Treatment with Zinc is Associated with Reduced In-Hospital Mortality Among COVID-19 Patients: A Multi-Center Cohort Study
Jennifer A Frontera, Joseph O Rahimian, Shadi Yaghi, Mengling Liu, Ariane Lewis, Adam De Havenon, Shraddha Mainali, Joshua Huang, Erica Scher, Thomas Wisniewski, Andrea B Troxel, Sharon Meropol, Laura J Balcer, Steven L Galetta
doi:10.21203/rs.3.rs-94509/v1
Background: Zinc impairs replication of RNA viruses such as SARS-CoV-1, and may be effective against SARS-CoV-2. However, to achieve adequate intracellular zinc levels, administration with an ionophore, which increases intracellular zinc levels, may be necessary. We evaluated the impact of zinc with an ionophore (Zn+ionophore) on COVID-19 in-hospital mortality rates. Methods: A multicenter cohort study was conducted of 3,473 adult hospitalized patients with reverse-transcriptase-polymerase-chain-reaction (RT-PCR) positive SARS-CoV-2 infection admitted to four New York City hospitals between March 10 through May 20, 2020. Exclusion criteria were: death or discharge within 24h, comfort-care status, clinical trial enrollment, treatment with an IL-6 inhibitor or remdesivir. Patients who received Zn+ionophore were compared to patients who did not using multivariable time-dependent cox proportional hazards models for time to in-hospital death adjusting for confounders including age, sex, race, BMI, diabetes, week of admission, hospital location, sequential organ failure assessment (SOFA) score, intubation, acute renal failure, neurological events, treatment with corticosteroids, azithromycin or lopinavir/ritonavir and the propensity score of receiving Zn+ionophore. A sensitivity analysis was performed using a propensity score-matched cohort of patients who did or did not receive Zn+ionophore matched by age, sex and ventilator status. Results: Among 3,473 patients (median age 64, 1947 [56%] male, 522 [15%] ventilated, 545[16%] died), 1,006 (29%) received Zn+ionophore. Zn+ionophore was associated with a 24% reduced risk of in-hospital mortality (12% of those who received Zn+ionophore died versus 17% who did not; adjusted Hazard Ratio [aHR] 0.76, 95% CI 0.60-0.96, P=0.023). More patients who received Zn+ionophore were discharged home (72% Zn+ionophore vs 67% no Zn+ionophore, P=0.003) Neither Zn nor the ionophore alone were associated with decreased mortality rates. Propensity scorematched sensitivity analysis (N=1356) validated these results (Zn+ionophore aHR for mortality 0.63, 95%CI 0.44-0.91, P=0.015). There were no signi cant interactions for Zn+ionophore with other COVID-19 speci c medications. Conclusions: Zinc with an ionophore was associated with increased rates of discharge home and a 24% reduced risk of in-hospital mortality among COVID-19 patients, while neither zinc alone nor the ionophore alone reduced mortality. Further randomized trials are warranted.
Summery In this study of 3,473 hospitalized COVID-19 patients, treatment with zinc and an ionophore was associated with a 24% reduced risk of in-hospital mortality in multivariable Cox regression analysis. A sensitivity analysis in a propensity score-matched cohort supported this nding.
Figure 2 Forest plot of subgroups evaluating the impact of treatment with zinc plus an ionophore on in-hospital mortality Supplementary Files This is a list of supplementary les associated with this preprint. Click to download.
SupplementaryAppendixZincBMCID.docx
References
Bhimraj, Morgan, Shumaker, Lavergne, Baden et al., Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19, Clin Infect Dis
Cavalcanti, Zampieri, Rosa, Azevedo, Veiga et al., Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19, N Engl J Med
Dabbagh-Bazarbachi, Clergeaud, Quesada, Ortiz, Sullivan et al., Zinc ionophore activity of quercetin and epigallocatechin-gallate: from Hepa 1-6 cells to a liposome model, J Agric Food Chem
Ferreira, Bota, Bross, Melot, Vincent, Serial evaluation of the SOFA score to predict outcome in critically ill patients, JAMA
Frontera, Mainali, Fink, Robertson, Schober et al., ): Study Design and Rationale
Gautret, Lagier, Parola, Hoang, Meddeb et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, Int J Antimicrob Agents
Group, Horby, Lim, Emberson, Mafham et al., Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report, N Engl J Med
Jaf, Jo, Ml, Adh, Sm et al., P. Ongoing Clinical Trials for the Management of the COVID-19 Pandemic
Krenn, Gaudernak, Holzer, Lanke, Van Kuppeveld et al., Antiviral activity of the zinc ionophores pyrithione and hinokitiol against picornavirus infections, J Virol
Kumar, Gross, Ahlskog, Copper de ciency myelopathy produces a clinical picture like subacute combined degeneration, Neurology
Levesque, Hanley, Kezouh, Suissa, Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes, BMJ
Liu, Cao, Xu, Wang, Zhang et al., Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov
Maret, Zinc in Cellular Regulation: The Nature and Signi cance of "Zinc Signals, Int J Mol Sci
Maywald, Wessels, Rink, Zinc Signals and Immunity, Int J Mol Sci
Oakes, Lyon, Gray, Talwar, Reilly, Acute in ammatory response does not affect erythrocyte concentrations of copper, zinc and selenium, Clin Nutr
Rahman, Idid, Can Zn Be a Critical Element in COVID-19 Treatment?, Biol Trace Elem Res
Read, Obeid, Ahlenstiel, Ahlenstiel, The Role of Zinc in Antiviral Immunity, Adv Nutr
Rosenthal, Otterman, Fink, Why Surviving the Virus Might Come Down to Which Hospital Admits You
Skalny, Rink, Ajsuvakova, Aschner, Gritsenko et al., Zinc and respiratory tract infections: Perspectives for COVID19 (Review), Int J Mol Med
Skipper, Pastick, Engen, Bangdiwala, Abassi et al., Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19: A Randomized Trial, Ann Intern Med
Uptodate, Hydroxychloroquine: Drug Information Lexicomp
Uptodate, Tocilizumab: Drug Information Lexicomp
Uptodate, Zinc: Drug Information Lexicomp
Velthuis, Van Den Worm, Sims, Baric, Snijder et al., Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture, PLoS Pathog
Vincent, De Mendonca, Cantraine, Moreno, Takala et al., Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on "sepsis-related problems" of the European Society of Intensive Care Medicine, Crit Care Med
Vincent, Moreno, Takala, Willatts, Mendonca et al., The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine, Intensive Care Med
Wessels, Maywald, Rink, Zinc as a Gatekeeper of Immune Function, Nutrients
Xue, Moyer, Peng, Wu, Hannafon et al., Chloroquine is a zinc ionophore, PLoS One
Zhang, Wu, Schoene, Cheng, Wang et al., Effect of resveratrol and zinc on intracellular zinc status in normal human prostate epithelial cells, Am J Physiol Cell Physiol
