Serum Zinc, Copper, and Other Biometals Are Associated with COVID-19 Severity Markers
Anatoly V Skalny, Peter S Timashev, Michael Aschner, Jan Aaseth, Lyubov N Chernova, Vladimir E Belyaev, Andrey R Grabeklis, Svetlana V Notova, Ryszard Lobinski, Aristides Tsatsakis, Andrey A Svistunov, Victor V Fomin, Alexey A Tinkov, Peter V Glybochko
Metabolites, doi:10.3390/metabo11040244
The objective of the present study was to evaluate of serum metal levels in COVID-19 patients with different disease severity, and to investigate the independent association between serum metal profile and markers of lung damage. The cohort of COVID-19 patients consisted of groups of subjects with mild, moderate, and severe illness, 50 examinees each. Forty-four healthy subjects of the respective age were involved in the current study as the control group. Serum metal levels were evaluated using inductively-coupled plasma mass-spectrometry. Examination of COVID-19 patients demonstrated that heart rate, respiratory rate, body temperature, C-reactive protein levels, as well as lung damage increased significantly with COVID-19 severity, whereas SpO 2 decreased gradually. Increasing COVID-19 severity was also associated with a significant gradual decrease in serum Ca, Fe, Se, Zn levels as compared to controls, whereas serum Cu and especially Cu/Zn ratio were elevated. No significant group differences in serum Mg and Mn levels were observed. Serum Ca, Fe, Se, Zn correlated positively with SpO 2 , being inversely associated with fever, lung damage, and C-reactive protein concentrations. Opposite correlations were observed for Cu and Cu/Zn ratio. In regression models, serum Se levels were inversely associated with lung damage independently of other markers of disease severity, anthropometric, biochemical, and hemostatic parameters. Cu/Zn ratio was also considered as a significant predictor of lower SpO 2 in adjusted regression models. Taken together, these findings demonstrated that metal metabolism significantly interferes with COVID-19 pathogenesis, although the causal relations as well as precise mechanisms are yet to be characterized.
Author Contributions: Conceptualization: A.V.S., P.S.T., A.A.T.; methodology: A.V.S., R.L.; validation: J.A., M.A., R.L., A.T.; formal analysis: L.N.C., J.A., A.R.G., S.V.N.; investigation: L.N.C., V.E.B., S.V.N.; resources: A.A.S., V.V.F., P.V.G.; data curation: A.T., A.A.T.; writing-original draft preparation: P.S.T., L.N.C., V.E.B., A.R.G., S.V.N., A.A.S., V.V.F., A.A.T.; writing-review & editing: A.V.S., P.V.G., M.A., J.A., R.L., A.T.; visualization: A.A.T.; supervision: A.V.S., P.S.T.; project administration: A.V.S., P.S.T., A.A.T. All authors have read and agreed to the published version of the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
References
Alexander, Tinkov, Strand, Alehagen, Skalny et al., Early Nutritional Interventions with Zinc, Selenium and Vitamin D for Raising Anti-Viral Resistance Against Progressive COVID-19, Nutrients,
doi:10.3390/nu12082358Anuk, Polat, Akdas, Erol, Tanacan et al., The Relation Between Trace Element Status (Zinc, Copper, Magnesium) and Clinical Outcomes in COVID-19 Infection during Pregnancy, Biol. Trace Element Res,
doi:10.1007/s12011-020-02496-yBolondi, Russo, Gamberini, Circelli, Meca et al., Iron metabolism and lymphocyte characterisation during Covid-19 infection in ICU patients: An observational cohort study, World J. Emerg. Surg,
doi:10.1186/s13017-020-00323-2Cappellini, Brivio, Casati, Cavallero, Contro et al., Low levels of total and ionized calcium in blood of COVID-19 patients, Clin. Chem. Lab. Med,
doi:10.1515/cclm-2020-0611Carlucci, Ahuja, Petrilli, Rajagopalan, Jones et al., Zinc sulfate in combination with a zinc ionophore may improve outcomes in hospitalized COVID-19 patients, J. Med. Microbiol,
doi:10.1099/jmm.0.001250Di Filippo, Formenti, Giustina, Hypocalcemia: The quest for the cause of a major biochemical feature of COVID-19, Endocrine,
doi:10.1007/s12020-020-02525-9Di Filippo, Formenti, Rovere-Querini, Carlucci, Conte et al., Hypocalcemia is highly prevalent and predicts hospitalization in patients with COVID-19, Endocrine,
doi:10.1007/s12020-020-02383-5Gonçalves, Gonçalves, Guarnieri, Risegato, Guimarães et al., Association Between Low Zinc Levels and Severity of Acute Respiratory Distress Syndrome by New Coronavirus SARS-CoV-2, Nutr. Clin. Pr,
doi:10.1002/ncp.10612Heller, Sun, Hackler, Seelig, Seibert et al., Prediction of survival odds in COVID-19 by zinc, age and selenoprotein P as composite biomarker, Redox Biol
Henderson, Canna, Schulert, Volpi, Lee et al., On the Alert for Cytokine Storm: Immunopathology in COVID-19, Arthritis Rheumatol,
doi:10.1002/art.41285Hiffler, Rakotoambinina, Selenium and RNA Virus Interactions: Potential Implications for SARS-CoV-2 Infection (COVID-19), Front. Nutr,
doi:10.3389/fnut.2020.00164Jothimani, Kailasam, Danielraj, Nallathambi, Ramachandran et al., COVID-19: Poor outcomes in patients with zinc deficiency, Int. J. Infect. Dis,
doi:10.1016/j.ijid.2020.09.014Laine, Tuomainen, Salonen, Virtanen, Serum copper-to-zinc-ratio and risk of incident infection in men: The Kuopio Ischaemic Heart Disease Risk Factor Study, Eur. J. Epidemiol,
doi:10.1007/s10654-020-00644-1Liu, Han, Wu, Gong, Tian, Prevalence and predictive value of hypocalcemia in severe COVID-19 patients, J. Infect. Public Health,
doi:10.1016/j.jiph.2020.05.029Majeed, Nagabhushanam, Gowda, Mundkur, An Exploratory Study of Selenium Status in Normal Subjects and COVID-19 Patients in South Indian population: Case for Adequate Selenium Status: Selenium Status in COVID-19 Patients, Nutrition,
doi:10.1016/j.nut.2020.111053Malavoltarobertina, Giacconi, Piacenza, Santarelli, Cipriano et al., Plasma copper/zinc ratio: An inflammatory/nutritional biomarker as predictor of all-cause mortality in elderly population, Biogerontology,
doi:10.1007/s10522-009-9251-1Moghaddam, Heller, Sun, Seelig, Cherkezov et al., Selenium Deficiency Is Associated with Mortality Risk from COVID-19, Nutrients,
doi:10.3390/nu12072098Munblit, Nekliudov, Bugaeva, Blyuss, Kislova et al., StopCOVID cohort: An observational study of 3,480 patients admitted to the Sechenov University hospital network in Moscow city for suspected COVID-19 infection, Clin. Infect. Dis,
doi:10.1093/cid/ciaa1535Osredkar, Sustar, Copper and Zinc, Biological Role and Significance of Copper/Zinc Imbalance, J. Clin. Toxicol,
doi:10.4172/2161-0495.S3-001Pal, Squitti, Picozza, Pawar, Rongioletti et al., Zinc and COVID-19: Basis of Current Clinical Trials, Biol. Trace Elem. Res,
doi:10.1007/s12011-020-02437-9Pereira, Campos, Bogo, Copper toxicology, oxidative stress and inflammation using zebrafish as experimental model, J. Appl. Toxicol,
doi:10.1002/jat.3303Petrakis, Margină, Tsarouhas, Tekos, Stan et al., Obesity-A risk factor for increased COVID-19 prevalence, severity and lethality (Review), Mol. Med. Rep,
doi:10.3892/mmr.2020.11127Richardson, Lovegrove, Nutritional status of micronutrients as a possible and modifiable risk factor for COVID-19: A UK perspective, Br. J. Nutr,
doi:10.1017/S000711452000330XShah, Frost, Aaron, Donovan, Drakesmith et al., Systemic hypoferremia and severity of hypoxemic respiratory failure in COVID-19, Crit. Care,
doi:10.1186/s13054-020-03051-wSkalny, Rink, Ajsuvakova, Aschner, Gritsenko et al., Zinc and respiratory tract infections: Perspectives for COVID-19 (Review), Int. J. Mol. Med
Sonnweber, Boehm, Sahanic, Pizzini, Aichner et al., Persisting alterations of iron homeostasis in COVID-19 are associated with non-resolving lung pathologies and poor patients' performance: A prospective observational cohort study, Respir. Res,
doi:10.1186/s12931-020-01546-2Torres, Alcubilla, González-Cordón, Inciarte, Chumbita et al., COVID19 Hospital Clínic Infectious Diseases research group. Impact of low serum calcium at hospital admission on SARS-CoV-2 infection outcome, Int. J. Infect. Dis,
doi:10.1016/j.ijid.2020.11.207Tsatsakis, Calina, Falzone, Petrakis, Mitrut et al., SARS-CoV-2 pathophysiology and its clinical implications: An integrative overview of the pharmacotherapeutic management of COVID-19, Food Chem. Toxicol,
doi:10.1016/j.fct.2020.111769Velthuis, Worm, Sims, Baric, Snijder et al., Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture, PLoS Pathog,
doi:10.1371/journal.ppat.1001176Wiersinga, Rhodes, Cheng, Peacock, Prescott, Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review, JAMA,
doi:10.1001/jama.2020.12839Yang, Ma, Wu, Han, Zheng et al., Low serum calcium and phosphorus and their clinical performance in detecting COVID-19 patients, J. Med. Virol,
doi:10.1002/jmv.26515Yao, Paguio, Dee, Tan, Moulick et al., The Minimal Effect of Zinc on the Survival of Hospitalized Patients With COVID-19: An Observational Study, Chest,
doi:10.1016/j.chest.2020.06.082Yasui, Yasui, Suzuki, Saitou, Yamamoto et al., Analysis of the predictive factors for a critical illness of COVID-19 during treatment-relationship between serum zinc level and critical illness of COVID-19, Int. J. Infect. Dis,
doi:10.1016/j.ijid.2020.09.008Zhang, Taylor, Bennett, Saad, Rayman, Association between regional selenium status and reported outcome of COVID-19 cases in China, Am. J. Clin. Nutr,
doi:10.1093/ajcn/nqaa095Zhao, Huang, Dai, Feng, Liu et al., Serum Iron Level as a Potential Predictor of Coronavirus Disease 2019 Severity and Mortality: A Retrospective Study, Open Forum Infect. Dis,
doi:10.1093/ofid/ofaa250Zhou, Chen, Ji, He, Xue, Increased Serum Levels of Hepcidin and Ferritin Are Associated with Severity of COVID-19, Med. Sci. Monit,
doi:10.12659/MSM.926178Zhou, Chen, Wang, Zhao, Wei et al., Low serum calcium: A new, important indicator of COVID-19 patients from mild/moderate to severe/critical, Biosci. Rep,
doi:10.1042/BSR20202690
