Clinical Significance of Micronutrient Supplementation in Critically Ill COVID-19 Patients with Severe ARDS
Quirin Notz, Johannes Herrmann, Tobias Schlesinger, Philipp Helmer, Stephan Sudowe, Qian Sun, Julian Hackler, Daniel Roeder, Christopher Lotz, Patrick Meybohm, Peter Kranke, Lutz Schomburg, Christian Stoppe
Nutrients, doi:10.3390/nu13062113
The interplay between inflammation and oxidative stress is a vicious circle, potentially resulting in organ damage. Essential micronutrients such as selenium (Se) and zinc (Zn) support anti-oxidative defense systems and are commonly depleted in severe disease. This single-center retrospective study investigated micronutrient levels under Se and Zn supplementation in critically ill patients with COVID-19 induced acute respiratory distress syndrome (ARDS) and explored potential relationships with immunological and clinical parameters. According to intensive care unit (ICU) standard operating procedures, patients received 1.0 mg of intravenous Se daily on top of artificial nutrition, which contained various amounts of Se and Zn. Micronutrients, inflammatory cytokines, lymphocyte subsets and clinical data were extracted from the patient data management system on admission and after 10 to 14 days of treatment. Forty-six patients were screened for eligibility and 22 patients were included in the study. Twenty-one patients (95%) suffered from severe ARDS and 14 patients (64%) survived to ICU discharge. On admission, the majority of patients had low Se status biomarkers and Zn levels, along with elevated inflammatory parameters. Se supplementation significantly elevated Se (p = 0.027) and selenoprotein P levels (SELENOP; p = 0.016) to normal range. Accordingly, glutathione peroxidase 3 (GPx3) activity increased over time (p = 0.021). Se biomarkers, most notably SELENOP, were inversely correlated with CRP (r s = −0.495), PCT (r s = −0.413), IL-6 (r s = −0.429), IL-1β (r s = −0.440) and IL-10 (r s = −0.461). Positive associations were found for CD8 + T cells (r s = 0.636), NK cells (r s = 0.772), total IgG (r s = 0.493) and PaO 2 /FiO 2 ratios (r s = 0.504). In addition, survivors tended to have higher Se levels after 10 to 14 days compared to non-survivors (p = 0.075). Sufficient Se and Zn levels may potentially be of clinical significance for an adequate immune response in critically ill patients with severe COVID-19 ARDS.
Conflicts of Interest: Stephan Sudowe is employed at Ganzimmun Diagnostics AG. Lutz Schomburg holds shares in selenOmed GmbH, a company involved in Se status assessment and supplementation. Christian Stoppe reports grants and non-financial support from Biosyn Arzneimittel GmbH, outside the submitted work. The other authors declare no competing interest.
References
Angstwurm, Engelmann, Zimmermann, Lehmann, Spes et al., Selenium in Intensive Care (SIC): Results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock, Crit. Care Med,
doi:10.1097/01.CCM.0000251124.83436.0EArentz, Yim, Klaff, Lokhandwala, Riedo et al., Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State, JAMA,
doi:10.1001/jama.2020.4326Bhatraju, Ghassemieh, Nichols, Kim, Jerome et al., Covid-19 in Critically Ill Patients in the Seattle Region-Case Series, N. Engl. J. Med,
doi:10.1056/NEJMoa2004500Forceville, Laviolle, Annane, Vitoux, Bleichner et al., Effects of high doses of selenium, as sodium selenite, in septic shock: A placebo-controlled, randomized, double-blind, phase II study, Crit. Care,
doi:10.1186/cc5960Forceville, Vitoux, Gauzit, Combes, Lahilaire et al., Selenium, systemic immune response syndrome, sepsis, and outcome in critically ill patients, Crit. Care Med,
doi:10.1097/00003246-199809000-00021Gombart, Pierre, Maggini, A Review of Micronutrients and the Immune System-Working in Harmony to Reduce the Risk of Infection, Nutrients,
doi:10.3390/nu12010236Grasselli, Greco, Zanella, Albano, Antonelli et al., Risk Factors Associated with Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy, JAMA Intern. Med,
doi:10.1001/jamainternmed.2020.3539Guillin, Vindry, Ohlmann, Chavatte, Selenium, Selenoproteins and Viral Infection, Nutrients,
doi:10.3390/nu11092101Heller, Sun, Hackler, Seelig, Seibert et al., Prediction of survival odds in COVID-19 by zinc, age and selenoprotein P as composite biomarker, Redox Biol,
doi:10.1016/j.redox.2020.101764Heyland, Muscedere, Wischmeyer, Cook, Jones et al., A randomized trial of glutamine and antioxidants in critically ill patients, N. Engl. J. Med,
doi:10.1056/NEJMoa1212722Huang, Shyu, Chen, Lin, Lo et al., Effect of parenteral selenium supplementation in critically ill patients: A systematic review and meta-analysis, PLoS ONE,
doi:10.1371/journal.pone.0054431Hughes, Fedirko, Jenab, Schomburg, Méplan et al., Selenium status is associated with colorectal cancer risk in the European prospective investigation of cancer and nutrition cohort, Int. J. Cancer,
doi:10.1002/ijc.29071Hui, Azhar, Madani, Ntoumi, Kock et al., The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health-The latest 2019 novel coronavirus outbreak in Wuhan, China, Int. J. Infect. Dis,
doi:10.1016/j.ijid.2020.01.009Imai, Kuba, Neely, Yaghubian-Malhami, Perkmann et al., Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury, Cell,
doi:10.1016/j.cell.2008.02.043Jo, Kim, Shin, Sasakawa, Molecular mechanisms regulating NLRP3 inflammasome activation, Cell Mol. Immunol,
doi:10.1038/cmi.2015.95Leisman, Ronner, Pinotti, Taylor, Sinha et al., Cytokine elevation in severe and critical COVID-19: A rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes, Lancet Respir. Med,
doi:10.1016/S2213-2600(20)30404-5Li, Zhao, Zhang, Sun, Jia et al., Se deficiency induces renal pathological changes by regulating selenoprotein expression, disrupting redox balance, and activating inflammation, Metallomics,
doi:10.1039/D0MT00165ALiu, Li, Xu, Wu, Luo et al., Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19, J. Clin. Virol. Off. Publ. Pan Am. Soc. Clin. Virol,
doi:10.1016/j.jcv.2020.104370Luo, Zhou, Yan, Guo, Wang et al., Prognostic Value of C-Reactive Protein in Patients With Coronavirus, Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am,
doi:10.1093/cid/ciaa641Mahmoodpoor, Hamishehkar, Shadvar, Ostadi, Sanaie et al., The Effect of Intravenous Selenium on Oxidative Stress in Critically Ill Patients with Acute Respiratory Distress Syndrome, Immunol. Investig,
doi:10.1080/08820139.2018.1496098Manzanares, Biestro, Galusso, Torre, Mañay et al., Serum selenium and glutathione peroxidase-3 activity: Biomarkers of systemic inflammation in the critically ill?, Intensive Care Med,
doi:10.1007/s00134-008-1356-5Manzanares, Lemieux, Elke, Langlois, Bloos et al., High-dose intravenous selenium does not improve clinical outcomes in the critically ill: A systematic review and meta-analysis, Crit. Care,
doi:10.1186/s13054-016-1529-5Manzanares, Moreira, Hardy, Pharmaconutrition revisited for critically ill patients with coronavirus disease 2019 (COVID-19): Does selenium have a place?, Nutrition,
doi:10.1016/j.nut.2020.110989Martitz, Becker, Renko, Stoedter, Hybsier et al., Gene-specific regulation of hepatic selenoprotein expression by interleukin-6, Metallomics,
doi:10.1039/C5MT00211GMeduri, Annane, Chrousos, Marik, Sinclair, Activation and regulation of systemic inflammation in ARDS: Rationale for prolonged glucocorticoid therapy, Chest,
doi:10.1378/chest.08-2408Moghaddam, Heller, Sun, Seelig, Cherkezov et al., Selenium Deficiency Is Associated with Mortality Risk from COVID-19, Nutrients,
doi:10.3390/nu12072098Motoyama, Okamoto, Kukita, Hamaguchi, Kinoshita et al., Possible role of increased oxidant stress in multiple organ failure after systemic inflammatory response syndrome, Crit. Care Med,
doi:10.1097/01.CCM.0000055371.27268.36Mrityunjaya, Pavithra, Neelam, Janhavi, Halami et al., Immune-Boosting, Antioxidant and Antiinflammatory Food Supplements Targeting Pathogenesis of COVID-19, Front. Immunol,
doi:10.3389/fimmu.2020.570122Notz, Schmalzing, Wedekink, Schlesinger, Gernert et al., Pro-and Anti-Inflammatory Responses in Severe COVID-19-Induced Acute Respiratory Distress Syndrome-An Observational Pilot Study, Front. Immunol,
doi:10.3389/fimmu.2020.581338Qin, Zhou, Hu, Zhang, Yang et al., Dysregulation of immune response in patients with COVID-19 in Wuhan, China, Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am,
doi:10.2139/ssrn.3541136Ranieri, Rubenfeld, Thompson, Ferguson, Caldwell et al., Acute respiratory distress syndrome: The Berlin Definition, JAMA,
doi:10.1001/jama.2012.5669Schlesinger, Weißbrich, Wedekink, Notz, Herrmann et al., Biodistribution and serologic response in SARS-CoV-2 induced ARDS: A cohort study, PLoS ONE,
doi:10.1371/journal.pone.0242917Schmidt, Pargger, Seeberger, Eckhart, Von Felten et al., Effect of high-dose sodium selenite in cardiac surgery patients: A randomized controlled bi-center trial, Clin. Nutr. Edinb. Scotl,
doi:10.1016/j.clnu.2017.04.019Shankar, Prasad, Zinc and immune function: The biological basis of altered resistance to infection, Am. J. Clin. Nutr,
doi:10.1093/ajcn/68.2.447SSinger, Blaser, Berger, Alhazzani, Calder et al., ESPEN guideline on clinical nutrition in the intensive care unit, Clin. Nutr. Edinb. Scotl,
doi:10.1016/j.clnu.2018.08.037Steinbrenner, Al-Quraishy, Dkhil, Wunderlich, Sies, Dietary selenium in adjuvant therapy of viral and bacterial infections, Adv. Nutr. Bethesda Md,
doi:10.3945/an.114.007575Stepien, Jenab, Freisling, Becker, Czuban et al., Pre-diagnostic copper and zinc biomarkers and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort, Carcinogenesis,
doi:10.1093/carcin/bgx051Stoppe, Spillner, Rossaint, Coburn, Schälte et al., Selenium blood concentrations in patients undergoing elective cardiac surgery and receiving perioperative sodium selenite, Nutrition,
doi:10.1016/j.nut.2012.05.013Takebe, Yarimizu, Saito, Hayashi, Nakamura et al., A comparative study on the hydroperoxide and thiol specificity of the glutathione peroxidase family and selenoprotein P, J. Biol. Chem
Wang, Tan, Li, Xu, Guo et al., Supplementation of Micronutrient Selenium in Metabolic Diseases: Its Role as an Antioxidant, Oxid. Med. Cell. Longev,
doi:10.1155/2017/7478523Warnatz, Schlesier, Flowcytometric phenotyping of common variable immunodeficiency, Cytometry. Part B Clin. Cytom,
doi:10.1002/cyto.b.20432Wessels, Haase, Engelhardt, Rink, Uciechowski, Zinc deficiency induces production of the proinflammatory cytokines IL-1β and TNFα in promyeloid cells via epigenetic and redox-dependent mechanisms, J. Nutr. Biochem,
doi:10.1016/j.jnutbio.2012.06.007Wu, Leung, Leung, Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: A modelling study, Lancet,
doi:10.1016/S0140-6736(20)30260-9Xiang, Feng, Diao, Tu, Qiao et al., SARS-CoV-2 Induces Lymphocytopenia by Promoting Inflammation and Decimates Secondary Lymphoid Organs, Front. Immunol
Yang, Yu, Xu, Shu, Xia et al., Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study, Lancet Respir. Med,
doi:10.1016/S2213-2600(20)30079-5Zheng, Gao, Wang, Song, Liu et al., Functional exhaustion of antiviral lymphocytes in COVID-19 patients, Cell. Mol. Immunol,
doi:10.1038/s41423-020-0402-2{ 'indexed': {'date-parts': [[2024, 5, 9]], 'date-time': '2024-05-09T16:36:35Z', 'timestamp': 1715272595114},
'reference-count': 64,
'publisher': 'MDPI AG',
'issue': '6',
'license': [ { 'start': { 'date-parts': [[2021, 6, 20]],
'date-time': '2021-06-20T00:00:00Z',
'timestamp': 1624147200000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0/'}],
'content-domain': {'domain': [], 'crossmark-restriction': False},
'abstract': '<jats:p>The interplay between inflammation and oxidative stress is a vicious circle, '
'potentially resulting in organ damage. Essential micronutrients such as selenium (Se) and '
'zinc (Zn) support anti-oxidative defense systems and are commonly depleted in severe disease. '
'This single-center retrospective study investigated micronutrient levels under Se and Zn '
'supplementation in critically ill patients with COVID-19 induced acute respiratory distress '
'syndrome (ARDS) and explored potential relationships with immunological and clinical '
'parameters. According to intensive care unit (ICU) standard operating procedures, patients '
'received 1.0 mg of intravenous Se daily on top of artificial nutrition, which contained '
'various amounts of Se and Zn. Micronutrients, inflammatory cytokines, lymphocyte subsets and '
'clinical data were extracted from the patient data management system on admission and after '
'10 to 14 days of treatment. Forty-six patients were screened for eligibility and 22 patients '
'were included in the study. Twenty-one patients (95%) suffered from severe ARDS and 14 '
'patients (64%) survived to ICU discharge. On admission, the majority of patients had low Se '
'status biomarkers and Zn levels, along with elevated inflammatory parameters. Se '
'supplementation significantly elevated Se (p = 0.027) and selenoprotein P levels (SELENOP; p '
'= 0.016) to normal range. Accordingly, glutathione peroxidase 3 (GPx3) activity increased '
'over time (p = 0.021). Se biomarkers, most notably SELENOP, were inversely correlated with '
'CRP (rs = −0.495), PCT (rs = −0.413), IL-6 (rs = −0.429), IL-1β (rs = −0.440) and IL-10 (rs = '
'−0.461). Positive associations were found for CD8+ T cells (rs = 0.636), NK cells (rs = '
'0.772), total IgG (rs = 0.493) and PaO2/FiO2 ratios (rs = 0.504). In addition, survivors '
'tended to have higher Se levels after 10 to 14 days compared to non-survivors (p = 0.075). '
'Sufficient Se and Zn levels may potentially be of clinical significance for an adequate '
'immune response in critically ill patients with severe COVID-19 ARDS.</jats:p>',
'DOI': '10.3390/nu13062113',
'type': 'journal-article',
'created': {'date-parts': [[2021, 6, 21]], 'date-time': '2021-06-21T01:50:15Z', 'timestamp': 1624240215000},
'page': '2113',
'source': 'Crossref',
'is-referenced-by-count': 36,
'title': 'Clinical Significance of Micronutrient Supplementation in Critically Ill COVID-19 Patients with '
'Severe ARDS',
'prefix': '10.3390',
'volume': '13',
'author': [ { 'ORCID': 'http://orcid.org/0000-0002-4042-4436',
'authenticated-orcid': False,
'given': 'Quirin',
'family': 'Notz',
'sequence': 'first',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-2169-3761',
'authenticated-orcid': False,
'given': 'Johannes',
'family': 'Herrmann',
'sequence': 'additional',
'affiliation': []},
{'given': 'Tobias', 'family': 'Schlesinger', 'sequence': 'additional', 'affiliation': []},
{'given': 'Philipp', 'family': 'Helmer', 'sequence': 'additional', 'affiliation': []},
{'given': 'Stephan', 'family': 'Sudowe', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-4458-6555',
'authenticated-orcid': False,
'given': 'Qian',
'family': 'Sun',
'sequence': 'additional',
'affiliation': []},
{'given': 'Julian', 'family': 'Hackler', 'sequence': 'additional', 'affiliation': []},
{'given': 'Daniel', 'family': 'Roeder', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0003-2574-624X',
'authenticated-orcid': False,
'given': 'Christopher',
'family': 'Lotz',
'sequence': 'additional',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-2666-8696',
'authenticated-orcid': False,
'given': 'Patrick',
'family': 'Meybohm',
'sequence': 'additional',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0001-5324-981X',
'authenticated-orcid': False,
'given': 'Peter',
'family': 'Kranke',
'sequence': 'additional',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0001-9445-1555',
'authenticated-orcid': False,
'given': 'Lutz',
'family': 'Schomburg',
'sequence': 'additional',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-2028-2039',
'authenticated-orcid': False,
'given': 'Christian',
'family': 'Stoppe',
'sequence': 'additional',
'affiliation': []}],
'member': '1968',
'published-online': {'date-parts': [[2021, 6, 20]]},
'reference': [ {'key': 'ref1', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0140-6736(20)30260-9'},
{'key': 'ref2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ijid.2020.01.009'},
{'key': 'ref3', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0140-6736(20)30183-5'},
{'key': 'ref4', 'doi-asserted-by': 'publisher', 'DOI': '10.2139/ssrn.3541136'},
{'key': 'ref5', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.mito.2020.06.008'},
{'key': 'ref6', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/cmi.2015.95'},
{'key': 'ref7', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0140-6736(20)30628-0'},
{'key': 'ref8', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/molecules24081583'},
{'key': 'ref9', 'doi-asserted-by': 'publisher', 'DOI': '10.2174/1381612825666190112165206'},
{'key': 'ref10', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.cell.2008.02.043'},
{'key': 'ref11', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.burns.2016.09.023'},
{'key': 'ref12', 'doi-asserted-by': 'publisher', 'DOI': '10.3389/fimmu.2020.570122'},
{'key': 'ref13', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.nut.2020.110989'},
{'key': 'ref14', 'doi-asserted-by': 'publisher', 'DOI': '10.3389/fimmu.2020.01712'},
{'key': 'ref15', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/nu10091203'},
{'key': 'ref16', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/nu9121286'},
{'key': 'ref17', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.abb.2016.03.022'},
{'key': 'ref18', 'doi-asserted-by': 'publisher', 'DOI': '10.3945/an.114.007575'},
{'key': 'ref19', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/nu11092101'},
{'key': 'ref20', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/nu12072098'},
{'key': 'ref21', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.redox.2020.101764'},
{ 'key': 'ref22',
'doi-asserted-by': 'publisher',
'DOI': '10.7326/0003-4819-147-8-200710160-00010-w1'},
{ 'key': 'ref23',
'doi-asserted-by': 'publisher',
'DOI': '10.2807/1560-7917.ES.2020.25.3.2000045'},
{'key': 'ref24', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/s0076-6879(84)05015-1'},
{'key': 'ref25', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/ijc.29071'},
{'key': 'ref26', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/carcin/bgx051'},
{'key': 'ref27', 'doi-asserted-by': 'publisher', 'DOI': '10.1001/jama.2012.5669'},
{'key': 'ref28', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/cyto.b.20432'},
{'key': 'ref29', 'doi-asserted-by': 'publisher', 'DOI': '10.1111/j.1365-2249.2010.04206.x'},
{'key': 'ref30', 'doi-asserted-by': 'publisher', 'DOI': '10.1001/jamainternmed.2020.3539'},
{'key': 'ref31', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMoa2004500'},
{'key': 'ref32', 'doi-asserted-by': 'publisher', 'DOI': '10.1001/jama.2020.4326'},
{'key': 'ref33', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S2213-2600(20)30079-5'},
{'key': 'ref34', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.immuni.2020.05.002'},
{ 'key': 'ref35',
'doi-asserted-by': 'publisher',
'DOI': '10.1097/01.CCM.0000055371.27268.36'},
{'key': 'ref36', 'doi-asserted-by': 'publisher', 'DOI': '10.1097/00003246-199809000-00021'},
{'key': 'ref37', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s00134-008-1356-5'},
{'key': 'ref38', 'doi-asserted-by': 'publisher', 'DOI': '10.1080/08820139.2018.1496098'},
{ 'key': 'ref39',
'doi-asserted-by': 'publisher',
'DOI': '10.1097/01.CCM.0000251124.83436.0E'},
{'key': 'ref40', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMoa1212722'},
{'key': 'ref41', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/14651858.CD003703.pub3'},
{'key': 'ref42', 'doi-asserted-by': 'publisher', 'DOI': '10.1186/s13054-016-1529-5'},
{'key': 'ref43', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pone.0054431'},
{'key': 'ref44', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.clnu.2018.08.037'},
{'key': 'ref45', 'doi-asserted-by': 'publisher', 'DOI': '10.1074/jbc.M202773200'},
{'key': 'ref46', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jnutbio.2012.06.007'},
{'key': 'ref47', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/ajcn/68.2.447S'},
{'key': 'ref48', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/cid/ciaa641'},
{'key': 'ref49', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jcv.2020.104370'},
{'key': 'ref50', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S2213-2600(20)30404-5'},
{'key': 'ref51', 'doi-asserted-by': 'publisher', 'DOI': '10.1039/D0MT00165A'},
{'key': 'ref52', 'doi-asserted-by': 'publisher', 'DOI': '10.1039/C5MT00211G'},
{'key': 'ref53', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.cytogfr.2011.10.001'},
{'key': 'ref54', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41423-020-0402-2'},
{'key': 'ref55', 'doi-asserted-by': 'publisher', 'DOI': '10.1182/blood-2005-02-0456'},
{'key': 'ref56', 'doi-asserted-by': 'publisher', 'DOI': '10.3389/fimmu.2021.661052'},
{'key': 'ref57', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pone.0242917'},
{'key': 'ref58', 'doi-asserted-by': 'publisher', 'DOI': '10.3389/fimmu.2020.581338'},
{'key': 'ref59', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/nu12010236'},
{'key': 'ref60', 'doi-asserted-by': 'publisher', 'DOI': '10.1378/chest.08-2408'},
{'key': 'ref61', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.nut.2012.05.013'},
{'key': 'ref62', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.clnu.2017.04.019'},
{'key': 'ref63', 'doi-asserted-by': 'publisher', 'DOI': '10.1186/cc5960'},
{'key': 'ref64', 'doi-asserted-by': 'publisher', 'DOI': '10.1155/2017/7478523'}],
'container-title': 'Nutrients',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://www.mdpi.com/2072-6643/13/6/2113/pdf',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2021, 6, 21]],
'date-time': '2021-06-21T01:56:54Z',
'timestamp': 1624240614000},
'score': 1,
'resource': {'primary': {'URL': 'https://www.mdpi.com/2072-6643/13/6/2113'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2021, 6, 20]]},
'references-count': 64,
'journal-issue': {'issue': '6', 'published-online': {'date-parts': [[2021, 6]]}},
'alternative-id': ['nu13062113'],
'URL': 'http://dx.doi.org/10.3390/nu13062113',
'relation': {},
'ISSN': ['2072-6643'],
'subject': [],
'container-title-short': 'Nutrients',
'published': {'date-parts': [[2021, 6, 20]]}}
