Selenium Deficiency Is Associated with Mortality Risk from COVID-19
Arash Moghaddam, Raban Arved Heller, Qian Sun, Julian Seelig, Asan Cherkezov, Linda Seibert, Julian Hackler, Petra Seemann, Joachim Diegmann, Maximilian Pilz, Manuel Bachmann, Waldemar B Minich, Lutz Schomburg
Nutrients, doi:10.3390/nu12072098
SARS-CoV-2 infections underlie the current coronavirus disease (COVID-19) pandemic and are causative for a high death toll particularly among elderly subjects and those with comorbidities. Selenium (Se) is an essential trace element of high importance for human health and particularly for a well-balanced immune response. The mortality risk from a severe disease like sepsis or polytrauma is inversely related to Se status. We hypothesized that this relation also applies to COVID-19. Serum samples (n = 166) from COVID-19 patients (n = 33) were collected consecutively and analyzed for total Se by X-ray fluorescence and selenoprotein P (SELENOP) by a validated ELISA. Both biomarkers showed the expected strong correlation (r = 0.7758, p < 0.001), pointing to an insufficient Se availability for optimal selenoprotein expression. In comparison with reference data from a European cross-sectional analysis (EPIC, n = 1915), the patients showed a pronounced deficit in total serum Se (mean ± SD, 50.8 ± 15.7 vs. 84.4 ± 23.4 µg/L) and SELENOP (3.0 ± 1.4 vs. 4.3 ± 1.0 mg/L) concentrations. A Se status below the 2.5th percentile of the reference population, i.e., [Se] < 45.7 µg/L and [SELENOP] < 2.56 mg/L, was present in 43.4% and 39.2% of COVID samples, respectively. The Se status was significantly higher in samples from surviving COVID patients as compared with non-survivors (Se; 53.3 ± 16.2 vs. 40.8 ± 8.1 µg/L, SELENOP; 3.3 ± 1.3 vs. 2.1 ± 0.9 mg/L), recovering with time in survivors while remaining low or even declining in non-survivors. We conclude that Se status analysis in COVID patients provides diagnostic information. However, causality remains unknown due to the observational nature of this study. Nevertheless, the findings strengthen the notion of a relevant role of Se for COVID convalescence and support the discussion on adjuvant Se supplementation in severely diseased and Se-deficient patients.
References
Alehagen, Johansson, Bjornstedt, Rosen, Post et al., Relatively high mortality risk in elderly swedish subjects with low selenium status, Eur. J. Clin. Nutr,
doi:10.1038/ejcn.2015.92Becker, Martitz, Renko, Stoedter, Hybsier et al., Hypoxia reduces and redirects selenoprotein biosynthesis, Metallomics,
doi:10.1039/C4MT00004HBomer, Grote Beverborg, Hoes, Streng, Vermeer et al., Selenium and outcome in heart failure, Eur. J. Heart Fail,
doi:10.1002/ejhf.1644Boschloo, Raised conditional level of significance for 2x2 table when testing equality of 2 probabilities, Ann. Math. Stat
Braunstein, Kusmenkov, Zuck, Angstwurm, Becker et al., Selenium and selenoprotein p deficiency correlates with complications and adverse outcome after major trauma, Shock,
doi:10.1097/SHK.0000000000001344Calder, Carr, Gombart, Eggersdorfer, Optimal nutritional status for a well-functioning immune system is an important factor to protect against viral infections, Nutrients,
doi:10.3390/nu12041181Core, R: A Language and Environment for Statistical Computing; The R Foundation for Statistical Computing
Fakhrolmobasheri, Nasr-Esfahany, Khanahmad, Zeinalian, Selenium supplementation can relieve the clinical complications of covid-19 and other similar viral infections, Int. J. Vitam. Nutr. Res,
doi:10.1024/0300-9831/a000663Forceville, Vitoux, Gauzit, Combes, Lahilaire et al., Selenium, systemic immune response syndrome, sepsis, and outcome in critically ill patients, Crit. Care Med,
doi:10.1097/00003246-199809000-00021Guan, Liang, Zhao, Liang, Chen et al., Comorbidity and its impact on 1590 patients with covid-19 in china: A nationwide analysis, Eur. Respir. J,
doi:10.1183/13993003.00547-2020Guillin, Vindry, Ohlmann, Chavatte, Selenium, selenoproteins and viral infection, Nutrients,
doi:10.3390/nu11092101Harthill, Review: Micronutrient selenium deficiency influences evolution of some viral infectious diseases, Biol. Trace Elem. Res,
doi:10.1007/s12011-011-8977-1Hoffman, Punjabi, Kumala, Moechtar, Pulungsih et al., Reduction of mortality in chloramphenicol-treated severe typhoid fever by high-dose dexamethasone, N. Engl. J. Med,
doi:10.1056/NEJM198401123100203Hu, Stranges, Chan, Circulating selenium concentration is inversely associated with the prevalence of stroke: Results from the canadian health measures survey and the national health and nutrition examination survey, J. Am. Heart Assoc,
doi:10.1161/JAHA.119.012290Hughes, Fedirko, Jenab, Schomburg, Meplan et al., Selenium status is associated with colorectal cancer risk in the european prospective investigation of cancer and nutrition cohort, Int. J. Cancer
Hybsier, Schulz, Wu, Demuth, Minich et al., Sex-specific and inter-individual differences in biomarkers of selenium status identified by a calibrated elisa for selenoprotein p, Redox Biol,
doi:10.1016/j.redox.2016.12.025Joshi, Joshi, Degani, Tackling sars-cov-2: Proposed targets and repurposed drugs, Future Med. Chem,
doi:10.4155/fmc-2020-0147Mahase, COVID-19: Demand for dexamethasone surges as recovery trial publishes preprint, BMJ,
doi:10.1136/bmj.m2512Manzanares, Langlois, Heyland, Pharmaconutrition with selenium in critically ill patients: What do we know?, Nutr. Clin. Pract,
doi:10.1177/0884533614561794Martitz, Becker, Renko, Stoedter, Hybsier et al., Gene-specific regulation of hepatic selenoprotein expression by interleukin-6, Metallomics,
doi:10.1039/C5MT00211GMehl, Sun, Gorlich, Hackler, Kopp et al., Cross-sectional analysis of trace element status in thyroid disease, J. Trace Elem. Med. Biol
Renko, Hofmann, Stoedter, Hollenbach, Behrends et al., Down-regulation of the hepatic selenoprotein biosynthesis machinery impairs selenium metabolism during the acute phase response in mice, FASEB J,
doi:10.1096/fj.08-119370Robin, Turck, Hainard, Tiberti, Lisacek et al., Proc: An open-source package for r and s+ to analyze and compare roc curves, BMC Bioinform,
doi:10.1186/1471-2105-12-77Saito, Misu, Takayama, Takashima, Usui et al., Comparison of human selenoprotein p determinants in serum between our original methods and commercially available kits, Biol. Pharm. Bull,
doi:10.1248/bpb.b18-00046Saito, Rehmsmeier, The precision-recall plot is more informative than the roc plot when evaluating binary classifiers on imbalanced datasets, PLoS ONE,
doi:10.1371/journal.pone.0118432Schomburg, Hughes, The missing link? The potential role of selenium in the development of liver cancer and significance for the general population, Expert Rev. Gastroenterol. Hepatol,
doi:10.1080/17474124.2017.1320219Schomburg, Melander, Letter by schomburg and melander regarding article, "selenoprotein p promotes the development of pulmonary arterial hypertension: A possible novel therapeutic target, Circulation,
doi:10.1161/CIRCULATIONAHA.118.035782Schomburg, Orho-Melander, Struck, Bergmann, Melander, Selenoprotein-p deficiency predicts cardiovascular disease and death, Nutrients,
doi:10.3390/nu11081852Schomburg, Schweizer, Holtmann, Flohe, Sendtner et al., Gene disruption discloses role of selenoprotein p in selenium delivery to target tissues, Biochem. J,
doi:10.1042/bj20021853Schomburg, The other view: The trace element selenium as a micronutrient in thyroid disease, diabetes, and beyond, Hormones,
doi:10.1007/s42000-019-00150-4Seale, Torres, Berry, Pitts, A role for selenium-dependent gpx1 in sars-cov-2 virulence, Am. J. Clin. Nutr,
doi:10.1093/ajcn/nqaa177Steinbrenner, Al-Quraishy, Dkhil, Wunderlich, Sies, Dietary selenium in adjuvant therapy of viral and bacterial infections, Adv. Nutr,
doi:10.3945/an.114.007575Villar, Ferrando, Martinez, Ambros, Munoz et al., Dexamethasone treatment for the acute respiratory distress syndrome: A multicentre, randomised controlled trial, Lancet Respir. Med,
doi:10.1016/S2213-2600(19)30417-5Wang, Li, Lu, Huang, Does comorbidity increase the risk of patients with COVID-19: Evidence from meta-analysis, Aging,
doi:10.18632/aging.103000Wickham, Francois, Henry, Müller, Dplyr, A Grammar of Data Manipulation; R Package Version 1.0.0; The R Foundation for Statistical Computing
Wickham, Ggplot2: Elegant Graphics for Data Analysis; R Package Version 2
Wickham, Henry, Tidyr, Tidy Messy Data; R Package Version 1.1.0; The R Foundation for Statistical Computing
Wu, Leung, Bushman, Kishore, Niehus et al., Estimating clinical severity of covid-19 from the transmission dynamics in Wuhan, China, Nat. Med,
doi:10.1038/s41591-020-0822-7Zhang, 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/nqaa095Zhou, Wang, Li, Li, Prevention of keshan disease by selenium supplementation: A systematic review and meta-analysis, Biol. Trace Elem. Res,
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'abstract': '<jats:p>SARS-CoV-2 infections underlie the current coronavirus disease (COVID-19) pandemic '
'and are causative for a high death toll particularly among elderly subjects and those with '
'comorbidities. Selenium (Se) is an essential trace element of high importance for human '
'health and particularly for a well-balanced immune response. The mortality risk from a severe '
'disease like sepsis or polytrauma is inversely related to Se status. We hypothesized that '
'this relation also applies to COVID-19. Serum samples (n = 166) from COVID-19 patients (n = '
'33) were collected consecutively and analyzed for total Se by X-ray fluorescence and '
'selenoprotein P (SELENOP) by a validated ELISA. Both biomarkers showed the expected strong '
'correlation (r = 0.7758, p < 0.001), pointing to an insufficient Se availability for '
'optimal selenoprotein expression. In comparison with reference data from a European '
'cross-sectional analysis (EPIC, n = 1915), the patients showed a pronounced deficit in total '
'serum Se (mean ± SD, 50.8 ± 15.7 vs. 84.4 ± 23.4 µg/L) and SELENOP (3.0 ± 1.4 vs. 4.3 ± 1.0 '
'mg/L) concentrations. A Se status below the 2.5th percentile of the reference population, '
'i.e., [Se] < 45.7 µg/L and [SELENOP] < 2.56 mg/L, was present in 43.4% and 39.2% of '
'COVID samples, respectively. The Se status was significantly higher in samples from surviving '
'COVID patients as compared with non-survivors (Se; 53.3 ± 16.2 vs. 40.8 ± 8.1 µg/L, SELENOP; '
'3.3 ± 1.3 vs. 2.1 ± 0.9 mg/L), recovering with time in survivors while remaining low or even '
'declining in non-survivors. We conclude that Se status analysis in COVID patients provides '
'diagnostic information. However, causality remains unknown due to the observational nature of '
'this study. Nevertheless, the findings strengthen the notion of a relevant role of Se for '
'COVID convalescence and support the discussion on adjuvant Se supplementation in severely '
'diseased and Se-deficient patients.</jats:p>',
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