Early Fluvoxamine Reduces the Risk for Clinical Deterioration in Symptomatic Outpatients with COVID-19: A Real-World, Retrospective, before-after Analysis
Aristotelis Tsiakalos, Panayiotis D Ziakas, Eleni Polyzou, Georgios Schinas, Karolina Akinosoglou
doi:10.3390/microorganisms11082073
Fluvoxamine, a selective serotonin reuptake inhibitor with anti-inflammatory properties, has gained attention as a repurposed drug to treat COVID-19. We aimed to explore the potential benefit of fluvoxamine on outpatients with early SARS-CoV-2 infection. We performed a retrospective study of fluvoxamine adult outpatients with symptomatic COVID-19 disease of early onset (<5 days), in the context of an infectious diseases private practice, between September-December 2021, in Greece. Patients with disease duration ≥5 days, dyspnea and/or hypoxemia with oxygen saturation <94% in room air and pregnancy were excluded from the analysis. In total, 103 patients, 54 males/49 females with a median age of 47 years (39-56), were included in this study. Patient characteristics were balanced before and after the introduction of fluvoxamine. Two patients in the fluvoxamine arm (3.8%; 95% CI 0.4-13) had clinical deterioration compared to 8 patients in the standard of care group (16%; 95% CI 7.2-29.1, p < 0.04). After controlling for age, sex, body mass index > 30 and vaccination status, fluvoxamine was independently associated with a lower risk of clinical deterioration (adj. OR 0.12; 95% CI 0.02-0.70, p < 0.02). Adding on fluvoxamine to treatment for early symptomatic COVID-19 patients may protect them from clinical deterioration and hospitalization, and it is an appealing low-cost, low-toxicity option in the community setting and warrants further investigation.
Author Contributions: A.T. and P.D.Z. conceived the idea, A.T. and P.D.Z. collected and analyzed data, A.T., P.D.Z., K.A., E.P. and G.S. wrote the manuscript, K.A. and P.D.Z. critically corrected the manuscript, A.T. oversaw the study. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
References
Berwanger, Antithrombotic Therapy for Outpatients with COVID-19: Implications for Clinical Practice and Future Research, JAMA,
doi:10.1001/jama.2021.17460Bramante, Buse, Liebovitz, Nicklas, Puskarich et al., Outpatient treatment of COVID-19 and incidence of post-COVID-19
Bramante, Huling, Tignanelli, Buse, Liebovitz et al., Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for COVID-19, N. Engl. J. Med,
doi:10.1056/NEJMoa2201662Calusic, Marcec, Luksa, Jurkovic, Kovac et al., Safety and efficacy of fluvoxamine in COVID-19 ICU patients: An open label, prospective cohort trial with matched controls, Br. J. Clin. Pharmacol,
doi:10.1111/bcp.15126Carpinteiro, 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.2020.100142Chakraborty, Sharma, Bhattacharya, Agoramoorthy, Lee, The Drug Repurposing for COVID-19 Clinical Trials Provide Very Effective Therapeutic Combinations: Lessons Learned From Major Clinical Studies, Front. Pharmacol,
doi:10.3389/fphar.2021.704205Chalmers, Chotirmall, Rewiring the Immune Response in COVID-19, Am. J. Respir. Crit. Care Med
Coveney, Firthlogit, Stata Module to Calculate Bias Reduction in Logistic Regression
Deng, Rayner, Ramaraju, Abbas, Garcia et al., Efficacy and safety of selective serotonin reuptake inhibitors in COVID-19 management: A systematic review and meta-analysis, Clin. Microbiol. Infect,
doi:10.1016/j.cmi.2023.01.010Diao, Wang, Tan, Chen, Liu et al., Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19), Front. Immunol,
doi:10.3389/fimmu.2020.00827Dicker, Bettini, Farpour-Lambert, Fruhbeck, Golan et al., Obesity and COVID-19: The Two Sides of the Coin, Obes. Facts,
doi:10.1159/000510005Ebell, Inhaled Budesonide Reduces the Risk of Emergency Department Evaluation or Hospitalization in Early COVID-19, Am. Fam. Physician
Fergal, Gilmar, Kristian, Jamie, Christina et al., TOGETHER Investigators. Early Treatment with Fluvoxamine among Patients with COVID-19: A Cost-Consequence Model. medRxiv 2021,
doi:10.1101/2021.12.23.21268352Fico, Isayeva, De Prisco, Oliva, Sole et al., Psychotropic drug repurposing for COVID-19: A Systematic Review and Meta-Analysis, Eur. Neuropsychopharmacol,
doi:10.1016/j.euroneuro.2022.10.004Finley, Is Fluvoxamine the Covid Drug We've Been Waiting for? Available online
He, Zhao, Dong, Zhuang, Song et al., Effects of severe acute respiratory syndrome (SARS) coronavirus infection on peripheral blood lymphocytes and their subsets, Int. J. Infect. Dis,
doi:10.1016/j.ijid.2004.07.014Heinze, Schemper, A solution to the problem of separation in logistic regression, Stat. Med,
doi:10.1002/sim.1047Hoertel, Do the Selective Serotonin Reuptake Inhibitor Antidepressants Fluoxetine and Fluvoxamine Reduce Mortality among Patients with COVID-19?, JAMA Netw. Open,
doi:10.1001/jamanetworkopen.2021.36510Huang, Pranata, Lymphopenia in severe coronavirus disease-2019 (COVID-19): Systematic review and meta-analysis, J. Intensive Care,
doi:10.1186/s40560-020-00453-4Kirenga, Mugenyi, Sanchez-Rico, Kyobe, Muttamba et al., Association of fluvoxamine with mortality and symptom resolution among inpatients with COVID-19 in Uganda: A prospective interventional open-label cohort study, Mol. Psychiatry,
doi:10.1038/s41380-023-02004-3Lee, Vigod, Bortolussi-Courval, Hanula, Boulware et al., Fluvoxamine for Outpatient Management of COVID-19 to Prevent Hospitalization: A Systematic Review and Meta-analysis, JAMA Netw. Open,
doi:10.1001/jamanetworkopen.2022.6269Lenze, 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.2020.22760Marcec, Dodig, Likic, A meta-analysis regarding fluvoxamine and hospitalization risk of COVID-19 patients: TOGETHER making a difference, J. Infect,
doi:10.1016/j.jinf.2022.11.011Maxwell, Sanders, Sabot, Hachem, Llanos-Cuentas et al., COVID-19 Therapeutics for Low-and Middle-Income Countries: A Review of Candidate Agents with Potential for Near-Term Use and Impact, Am. J. Trop. Med. Hyg,
doi:10.4269/ajtmh.21-0200Mccarthy, Naggie, Boulware, Lindsell, Stewart et al., Effect of Fluvoxamine vs Placebo on Time to Sustained Recovery in Outpatients with Mild to Moderate COVID-19: A Randomized Clinical Trial, JAMA,
doi:10.1001/jama.2022.24100Mills, Reis, Wilson, Thorlund, Forrest et al., Early Treatment with Fluvoxamine among Patients with COVID-19: A Cost-Consequence Model, Am. J. Trop. Med. Hyg. 2023,
doi:10.4269/ajtmh.22-0106Niu, Sareli, Mayer, Visbal, Sareli, Lymphopenia as a Predictor for Adverse Clinical Outcomes in Hospitalized Patients with COVID-19: A Single Center Retrospective Study of 4485 Cases, J. Clin. Med,
doi:10.3390/jcm11030700Oskotsky, Maric, Tang, Oskotsky, Wong et al., Mortality Risk among Patients with COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants, JAMA Netw. Open,
doi:10.1001/jamanetworkopen.2021.33090Pericat, Leon-Icaza, Sanchez Rico, Muhle, Zoicas et al., Antiviral and Anti-Inflammatory Activities of Fluoxetine in a SARS-CoV-2 Infection Mouse Model, Int. J. Mol. Sci,
doi:10.3390/ijms232113623Pontelli, Castro, Martins, La Serra, Veras et al., SARS-CoV-2 productively infects primary human immune system cells in vitro and in COVID-19 patients, J. Mol. Cell Biol,
doi:10.1093/jmcb/mjac021Prices, None
Rafiee, Hajhashemi, Javanmard, Fluvoxamine inhibits some inflammatory genes expression in LPS/stimulated human endothelial cells, U937 macrophages, and carrageenan-induced paw edema in rat, Iran. J. Basic. Med. Sci
Rahman, Mahi, Melamed, Alam, Effects of Antidepressants on COVID-19 Outcomes: Retrospective Study on Large-Scale Electronic Health Record Data. Interact, J. Med. Res,
doi:10.2196/39455Ramakrishnan, Nicolau, Jr, Langford, Mahdi et al., Inhaled budesonide in the treatment of early COVID-19 (STOIC): A phase 2, open-label, randomised controlled trial, Lancet Respir. Med,
doi:10.1016/S2213-2600(21)00160-0Ratajczak, Kucia, SARS-CoV-2 infection and overactivation of Nlrp3 inflammasome as a trigger of cytokine "storm" and risk factor for damage of hematopoietic stem cells, Leukemia,
doi:10.1038/s41375-020-0887-9Reis, 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)00448-4Reis, Dos, Silva, Medeiros Silva, Thabane et al., Oral Fluvoxamine with Inhaled Budesonide for Treatment of Early-Onset COVID-19: A Randomized Platform Trial, Ann. Intern. Med,
doi:10.7326/M22-3305Rosen, 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
Sawadogo, Tsegaye, Gizaw, Adera, Overweight and obesity as risk factors for COVID-19-associated hospitalisations and death: Systematic review and meta-analysis, BMJ Nutr. Prev. Health,
doi:10.1136/bmjnph-2021-000375Talasaz, Sadeghipour, Kakavand, Aghakouchakzadeh, Kordzadeh-Kermani et al., Recent Randomized Trials of Antithrombotic Therapy for Patients with COVID-19: JACC State-of-the-Art Review, J. Am. Coll. Cardiol,
doi:10.1016/j.jacc.2021.02.035Varghese, Sandmann, Ochs, Schrempf, Frommel et al., Persistent symptoms and lab abnormalities in patients who recovered from COVID-19, Sci. Rep,
doi:10.1038/s41598-021-91270-8Wang, Hu, Hu, Zhu, Liu et al., Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan
Wen, Chen, Tang, Wang, Zhou et al., Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19: A meta-analysis, Ann. Med,
doi:10.1080/07853890.2022.2034936Wu, Joyal-Desmarais, Ribeiro, Vieira, Stojanovic et al., Long-term effectiveness of COVID-19 vaccines against infections, hospitalisations, and mortality in adults: Findings from a rapid living systematic evidence synthesis and meta-analysis up to December, Lancet Respir. Med,
doi:10.1016/S2213-2600(23)00015-2Yu, Bafadhel, Dorward, Hayward, Saville et al., Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): A randomised, controlled, open-label, adaptive platform trial, Lancet,
doi:10.1016/S0140-6736(21)01744-XZhao, Meng, Kumar, Wu, Huang et al., Lymphopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A systemic review and meta-analysis, Int. J. Infect. Dis,
doi:10.1016/j.ijid.2020.04.086Zhou, Yu, Du, Fan, Liu et al., Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan
Zimniak, Kirschner, Hilpert, Geiger, Danov et al., The serotonin reuptake inhibitor Fluoxetine inhibits SARS-CoV-2 in human lung tissue. Sci,
doi:10.1038/s41598-021-85049-0
