inflammatory Properties and Evidence for No Sedation Liability for the Novel Antihistamine SUN-1334, H. Int. Arch. Allergy Immunol,
doi:10.1159/000232571Marín-Corral, Rodríguez-Morató, Gomez-Gomez, Pascual-Guardia, Muñoz-Bermúdez et al., Metabolic Signatures Associated with Severity in Hospitalized COVID-19 Patients, Int. J. Mol. Sci,
doi:10.3390/ijms22094794Matta, Wiernik, Robineau, Carrat, Touvier et al., Association of Self-Reported COVID-19 Infection and SARS-CoV-2 Serology Test Results with Persistent Physical Symptoms among French Adults during the COVID-19 Pandemic, JAMA Intern. Med,
doi:10.1001/jamainternmed.2021.6454Norinder, Tuck, Norgren, Munic Kos, Existing Highly Accumulating Lysosomotropic Drugs with Potential for Repurposing to Target COVID-19, Biomed. Pharmacother. Biomed. Pharmacother,
doi:10.1016/j.biopha.2020.110582Reis, Dos, Moreira-Silva, Silva, Thabane et al., Effect of Early Treatment with Fluvoxamine on Risk of Emergency Care and Hospitalisation among Patients with COVID-19: The TOGETHER Randomised, Platform Clinical Trial, Lancet Glob. Health,
doi:10.1016/S2214-109X(21)00448-4Reznikov, Norris, Vashisht, Bluhm, Li et al., Identification of Antiviral Antihistamines for COVID-19 Repurposing, Biochem. Biophys. Res. Commun,
doi:10.1016/j.bbrc.2020.11.095Rivas, Saponi-Cortes, Zamorano, Hydroxyzine Inhibits SARS-CoV-2 Spike Protein Binding to ACE2 in a Qualitative in Vitro Assay, bioRxiv,
doi:10.1101/2021.01.04.424792Rosen, Seki, Fernández-Castañeda, Beiter, Eccles et al., Modulation of the Sigma-1 Receptor-IRE1 Pathway Is Beneficial in Preclinical Models of Inflammation and Sepsis, Sci. Transl. Med,
doi:10.1126/scitranslmed.aau5266Rosenbaum, Rubin, The Central Role of the Propensity Score in Observational Studies for Causal Effects, Biometrika,
doi:10.1093/biomet/70.1.41Schloer, Brunotte, Goretzko, Mecate-Zambrano, Korthals et al., 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:10.1080/22221751.2020.1829082Schneeweiss, Sensitivity Analysis and External Adjustment for Unmeasured Confounders in Epidemiologic Database Studies of Therapeutics, Pharmacoepidemiol. Drug Saf,
doi:10.1002/pds.1200Seftel, Boulware, Prospective Cohort of Fluvoxamine for Early Treatment of Coronavirus Disease 19, Open Forum Infect. Dis,
doi:10.1093/ofid/ofab050Serdar, Cihan, Yücel, Serdar, Sample Size, Power and Effect Size Revisited: Simplified and Practical Approaches in Pre-Clinical, Clinical and Laboratory Studies, Biochem. Med,
doi:10.11613/BM.2021.010502Stebbing, Phelan, Griffin, Tucker, Oechsle et al., COVID-19: Combining Antiviral and Anti-Inflammatory Treatments, Lancet Infect. Dis,
doi:10.1016/S1473-3099(20)30132-8Sukhatme, Reiersen, Vayttaden, Sukhatme, Fluvoxamine: A Review of Its Mechanism of Action and Its Role in COVID-19, Front. Pharmacol,
doi:10.3389/fphar.2021.652688Torretta, Poliseno, Capitanio, Biasin, Santantonio et al., Severity of COVID-19 Patients Predicted by Serum Sphingolipids Signature, Int. J. Mol. Sci,
doi:10.3390/ijms221910198Villoutreix, Beaune, Tamouza, Krishnamoorthy, Leboyer, Prevention of COVID-19 by Drug Repurposing: Rationale from Drugs Prescribed for Mental Disorders, Drug Discov. Today,
doi:10.1016/j.drudis.2020.06.022Villoutreix, Krishnamoorthy, Tamouza, Leboyer, Beaune, Chemoinformatic Analysis of Psychotropic and Antihistaminic Drugs in the Light of Experimental Anti-SARS-CoV-2 Activities, Adv. Appl. Bioinforma. Chem,
doi:10.2147/AABC.S304649Williamson, Walker, Bhaskaran, Bacon, Bates et al., Factors Associated with COVID-19-Related Death Using OpenSAFELY, Nature,
doi:10.1038/s41586-020-2521-4Zhou, Dai, Tong, COVID-19: A Recommendation to Examine the Effect of Hydroxychloroquine in Preventing Infection and Progression, J. Antimicrob. Chemother,
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'abstract': '<jats:p>(1) Background: Based on its antiviral activity, anti-inflammatory properties, and '
'functional inhibition effects on the acid sphingomyelinase/ceramide system (FIASMA), we '
'sought to examine the potential usefulness of the H1 antihistamine hydroxyzine in patients '
'hospitalized for COVID-19. (2) Methods: In a multicenter observational study, we included '
'15,103 adults hospitalized for COVID-19, of which 164 (1.1%) received hydroxyzine within the '
'first 48 h of hospitalization, administered orally at a median daily dose of 25.0 mg (SD = '
'29.5). We compared mortality rates between patients who received hydroxyzine at hospital '
'admission and those who did not, using a multivariable logistic regression model adjusting '
'for patients’ characteristics, medical conditions, and use of other medications. (3) Results: '
'This analysis showed a significant association between hydroxyzine use and reduced mortality '
'(AOR, 0.51; 95%CI, 0.29–0.88, p = 0.016). This association was similar in multiple '
'sensitivity analyses. (4) Conclusions: In this retrospective observational multicenter study, '
'the use of the FIASMA hydroxyzine was associated with reduced mortality in patients '
'hospitalized for COVID-19. Double-blind placebo-controlled randomized clinical trials of '
'hydroxyzine for COVID-19 are needed to confirm these results, as are studies to examine the '
'potential usefulness of this medication for outpatients and as post-exposure prophylaxis for '
'individuals at high risk for severe COVID-19.</jats:p>',
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