Essential metals, vitamins and antioxidant enzyme activities in COVID-19 patients and their potential associations with the disease severity
Iman Al-Saleh, Alrushud Nujud, Alnuwaysir Hissah, Elkhatib Rola, Shoukri Mohamed, Aldayel Fouad, Bakheet Maha Razan, Almozaini, N Alrushud, Á H Alnuwaysir, Á R Elkhatib, M Shoukri, F Aldayel, R Bakheet, M Almozaini
doi:10.1007/s10534-021-00355-4(
The role of micronutrient deficiency in the pathogenesis of COVID-19 has been reviewed in the literature; however, the data are limited and conflicting. This study investigated the association between the status of essential metals, vitamins, and antioxidant enzyme activities in COVID-19 patients and disease severity. We recruited 155 patients, who were grouped into four classes based on the Adults guideline for the Management of Coronavirus Disease 2019 at King Faisal Specialist & Research Centre (KFSH&RC): asymptomatic (N = 16), mild (N = 49), moderate (N = 68), and severe (N = 22). We measured serum levels of copper (Cu), zinc (Zn), selenium (Se), vitamin D 3 , vitamin A, vitamin E, total antioxidant capacity, and superoxide dismutase (SOD). Among the patients, 30%, 25%, 37%, and 68% were deficient in Se (\ 70.08 lg/L), Zn (\ 0.693 lg/mL), vitamin A (\ 0.343 lg/mL), and vitamin D 3 (\ 20.05 lg/L), respectively, and SOD activity was low. Among the patients, 28% had elevated Cu levels ([ 1.401 lg/mL, KFSH&RC upper reference limit). Multiple regression analysis revealed an 18% decrease in Se levels in patients with severe symptoms, which increased to 30% after adjusting the model for inflammatory markers. Regardless of inflammation, Se was independently associated with COVID-19 severity. In contrast, a 50% increase in Cu levels was associated with disease severity only after adjusting for C-reactive protein, reflecting its possible inflammatory and pro-oxidant role in COVID-19 pathogenesis. We noted an imbalance in the ratio between Cu and Zn, with * 83% of
Author contributions IAS-study design, data analysis, results interpretation and writing the manuscript. NA-collection of clinical data. HA-methodology/validation. REmethodology/validation. MS-sampling design. FA-samples provision. RB-methodology. MA-resources.
Conflict of interest The authors reported no potential conflict of interest.
References
Al-Alyani, Ha, On, Alani, Sadat-Ali, Vitamin D deficiency in Saudi Arabians: a reality or simply hype: a meta-analysis (2008-2015), J Family Community Med,
doi:10.4103/jfcm.JFCM_73_17
Alsafar, Grant, Hijazi, Uddin, Alkaabi et al., COVID-19 disease severity and death in relation to vitamin D status among SARS-CoV-2-positive UAE residents, Nutrients,
doi:10.3390/nu13051714
Anurag, Jha, Kumar, Differential white blood cell count in the COVID-19: a cross-sectional study of 148 patients, Diabet Metab Syndr,
doi:10.1016/j.dsx.2020.10.029
Asl, Nikfarjam, Zolbanin, Nassiri, Jafari, Immunopharmacological perspective on zinc in SARS-CoV-2 infection, Int Immunopharmacol,
doi:10.1016/j.intimp.2021.107630
Bae, Kim, Mini-review on the roles of vitamin C, vitamin D, and selenium in the immune system against COVID-19, Molecules,
doi:10.3390/molecules25225346
Bahi, Boyvin, Me ´ite ´s, Boh, Yeo et al., Assessments of serum copper and zinc concentration, and the Cu/Zn ratio determination in patients with multidrug resistant pulmonary tuberculosis (MDR-TB) in Co ˆte d'Ivoire, BMC Infect Dis,
doi:10.1186/s12879-017-2343-7
Banerjee, Mondal, Das, Ray, Neutrophilic inflammatory response and oxidative stress in premenopausal women chronically exposed to indoor air pollution from biomass burning, Inflammation,
doi:10.1007/s10753-011-9360-2
Barffour, Schulze, Kalungwana, Moss, West et al., Relative contributions of malaria, inflammation, and deficiencies of iron and vitamin A to the burden of anemia during low and high malaria seasons in rural zambian children, J Pediatr,
doi:10.1016/j.jpeds.2019.06.039
Barocas, So-Armah, Cheng, Lioznov, Baum et al., Zinc deficiency and advanced liver fibrosis among HIV and hepatitis C co-infected antiretroviral naı ¨ve persons with alcohol use in Russia, PLoS ONE,
doi:10.1371/journal.pone.0218852
Beck, Nelson, Shi, Van Dael, Schiffrin et al., Selenium deficiency increases the pathology of an influenza virus infection, FASEB J
Beltra ´n-Garcı ´a, Osca-Verdegal, Pallardo, Ferreres, Rodrı ´guez et al., Oxidative stress and inflammation in COVID-19-associated sepsis: the potential role of anti-oxidant therapy in avoiding disease progression, Antioxidants,
doi:10.3390/antiox9100936
Bo, Durazzo, Gambino, Berutti, Milanesio et al., Associations of dietary and serum copper with inflammation, oxidative stress, and metabolic variables in adults, J Nutr,
doi:10.1093/jn/138.2.305
Booth, Golly, Sacheck, Roubenoff, Dallal et al., Effect of vitamin E supplementation on vitamin K status in adults with normal coagulation status, Am J Clin Nutr,
doi:10.1093/ajcn/80.1.143
Bourbour, Dahka, Gholamalizadeh, Akbari, Shadnoush et al., Nutrients in prevention, treatment, and management of viral infections; special focus on coronavirus, Arch Physiol Biochem,
doi:10.1080/13813455.2020.1791188
Branda ˜o, Chiamolera, Biscolla, Lima, De et al., No association between vitamin D status and COVID-19 infection in Sa ˜o Paulo, Brazil, Arch Endocrinol Metab,
doi:10.20945/2359-3997000000343
Brenner, Vitamin D supplementation to prevent COVID-19 infections and deaths-accumulating evidence from epidemiological and intervention studies calls for immediate action, Nutrients,
doi:10.3390/nu13020411
Campi, Gennari, Merlotti, Mingiano, Frosali et al., Vitamin D and COVID-19 severity and related mortality: a prospective study in Italy, BMC Infect Dis,
doi:10.1186/s12879-021-06281-7
Chan, Kok, Zhu, Chu, To et al., Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan, Emerg Microbes Infect,
doi:10.1080/22221751.2020.1719902
Chan, Yuan, Kok, To, Chu et al., A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster, Lancet,
doi:10.1016/s0140-6736(20)30154-9
Danwang, Endomba, Nkeck, Wouna, Robert et al., A meta-analysis of potential biomarkers associated with severity of coronavirus disease 2019 (COVID-19), Biomark Res,
doi:10.1186/s40364-020-00217-0
Davoudi, Najafi, Aarabi, Tayebi, Nikaeen et al., Lack of association between vitamin D insufficiency and clinical outcomes of patients with COVID-19 infection, BMC Infect Dis,
doi:10.1186/s12879-021-06168-7
De Roman ˜a, Olivares, Uauy, Araya, Risks and benefits of copper in light of new insights of copper homeostasis, J Trace Elem Med Biol,
doi:10.1016/j.jtemb.2010.11.004
Djoko, Ong, Walker, Mcewan, The role of copper and zinc toxicity in innate immune defense against bacterial pathogens, J Biol Chem,
doi:10.1074/jbc.R115.647099
Domingo, Marque, The effects of some essential and toxic metals/metalloids in COVID-19: a review, Food Chem Toxicol,
doi:10.1016/j.fct.2021.112161
Fedele, Francesco, Riso, Collo, Obesity, malnutrition, and trace element deficiency in the coronavirus disease (COVID-19) pandemic: an overview, Nutrition,
doi:10.1016/j.nut.2020.111016
Fernandes, De Brito, Reis, Sato, Pereira, SARS-CoV-2 and other respiratory viruses: what does oxidative stress have to do with it?, Oxid Med Cell Longev,
doi:10.1155/2020/8844280
Forcados, Muhammad, Oladipo, Makama, Meseko, Metabolic implications of oxidative stress and inflammatory process in SARS-CoV-2 pathogenesis: therapeutic potential of natural antioxidants, Front Cell Infect Microbiol,
doi:10.3389/fcimb.2021.654813
Gadotti, Lipinski, Vasconcellos, Marqueze, Cunha et al., Susceptibility of the patients infected with Sars-Cov2 to oxidative stress and possible interplay with severity of the disease, Free Radic Biol Med,
doi:10.1016/j.freeradbiomed.2021.01.044
Gaziano, Pistoia, Campione, Fontana, Marino et al., Immunomodulatory agents as potential therapeutic or preventive strategies for COVID-19, Eur Rev Med Pharmacol Sci,
doi:10.26355/eurrev_202106_26061
Ghiselli, Serafini, Natella, Scaccini, Total antioxidant capacity as a tool to assess redox status: critical view and experimental data, Free Radic Biol Med,
doi:10.1016/s0891-5849(00)00394-4
Gombart, Pierre, Maggini, A review of micronutrients and the immune system-working in harmony to reduce the risk of infection, Nutrients,
doi:10.3390/nu12010236
Gonc ¸alves, Gonc ¸alves, Guarnieri, Risegato, Guimara ˜es et al., Association between low zinc levels and severity of acute respiratory distress syndrome by new coronavirus SARS-CoV-2, Nutr Clin Pract,
doi:10.1002/ncp.10612
Goud, Bai, Hm, A multiple-hit hypothesis involving reactive oxygen species and myeloperoxidase explains clinical deterioration and fatality in COVID-19, Int J Biol Sci,
doi:10.7150/ijbs.51811
Greiller, Martineau, Modulation of the immune response to respiratory viruses by vitamin D, Nutrients,
doi:10.3390/nu7064240
Grove, Osokogu, Al-Khudairy, Mehrabian, Zanganeh et al., Association between vitamin D supplementation or serum vitamin D level and susceptibility to SARS-CoV-2 infection or COVID-19 including clinical course, morbidity and mortality outcomes? A systematic review, BMJ Open,
doi:10.1136/bmjopen-2020-043737
Guan, Ni, Hu, Liang, Ou et al., Clinical characteristics of coronavirus disease 2019 in china, N Engl J Med,
doi:10.1056/NEJMoa2002032
Guillin, Vindry, Ohlmann, Chavatte, Selenium, selenoproteins and viral infection, Nutrients,
doi:10.3390/nu11092101
Hastie, Mackay, Ho, Celis-Morales, Katikireddi et al., Vitamin D concentrations and COVID-19 infection in UK Biobank, Diabet Metab Syndr,
doi:10.1016/j.dsx.2020.04.050
Henry, De Oliveira, Benoit, Plebani, Lippi, Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis, Clin Chem Lab Med,
doi:10.1515/cclm-2020-0369
Huang, Rose, Hoffmann, The role of selenium in inflammation and immunity: from molecular mechanisms to therapeutic opportunities, Antioxid Redox Signal,
doi:10.1089/ars.2011.4145
Ivanov, Bartosch, Isaguliants, Oxidative stress in infection and consequent disease, Oxid Med Cell Longev,
doi:10.1155/2017/3496043
Jolliffe, Camargo, Jr, Sluyter, Aglipay et al., Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials, Lancet Diabet Endocrinol,
doi:10.1016/s2213-8587(21)00051-6
Jothimani, Kailasam, Danielraj, Nallathambi, Ramachandran et al., COVID-19: poor outcomes in patients with zinc deficiency, Int J Infect Dis,
doi:10.1016/j.ijid.2020.09.014
Karkhanei, Ghane, Mehri, Evaluation of oxidative stress level: total antioxidant capacity, total oxidant status and glutathione activity in patients with COVID-19, New Microbes New Infect,
doi:10.1016/j.nmni.2021.100897
Larson, Guo, Williams, Young, Ismaily et al., Approaches to assess vitamin a status in settings of inflammation: biomarkers reflecting inflammation and nutritional determinants of anemia (BRINDA) project, Nutrients,
doi:10.3390/nu10081100
Li, Fan, Lai, Han, Li et al., Coronavirus infections and immune responses, J Med Virol,
doi:10.1002/jmv.25685
Li, Geng, Peng, Meng, Lu, Molecular immune pathogenesis and diagnosis of COVID-19
Maggini, Pierre, Calder, Immune function and micronutrient requirements change over the life course, Nutrients,
doi:10.3390/nu10101531
Majeed, Nagabhushanam, Gowda, Mundkur, An exploratory study of selenium status in healthy individuals and in patients with COVID-19 in a south Indian population: the case for adequate selenium status, Nutrition,
doi:10.1016/j.nut.2020.111053
Malavolta, Piacenza, Basso, Giacconi, Costarelli et al., Serum copper to zinc ratio: relationship with aging and health status, Mech Ageing Dev,
doi:10.1016/j.mad.2015.01.004
Man, Rajnoveanu, Motoc, Bondor, Chis et al., Neutrophil-to-lymphocyte ratio, platelets-to-lymphocyte ratio, and eosinophils correlation with high-resolution computer tomography severity score in COVID-19 patients, PLoS ONE,
doi:10.1371/journal.pone.0252599
Maqsood, Dancheck, Gamble, Palafox, Ricks et al., Vitamin A deficiency and inflammatory markers among preschool children in the Republic of the Marshall Islands, Nutr J,
doi:10.1186/1475-2891-3-21
Marcinowska-Suchowierska, Kupisz-Urban ´ska, Łukaszkiewicz, Płudowski, Jones, Vitamin D toxicity-A clinical perspective, Front Endocrinol,
doi:10.3389/fendo.2018.00550
Mawson, Croft, Gonzalez-Fernandez, Liver damage and exposure to toxic concentrations of endogenous retinoids in the pathogenesis of COVID-19 disease: hypothesis, Viral Immunol,
doi:10.1089/vim.2020.0330
Mawson, Role of fat-soluble vitamins A and D in the pathogenesis of influenza: a new perspective, ISRN Infect Dis,
doi:10.5402/2013/246737
Mitra, Alvarez, Wahed, Fuchs, Stephensen, Predictors of serum retinol in children with shigellosis, Am J Clin Nutr,
doi:10.1093/ajcn/68.5.1088
Moghaddam, Heller, Sun, Seelig, Cherkezov et al., Selenium deficiency is associated with mortality risk from COVID-19, Nutrients,
doi:10.3390/nu12072098
Muhammad, Kani, Iliya, Muhammad, Binji et al., Deficiency of antioxidants and increased oxidative stress in COVID-19 patients: a cross-sectional comparative study in Jigawa, Northwestern Nigeria, SAGE Open Med,
doi:10.1177/2050312121991246
Nelson, Shi, Van Dael, Schiffrin, Blum et al., Host nutritional selenium status as a driving force for influenza virus mutations, FASEB J
Oh, Shin, Choi, Kim, Park et al., Assessment of 7 trace elements in serum of patients with nontuberculous mycobacterial lung disease, J Trace Elem Med Biol,
doi:10.1016/j.jtemb.2019.02.004
Oscanoa, Amado, Vidal, Laird, Ghashut et al., The relationship between the severity and mortality of SARS-CoV-2 infection and 25-hydroxyvitamin D concentration-a metaanalysis, Adv Respir Med,
doi:10.5603/ARM.a2021.0037
Owen, Dewald, Vitamin E toxicity
Pecora, Persico, Argentiero, Neglia, Esposito, The role of micronutrients in support of the immune response against viral infections, Nutrients,
doi:10.3390/nu12103198
Peng, Liu, Zheng, Lu, Hou et al., Immunological aspects of SARS-CoV-2 infection and the putative beneficial role of vitamin-D, Int J Mol Sci,
doi:10.3390/ijms22105251
Rubin, Ross, Stephensen, Bohn, Tanumihardjo, Metabolic effects of inflammation on vitamin A and carotenoids in humans and animal models, Adv Nutr,
doi:10.3945/an.116.014167
Rubio, Herna ´ndez-Ruiz, Martinez-Subiela, Tvarijonaviciute, Ceron, Spectrophotometric assays for total antioxidant capacity (TAC) in dog serum: an update, BMC Vet Res,
doi:10.1186/s12917-016-0792-7
Sepehri, Mirzaei, Sargazi, Sargazi, Mishkar et al., Essential and toxic metals in serum of individuals with active pulmonary tuberculosis in an endemic region, J Clin Tuberc Other Mycobact Dis,
doi:10.1016/j.jctube.2017.01.001
Shah, Saxena, Mavalankar, Vitamin D supplementation, COVID-19 and disease severity: a meta-analysis, QJM: Int J Med,
doi:10.1093/qjmed/hcab009
Skalny, Timashev, Aschner, Aaseth, Chernova et al., Serum zinc, copper, and other biometals are associated with COVID-19 severity markers, Metabolites,
doi:10.3390/metabo11040244
Ukleja, Scolapio, Mcconnell, Spivey, Dickson et al., Nutritional assessment of serum and hepatic vitamin A levels in patients with cirrhosis, J Parenter Enter Nutr,
doi:10.1177/0148607102026003184
Vogel-Gonza ´lez, Tallo, -Parra, Herrera-Ferna ´ndez, ´rez-Vilaro et al., Low zinc levels at admission associates with poor clinical outcomes in SARS-CoV-2 infection, Nutrients,
doi:10.3390/nu13020562
Watkins, Lemonovich, Salata, An update on the association of vitamin D deficiency with common infectious diseases, Can J Physiol Pharmacol,
doi:10.1139/cjpp-2014-0352
Weitkunat, Wildner, Exploratory causal modeling in epidemiology: are all factors created equal?, J Clin Epidemiol
Wilhelm, Benjamin, Rainer, Interpretation of statistical significance-exploratory versus confirmative testing in clinical trials, epidemiological studies, metaanalyses and toxicological screening (using Ginkgo biloba as an example), J Clin Exp Pharmacol
Winbauer, Pingree, Nuttall, Evaluating serum alpha-tocopherol (vitamin E) in terms of a lipid ratio, Ann Clin Lab Sci
Wu, Meydani, Vitamin E, immune function, and protection against infection
Wu, Wang, Li, Meng, Jie et al., Circulating white blood cells and lung function impairment: the observational studies and Mendelian randomization analysis, Ann Med,
doi:10.1080/07853890.2021.1948603
Younesian, Khodabakhshi, Abdolahi, Norouzi, Behnampour et al., Decreased serum selenium levels of COVID-19 patients in comparison with healthy individuals, Biol Trace Elem Res,
doi:10.1007/s12011-021-02797-w
Yu, Du, Ojcius, Pan, Jiang, Measures for diagnosing and treating infections by a novel coronavirus responsible for a pneumonia outbreak originating in Wuhan, China, Microbes Infect,
doi:10.1016/j.micinf.2020.01.003
Zeng, Yang, Yuan, Wang, Cheng, Associations of essential and toxic metals/metalloids in whole blood with both disease severity and mortality in patients with COVID-19, FASEB J,
doi:10.1096/fj.202002346RR
Zeng, Zhang, Wang, Yang, Cheng, Urinary trace elements in association with disease severity and outcome in patients with COVID-19, Environ Res,
doi:10.1016/j.envres.2020.110670
Zhang, Liu, Potential interventions for novel coronavirus in China: a systematic review, J Med Virol,
doi:10.1002/jmv.25707
Zhang, 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/nqaa095
˜a, Lee, Thiele, A delicate balance: homeostatic control of copper uptake and distribution, J Nutr,
doi:10.1093/jn/129.7.1251